Podcasts about swog

El Dr. Iván Bustillo, oncólogo clínico de la Clínica Portoazul Auna en Barranquilla, Colombia, presentó un análisis de los estudios más relevantes del año 2024 en melanoma. El experto destacó los ensayos CheckMate 76K, KEYNOTE-716 y CheckMate 067 como los más importantes en el ámbito de la adyuvancia. En cuanto a la neoadyuvancia, mencionó el estudio SWOG con pembrolizumab y el ensayo OpACIN con ipilimumab y nivolumab. Sin embargo, el Dr. Bustillo resaltó especialmente el estudio NADINA como el más relevante, pues sus resultados marcan un cambio significativo en los esquemas de tratamiento para el melanoma. En este sentido, la investigación demostró que el tratamiento neoadyuvante con la combinación de nivolumab e ipilimumab, frente a nivolumab solo como tratamiento adyuvante, ofrece una mejora notable en la supervivencia libre de metástasis a distancia en pacientes con melanoma resecable en estadio III macroscópico. El estudio NADINA fue un ensayo internacional, aleatorizado y fase III, cuyo objetivo primario fue evaluar la supervivencia libre de eventos. En él participaron 420 pacientes diagnosticados con melanoma recurrente o de novo, que presentaban al menos un ganglio linfático clínicamente detectable y patológicamente confirmado, permitiéndose hasta tres metástasis en tránsito. Los pacientes fueron aleatorizados en dos grupos para recibir: en el brazo A, dos ciclos de 80 mg de ipilimumab más 240 mg de nivolumab, seguidos de una disección de ganglios linfáticos terapéutica a las seis semanas. En caso de que después de la cirugía los pacientes presentaran una respuesta parcial patológica o no respondieran, se les continuó con nivolumab adyuvante (11 ciclos) o, si tenían la mutación BRAFV600, con tratamiento adyuvante con dabrafenib más trametinib durante 46 semanas. En el brazo B, los pacientes se sometieron inicialmente a la disección de ganglios linfáticos terapéutica y luego recibieron 12 ciclos de nivolumab 480 mg. Fecha de grabación: 3 de noviembre de 2024.                               Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente.

In de podcastserie proefschriften spreekt aios interne geneeskunde dr. Tessa Steenbruggen met promovendi. In deze aflevering spreekt zij met dr. Lisette Rozeman over haar proefschrift, getiteld: “Improving outcome of melanoma patients upon immunotherapy”. Lisette vertelt over de verschillende studies met immunotherapie, die zij samen met haar promotor prof. dr. Christian Blank heeft opgezet, gecoördineerd en geanalyseerd, en die de behandeling van patiënten met een melanoom significant hebben veranderd. Lisette heeft op 7 januari jl. haar proefschrift succesvol verdedigd aan de Universiteit van Leiden. Referenties Podcast: The fellow on call OPACIN: Blank CU, et al. Nature Medicine 2018;24:1655–6. OPACIN-neo: Rozeman EA, et al. Lancet Oncol 2019;20:948-60. SWOG 1801: Patel SP, et al. N Eng J Med 2023;388:813-23. NADINA: Blank CU, et al. N Eng J Med 2024;391:1696-708. IMPEMBRA: Rozeman EA, et al. J Immunother Cancer 2023;11:e006821. Sequentiële combinatietherapie: Reijers IL, et al. https://onlinelibrary.wiley.com/doi/10.1111/pcmr.12835 Antistoffen en toxiciteit 1: De Moel EC, et al. Cancer Immunol Res 2019;7:6-11. Antistoffen en toxiciteit 2: Borgers JS, et al. J Immunother Cancer 2024;12:e009215.

JCO PO author Dr. David R. Gandara at UC Davis Comprehensive Cancer Center, shares insights into his JCO PO article, “Plasma Proteome–Based Test for First-Line Treatment Selection in Metastatic Non–Small Cell Lung Cancer,” one of the Top Articles of 2024. Host Dr. Rafeh Naqash and Dr. Gandara discuss how the PROphet® blood test supports first-line immunotherapy treatment decisions for metastatic NSCLC patients. TRANSCRIPT  Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.  Today, we are absolutely thrilled to be joined by Dr. David R. Gandara, Professor of Medicine Emeritus, Co-Director of the Center for Experimental Therapeutics and Cancer and Senior Advisor to the Director at UC Davis Comprehensive Cancer Center and also the senior author of the JCO Precision Oncology article entitled “Plasma Proteome–Based Test for First-Line Treatment Selection in Metastatic Non–Small Cell Lung Cancer.” This was one of the top performing articles of 2024, which is one of the reasons why we wanted to bring it in for a podcast discussion. At the time of this recording, our guest's disclosures will be linked in the transcript.  David, it is an absolute pleasure to have you today. For somebody like you who's led the field of lung cancer over the years, I'm really excited that you are going to be talking to us about this very interesting article, especially given that I think you're one of the big proponents of liquid biopsies and plasma-based testing. So, for the sake of our listeners - which comprises of academic oncologists, community oncologists, trainees - could you tell us where the biomarker landscape for non-small cell lung cancer is currently, and then we can try to take a deeper dive into this article. Dr. David Gandar: Okay. Well, thank you, Rafeh. It's a pleasure to be with you here today. And I think the current landscape for biomarkers for immunotherapy in non-small cell lung cancer is a mess. There's no better way to describe it. That makes this paper describing a new plasma proteomic assay even more important. So I'll just give you a perspective. There are 14 trials, phase three trials, that were done in first line non-small cell lung cancer advanced stage of immunotherapy versus chemotherapy and some other aspects, although they vary tremendously. Some of them were checkpoint monotherapy, some combined with chemotherapy, some combined with CTLA-4 inhibitors and so forth. 12 out of the 14 were positive, 12 got FDA approval. So there are 12 different options that an oncologist could use. Some of them were squamous cell only, some non-squamous, some used PD-L1 as a biomarker driven part of the study. Some used TMB, tumor mutational burden, some were agnostic. So when you put all of this together, an oncologist can pick and choose among all these various regimens. And by and large, it's PD-L1 that is the therapeutic decision maker.  ASCO actually, I think, has done the very best job of making a guideline, and it's, as you well know, called a living guideline, it's dynamic. And it is much easier to interpret, for me and I think for oncologists, than some of the other guidelines. It's got a green light and a red light, it may be kind of orange. And so the green light means this is a strong recommendation by the guideline committee. The orange means it's weak. For this purpose, non-small cell lung cancer, advanced stage, only a very few of the recommendations were green. It's mainly monotherapy and patients with cancers with a PD-L1 over 50%. In our surveys, at our meetings, less than 50% of oncologists in the United States are following these guidelines. Why? Because they don't trust the biomarker. And TMB has the same sort of limitations. They're not bad biomarkers, they're incomplete. They're only looking at a part of the story. So that means we need a new biomarker. And this is one that, I think, the data are quite impressive and we'll discuss it more. Dr. Rafeh Naqash: Absolutely. Like you said, abundance of many therapy options, but not necessarily everything works the same in different subsets of PD-L1 positivity or different subsets of patients with different levels of tumor burden. And like you said, again, difficulty in trying to identify the right biomarker. And that's a nice segue to this PROphet test that you guys ran. So can you tell us a little bit about the plasma proteomic assay? Because to the best of my knowledge, there's not a lot of validated plasma proteomic assays. A lot has been done on the tumor tissue side as far as biomarkers are concerned, but not much on the blood side, except for maybe ctDNA MRD testing. So what was the background for trying to develop a plasma-based proteomic test? And then how did this idea of testing it in the lung cancer setting come into play? And then we can go into the patient population specifics, the cohort that you guys have. Dr. David Gandara: Okay. Well, of course there's a company behind this assay, it's called OncoHost, and I'm a consultant for them. And they came to me two years ago and they said, “We have something different from anyone else.” And they explained the science to me, as well as some other lung cancer experts here in the United States. I'm not a proteomic expert, of course, but they developed an AI machine learning platform to assess plasma proteins in normal people and in people with cancer, and specifically then in people with non-small cell lung cancer. They identified over 7,000 proteins that had cancer implications for therapy, for resistance, for prognosis, etc., and they categorized them based on the literature, TCGA data, etc., and used this machine learning process to figure out which proteins might be most specific for non-small cell lung cancer. And that's where they started. And so out of that 7,000 proteins, where they've identified which ones are angiogenic, which ones are involved with EMT or cell cycle or whatever it might be, they distilled it down to 388 proteins which they thought were worth testing in non-small cell lung cancer. And that's when I became involved.  They had a retrospective cohort of patients that had been treated with various immunotherapies. They looked at the analytic validation first, then applied it to this cohort. It looked good. Then they had a very large cohort, which they split, as you usually do with an assay, into a test set and then a validation set. For the test set, they wanted something more than a response. They wanted some indicator of long term benefit because that's where immunotherapy differentiates itself from chemotherapy and even targeted therapy. And so they picked PFS at 12 months. And I became involved at that point and it looked really good. I mean, if you look at the figures in the manuscript, the AUC is superb about their prediction and then what actually happened in the patient. And then in this paper, we applied it to a validation set of over 500 patients in a prospective trial, not randomized, it's called an observational trial. The investigator got to pick what they thought was the best therapy for that patient. And then in a blinded fashion, the proteomic assay experts did the analysis and applied it to the group.  And so what that means is some of the patients got chemotherapy alone, some got checkpoint immunotherapy monotherapy, some got in combination with chemotherapy. None of the patients in this study got a CTLA-4 inhibitor. That work is ongoing now. But what the study showed was that this assay can be used together with PD-L1 as what I would call a composite biomarker. You take the two together and it informs the oncologist about the meaning of that PD-L1. I'll give you an example. If that patient has a PD-L1 over 50% in their cancer and yet the PROphet test is negative, meaning less than 5 - it's a 0 to 10 scale - that patient for survival is better served by getting chemotherapy and immunotherapy. However, if the PROphet test is positive and the PD-L1 is over 50%, then the survival curves really look equivalent. As I said earlier, even in that group of patients, a lot of oncologists are reluctant to give them monotherapy. So if you have a test and the same sort of example is true for PD-L1 0, that you can differentiate. So this can really help inform the oncologist about what direction to go. And of course then you use your clinical judgment, you look at what you think of as the aggressiveness of the tumor or their liver metastases, etc. So again, that's how this test is being used for non-small cell lung cancer. And maybe I'll stop there and then I'll come back and add some other points. Dr. Rafeh Naqash: I definitely like your analogy of this therapy de-escalation strategy. Like you mentioned for PD-L1 high where the PROphet test is negative, then perhaps you could just go with immunotherapy alone. In fact, interestingly enough, I was invited to a talk at SITC a couple of weeks back and this exact figure that you're referring to was one of the figures in my slide deck. And it happened by chance that I realized that we were doing a podcast on the same paper today.  So I guess from a provocative question standpoint, when you look at the PD-L1 high cohort in the subset where you didn't see a survival difference for chemo plus immunotherapy versus immunotherapy alone, do you think any element of that could have been influenced by the degree of PD-L1 positivity above 50%? Meaning could there have been a cohort that is, let's say PD-L1 75 and above, and that kind of skews the data because I know you've published on this yourself also where the higher the PD-L1 above 50%, like 90% PD-L1 positivity survival curves are much better than 50% to 89%. So could that have somehow played a role? Dr. David Gandara: The first thing to say is that PD-L1 and the PROphet score, there's very little overlap. I know that sounds surprising, but it's also true for tumor mutational burden. There's very little overlap. They're measuring different things. The PD-L1 is measuring a specific regulatory protein that is applicable to some patients, but not all. That's why even in almost all of the studies, people with PD-L1 0 could still have some survival benefit. But in this case they're independent. And not in this paper, but in other work done by this group, the PROphet group, they've shown that the PROphet score does not seem to correlate with super high PD-L1. So it's not like the cemiplimab data where if you have a PD-L1 of greater than 90%, then of course the patient does spectacularly with monotherapy. The other thing that's important here is they had a group of around a little less than 100 patients that got chemotherapy alone. The PROphet score is agnostic to chemotherapy. And so that means that you're not just looking at some prognostic factor. It's actually clinical utility on a predictive basis. Dr. Rafeh Naqash: I think those are very important points. I was on a podcast a couple of days back. I think there's a theme these days we're trying to do for JCO Precision Oncology, we're trying to do a few biomarker based podcasts, and the most recent one that we did was using a tissue transcriptome with ctDNA MRD and you mentioned the composite of the PD-L1 and the PROphet test and they use a composite of the tissue transcriptome. I believe they called it the VIGex test as well as MRD ctDNA. And when your ctDNA was negative at, I believe, the three month mark, those individuals had the highest inflamed VIGex test or highest infiltration of T cells, STING pathway, etc. So are there any thoughts of trying to add or correlate tissue based biomarkers or ctDNA based correlations as a further validation in this research with the company? Dr. David Gandara: Right. So there are many things that are being looked at, various composites looking at the commutations that might affect the efficacy of immunotherapy and how they correlate with profit positivity or negativity. And I'll just give the examples of STK11 and KEAP1. As you know, there's some controversy about whether these are for immunotherapy, whether they're more prognostic or predictive. I'm one of the co-authors among many in the recently published Nature paper by Dr. Skoulidis and the group at MD Anderson which report that for KEAP1 positive especially, but also SDK11 mutated getting immunotherapy, that that's where the CTLA-4 inhibitors actually play the greatest role. So realizing that this is still controversial, there are preliminary data, not published yet, that'll be presented at an upcoming meeting, looking at many of these other aspects, P53, SCK11, KEAP1, other aspects, TMB, that's actually already published, I think in one of their papers. So yes, there's lots of opportunities.  The other cool thing is that this isn't a test, it's a platform. And so that means that the OncoHost scientists have already said, “What if we look at this test, the assay in a group of patients with small cell lung cancer?” And so I just presented this as a poster at the world conference in San Diego. And it turns out if you look at the biology of small cell, where neither PD-L1 nor TMB seem to be very important, if you look at the biology of small cell and you form an assay, it only shares 44 proteins out of the 388 with non-small cell. It's a different biology. And when we applied that to a group of patients with small cell lung cancer, again it had really pretty impressive results, although still a fairly small number of patients. So we have a big phase three study that we're doing with a pharmaceutical company developing immunotherapy where we are prospectively placing the PROphet test in a small cell trial.  The platform can also be altered for other cancer types. And at AACR, Dr. Jarushka Naidoo presented really impressive data that you can modify the proteins and you can predict immunotherapy side effects. So this is not like a company that says, “We have one test that's great for everything.” You know how some companies say, “Our test, you can use it for everything.” This company is saying we can alter the protein structures using AI machine learning assisted process to do it and we can have a very informed assay in different tumor types and different situations. So to me, it's really exciting. Dr. Rafeh Naqash: Definitely to me, I think, combining the AI machine learning aspect with the possibility of finding or trying to find a composite biomarker using less invasive approaches such as plasma or blood, definitely checks a lot of boxes. And as you mentioned, trying to get it to prospective trials as an integral biomarker perhaps would be likely the next step. And hopefully we see some interesting, exciting results where we can try to match or stratify patients into optimal combination therapies based on this test.  So now to the next aspect of this discussion, David, which I'm really excited about. You've been a leader and a mentor to many. You've led ISLC and several other corporate group organizations, et cetera. Can you tell us, for the sake of all the listeners, junior investigators, trainees, what being a mentor has meant for you? How your career has started many years back and how it's evolved? And what are some of the things that you want to tell people for a successful and a more exciting career as you've led over the years? Dr. David Gandara: Well, thank you for the question. Mentoring is a very important part of my own career. I didn't have an institutional mentor when I was a junior investigator, but I had a lot of senior collaborators, very famous people that kind of took me under their wing and guided me. And I thought when I basically establish myself, I want to give back by being a mentor to other people. And you wouldn't believe the number of people that I'm even mentoring today. And some of them are not medical oncologists, they're surgeons, they're radiation oncologists, they're basic scientists. Because you don't have to be an expert in that person's field to be a mentor. It helps, but in other words, you can guide somebody in what are the decision making processes in your career. When is it time to move from this institution onward because you can't grow in the institution you're in, either because it's too big or it's too small? So I established a leadership academy in the Southwest Oncology Group, SWOG. I've led many mentoring courses, for instance, for ISLC, now for International Society Liquid Biopsy, where I'm the executive committee liaison for what's called The Young Committee. So ISLB Society, totally devoted to liquid biopsy, six years old now, we have a Young Committee that has a budget. They develop projects, they publish articles on their own, they do podcasts. So what I'm saying is those are all things that I think opens up opportunities. They're not waiting behind senior people, they are leading themselves.  We just, at our International Lung Cancer Congress, reestablished a fellows program where a group of fellows are invited to that Huntington beach meeting. It's now in its 25th year and we spend a day and a half with them, mentoring them on career building. I'll just give you my first, I have the “Letterman Top 10”. So my first recommendation is if all you have is lemons, make lemonade. And what I'm meaning is find what you can do at your institution if you're a junior person, what you can claim to be your own and make the very best of it. But then as you get further along in my recommendations, one of them is learn when to say ‘no'. Because as a junior investigator the biggest threat to your career is saying ‘yes' to everybody and then you become overwhelmed and you can't concentrate. So I'll stop there. But anyway, yes, mentoring is a big part of my life. Dr. Rafeh Naqash: Well, thank you, David. This is definitely something that I'm going to try to apply to my career as well. And this has been an absolute pleasure, especially with all the insights that you provided, not just on the scientific side but also on the personal career side and the mentorship side. And hopefully we'll see more of this work that you and other investigators have led and collaborated on. perhaps more interesting plasma based biomarkers. And hopefully some of that work will find its home in JCO Precision Oncology. Thank you again for joining us today. Dr. David Gandara: My pleasure. Dr. Rafeh Naqash: And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service organization, activity or therapy should not be construed as an ASCO endorsement.   Dr. David Gandara Disclosures: Consulting or Advisory Role Company: Henlius USA, Foundation Medicine, Janssen Pharma, Merck & Co, Mirati Therapeutics, Regeneron, AstraZeneca, Guardant Health, Genentech, Exact Sciences  Research Funding Company: Amgen, Genentech, Astex Pharma  

As part of Oncology On the Go, CancerNetwork® spoke with Andrew M. Evens, DO, MBA, MSc, about developments in the treatment landscape for adolescents and young adults (AYA) with lymphoma. He highlighted collaboration between adult and pediatric oncologists that may better standardize treatment for this population.  Evens is the deputy director for clinical services at the Rutgers Cancer Institute and system director of medical oncology and oncology lead at RWJBarnabas Health Medical Group. Of note, Evens discussed an effort to “harmonize” efforts between adult and pediatric oncologists in treating AYA patients who may receive different treatment regimens, despite being similar in age. Furthermore, he highlighted 2 prominent trials that illustrated collaborative efforts from both adult and pediatric oncologists: the phase 3 SWOG S1826 trial (NCT03907488) and the phase 3 AHOD2131 trial (NCT05675410). Regarding the SWOG trial, Evens highlighted the greater efficacy and tolerability of nivolumab (Opdivo) with doxorubicin hydrochloride (Adriamycin), vinblastine sulfate, and dacarbazine (AVD) vs the standard of care brentuximab vedotin (Adcetris) plus AVD.  “You could say it was, generally speaking, a double winner. [The nivolumab combination] was more effective at 2 years; the progression-free survival [PFS] was greater than 90%, [which was] a remarkable output. When I say a double winner, it was also largely better tolerated. There was less neuropathy, [fewer] infections, and less sepsis [vs brentuximab vedotin plus AVD]. Surprisingly, to a certain extent, [there were] not many immune-related adverse events outside of thyroid [events],” Evens said. Furthermore, Evens discussed how collaboration between adult and pediatric oncology has impacted developments in the AYA lymphoma sphere. He placed a particular emphasis on the efforts of the Lymphoma Research Foundation, which convened multiple AYA lymphoma symposiums and established an AYA consortium. He then outlined unmet needs for this patient population, which included mitigating late toxicities following treatment and addressing inconsistencies in guidelines for lymphoma treatment in the AYA group. Evens then discussed mitigating disparities and addressing barriers to care, underscoring a need to navigate the complexities of treatment for a patient population with a myriad of stressors. He concluded by highlighting resources available to AYA lymphoma groups, which include educational, medical, and psychosocial resources to best educate patients and express to them that they are not alone.  “At the end of the day, be an advocate. Be an advocate for yourself. Be an advocate for others and know that there are [many] resources and people out there to help. We want to make sure nobody has to go through this alone, and that they have the medical and other psychosocial resources available to them,” Evens concluded.

Dr. Rick Greene discusses with Dr. Dana Dominguez the association of adjuvant chemoradiation in resected biliary cancer with improved overall survival compared to chemotherapy alone, as reported in her article, "Adjuvant Chemoradiation in Resected Biliary Adenocarcinoma: Evaluation of SWOG S0809 with a Large National Database.” Article: Adjuvant Chemoradiation in Resected Biliary Adenocarcinoma: Evaluation of SWOG S0809 with a Large National Database | Annals of Surgical Oncology (springer.com)

Dr. Diwakar Davar and Dr. Jason Luke discuss advances in the neoadjuvant immunotherapy space that were presented at the 2024 ASCO Annual Meeting, including promising outcomes in high-risk melanoma from the NADINA trial, as well as other new treatment options for patients with advanced cancers.    TRANSCRIPT Dr. Diwakar Davar: Hello and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar, and I am an associate professor of medicine and the clinical director of the Melanoma Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I am delighted to have my colleague and friend Dr. Jason Luke on the podcast today to discuss key late-breaking abstracts and advances in immunotherapy that were presented at the 2024 ASCO Annual Meeting. Dr. Luke is an associate professor of medicine, the associate director of clinical research, and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh Hillman Cancer Center.   You will find our full disclosures in the transcript of this episode.  Jason, it's always a pleasure to hear your insights on the key trials in these spaces and to have you back as a guest on this podcast that highlights some of the work, especially advances, that were just presented. Dr. Jason Luke: Well, thanks very much for the invitation. I always love joining the podcast. Dr. Diwakar Davar: We'll start very quickly by talking about some advances and really interesting things that happened both in the context of melanoma but also in immunotherapy in general. And we'll start with what I think was certainly one highlight for me, which was LBA2, the late-breaking abstract on the NADINA trial. It was featured in the Plenary Session, and in this abstract, Dr. Christian Blank and colleagues reported on the results of this phase 3 trial of neoadjuvant ipi-nivo. This is the flipped dose of ipi1/nivo3 versus adjuvant nivolumab in PD-1 naive, macroscopic, resectable, high-risk stage 3 melanoma.  By way of background, neoadjuvant immunotherapy for those listening is an area of increasing interest for drug developers and development for both approved and novel agents. Neoadjuvant immunotherapy has been studied with multiple approved agents, including PD-1 monotherapy, PD-1 LAG-3, PD-1 CTLA-4, T-VEC, as well as investigational agents and multiple randomized and non-randomized studies. The benchmark pathologic response rates with these agents range from 17% PCR with PD-1 monotherapy, 45% to 55% PCR with PD-1 CTLA-4 combination therapy, and slightly higher 57% PCR with PD-1 LAG-3 has recently reported by Dr. Rodabe Amaria from MD Anderson. However, as we embark on phase 3 comparisons for various neoadjuvant compared to adjuvant immunotherapy trials and combinations, we're increasingly moving towards event-free survival as the primary endpoint for neoadjuvant versus adjuvant studies. And this was most recently studied in the context of SWOG S1801, a study that was led by Dr. Sapna Patel.  So, Jason, before we start on NADINA, can you briefly summarize the SWOG S1801 trial and the event-free survival statistic reported by Dr. Patel and her colleagues? Dr. Jason Luke: Well, absolutely. And these data were reported at ESMO about two years ago and then in the New England Journal last year. The S1801 study answered a very simple question: What would happen if you took three of the doses of standard adjuvant therapy with pembrolizumab and moved them prior to surgery? And on a high level, the study is as simple as that. And many of us were somewhat skeptical of this trial design because we thought that just moving the doses earlier may not actually have a major impact.  In the study, you alluded to the event-free survival statistic, and that alludes to what was considered an event. And so, without reading all of it, there were several different aspects that were included in terms of time, based on the date of randomization until the first of a series of events, such as disease progression, toxicity from treatment, if the patient was unable to go to surgery or had surgical complications, or if they had delay in starting the adjuvant therapy due to toxicity, and obviously, recurrence of melanoma or death from any cause. In that context, merely moving the 3 doses of pembrolizumab to the neoadjuvant setting saw an improvement in this two-year event free survival to 72% for the neoadjuvant therapy compared to 49% for the adjuvant therapy. That was quite an outstanding change. And again, noting the power of neoadjuvant treatment, really dictating the impact of anti PD-1, again, just with 3 doses moving from adjuvant into the neoadjuvant setting, and I think all of us were somewhat surprised to see that magnitude of a benefit. But it set up the current study very well, where we now look at combination therapy. Dr. Diwakar Davar: So let's move on to the phase 3 NADINA trial. Do you want to perhaps discuss the study design, particularly focusing on the EFS primary endpoint and maybe also touching on the different schedules? So, SWOG S1801 was a neoadjuvant study of 3 cycles of pembrolizumab and how did that compare and contrast to the neoadjuvant combination that was studied in NADINA? Dr. Jason Luke: Well, as you alluded to, NADINA investigated the regimen of nivolumab plus ipilimumab and compared that against adjuvant therapy with nivolumab alone. So, in the study, as you alluded, the dose and schedule of the two drugs used was nivolumab at 3 milligrams per kilogram, and ipilimumab with 1 milligram per kilogram. That was based on a series of signal finding and safety studies that had been previously done by the same group of authors identifying that as the optimal treatment regimen. And it's worth noting that's slightly different than the labeled indication that's generally used for those same drugs for metastatic melanoma, albeit that the NCCN also endorses this schedule. So, in the trial, 423 patients were randomized, 1:1 to receive either neoadjuvant therapy with those 2 doses of nivolumab plus ipilimumab as compared with standard adjuvant therapy with nivolumab following surgery.   Now, one interesting tweak was that there was an adaptive nature to the study, meaning that patients had a fiducial placed at the index lymph node, and after the neoadjuvant therapy in that arm, that lymph node was removed. And if the patient had a major pathological response, they did not go on to receive the adjuvant portion of the treatment. So it was adaptive because those patients who did very well to the neoadjuvant did not require the adjuvant portion. And in those patients who did not achieve a major pathological response, they could go on to have the adjuvant therapy. And that also included the BRAF therapy for those whose tumors were BRAF mutants.  It's also worth pointing out that the definition of event free survival was slightly different than in the S1801 study that was alluded to just a second ago. And here, EFS was defined from the date of randomization until progression due to melanoma or due to treatment. So that's slightly different than the definition in the S1801 trial. So, a somewhat complicated study, but I really applaud the authors because I think this study does mirror what we would likely be doing in actual clinical practice.  Dr. Diwakar Davar: So, just to briefly summarize the efficacy, and then to get your comments on this, the path response, the PCR rate was 47%. The major pathologic response rate, which is the proportion of patients with between 0% to 1/10% of residual viable tumors, was about 12%. And for a major pathologic response rate of 0% to 10% of 59%. And then the rest of the patients had either pathologic partial response, which was 10% to 50%, or pathologic non response or 50% or greater residual viable tumor, all assessed using central pathology grades. The one year RFS was 95% in the FDR patient population versus 76% in the pathologic partial response patient population, 57% in the pathologic non response patient population. So how do you view these results? Can you context the FDR rates and the EFS rates from NADINA relative to nivo-rela and also potentially SWOG 1801? Dr. Jason Luke: Well, I think these are very exciting results. I think that for those of us that have been following the field closely, they're actually not especially surprising because they mirror several studies that have come before them. When we put them in context with other studies, we see that these rates of major pathological response are consistent with what we've seen in phase 2 studies. They're relatively similar. Or I should say that the results from nivolumab and relatlimab, which was also pursued in a phase 2 study of somewhat similar design, are somewhat similar to this. So, combination immunotherapy does look to deliver a higher major pathological response than pembrolizumab alone, as was known in S1801. Which of course, the caveat being is these are cross control comparisons that we need to be careful about. So I think all of these are active regimens, and I think adding a second agent does appear to enhance the major pathologic response rates. When we look at the event free survival, we see something similar, which is that numerically it looks to be that combination immunotherapy delivers a higher event free survival rate. And that looks to be rather meaningful given the difference in the hazard ratios that were observed between these various studies. And here in the NADINA study, we see that 0.3 hazard ratio for EFS is just extremely impressive.  So the abstract then, from ourselves, out of these specific studies, what does this mean more broadly in the real world, where patients exist and the rest of the landscape for clinical trials? I think we can't take enough time to stop for a second and just think about what a revolution we've come forward in with immune checkpoint blockade and melanoma. When I started my career, now, more than 15 years ago, melanoma was the cancer that made cancer bad. And now here we say, in the highest risk of perioperative patients, we can deliver 2 doses of nivolumab and ipilimumab, and essentially half of the patients then don't need to go on, and more than half the patients don't need to go on to have a full surgery and don't need adjuvant therapy. And from what we could tell of a very, very low risk of every heavy recurrence of melanoma. Of course, there's the other half of patients where we still need to do better, but these are just fantastic results and I think highly meaningful for patients.   In the context of ongoing clinical trials, another abstract that was presented during the meeting was the update to the individualized neoantigen therapy, or V940 with pembrolizumab or against pembrolizumab alone. That's the KEYNOTE-942 study. In that study, they presented updated data at two and a half years for relapse free survival, noting a 75% rate without relapse. So those results are also highly intriguing. And these are in a similar population of very high risk patients. And so I think most of us believe that neoadjuvant therapy with this study in NADINA is now confirmed as the priority approach for patients who present with high-risk stage 3 disease. So that would be bulky disease picked up on a scan or palpable in a clinic. I think essentially all of us now believe patients should get preoperative immunotherapy. We can debate which approach to take, and it may vary by an individual patient's ability to tolerate toxicity, because, of course, multi agent immunotherapy does have increased toxicity relative to anti PD-1 alone. But we'll have to wait now for the full phase 3 results from the V940 individualized neoantigen therapy. And if those come forward, that will be an extremely attractive approach to think about for patients who did not achieve a major pathological response to neoadjuvant therapy, as well as of course to the other populations of patients with melanoma where we otherwise currently give adjuvant therapy stage 2B all the way through stage 4 resected. It's an amazing time to think about perioperative therapy in melanoma. Dr. Diwakar Davar: So this is clearly outstanding data, outstanding news. Congratulations to the investigators for really doing what is an investigative initiated trial conducted across multiple continents with a huge sample size. So this clearly appears to be, at this point in time at least, a de facto standard. But is this going to be FDA-approved, guideline-approved, or is it possible in your mind? Dr. Jason Luke: Well, that's an interesting question. This study was not designed with the intent to necessarily try to register this treatment regimen with the FDA. One would have to take a step back and say, with how powerful these data appear, it sort of seemed like it would be too bad if that doesn't happen. But all the same, I think the community and those of us who participate in guideline recommendations are fully supportive of this. So, I think we will see this move into compendium listings that support insurance approval, I think, very, very quickly. So, whether or not this actually becomes formally FDA approved or is in the guidelines, I think this should become the standard approach that is considered for patients, again presenting with high-risk stage 3 disease.  Dr. Diwakar Davar: Fantastic. So now we're going to go in and talk about a slightly different drug, but also from the melanoma context, and that is the safety and efficacy of RP1 with nivolumab in the context of patients with melanoma who are PD-1 failures. So, this is Abstract 9517. And in this abstract, our academic colleagues essentially talked about these data, and we'll start by describing what RP1 is. RP1 essentially is a HSV-1 based oncolytic immunotherapy. And RP1 expresses GM-CSF as well as a fusogenic protein, GALV-GP-R-. And in this abstract, Dr. Michael Wong from MD Anderson and colleagues are reporting the results of IGNYTE, which is a phase I trial of intratumoral RP1 co-administered with systemic nivolumab in patients with advanced metastatic treatment refractory cutaneous melanoma. And the data presented in this abstract represents data from a registration directed, abbreviated as RD, registration directed cohort of RP1 plus nivolumab in PD-1 refractory melanoma. So, let's start with the description of the cohort.  Dr. Jason Luke: Right. So, in this study, there were a total of 156 patients who were presented, and that included an initial safety and dose finding group of 16, as well as the RD cohort, as you noted, of 140 patients. And it's important to point out that this was a cohort that was selected for a very strict definition of progression on anti PD-1, or a combination immunotherapy as their immediately prior treatment. So, all of the patients in the cohort had exposure to anti PD-1, and 46% of them had anti PD-1 plus anti CTLA4, nivolumab and ipilimumab as their immediately prior therapy. This was also a group of relatively high-risk patients when one considers stage. So, within the stage 4 population, the entry here included 51% who had stage M1B, C, and D melanoma. And that is worth pointing out because this is an injectable therapy. So, trials like this in the past have tended to be biased towards earlier stage, unresectable or metastatic melanoma, meaning stage 3B, 3C, 3D and then stage 4m1a. Again, to emphasize the point here, these were pretreated patients who had a strict definition of anti PD-1 resistance, and over half of them, in fact, had high-risk visceral metastatic disease.  In that context, it's very interesting to observe that the overall response rate was described in the total population, as 31%, and that included 12% who achieved complete response. And so, again, to make sure it's clear, we're talking about a treatment where the oncolytic virus is injected into one or multiple sites of recurrent disease, and then the patients administer nivolumab as per standard. And so, I think these data are quite intriguing. Again, such a high- risk population and their maturity now, with a follow-up of over a year, I think, makes this look to be a very interesting treatment option.  Dr. Diwakar Davar: I guess on that topic of mature follow-up, it probably would be important for us to inform our audience that the top line data for the primary analysis was actually just released, I think, earlier today, and wherein the central confirmed objective response rate was 34% by modified RECIST and 33% by RECIST, clearly indicating that these responses, as you noted, very treatment refractory patient population, these responses were clearly very durable. So, you mentioned that there were responses seen in uninjected visceral lesions, responses seen in both PD-1 and PD-1 CTLA-4 refractory patients. Can you talk a little bit about the response rate in these high-risk subgroups, the uninjected visceral lesions, the patients who had both combination checkpoint and epidural refractory response rate by primary PD-1 resistance.  Dr. Jason Luke: Sure. You know, I think, again, to emphasize this point in the study, we saw that there were responses in the non-injected lesions, and I think it's really important to emphasize that. Some have referred to this as a putative abscopal like effect, similar to what is described in radiation. But it implies that local treatment with the oncolytic virus is triggering a systemic immune response. In the higher risk patient population, we'll note that whereas the overall response rate in PD-1 refractory patients was 34%, in the combination of PD-1 and CTLA-4 refractory patients, the response rate was 26%. So, [this is] still very good. And when we looked at that split by stage, as I alluded to before, in the population of patients that had, what you might call earlier unresectable diseases, so 3B through 4A, the response rate was 38%, and in the stage 4 M1b through M1d, it was 25%. So slightly lower, but still very good. And that would be as expected, because, of course, the patients with visceral metastatic disease have more advanced disease, but those response rates look quite good. Again, looking at the combination refractory population as well as the more high-risk disease. Dr. Diwakar Davar: So, clearly, these are very promising data and exciting times for multiple investigators in the field and the company, Replimune, as well. So, what are the next steps? I believe that a registration trial is planned, essentially, looking at this with the goal of trying to get this combination registered. Can you tell us a little bit about IGNYTE-3, the trial design, the control arm, and what you foresee this trial doing over the next couple of years?  Dr. Jason Luke: So, as this agent has been maturing, it's worth pointing out that the company that makes this molecule, called RP1, but I guess now we'll have to get used to this name vusolimogene oderparepvec as the actual scientific term, they have been having ongoing discussions with the FDA, and there is the potential that this agent could come forward on an accelerated path prior to the results being released from a phase 3 trial. That being said, the phase 3 confirmatory study, which is called the IGNYTE-3 study, is in the process of being launched now. And that's a study investigating this molecule in combination with nivolumab, as was alluded to earlier, and a randomized phase 3 design, where that combination is compared with a physician's choice, essentially a chemotherapy-based option.   In that study, it will be 400 patients with stage 3B through stage 4; patients will have progressed on anti PD-1, either as a combination or in sequence, and then come on the study to be randomized to either vusolimogene oderparepvec plus nivolumab versus that physician's choice. And the physician's choice includes chemotherapy agents, but also nivolumab plus relatlimab as another option, or an anti PD-1 monotherapy, if that's deemed to be a reasonable option by the treating investigator. And the primary endpoint of that study is overall survival. And unfortunately, in this highly refractory patient population, that's something that may not take long to identify with key secondary endpoints of progression free survival, as well as overall response rate. I'm quite enthusiastic about this study, given these data, which have now been centrally confirmed as you alluded to before. I think this is a very exciting area of investigation and really crossing my fingers that this may be perhaps the first locally administered therapy which does appear to have a systemic impact that can hold up in phase 3. Dr. Diwakar Davar: Very, very, very exciting results. And I guess it's worthwhile pointing out that this company also has got, I think, multiple studies planned with both RP1 and cutaneous squamous cell carcinoma in a solid organ transplant patient population where single agent activity has already been reported by Dr. Migden at prior meetings, as well as a novel trial of potentially RP2 metastatic uveal melanoma. So we'll now pivot to Abstract 6014. So, 6014 is a drug by a company known as Merus. Essentially, it's a very novel agent. Merus essentially is a company that is specialized in making bicyclics and tricyclics. And these are not bicycles or tricycles, but rather drugs that essentially are bispecific antibodies. And Merus essentially has come up with petosemtamab. I think we're going to have to figure out better names for all of these drugs at some point. But petosemtamab, or MCLA-158, essentially is a bicyclic, targeting both EGFR as well as LGR-5. So EGR-5, of course, is a known oncogenic driver in multiple tumor types, squamous, including non small cell lung cancer, cutaneous squamous cell carcinoma, but also head and neck squamous cell carcinoma. And LGR-5 essentially is leucine-rich repeat-containing G-protein coupled receptor 5, but it's a receptor in cancer stem cells and certainly highly expressed in head neck squam. And MCLA-158, or petosemtamab is a IgG one bispecific with ADCC-activity because of IgG1 backbone co-targeting EGFR and LGR5. Merus had earlier results that evaluated petosemtamab monotherapy. They defined the RP2D and second- and third-line head and neck blastoma patients with a respectable response rate of 37% investigator-assessed ORR with six months median DoR, and this was published by Ezra Cohen about a year or so ago.  In this abstract, Dr. Fayette and colleagues report on the results of the MCLA-158-CL01 trial, which is a trial of pembrolizumab plus petosemtamab in one front line head and neck squamous cell population. So maybe let's start with the description of the cohort. And it is a small trial, but we'll be able, I think, to dig into a little bit about why this might be exciting. Dr. Jason Luke: Yes. So, as alluded to, it's not the biggest trial as yet, but there were 26 patients with anti PD-1 treatment naive head and neck squamous cell carcinoma. And all the patients in the study did receive, as you alluded to, pembrolizumab plus petosemtamab. Based on the label for pembrolizumab, all the patients in this study were PDL-1 positive. So that's one point that it's worth pointing out to make sure that that's understood. This is the population of patients who would be expected to benefit from pembrolizumab in the first place. Now, in the abstract, they reported out only 10 response evaluable patients, but they updated that in the actual slides of presentation at the meeting. So among 24 patients that were alluded to, 67% were described as having had a response, although some of those were yet to be confirmed responses. And when it was evaluated by PDL-1 status, there didn't seem to be a clear enrichment of response in the PD-1 positive more than 20% group, as compared to the 1-19% group. That isn't especially surprising because that was a trend that one would see, presumably with pembrolizumab alone. But overall, I think these data are pretty exciting in terms of a preliminary study. Dr. Diwakar Davar: You know, you mentioned that the objective response rate was high, almost 60-something%. The prognosis of these patients is generally poor. The OS is typically thought of as between 6-15 months. And based on KEYNOTE-048, which was led by Dr. Burtness and colleagues, the standard of care in the setting is pembrolizumab +/- platinum based chemotherapy regimens. Allowing for the fact that we only have 10 patients here, how do you think these results stack up against KEYNOTE-048? And you made a very important point earlier, which was, by definition, pembro is on label only for the CPS. So PDL-1 score, at least in head and neck squamous cell carcinoma CPS and not TPS. But in the CPS 1% or greater patient population, where pembro is on label, how do these results stack up against the KEYNOTE-048 results. Dr. Jason Luke: Right. KEYNOTE-048 is considered the seminal study that dictates frontline treatment in head and neck cancer. And before we dive into this too far, we do want to acknowledge that here we're comparing 26 patients versus a phase 3 trial. So, we're not trying to get too far ahead of ourselves, but this is just a preliminary comparison. But in KEYNOTE-048, as you alluded to, two regimens were superior to chemotherapy. One was the pembrolizumab monotherapy, as well as pembrolizumab plus chemotherapy. So again, the study overall survival, of course, was much higher, the PDL-1 positive subgroup, which is what dictated the unlabeled use of this. But response to pembro monotherapy in that population of patients is still modest. We're talking about upwards of 20-30%. So, if you compare that to, again, preliminary evidence here from this trial of only 24 patients, that response rate of 60% seems extremely high. And so even if that were to come down somewhat in a larger data series of patients, that still looks to be quite promising as a treatment regimen, that might eventually even be chemotherapy sparing for this population of patients. I think this raises a lot of eyebrows that perhaps this dual targeting approach, EGFR and LDR-5, may bring something really important to the field that evolves it. Dr. Diwakar Davar: So, what are the next steps for petosemtamab? You mentioned that the activity was interesting. Are we going to see a larger trial? Any thoughts on where things are going to go?  Dr. Jason Luke: Well, based on the phase 2 data of petosemtamab alone, even without pembrolizumab, the molecule had already been given fast track designation by FDA, which means allowing for greater communication between the drug sponsor in the FDA and designing a seminal study design. One would assume that this trial will be rapidly expanded quite greatly, perhaps to 100 or 200 patients, to try to flush out what the real response rate is in a more meaningful number of patients. But I think these data will probably also trigger the design and probably near-term evaluation or expedited acceleration of a phase III clinical trial design that would potentially validate this against the current standard of care. So, I'm pretty excited. I think we'll see a lot more about this agent in the relatively near future. Dr. Diwakar Davar: So, finally, we'll pivot to the last abstract that we're going to talk about, which is Abstract 2504. It's a relatively interesting target, CCR8 monoclonal antibody. But this is the efficacy and safety of LM-108, and LM-108 is an anti CCR8 monoclonal antibody that is being developed by LaNova Medicine. And the results that are described, actually a pool set of results of combinations of LM-108 with anti PD-1, two separate anti PD-1, in patients with gastric cancer, mostly done ex-U.S., which is interesting because of this patient population, and it's a pool result of several, 3 phase 1 and 2 studies.  LM-108 is an Fc-optimized anti CCR8 monoclonal antibody that selectively depletes tumor infiltrating Tregs. The abstract reported a pooled analysis of three phase 1, 2 trials with 3 different NCT numbers that all evaluated the efficacy of LM-108 and anti PD-1 in patients with gastric cancer. So, let's start with the description of the cohort. Maybe, Jason, you can tell us a little bit about before you start, as you describe the cohort, sort of what we know, editorially speaking, about the difficulty with which Tregs depletion has been tried and obviously failed up until now in the tumor microenvironment. Dr. Jason Luke: Right. I think that's a really interesting comment. And so, for decades, in fact, targeting regulatory T-cell to alleviate immune exclusion in the tumor microenvironment has been of interest in immuno-oncology. And in preclinical mouse models, it seems quite clear that such an approach can deliver therapeutic efficacy. However, by contrast, in human clinical trials, various different Treg depleting strategies have been attempted, and there's really little to no evidence that depleting Tregs from human tumors actually can deliver therapeutic responses. And by that we're referring to CD-25 antibodies. The drug ipilimumab, the CTLA-4 antibody, was punitively described as a Tregs depleter preclinically, but that doesn't seem to be the case in patients. And so, in that background, this is quite an eye raiser that an anti CCR8 antibody could be driving this effect. Now, before we talk about the results of this trial, I will point out, however, that given the Fc-optimization, it's entirely possible that the Tregs are being depleted by this mechanism, but that more could also be going on. Because Fc gamma RII binding by this antibody that could be nonspecific also has the potential to trigger immune responses in the tumor microenvironment, probably mediated by myeloid cells. So I think more to come on this. If this turns out to be the first meaningful Tregs depletor that leads to therapeutic efficacy, that would be very interesting. But it's also possible this drug could have multiple mechanisms.  So, having said all of that, in the clinical trial, which was a pooled analysis, like you mentioned, of LM-108 in combination with anti PD-1 of a couple different flavors, there were 48 patients treated either with LM-108, with pembrolizumab, or with toripalimab, which is another anti PD-1 antibody. On the drug combination was, generally speaking, pretty well tolerated, noting grade 3 treatment related adverse events in the range of 38%, which is somewhat expected given combination immunotherapy. We talked about nivolumab and ipilimumab before, which, of course, gives even higher rates of immune-related adverse events, with the most common toxicities being anemia, lipase elevations, rash, ALC decrease; albeit, quite manageable. Dr. Diwakar Davar: So, what about the objective response rate? Can you contextualize the efficacy? And as you do that, maybe we'll think about what you'd expect in the context of, say, gastric cancer, especially in patients who've never really had a prior checkpoint inhibitor before. What do you think about the ORR? What do you think about the relative efficacy of this combination? Dr. Jason Luke: Well, so, in the study, they described overall response rate in the 36 patients as 36% and described immediate progression for survival of about 6.5 months. And so that was among patients who were treatment naive. And in second-line patients, they actually described an even higher response rate, although it was only 11 patients, but they're at 64%. And so, I think those data look to be somewhat interesting. When I was actually scrutinizing the actual data presented, it was of some interest to note that the quality of responses seemed to be about as good on the lower dose of LM-108, so 3 milligrams per kilogram as compared to 10 milligrams per kilogram. I think there's definitely more to learn here to try to optimize the dose and to fully understand what the overall efficacy of this treatment combination would be.  I would emphasize that in this disease, I think novel treatment strategies are certainly warranted. While anti PD-1 with chemotherapy has moved the needle in terms of standard of care treatment, it's really only a minor subset of patients who derive durable long-term benefit like we normally associate with immune checkpoint blockade. I think these are preliminary data. They're very intriguing.   You alluded to earlier that this population of patients was an Asian data set, and it is well known that the efficacy of chemotherapy and immunotherapy does appear to be somewhat enhanced in Asian populations, and that goes to distributions of metastasis and tumor microenvironment effects, etc. Very difficult to try to tease any of that out in this abstract, other than to look at these data and suggest that this is pretty interesting, both from a novel therapeutic approach, we talked about the Tregs consideration, but also straight up on the efficacy because I think if these data could hold up in a larger number of patients, and particularly in a western population of patients, I think it would be very intriguing. Dr. Diwakar Davar: Certainly, ASCO 2024 had a lot of interesting data, including data from targeted agents, the LAURA trial, ADCs. But just focusing on the immune therapy subset, we certainly saw a lot of great advances in patients who were treated with neoadjuvant as well as relapse refractory disease in the context of RP1 and then a couple of newer agents such as this petosemtamab as well as LM-108. And of course, we cannot forget to highlight the extended DMFS data from the pembro vaccine study from KEYNOTE-942.  Jason, as always, thank you for taking a little bit of time out of your extremely busy schedule to come and give us insights as to how these agents are impacting the landscape. We really value your input and so thank you very much.  Dr. Jason Luke: Thank you for the opportunity. Dr. Diwakar Davar: And thank you to our listeners for your time today. You will find the links to all the abstracts that we discussed in the transcript of this episode. And finally, if you value the insights that you hear on this podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. So, thank you.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today's speakers:   Dr. Diwakar Davar   @diwakardavar   Dr. Jason Luke   @jasonlukemd      Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:       Dr. Diwakar Davar:     Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences    Consulting or Advisory Role: Instil Bio, Vedanta Biosciences    Consulting or Advisory Role (Immediate family member): Shionogi    Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences    Research Funding (Inst.): Zucero Therapeutics    Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy       Dr. Jason Luke:    Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX    Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine    Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure    Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)    Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

Dr Lunning sits down with Alex Herrera, MD, of City of Hope, to discuss the frontline management of Hodgkin lymphoma, including the rationale for the SWOG 1826 trial, the collaborative efforts between pediatric and adult oncologists that led to the successful initiation of this trial, potential future directions for this research, and more.

Drs. Hope Rugo and Sara Tolaney discuss the promise of antibody-drug conjugates (ADCs) in the treatment of breast cancer, highlighting key trials that shed light on matching the right ADC to the right patient in the right setting. They also explore how combinations and sequencing of ADCs can augment their efficacy, the mechanisms of resistance, and the future potential of biomarkers to predict patient response. TRANSCRIPT Dr. Hope Rugo: Hello, I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco's Comprehensive Cancer Center. Antibody-drug conjugates, or ADCs, are rapidly changing the treatment landscape for patients with breast cancer. ADCs consist of antibodies that target tumor-specific antigens on the cell surface, chemical linkers, and cytotoxic payloads that can act powerfully to kill cancer cells. On today's episode, we'll be discussing advances in research to match the right ADC to the right patients and in the right setting. We'll also talk about the next steps, assessing how combinations and sequencing of ADCs can augment their efficacy, improve options for patients, and identify biomarkers in the future to predict how patients will respond so that we can match the right treatment to the right patient and their tumor. We need to gain a better understanding of the mechanisms of resistance that occur upfront as well as under the pressure of treatment.  Joining me for this important discussion is Dr. Sara Tolaney. Dr. Tolaney is an associate professor of medicine at Harvard Medical School, associate director of the Susan Smith Center for Women's Cancer, and chief of the Division of Breast Oncology at the Dana-Farber Cancer Institute in Boston.  You'll find our full disclosures in the transcript of this episode and disclosures of all guests on the podcast are available at asco.org/DNpod. Dr. Tolaney, we're delighted to have you on the podcast today. Thanks for being here. Dr. Sara Tolaney: Thank you so much for having me. I'm looking forward to the discussion. Dr. Hope Rugo: Great! So, we'll move forward, and because we're friends and colleagues, I'm going to refer to you as Sara, and I'm Hope, since we'll dispense with formalities in our discussion.  A lot of the talks that we give about ADCs start out with “a revolution in breast cancer therapy.” And indeed, this is a really exciting time with ADCs as treatment for breast cancer, and we're rapidly moving these agents into earlier disease settings. Can you tell us a little bit about the possibilities and challenges of using ADCs for the treatment of breast cancer today? Dr. Sara Tolaney: It's interesting that you say antibody-drug conjugates as revolutionizing outcomes of breast cancer, which I think is true. But on the flip side, I think it's also bringing up a lot of questions about how to use them, when to use them, and how to manage side effects. So there are a lot of good strengths for these antibody-drug conjugates, but a lot of unknowns that we're still trying to figure out. We had an older antibody-drug conjugate T-DM1 that we were all very familiar with that for years had been a treatment that we used very commonly in metastatic disease and now even use in early breast cancer, and I think has changed outcomes for patients. But over time, we've been able to develop newer antibody-drug conjugates as the technology has really evolved so that these agents now are able to deliver a lot of chemotherapy into a cancer cell. We're seeing very high drug-to-antibody ratios, and we're also seeing that these drugs can function via bystander effect, whereas T-DM1, for example, was not able to do that. But our newer ADCs, like sacituzumab govitecan or trastuzumab deruxtecan, are agents that do allow chemotherapy to get into that cancer cell, but also to get into neighboring cells.  And I think the technology evolution in being able to build these so-called next-generation ADCs has allowed for really unprecedented efficacy that we've not seen before. And it's also allowed us to develop these drugs in a way that's been different. Originally, we were developing T-DM1 to turn off HER2 signaling and to deliver chemotherapy into a HER2 cell. At least that's what we thought originally. And now we're really evolving so that we can just find a tiny bit of protein on a cancer cell and use it as a target, really in a subtype-agnostic way. And I think it's just a different way of thinking about how to use these agents to really deliver a lot of chemotherapy into cancer cells and have very robust efficacy. Dr. Hope Rugo: Yes, it is fascinating that some of the suppositions that we made with the first ADC don't seem to really hold true as well. And maybe they hold true in varying levels for the different ADCs. For example, this bystander effect is thought to allow us to target cells that have very low expression of the receptor that can be internalized even lower than our ability to detect these receptors by immunohistochemistry. And maybe we'll talk about that in a little bit.   But first, you mentioned already sacituzumab and trastuzumab deruxtecan, the ADCs that are currently approved for breast cancer. But can you tell us a little more about those ADCs and the key trials that have led to approval of these targeted agents? Dr. Sara Tolaney: Yes, I think when we first saw the data that came out with T-DXd and DESTINY-Breast01, I think my jaw dropped because I had never seen a waterfall plot like that. This was a single-arm study that looked at T-DXd in patients with very heavily pretreated metastatic HER2-positive breast cancer and saw very high response rates of over 60% and a clinical benefit rate of almost 98%, meaning that almost every single patient who got the drug and had a median of six prior lines of therapy had reduction in tumor size. And that's unreal. I think it was revolutionary in the sense that we had never seen that kind of activity in such a pretreated population. The agent was studied in other registration trials, DESTINY-Breast03, which looked at T-DXd and compared it head to head with T-DM1 in a predominantly second-line metastatic HER2-positive population, and here, again, unprecedented results. I've never seen a p value like that or a hazard ratio of, again unreal, of a little under 0.3 and seeing a 28-month PFS with T-DXd relative to just a little under 7 months PFS with T-DM1. We have never seen patients with metastatic HER2-positive breast cancer have a PFS that long. Even in CLEOPATRA, it's a little under 19 months in the first-line setting, where people were predominantly naïve to HER2-directed therapies. This, again, is really changing outcomes for patients.   But then, I think, when we go to the next step, we studied T-DXd in patients with HER2-positive breast cancer and it had again these unprecedented results. But there was some early data suggesting that it could even work in tumors that weren't truly HER2-positive but what we call HER2-low, meaning that they weren't HER2/3+, they weren't HER2-0 but they were 1+ to 2+ and not FISH amplified. And so even with a little bit of protein there, they were seeing activity in the early phase studies and so it led to DESTINY-Breast04, which compared T-DXd to chemotherapy of physician's choice in people who had had one or two prior lines of chemotherapy in the metastatic setting. It was predominantly geared to look at outcomes in hormone receptor-positive breast cancer. But there was a small group of 58 patients with triple-negative disease that were also included in that trial. And here again, a very unprecedented outcome seeing a response rate of about 50%, which, again, we never see in pretreated hormone receptor-positive disease. And a PFS of 10 months, and again, these are people who already had one or two prior lines of chemotherapy. So it's, again, really changing outcomes. And so now I think it leads us to a lot of other questions that we are addressing in trials - can this drug work even if the tumor has maybe no HER2 expression, what about HER2-0, what about HER2-ultra low, meaning a little bit of staining but not quite 1+. And so these are questions that I think we will need to address and there are studies that will help us address that. On the flip side, we saw sacituzumab govitecan get developed in breast cancer. Initially, we saw very impressive results from a single arm study of sacituzumab in metastatic triple-negative disease where we saw response rates of a little over 30%. These are patients who were very heavily pretreated with metastatic triple negative breast cancer where, unfortunately, response rates end up being in a 5% range so it was a home run in that setting. So that led to the ASCENT trial, which compared sacituzumab govitecan to treatment of physician's choice therapy and that study really enrolled people who were, in essence, second line and beyond in the metastatic triple-negative setting and showed almost triple progression free survival, in essence, doubled overall survival. So again, very robust efficacy leading to confirming its approval. And then we saw data from TROPiCS-02, which looked at sacituzumab in metastatic hormone receptor-positive disease and also showed improvements in both progression free and overall survival. And this was in pre-treated populations of 2 to 4 prior lines of chemotherapy. These agents, again, have established robust efficacy, and so now the idea is can we move these drugs earlier in development into earlier line settings and can we even move these agents into the early disease setting and potentially cure more patients? So hopefully, we'll figure out ways to make that happen. Dr. Hope Rugo: Yeah, that was a great summary of this exciting data. And I think we really got an idea of what waterfall plots could tell us from DESTINY-Breast01 where you could count the number of patients whose cancers grew with therapy on one hand. It's been a huge advance. I think it's where we get this “revolution” even in patients with a median of 4 lines of prior chemo, and, in the ASCENT trial, we were able to see this improvement and survival in the hardest-treated subset of metastatic breast cancer triple negative disease. And then the remarkable data in HER2-positive and HER2-low breast cancer hormone receptor positive disease. We're really covering all of the subset of breast cancers.   When we introduce new therapies though, and of course, our interest is moving them earlier as lines of therapy in the metastatic setting, we really have to think about the adverse events and how those are going to affect their patients, and balancing the risk benefit ratio. Obviously when the benefit is so huge, we're more thinking about how do we proactively manage these side effects, educate our patients, use prophylaxis when possible. Can you share with us some of your insights on management strategies for toxicities?  Dr. Sara Tolaney: You bring up a very good point, and I will say the ADCs were designed with the idea being that we could deliver a ton of chemotherapy into a cancer cell. So obviously, my hope had been that we weren't going to see a lot of chemotherapy-like side effects because the goal was to try to spare normal cells of these side effects. But unfortunately, we do see that these agents do have real toxicities, and I think that is an important message. So, for example, with sacituzumab, for people who have hair going into it, they will lose their hair during the course of treatment, and so that's important to make patients aware of. It can lower blood counts, and about 50% of patients who are on sacituzumab will end up needing growth factor support while they're on treatment. So, that is again something that needs to be monitored and managed. But usually, we're pretty good at managing neutropenia, and with the growth factor support, I find that it actually works really well.  Another thing with sacituzumab is the potential risk of diarrhea, but most of the diarrhea is low-grade diarrhea. It's rare that you get someone who has high-grade diarrhea with sacituzumab. Usually, I find it works to just instruct patients to use loperamide as needed. And again, usually that works well. And certainly when needed, dose modification can also help with these side effects and so it is important to keep in mind that this is another option. With T-DXd, one thing that we do have to keep in mind as an unusual side effect is the potential risk of interstitial lung disease. We see that in about 10% to 15% of patients getting T-DXd. That is something that we do have to be very mindful of. For the most part it is low-grade ILD. But there are rare occasions where there have been deaths from ILD. And we're seeing with some of the newer trials, the death rate is usually under 1%, but it is a real potential risk. And so it is really important to counsel patients when getting T-DXd about this potential side effect, that way they are good about communicating with you if they get any new symptoms, such as shortness of breath or dry cough, to get you aware of it and can work it up and get imaging certainly if that occurs.  And then I think the management for ILD is a little unique and a little different truthfully than the way we manage pneumonitis from other drugs. Normally, when I am treating patients who develop pneumonitis, even if it is mildly symptomatic, we often will hold treatment, give steroids, and rechallenge them when it gets better. But with T-DXd, if anyone develops symptomatic pneumonitis, you actually have to permanently discontinue the T-DXd per the guidelines because we just don't know the safety of being able to rechallenge that patient once that pneumonitis resolves. For grade 1 ILD, meaning someone who has, for example, ground glass changes seen on imaging but doesn't have any symptoms, you have to hold the drug and wait until those imaging findings resolve and then you can restart. I usually do treat grade 1 ILD patients with steroids with the hope being that maybe it will allow for the pneumonitis to resolve more quickly, although in truth I don't know if that's the case. I have just taken that approach because I don't like leaving patients off the drug for too long if not needed. Again, I typically treat them with steroids, reimage in three to four weeks, and see if I'm able to restart. If they resolve within 28 days, you can restart at the same dose. If it takes longer to resolve, you need to dose modify.  And then I think the other big thing with T-DXd is to know that it is categorized as a highly emetogenic agent. Most of us are using three-drug prophylaxis, which I think works really well. It is also important to realize that there can be some delayed nausea, which is a little unusual with some of our other agents. And so to warn patients about that and I find that use of olanzapine or ondansetron for the delayed nausea tends to work pretty well.  Hope, do you have any pearls for us? Obviously, you are very experienced in using these agents; are there any things you would recommend for the management of ADCs?  Dr. Hope Rugo: Yes, it's such a great question and an important area because, particularly as we are using these agents earlier, we really need to have strategies for both how long to continue as well as manage the toxicities. I agree with the nausea, olanzapine has been really a great addition, and using a triplet as initial premedication makes a big difference for T-DXd and other deruxtecan ADCs that are in the pipeline. And then I think that the ILD issue, we're really learning more about the risk factors as well as retreatment. And hopefully, we'll have more data this year at ESMO Breast and maybe ASCO on retreatment for grade 1. We certainly now do not have any data on the safety of retreatment for grade 2, so that is really not accepted now. For sacituzumab, I think the interesting area is the metabolism and the impact. So with neutropenia, as we move the drug earlier, it's easier and easier to manage, we see less severe neutropenia. We can give growth factors, which we are all good at in oncology. But I think the question about managing diarrhea and who is at risk still exists. Understanding pharmacogenomics and UGT1A1 is an interesting area where patients who have diarrhea could be tested to see if they are poor metabolizers which affects a little under 10% of the overall population. Because in that group, you could give less drug and get the same benefit with less toxicity. So I think this is all very interesting. It is important for providers and patients to be educated so that we can manage this appropriately. And I think you gave an excellent overview.   We have new agents in the pipeline also and maybe we'll talk about those next, and then we'll talk a little bit about sequencing and resistance, as well as the unmet need for brain metastases. So lots of areas to talk about. There are a number of TROP-2 ADCs that are in the pipeline, and one that has presented phase III data, datopotamab deruxtecan. But other studies are being developed with new TROP-2 ADCs as well. But then there are a huge number of ADCs there with new targets, for example, immune effector targets, and new payloads, even immunotherapy and two different payloads or bispecific antibodies. And then there is interest in combining ADCs with immunotherapy and PARP inhibitors. We saw data in bladder cancer, I think it was bladder cancer, with combined 2 different ADCs at ESMO in 2023. So a lot of new approaches. How are we going to manage this moving forward? And where do you think we are going to position some of these next sort of "me-too" drugs?  Dr. Sara Tolaney: It's an excellent question, and you're right, the field is exploding with new antibody- drug conjugates. So, it's going to leave us with this conundrum of what to do. And you brought up the really interesting example of the fact that we have an approved TROP-2 ADC, we have as sacituzumab govitecan, and for example, we've recently seen some really exciting data come out from TROPION-Breast01 looking at another TROP-2 ADC, datopotamab deruxtecan or Dato-DXd where that ADC performed better than chemotherapy in a head-to-head trial in terms of progression-free survival in a hormone receptor-positive population. Then there's another TROP-2 ADC, moving forward in development moving to phase III that Merck is developing MK-2870. All three of these ADCs are targeting TROP-2 and have a TOPO 1 payload. So, it leaves you with the question of how do you think about that? Is there going to be a role for using serial TROP-2 ADCs? Could one work after the other, even when they have very similar payloads? How are we going to incorporate them? How do you pick one over the other? So, it is going to be tricky for us as we get more and more of these agents. I think we're all excited about seeing ADCs that may have different targets and different payloads, where maybe we will see that sequential utilization will have robust efficacy if we swap things out. Again, we don't have data here yet, but I think there are other agents in development. For example, you could think of like, disitamab vedotin targets HER2 and has an MMAE payload. So, could it be that someone progresses on T-DXd for HER2-low, but then could go on to disitamab vedotin? How will that work? So, we have a lot to learn, but it's really nice to have so many options.  Dr. Hope Rugo: Yeah, it'll be interesting to see whether or not we select the ADC based on a rational understanding of the tumor and the patient, or whether it's simply what's easier to give and has the right toxicity for that patient.  So, that sort of brings us to our next topic, which is how are we going to sequence these agents? How are we going to understand the mechanisms of ADC resistance? At San Antonio in 2023, we saw a presentation where there was a top-alteration, and the patient had a really long response to a top-directed ADC, or an agent that carried a topoisomerase inhibitor. And that really struck me that we're going to see these alterations. There was a fresh autopsy study that suggested that the alterations may be different in different organ sites of disease. How are we going to figure this out? Dr. Sara Tolaney: Yeah, I also was really puzzled to see those data from San Antonio where we've sort of simplified ADC resistance in our heads to say, well, maybe someone becomes resistant because they lose target expression, or maybe someone becomes resistant because they've developed resistance to the payload, kind of like the way we think of someone developing resistance to getting chemotherapy. But obviously, it's probably far more complex than that. With these ADCs, they need to be able to internalize the ADC and could there be mechanisms of resistance related to the internalization process? So, I think there are lots of potential areas where resistance could be occurring. I think, we don't understand it very well. We've seen patients, for example, who have responded. This is just anecdotal, but we have data, for example looking at, Dato-DXd in the phase 1 triple-negative study where there were some patients who responded despite having progressed on sacituzumab. Well, why is that? You would think if it's target resistance or payload resistance, it would be the same target and a very similar payload. So, why would those drugs work one after the other? And that's why I think we just don't understand this well enough at this point in time.   So, it's clearly an area where more research is needed because it does have significant implications on how we think about using these drugs sequentially. We will need to understand these resistance mechanisms because there do seem to be some rare patients who benefit from these sequencing strategies and then others who don't. So, it would be nice to be able to figure this out and hopefully in the future, we'll be able to test patients and know what drugs to give them. But I think we're far off from that, unfortunately, right now. Dr. Hope Rugo: Yeah, it does seem to be a relatively elusive approach, and I think, in part, it's due to the heterogeneity of cancer. And maybe, as we're better and better at analyzing tumor cells in the blood, which are a rare group, and ctDNA, which, of course, we do now to look for mutations, maybe that'll be an approach that we'll be able to take. And also, of course, moving the drugs earlier into the disease setting with less heterogeneity and mechanisms of resistance might help as well.  I was fascinated by the fact that although the PFS to the first ADC seems to be overall much greater than the PFS to the second ADC, when you sequence them, there are a few patients who have a longer PFS with the second, even if these are just sacituzumab T-DXd sequencing in various directions. So, it's clearly very complex. And right now, I think we're just sequencing and we don't really know how to do it. We just choose what we think is best for that patient first and go on to the next one later, which is interesting. And one of the choices might be treating brain metastases, which of course remains a huge unmet need. And if we could find effective treatment for brain metastases, maybe we could also prevent them in some patients more. What do we know about the central nervous system (CNS) penetration of ADCs and the clinical results? Dr. Sara Tolaney: At first, we were not optimistic that these drugs would have activity in the brain because we thought that these were very large agents that probably couldn't penetrate into the blood-brain barrier. But in fact, I think we were all very excited to see that there is actually data suggesting that these drugs can actually have robust efficacy in the CNS in patients who have active brain metastases. And so what we've seen so far is data with trastuzumab deruxtecan or T-DXd, there have been some trials that have been done, including studies like DEBRA and TUXEDO, which have looked at T-DXd in patients who have active brain metastases and are showing very robust response rates within the CNS. So, we're seeing intracranial response rates on the order of 40% to 50%. And clinically, this is what we're seeing as well. These are smaller studies and there's a larger trial, DESTINY-Breast12, which will hopefully validate the robust efficacy in the CNS with T-DXd. So, again, it's really nice to see this.  To your point, though, one area that I'm curious about, as you were alluding to, is will these drugs be able to prevent CNS disease? And I think that is a very different question because here the blood-brain barrier is not intact when patients have progressive brain metastases, and so these ADCs are causing robust activity. But if you look, for example, and I'll be curious to see what happens, DESTINY-Breast05 is looking at T-DXd in the post preoperative setting for patients who have residual disease and comparing it to T-DM1. And unfortunately, we saw that T-DM1 was not able to prevent brain metastases when looking at data from KATHERINE, where in fact, rates of CNS as the first site of recurrence were similar with T-DM1 and trastuzumab. So, now we'll be interested to see, will it be any different with T-DXd? Will T-DXd be able to have any role in prevention? I think we haven't seen anything like that with ADCs to date, so that would be a paradigm shift in our way of thinking.  Right now, there are strategies being taken from a prevention standpoint of trying to add a tyrosine kinase inhibitor in that early-stage setting, such as what is being done in the COMPASS-RD trying to add tucatinib to T-DM1 to see if that would do it. But again, we really need to understand, again, how these drugs work, particularly when the blood-brain barrier may not be intact. But again, very exciting data with T-DXd in an ongoing trial, actually through SWOG looking at sacituzumab for patients with CNS disease. And we've seen some preliminary data with sacituzumab showing that it actually does penetrate into the brain when they've looked at drug levels in the tumor in the brain, comparing it to plasma, it actually looks similar. So, we know it's getting in there and we'll have more robust efficacy data, hopefully coming soon. Dr. Hope Rugo: Yeah, that was a great summary of that data. It's been exciting also to see some responses in patients with leptomeningeal disease as well, where we've really been struggling with anything that works for more than a few weeks or months at the most. So I'm holding out great hope that we're going to see a big difference because even though TDM-1 had some efficacy, it was nothing like what we're seeing with T-DXd. So we'll see. And the same with sacituzumab with triple negative disease, where sometimes brain metastases can be an isolated site of recurrence, even in patients who have a pathologic complete response. So it has been a big challenge.  So I think that what we've learned from you is a lot about the mechanisms and the data about these new ADCs, the tremendous hope that these are bringing to our patients, but also the really exciting new approaches with new payloads, new targets of drugs that are in development, as well as potentially some different ADCs that have the same target and similar mechanisms of action of this payload. Really fascinating to hear about this, the future work on sequencing, on mechanisms of resistance, and on brain metastases. We have, of course, 2 prospective trials that we'll be looking at sequencing, one with T-DXd and Dato-DXd, and one registry trial with T-DXd and sacituzumab govitecan in the US. So that's also going to, I think, provide us with some important information.  We could talk for a long time about this, but I just wonder if you have any closing comments to sum up your thoughts.  Dr. Sara Tolaney: I think you did a great job leading us through thinking about ADCs, and I think it'll be really interesting to see what happens in the future. While again, these agents have become a standard for us for patients with metastatic disease, I'm going to be curious to see how everything evolves and to see if we'll be able to substitute chemotherapy with ADCs in early disease settings and change outcomes. Will we be able to have novel combinations? Will we be able to sequence these drugs one after another? Will we actually have biomarker predictors to help us sort out which drug to give when? So, still a lot to learn, but clearly a very exciting field right now. Dr. Hope Rugo: Indeed. Sara, thank you for sharing your valuable insights with us today on the ASCO Daily News Podcast on your great work to develop novel therapies for breast cancer. It's always a pleasure to talk to you, and even greater to work with you on the future progress of treatment for breast cancer. Dr. Sara Tolaney: Thank you so much, Hope. Again, really nice to always discuss these data with you. I always learn a lot, so thank you. Dr. Hope Rugo: Thank you. And thank you to our listeners for joining us today. You'll find a link to all of the studies discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of a product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today's speakers:   Dr. Hope Rugo  @hoperugo  Dr. Sara Tolaney @stolaney1     Follow ASCO on social media:   @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Hope Rugo:  Consulting or Advisory Role: Napo Pharmaceuticals, Puma Biotechnology, Mylan, Eisai, Daiichi Sankyo Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Astellas Pharma, Talho Oncology, Veru, GlaxoSmithKline, Hoffmann-LaRoche AG/Genentech, Inc, Stemline Therapeutics Travel, Accommodations, Expenses: Merck, AstraZeneca   Dr. Sara Tolaney: Consulting or Advisory Role: Novartis, Pfizer, Merck, AstraZeneca, Genentech, Eisai, Sanofi, Bristol-Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Immunomedics/Gilead, BeyondSpring Pharmaceuticals, OncXerna Therapeutics, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Umoja Biopharma, Menarini/Stemline, Aadi Bio, Artio Biopharmaceuticals, Incyte Corp, Zetagen, Bayer, Infinity Therapeutics, Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR Therapeutics, Hengrui Pharmaceutical (USA), Sumitovant Biopharma Research Funding (Inst.): Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol-Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Seattle Genetics, OncoPep, Gilead Travel, Accommodations, Expenses: Eli Lilly, Sanofi, Gilead Sciences

In discussion with Dr. Mazyar Shadman from the Fred Hutch Cancer Center, covering the Chronic Lymphocytic Leukemia and Lymphoma key practice changing/informing abstracts from American Society of Hematology (ASH) 2023 conference from Community Oncology perspective. We covered 4 important practice informing studies with Dr. Shadman: - ALPINE: Ph 3, Extended Follow-up Confirms Sustained Superior PFS of Zanubrutinib vs Ibrutinib for Treatment of R/R Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma - SEQUOIA: Ph 3, Broad Superiority of Zanubrutinib Over BR Across Multiple High-Risk Factors: Biomarker Subgroup Analysis in the Treatment-Naive Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) without del(17p) - SWOG S1826: Nivolumab-AVD Is Better Tolerated and Improves PFS Compared to Bv-AVD in Older Patients (Aged ≥60 Years) with Advanced Stage Hodgkin Lymphoma - POLARIX Update: Deciphering the Clinical Benefit of Pola-R-CHP versus R-CHOP in Different Genetic Subtypes Beyond Cell of Origin in the POLARIX Study

 JCO PO author Dr. Mary Redman shares insights into her JCO PO article, “Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP)” Host Dr. Rafeh Naqash and Dr. Redman discuss the background of LungMAP and how it was developed to accelerate drug development and biomarker-driven therapies in lung cancer. Dr. Redman shares the initiatives undertaken to increase participant diversity in LungMAP and invites junior investigators to get involved in the project. TRANSCRIPT  Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the OU Stevenson Cancer Center. Today I'm delighted to be joined by Dr. Mary Redman, Professor of the Clinical Research Division at the Fred Hutch Cancer Center and also Senior Author of the JCO Precision Oncology article, “Representativeness of Patients Enrolled in the Lung Cancer Master Protocol” or the Lung-MAP. Our guest disclosures will be linked in the transcript. Dr. Rafeh Naqash: Dr. Redman, welcome to the podcast, and thank you for joining us today. Dr. Mary Redman: Thank you very much for the invitation. Dr. Rafeh Naqash: And for the sake of this podcast, we'll just use each other's first names. If that's okay with you. Dr. Mary Redman: Please. Dr. Rafeh Naqash: And since you and I know each other through the lung working group, we've worked on some things, or planning to work on some things, this article was something that I came across recently that you published with some very well-known folks in the field of lung cancer. And I wanted to utilize the first few minutes of this discussion to understand what was the background behind Lung-MAP because I think it's very important for people to understand why this kind of an approach was started in the first place and how it has successfully created a mechanism for master protocol. So, if you could dive a little deeper into that for us, since you've been there, you've done that, and it would help our listeners understand the genesis or the origination of this whole process of Lung-MAP. Dr. Mary Redman: Happy to do so. So, Lung-MAP, the original concept goes back to February of 2012. And in February of 2012, the Thoracic Malignancy Steering Committee, the FDA and the NCI had a workshop. And the focus of the workshop was how we could accelerate drug development in lung cancer, and in particular, how we could accelerate biomarker driven therapies within lung cancer. And the outcome of that meeting was that master protocols or studies that set up infrastructures to evaluate multiple therapies, all within one infrastructure, were the way to go. And so born out of that, there were three master protocols. The Lung-MAP trial, the ALCHEMIST trials to evaluate studies in adjuvant therapy setting, and then the MATCH trial, which, of course, isn't just in lung cancer, it looks across different cancer types and looks on biomarker targets that transcend across.  So, when the Lung-MAP trial was being thought of, the idea was that while in non-squamous, non-small cell lung cancer, we had seen some advances with targeted therapies, that squamous cell lung cancer had essentially no targeted therapies that had been successfully evaluated. And therefore, there was an unmet need that squamous cell lung cancer being a more aggressive form of lung cancer than non-squamous lung cancers, and in particular in the second line setting, after patients had received platinum-based therapy, there was pretty much nothing other than docetaxel.  And so, the study was initially conceived of by Vassiliki Papadimitrakopoulou, who was at MD Anderson at the time and Roy Herbst who we had at Yale. And so therefore, we thought second line squamous cell lung cancer was an unmet need and that we could potentially have targeted therapies, given now that we had the genome atlas, the TCGA understanding of what all the potential biomarkers or targets that exist in squamous cell cancer. Concurrently, we also had the developments and improvements in next-gen sequencing. So, the technology improved for us to be able to detect these different genomic alterations that were present in these cancers. So, all of that together - an unmet need of an aggressive cancer, a better understanding of the biology and the potential to have these targeted therapies - led to the development of Lung-MAP. But in addition, what we had seen and I think most of you who have studied cancers across the country know, patients who live in urban areas or are financially more well off are more able to access therapies, whereas patients who are less well off, more rural areas, and then just in general, different race ethnicities, didn't have the access that other patients from other settings had. And so, when we conceived of Lung-MAP, it wasn't just about meeting the unmet need in terms of treatment, it was also about an unmet need in terms of accessibility of these types of studies for all types of patients who get lung cancer. And so, utilizing the National Clinical Trials Network system that has sites all over the country, I think there's something like 2500 sites around the country, which include community oncology sites and of course academic sites.  Dr. Rafeh Naqash: Excellent. Thank you so much Mary, for explaining that. Now, as you highlighted, this dates back to 2011-2012, when things were just picking up from a broad sequencing platform standpoint, rather than limited gene testing, which has been more and more, there's been more and more uptick of NGS, especially in the space of lung cancer. So, you and several others came up with this idea and eventually implemented it. And there's a significant process of thinking about something and implementing something. So, what were some of the challenges that you encountered in this process and successfully circumvented or dealt with appropriately over these years, some of the lessons or some of the processes that you were able to understand and navigate around. Dr. Mary Redman: We could spend the next hour probably talking on that topic. Anytime that you're setting up a big infrastructure, and I really do think the best way to describe Lung-MAP and a master protocol is that it's an infrastructure because the goal is to set up something where we can bring in new studies and so that everything is modular. And you complete one study, you add a new one. Things can be added while things are ongoing. And by things, I mean studies evaluating investigational therapies.   And so, anytime you're setting up an infrastructure that's never been done before, well, first of all, the complexities of different partners that had never worked together, so just understanding how best to work together, the infrastructure in terms of how to build it within our systems, the statistical and data management center had many complexities. The infrastructure in terms of how our systems at the statistical and data management center spoke to the NCI had challenges. How the NCI evaluated this protocol that had all these different studies that were coming and going.  The studies oftentimes involved therapies that were very new in their development. And so oftentimes you'd have some new safety signal that came up which required a rapid amendment. And how do you do that when you have this infrastructure, and you don't want to stop one thing for other studies to be moving forward. And that because it's a public-private partnership and the pharmaceutical partners that are partially supporting financially and scientifically, some of these studies, learning to work with them, they have a little bit more say because they are more financially involved with the studies than a study that's typically funded by the NCI. And maybe the company is only supplying drug. So, contracting had its challenges, budgets, how do we actually budget things appropriately in this new infrastructure? I talked about all of that. And then a challenge about running such a study is how do you educate the sites so that when they're approaching patients, how can they talk to a patient about, “You're going to have your tissues submitted to be tested, and then on the basis of that tumor testing you're going to be assigned to get to an investigational treatment study.” And how do you describe all of that? Dr. Rafeh Naqash: So definitely lots of lessons and experiences that you and your team have had. And the way I describe or look at Lung-MAP is one of those success stories that has redefined the way to run clinical trials from an NCTN and a SWOG cognitive group network standpoint. And going to this paper that you have published in this, your Precision Oncology, there's one aspect of clinical trials where we are always very focused on responses and survival and other clinical outcomes data. And then there is this important component that you and your team have looked at is, what is the distribution of the different kind of clinical trial participants? What kind of people are we getting in? What kind of people are we trying to cater to, and what is the unmet need gap that we still have not completely met? Could you tell us how this project started, the idea behind this project, and then some of the results that you can highlight for us today? Dr. Mary Redman: So, Lung-MAP also has a company advisory board, and we meet with them either quarterly or biannually. And one of the conversations that we were having with our industry partners or collaborators was especially after the FDA came out with some of their work saying, we think it's really important that industry does better that they enroll a more representative patient population in their studies. You see some of these studies in lung cancer with 1% or a very small percentage of Black participants, for example, whereas the US population has significantly higher levels. And so, one of the major objectives, as I said about Lung-MAP, was to enroll a more representative patient population to provide access. And as part of these conversations, we kept saying, “Well, we've done a better job.” And I was thinking, well, we actually could evaluate how we have done. And so, in thinking about that, I proposed within some of the researchers that are part of the SWOG Statistical and Data Management Center that we look at this question in particular, I approached Dr. Riha Vaidya, who is here at Fred Hutch with me, and she's a Health Economist with this idea. And she was very excited to look at this. And my initial thought was just to look at race, ethnicity, gender. And she took it one step further where she wanted to look at not only that, but also area deprivation index and then rural versus urban. So, getting at some of those other very important aspects of representativeness when we think about patient populations. And so that was how it came about.  Dr. Rafeh Naqash: Going back to some of the interesting things that you and the authors have done, is not only looked at the gender, age, but also looked at the socio-demographic representativeness. Now, there's definitely some things that you guys looked at and that Lung-MAP study did better on, and some things where maybe there's more room for improvement. Could you highlight some of those results for us today? Dr. Mary Redman: Happily. And one thing I think that it's important if one goes and looks at this paper, and as I talk through the results, so Lung-MAP opened to enrolling patients in June of 2014. And from June of 2014 to January of 2019, we exclusively enrolled patients with squamous cell histology. And then in 2019, we expanded the study to enroll all histologic types of non-small cell lung cancer. And so, in this paper that's published here in JCO Precision Oncology, we compare our patient population and Lung Map to other patients enrolled within advanced non-small cell lung cancer trials. So that's all-histologic types. And then we compared it to the SEER population, the US population evaluated by SEER. And that also is all histologic types of non-small cell lung cancer.  And so, one of the major results, as you pointed out, is that while we did well in certain areas, for example, we did not enroll as many females as the other SWOG trials and then the US population. And I think that is probably, I would attribute all of that to being the case that squamous cell lung cancer patients tend to be more male than female. So therefore, those results, I don't know that if we looked at only the data since 2019, we might actually see that we were comparable. Going through the results, as you were just asking about, compared to previous SWOG trials, we did better in terms of enrolling older patients, not as well as the SEER data. Some of the challenge is I'm not 100% clear that we'll ever be able to get perfectly there, in part because Lung-MAP, for the majority of the time, only enrolled patients who had performance status 0 or 1, and older patients tend to have higher performance status, and so they might just not have been eligible. And I do think, especially with these investigational treatments, particularly with immunotherapies, for safety reasons, we do need to enroll patients with performance status 0 or 1. We talked about the female sex versus male sex percentages and that our numbers were smaller. But if you look at SWOG trials versus SEER trials, they're pretty much identical numbers. So, I think that if we just looked at the later part of Lung-MAP, you'd see that they match. In terms of race ethnicity, the earlier part of Lung-MAP, we enrolled close to 15% of patients of nonwhite race or ethnicity. Historically, SWOG trials were slightly higher, but in the US population, it's around 21.5%, based on this year's data. And so, we did better than industry sponsored trials. So, if you look at those data, but there's definitely room for improvement. And that just in part, has to do with getting more sites, better outreach, more education, and better access.  And so, I think we have an accrual enhancement committee that does include patient advocacy groups. And I think that that is just going to be an area that we need to continue to work on. And then, as you mentioned, that we did better in terms of enrolling more patients from rural areas. We enrolled more patients from socioeconomically deprived neighborhoods, and more patients that were using Medicaid or no insurance for those who are under 65. Dr. Rafeh Naqash: Absolutely. I think those are very important results. Me, as somebody who sees people on clinical trials, both phase I and late phase, of the questions that I get commonly asked if somebody refers a patient from the community is, “Am I going to be treated on a placebo?” It's one of those common things. And the second question ends up being like, “Is my insurance going to cover some of the costs associated?” And I think understanding those concepts, whether it's from an educational standpoint or a financial barrier standpoint, is extremely important in clinical trials because at the end of the day, these are things that people use as metrics for enrolling or not enrolling themselves on a clinical trial. There are certain aspects or sensitivities associated with enrolling people, let's say, of Native American ethnicity or American Indian ethnicity, where outreach is extremely important. From a Lung-MAP standpoint, could you talk about some of the outreach initiatives that are being implemented or have already been implemented to potentially help decrease this gap of representation?  Dr. Mary Redman: I think that one of the major- and this isn't exactly outreach, but to start out with one of the things that we have, in addition, I mentioned that we had an accrual enhancement committee. We also have a site coordinators committee. And when we set up the site coordinators committee, we make certain that we have representation from the geographic regions within the country and different types of sites. And the major goal for our site coordinators committee is to give us input about how it is to implement Lung-MAP within their own institutions. And so, we want to be able to overcome any type of barriers or perceived barriers that are out there, and we want to hear it directly from those people who are working closely to enroll the patients. And so that's been a key part of everything that we've done. And so, part of that is that we've just developed educational materials. We have modified the protocol based on input that we've received from them. So that's, I think, been a major approach that we have used to try to reach more patients.  We do have a newsletter that we put out. The accrual enhancement committee has also contacted different sites to really have more conversations, one on one, just more, I guess, almost like focus type groups where you try to understand, really understanding what's coming on, what are the challenges from their perspectives. And then we've had webinars where we try, and we've had hundreds of attendees for these webinars, where we let the sites have direct access to those of us who are running the study to ask their questions. So those have been our major approaches. And I think that we're always trying to figure out how we can do better.  Dr. Rafeh Naqash: I agree with you, and I think as both physicians, providers, and the clinical trial staff as such become more and more cognizant of increasing diversity, these conversations end up happening earlier and earlier in an individual's patient's journey, where trying to see feasibility, trying to see financial aspects, getting a patient enrolled on a clinical trial gets evaluated earlier and earlier. And hopefully, with some of the measures that the SWOG or the Lung-MAP group is implementing, these percentages will see more spike in the long run for better clinical trial enrollment approach. So, Mary, now going to the science part of Lung-MAP for maybe some of the fellows or the investigators, early career investigators, who might be listening to this podcast, could you briefly explain what is the process of getting involved in Lung-MAP? Because for me, as a junior faculty a few years back, I was a fellow, and I remember at that point I hardly had any knowledge of corporate groups. SWOG, for example, was one of those that I'd heard about, but didn't necessarily know how to get involved. So, for trainees, for junior faculty, could you briefly say, what's the process? What does it involve? How would somebody propose something to Lung-MAP?  Dr. Mary Redman: Yeah, thank you for that question. And I really do hope that this actually is a way to get people to understand, and we'd love to have more engagement from more junior faculty and that's a major objective for the study. Because this infrastructure is in place, we are actually well suited to be able to mentor and bring junior faculty in. And so, the process is basically, you contact any of us that are in leadership within Lung-MAP and talk to us and we'll see if we can figure out a way. If you have an idea of a new study, wonderful. Our drug selection committee chair is Saima Waqar. She's a member of ASCO as well. I mean, one could find her and send her a note. The study chairs for Lung-MAP are Hoss Borghaei and Karen Reckamp. You can send them a note. You can send me an email, maryredman@fredhutch, and we will make certain that you are engaged and brought into the direct conversations that would lead to something.  So, it would be wonderful to have more junior faculty proposing ideas and leading sub studies, being a sub study chair. Each of our sub studies, as I mentioned before, are conducted independently, and then you are responsible for the development, conduct of the trial and writing of the paper and presenting. And so, we want all of that to happen. But we also would love to have ideas. If you think of this infrastructure as just being an amazing resource of data, we are happy to and would love to receive proposals for data analysis that could result in publication and presentation as well. So, if there's something that somebody sees as a question that they think we could answer, again, contact any of us and we will happily figure out a way how to work with you. We have a great team and a lot of capacity to be able to work with new people.   Dr. Rafeh Naqash: Thanks, Mary. And for all those listeners, trainees listening, you did get Mary's email, so try to send her an email, and hopefully she won't be complaining that there was a lot of requests. But I think all things considered, the Lung-MAP is a great data resource. As you mentioned, it's a great resource for junior investigators who are trying to build a career around clinical trials, precision medicine, and it's also a great resource, as you've shown, regarding diversity equity research from a clinical trial standpoint. So, I think it has all the components that are needed to run and create some interesting questions and answer those questions using the data set.  So now, Mary, going to the last part of the discussion here, one of the key components, we try to ask a few questions of the investigator, which in this case is yourself. Could you tell us briefly about your career trajectory, how you ended up doing what you're doing now, and what are some of the things that you've learned from and maybe advice to all the junior people listening to this podcast?  Dr. Mary Redman: Wow. Okay. Well, so if you hadn't already guessed, I'm a biostatistician. I started out in mathematics as an undergrad and then learned about biostatistics and thought that it sounded perfect for me. After I finished my doctorate, I did a year of postdoc and was starting to look for faculty positions. And if you haven't already inferred, I am a Seattle native. And so, when a position became available at the Fred Hutchinson Cancer Center here in Seattle, I applied for it, and the job happened to be with the SWOG Statistical Center. And so, you probably already guessed as well that I got the job. And so, I have been here at Fred Hutch since 2005. And when I joined Fred Hutch and the SWOG Statistical Center, which is co-located here and at Cancer Research and Biostatistics, just a mile west across Lake Union here in Seattle, the person who had been the lead statistician for the Lung Cancer Committee in SWOG, John Crowley, he was also the director of the SWOG Statistical Center and had been doing that for over 20 years, and he was ready to take some things off of his plate. And so, when I joined, they thought that I would be a great fit for the lung committee, in part because I had shown an ability to work with vibrant personalities, let's just say, which the lung community has in spades.  And so, when I started in the lung committee, David Gandara was the chair of the lung committee. And so, I worked for many, many years very closely with David, and we established a very close and really wonderful working relationship. And I learned a lot from him. I learned a lot from a lot of the other lung cancer researchers in the country and around the world. I pretty quickly became involved with the International Association for the Study of Lung Cancer and have attended most of the World Congress on Lung Cancer meetings and have gotten to know people around there. So as a biostatistician, obviously, I enjoy my mathematical and statistical skills, but I also just really enjoy learning and thinking about what I can bring to the problem where I come from a certain point of view and I love collaborating with the other people doing clinical research, in particular in lung cancer. And basically, my focus has always been on doing the best to answer our questions the most efficiently and effectively so that we can move the field forward and help people live longer. Dr. Rafeh Naqash: Thank you so much, Mary, for your time and giving us insights into your professional and personal journey. Also, thank you for listening to this JCO Precision Oncology conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

La Dra. Florencia Cuadros, oncóloga clínica del Hospital Eva Perón, y el Dr. Matías Chacón, oncólogo médico adscrito al Instituto Alexander Fleming ambos de Argentina, nos hablan sobre los estudios más relevantes en melanoma presentados durante ESMO 2023: Estadios tempranos SWOG 1801: estudio aleatorizado, fase II de pembrolizumab adyuvante vs. pembrolizumab neoadyuvante en pacientes con melanoma en estadio IIIB clínicamente detectable y estadio IVC que era susceptible de resección quirúrgica. El objetivo primario fue la supervivencia libre de eventos (SLE) en la población por intención de tratar. KEYNOTE-942: estudio abierto, aleatorizado, fase II, evaluó si la terapia adyuvante posoperatoria con mRNA-4157 y pembrolizumab mejoró la supervivencia libre de recurrencia (SLR) en comparación con pembrolizumab solo en pacientes con resección completa del melanoma cutáneo y un alto riesgo de recurrencia en estadio IIIB/C/D y IV. Estadios avanzados SECOMBIT: estudio fase II,  no comparativo, aleatorizado, de tres brazos, para pacientes con melanoma metastásico con mutación BRAF V600 no tratado, que fueron asignados aleatoriamente al grupo A (encorafenib + binimetinib hasta progresión de la enfermedad, seguido de ipilimumab + nivolumab), grupo B (ipilimumab + nivolumab hasta la progresión de la enfermedad, seguido de encorafenib + binimetinib), o grupo C (encorafenib + binimetinib seguido de ipilimumab + nivolumab hasta la progresión de la enfermedad seguida de encorafenib + binimetinib). CheckMate 204: estudio fase II, multicéntrico, abierto, incluyó a pacientes adultos (edad ≥18 años) con melanoma de metástasis cerebrales medible (0.5–3.0 cm de diámetro). Los pacientes asintomáticos (cohorte A) tenían un ECOG de 0 o 1 y no tenían síntomas neurológicos, ni uso inicial de corticosteroides; los pacientes sintomáticos (cohorte B) tenían un estado funcional ECOG de 0 a 2, con síntomas neurológicos estables y podrían estar recibiendo dosis bajas de dexametasona. NIBIT M2: estudio fase III, reclutó a pacientes >18 años con melanoma BRAF mutado y metástasis cerebrales activas, asintomáticas y no tratadas, aleatorizados (1:1:1) a fotemustina o ipilimumab + fotemustina o ipilimumab + nivolumab. TACo-BEAT-MBM: estudio fase II, que evaluó qué tan bien funcionaba bevacizumab y atezolizumab con o sin cobimetinib en el tratamiento en pacientes con melanoma no tratado que se ha diseminado al cerebro. NCT03025256: estudio fase I/Ib, para pacientes >18 años con melanoma metastásico y evidencia de enfermedad leptomeníngea por resonancia magnética y/o citología del LCR, ECOG PS ≤2 , que fueron tratados de forma simultánea con nivolumab intratecal e intravenoso. Se permitió el tratamiento concurrente con inhibidor de BRAF/MEK y dexametasona ≤4 mg/día. IMCgp100-202: estudio abierto, fase III, aleatorizados al azar, en pacientes con melanoma uveal metastásico positivo para HLA-A*02:01 no tratados previamente en una proporción de 2:1 para recibir tebentafusp o la terapia elegida por el investigador con un solo medicamento, pembrolizumab, ipilimumab o dacarbazina, estratificados según el nivel de lactato deshidrogenasa.

There was time during the early 70's when the field of oncology began to take hold where the singular focus was to extend the patient's life. In this ASCO Education podcast, our guest was one of the first to challenge that notion and rethink methods that focused the patient's QUALITY of life. Dr. Patricia Ganz joins us to describe her transition from cardiology to oncology (6:00), the moment she went beyond treating the disease and began thinking about treating the WHOLE patient (10:06) and the joy of the increasing numbers of patients who survive cancer (21:47).  Speaker Disclosures Dr. David Johnson: Consulting or Advisory Role – Merck, Pfizer, Aileron Therapeutics, Boston University Dr. Patrick Loehrer: Research Funding – Novartis, Lilly Foundation, Taiho Pharmaceutical Dr. Patricia Ganz: Leadership - Intrinsic LifeSciences  Stock and Other Ownership Interests - xenon pharma,  Intrinsic LifeSciences, Silarus Therapeutics, Disc Medicine, Teva,  Novartis, Merck. Johnson & Johnson, Pfizer, GlaxoSmithKline, Abbott Laboratories Consulting or Advisory Role - Global Blood Therapeutics, GSK, Ionis, akebia, Rockwell Medical Technologies, Disc Medicine, InformedDNA, Blue Note Therapeutics, Grail Patents, Royalties, Other Intellectual Property - related to iron metabolism and the anemia of chronic disease, Up-to-Date royalties for section editor on survivorship Resources If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org. TRANSCRIPT  Disclosures for this podcast are listed on the podcast page.   Pat Loehrer: Welcome to Oncology, Etc., an ASCO Education Podcast. I'm Pat Loehrer, Director of Global Oncology and Health Equity at Indiana University.  Dave Johnson: And I'm Dave Johnson, a Medical Oncologist at the University of Texas Southwestern in Dallas. If you're a regular listener to our podcast, welcome back. If you're new to Oncology, Etc., the purpose of the podcast is to introduce listeners to interesting and inspirational people and topics in and outside the world of oncology. Pat Loehrer: The field of oncology is relatively new. The first person treated with chemotherapy was in the 1940s. Medical oncology was just recognized as a specialty during the 1970s. And while cancer was considered by most people to be a death sentence, a steady growth of researchers sought to find cures. And they did for many cancers. But sometimes these treatments came at a cost. Our next guest challenged the notion that the singular focus of oncology is to extend the patient's duration of life. She asked whether an oncologist should also focus on addressing the patient's quality of life.  Dave Johnson: The doctor asking that question went to UCLA Medical School, initially planning to study cardiology. However, a chance encounter with a young, dynamic oncologist who had started a clinical cancer ward sparked her interest in the nascent field of oncology. She witnessed advances in cancer treatment that seemingly took it from that inevitable death sentence to a potentially curable disease. She also recognized early on that when it came to cancer, a doctor must take care of the whole patient and not just the disease.  From that point forward, our guest has had a storied career and an incredible impact on the world of cancer care. When initially offered a position at the West LA VA Medical Center, she saw it as an opportunity to advance the field of palliative care for patients with cancer. This proved to be one of her first opportunities to develop a program that incorporated a focus on quality of life into the management of cancer. Her work also focused on mental, dietary, physical, and emotional services to the long-term survivors of cancer.  That career path has led to many accomplishments and numerous accolades for our guest. She is a founding member of the National Coalition for Cancer Survivorship, served as the 2004 Co-chair of ASCO's Survivorship Task Force, and currently directs UCLA's Cancer Survivorship Center of Excellence, funded in part from a grant from Livestrong. Our guest is Dr. Patricia Ganz. Dr. Patricia Ganz: It's great to be with both of you today. Dave Johnson: We always like to ask our guests a little about their background, where they grew up, a little about their family. Dr. Patricia Ganz: Yes. I grew up in the city of Beverly Hills where my parents moved when I was about five years old because of the educational system. Unlike parts of the East Coast, we didn't have very many private schools in Los Angeles, and so public education was very good in California at that time. So I had a good launch and had a wonderful opportunity that many people didn't have at that time to grow up in a comfortable setting. Dave Johnson: Tell us about your mom. I understand she was a businesswoman, correct? Dr. Patricia Ganz: Yes, actually, my parents got married when my mom was 19 and my dad was 21. He was in medical school at the University of Michigan. His father and mother weren't too happy with him getting married before he could support a wife. But she worked in a family business in the wholesale produce business in Detroit. One of six children, she was very involved with her family in the business. And they were married, and then World War II started, my father was a physician in the military, so she worked in the family business during the war. After finally having children and growing up and being in Beverly Hills, she sat back and was a homemaker, but she was always a bit restless and was always looking for something to do. So wound up several years later, when I was in my early teens, starting a business with one of my uncles, an automobile parts business. They ultimately sold it out to a big company that bought it out.  Pat Loehrer: Where did your father serve in World War II? Dr. Patricia Ganz: He was actually D-Day Plus 21. He was in Wales during the war. They had to be stationed and moved down into the south before he was deployed. I have my parents' correspondence and letters from the war. He liberated some of the camps. Actually, as I have learned about the trauma of cancer and post-traumatic stress that happens in so many people, our military veterans, most recently, I think he had post-traumatic stress. He didn't talk very much about it, but I think liberating the camps, being overseas during that time, as it was for that silent generation, was very profound in terms of their activities.   He wound up practicing medicine, and Los Angeles had a practice in industrial medicine, and it was a comfortable life. He would work early in the morning till maybe three or four in the afternoon and then go to the gym, there were moonlighting physicians who worked in the practice. But I kind of saw an easy kind of medicine, and he was always very encouraging and wanted me to go into medicine -- that I could be an ophthalmologist or a radiologist, good job for a woman. But I didn't really see the tough life of some of the internists and other people who were really working more 24/7, taking care of patients in the way medicine used to be practiced. Dave Johnson: Yeah. So you were interested in, early in your career, in cardiology. Could you tell us about that, and then a little bit more about the transition to oncology?  Dr. Patricia Ganz: I went away to college, I went to Harvard Radcliffe and I came home during the summers. And was interested in doing something during the summer so I actually in a pediatric cardiology research laboratory as a volunteer at UCLA for a couple of summers between my freshman and sophomore year then my sophomore and junior year. And then I actually got a California Heart Association Fellowship between my junior and senior year in college.  And this pediatric cardiology lab was very interesting. They were starting to give ketamine, it had an identification number, it wasn't called ketamine. But they were giving it to children in the cardiac cath lab and then were very worried about whether it would interfere with measuring the pressures in the heart. So we had intact dogs that had catheters implanted in the heart, and the drug would be given to the animals and we would then measure their pressures in the heart.  That cardiology experience in 1970, the summer between my first and second year of medical school, the Swan-Ganz catheter was being tested. I worked at Cedars that summer and was watching them do the various studies to show the value of the catheter. And so by the time I was kind of finishing up medical school, I'd already invested all this time as an undergraduate. And then a little bit when I was in medical school and I kind of understood the physiology of the heart, very exciting. So that's kind of where I was headed until we started my internship. And I don't know if any of you remembered Marty Cline, but he was the oncologist who moved from UCSF to Los Angeles to start our hem-onc division. And very exciting, a wonderful bedside teacher.   And so all of a sudden, I've never been exposed to oncology and this was very interesting. But at the same time, I was rotating through the CCU, and in came two full-arrest patients, one of whom was a campus cop who was very obese, had arrested at his desk in the police station. And we didn't have emergency vehicles to help people get on campus at that time. This was 1973 or 1974, something like that. And he came in full arrest, vegetable. And then another man had been going out of his apartment to walk his dog and go downstairs, and then all of a sudden his wife saw him out on the street being resuscitated by people. And he came in also in full arrest.   So those two experiences, having to deal with those patients, not being able to kind of comfort the families, to do anything about it. As well as taking care of patients in my old clinic who had very bad vascular disease. One man, extremely depressed with claudication and angina, all of a sudden made me feel, “Well, you know what? I'm not sure I really want to be a cardiologist. I'm not sure I like the acute arrest that I had to deal with and the families. And also, the fact that people were depressed and you couldn't really talk to them about how serious their disease was.” Whereas I had patients with advanced cancer who came in, who had equally difficult prognoses, but because of the way people understood cancer, you could really talk about the problems that they would be facing and the end-of-life concerns that they would have.  So it was all of those things together that made me say, “Hmm.” And then also, Pat, you'll appreciate this, being from Indiana, we were giving phase II platinum to advanced testicular cancer patients, and it was miraculous. And so I thought, “Oh my gosh, in my lifetime, maybe cancer is going to be cured! Heart disease, well, that's not going to happen.” So that was really the turning point.   Pat Loehrer: When many of us started, we were just hoping that we could get patients to live a little bit longer and improve the response rate. But you took a different tack. You really looked at treating the whole patient, not just the disease. That was really a novel approach at the time. What influenced you to take that step forward? Dr. Patricia Ganz: Well, it was actually my starting– it was thought to be in a hospice ward. It would turn out it was a Sepulveda VA, not the West LA VA, but in any case, we have two VAs that are affiliated with UCLA. And it was an intermediate care ward, and there was an idea that we would in fact put our cancer patients there who had to have inpatient chemotherapy so they wouldn't be in the acute setting as well as patients who needed to travel for radiation. Actually, the West LA VA had a hospice demonstration project. This is 1978. It's really the beginning of the hospice movement in England, then in Canada, Balfour Mount at Montreal and McGill was doing this. And so I was very much influenced by, number one, most of our patients didn't live very long. And if you were at a VA Hospital, as I was at that time, you were treating patients with advanced lung cancer, advanced colon cancer, advanced prostate cancer, other GI malignancies, and lung cancer, of course. So it was really the rare patient who you would treat for curative intent.  In fact, small cell lung cancer was so exciting to be treating in a particularly limited small cell. Again, I had a lot of people who survived. We gave them chemo, radiation, whole brain radiation, etc. So that was exciting. This was before cisplatin and others were used in the treatment of lung cancer. But really, as I began to develop this ward, which I kind of thought, “Well, why should we wait just to give all the goodies to somebody in the last few weeks of life here? I'm treating some patients for cure, they're getting radiation. Some of them are getting radiation and chemo for palliation.” But it was a mixed cancer ward. And it was wonderful because I had a team that would make rounds with me every week: a pharmacist, a physiatrist, a psychologist, a social worker, a dietitian. This was in 1978 or ‘79, and the nurses were wonderful. They were really available to the patients. It wasn't a busy acute ward. If they were in pain, they would get their medication as soon as possible. I gave methadone. It was before the days of some of the newer medications, but it was long-acting. I learned how to give that. We gave Dilaudid in between if necessary. And then we had Brompton solution, that was before there was really oral morphine.  And so the idea was all of these kinds of services should really be available to patients from the time of diagnosis until death. We never knew who was going to be leaving us the next few days or who was going to be living longer and receiving curative intent. We had support groups for the patients and their families. It was a wonderful infrastructure, something that I didn't actually have at UCLA, so it was a real luxury. And if you know the VA system, the rehabilitation services are wonderful. They had dental services for patients. We had mostly World War II veterans, some Korean, and for many of these individuals, they had worked and lived a good life, and then they were going to retire and then they got cancer. So this was kind of the sadness. And it was a suburban VA, so we had a lot of patients who were in the San Fernando Valley, had a lot of family support, and it was a wonderful opportunity for me to learn how to do good quality care for patients along the continuum.  Dave Johnson: How did you assemble this team? Or was it in place in part when you arrived, or what? Nobody was thinking about this multidisciplinary approach?  Dr. Patricia Ganz: I just designed it because these were kind of the elements that were in a hospice kind of program. And I actually worked with the visiting nurses and I was part of their boards and so forth. And UCLA didn't have any kind of hospice or palliative care program at that time. But because the VA infrastructure had these staff already, I didn't have to hire them, you didn't have to bill for anything. They just became part of the team. Plus there was a psychiatrist who I ultimately began doing research with. He hired a psychologist for the research project. And so there was kind of this infrastructure of interest in providing good supportive care to cancer patients. A wonderful social worker, a wonderful psychologist, and they all saw this patient population as very needy, deserving, and they were glad to be part of a team.  We didn't call it a hospice, we called it a palliative care unit. These were just regular staff members who, as part of their job, their mission was to serve that patient population and be available. I had never been exposed to a physiatrist before. I trained at UCLA, trained and did my residency and fellowship. We didn't have physiatry. For whatever reason, our former deans never thought it was an important physical medicine, it wasn't, and still isn't, part of our system. Pat Loehrer: Many decisions we make in terms of our careers are based on singular people. Your dad, maybe, suggesting going into medicine, but was there a patient that clicked with you that said, "Listen, I want to take this different direction?" Or was it just a collection of patients that you were seeing at the VA? Is there one that you can reflect back on? Dr. Patricia Ganz: I don't know if you all remember, but there was something called Consultation Liaison Psychiatry where, in that time, the psychiatrist really felt that they had to see medical patients because there were psychological and sometimes psychiatric problems that occurred on the medical ward, such as delirium. That was very common with patients who were very sick and very toxic, which was again due to the medical condition affecting the brain. And so I was exposed to these psychiatrists who were very behaviorally oriented when I was a resident and a fellow, and they often attended our team meetings in oncology on our service, they were on the transplant service, all those kinds of things. So they were kind of like right by our side.  And when I went to the VA, the psychiatry service there also had a couple of really excellent psychiatrists who, again, were more behaviorally focused. Again, you have to really remember, bless her heart, Jimmie Holland was wonderful as a psychiatrist. She and Barrie Cassileth were the kind of early people we would see at our meetings who were kind of on the leading edge of psychosocial oncology, but particularly, Jimmie was more in a psychiatric mode, and there was a lot of focus on coping. But the people that I began to work with were more behaviorally focused, and they were kind of interested in the impact of the disease and the treatment on the patient's life and, backwards, how could managing those kinds of problems affect the well-being of the patient. And this one psychiatrist, Richard Heinrich, had gotten money from the VA, had written a grant to do an intervention study with the oncology patients who I was serving to do a group intervention for the patients and their families. But, in order to even get this grant going, he hired a project manager who was a psychologist, a fresh graduate whose name was Anne Coscarelli, and her name was Cindie Schag at that time. But she said, "I don't know much about cancer. I've got to interview patients. I've got to understand what's going on." And they really, really showed me that, by talking to the patient, by understanding what they were experiencing, they could get a better handle on what they were dealing with and then, potentially, do interventions. So we have a wonderful paper if you want to look it up. It's called the “Karnofsky Performance Status Revisited.” It's in the second issue of JCO, which we published; I think it was 1984.  Dave Johnson: In the early 90s, you relocated back to UCLA. Why would you leave what sounds like the perfect situation to go back to a site that didn't have it? Dr. Patricia Ganz: Okay, over that 13 years that I was at the VA, I became Chief of the Division of Hem-Onc. We were actually combined with a county hospital. It was a wonderful training program, it was a wonderful patient population at both places. And we think that there are troubles in financing health care now, well, there were lots of problems then. Medicaid came and went. We had Reagan as our governor, then he became president, and there were a lot of problems with people being cared for. So it was great to be at the VA in the county, and I always felt privileged. I always had a practice at UCLA, which was a half-day practice, so I continued there, and I just felt great that I could practice the same wherever I was, whether it was in a public system, veteran system, or in the private system.   But what happened was, I took a sabbatical in Switzerland, '88 to '89. I worked with the Swiss International Breast Cancer Consortium group there, but it was really a time for me to take off and really learn about quality of life assessment, measurement, and so forth. When I came back, I basically said, "I want to make a difference. I want to do something at a bigger arena." If I just continue working where I am, it's kind of a midlife crisis. I was in my early 40s, and my office was in the San Fernando Valley at the VA, but my home was in West Los Angeles. One day I was in UCLA, one day I was at the VA, one day I was at the county, it was like, "Can I practice like this the next 20 years? I don't know that I can do this. And I really want to have some bigger impact.” So I went to Ellen Gritz who was my predecessor in my current position, and I was doing my NCI-funded research at UCLA still, and I said, “Ellen, I really would like to be able to do research full time. I really want to make a difference. Is there anything available? Do you know of anything?" And she said, "Well, you know, we're actually recruiting for a position that's joint between the School of Public Health and the Cancer Center. And oh my goodness, maybe I can compete for that, so that's what I did. And it was in what was then the department called Health Services, it's now called Health Policy and Management. I applied, I was competing against another person who I won't name, but I got the position and made that move.  But again, it was quite a transition because I had never done anything in public health, even though UCLA had a school of public health that was right adjacent to the medical school. I had had interactions with the former dean, Lester Breslow, who I actually took an elective with when I was a first-year medical student on Community Medicine. So it kind of had some inklings that, of what I was interested in. I had actually attendings in my medical clinic, Bob Brook, a very famous health policy researcher, Sheldon Greenfield. So I'd been exposed to a lot of these people and I kind of had the instinctive fundamentals, if you will, of that kind of research, but hadn't really been trained in it. And so it was a great opportunity for me to take that job and really learn a lot and teach with that.  And then took, part of my time was in the cancer center with funding from the core grant. And then, within a year of my taking this position, Ellen left and went to MD Anderson, so all of a sudden I became director of that whole population science research group. And it was in the early ‘90s, had to scramble to get funding, extramural funding. Everybody said to me, "How could you leave a nearly full-time position at the VA for a soft money position?" But, nevertheless, it worked out. And it was an exciting time to be able to go into a new career and really do things that were not only going to be in front and center beneficial to patients, but to a much larger group of patients and people around the world.  Pat Loehrer: Of all the work that you have done, what one or two things are you most proud of in terms of this field? Dr. Patricia Ganz: Recognizing the large number of people who are surviving cancer. And I think today we even have a more exciting part of that. I mean, clearly, many people are living long-term disease-free with and without sequelae of the disease. But we also have this new group of survivors who are living on chronic therapy. And I think the CML patients are kind of the poster children for this, being on imatinib or other newer, targeted agents over time, living with cancer under control, but not necessarily completely gone. And then melanoma with the immunotherapy, lung cancer, all of these diseases now being converted to ones that were really fatal, that are now enjoying long-term treatment.   But along with that, we all know, is the financial toxicity, the burdens, and even the ongoing symptoms that patients have. So the fact that we all call people survivors and think about people from the time of diagnosis as potentially being survivors, I think was very important. And I would say that, from the clinical side, that's been very important to me. But all of the work that I was able to do with the Institute of Medicine, now the National Academy of Medicine, the 2013 report that we wrote on was a revisit of Joe Simone's quality of care report, and to me was actually a very pivotal report. Because in 2013, it looked like our health care system was in crisis and the delivery of care. We're now actually doing a National Cancer Policy Forum ten-year follow-up of that report, and many of the things that we recommended, surprisingly, have been implemented and are working on. But the healthcare context now is so much more complicated.  Again, with the many diseases now becoming rare diseases, the cost of drugs, the huge disparities, even though we have access through the Affordable Care Act and so forth, there's still huge disparities in who gets care and treatment. And so we have so many challenges. So for me, being able to engage in the policy arena and have some impact, I think has been also very important to me. Dave Johnson: 20 years ago, the topic of survivorship was not that common within ASCO, and you led a 2004 task force to really strengthen that involvement by that organization, and you also were a founding member of the National Coalition for Cancer Survivorship. I wonder if you might reflect on those two activities for us for a moment. Dr. Patricia Ganz: In 1986, Fitzhugh Mullen, who in 1985 had written a really interesting special article for the New England Journal called "Seasons of Survivorship" - he was a young physician when he was found to have a mediastinal germ cell tumor and got very intensive chemotherapy and radiation therapy and survived that, but realized that there was no place in the healthcare system where he could turn to to get his questions answered, nor get the kind of medical care that was needed, and really wrote this very important article. He then, being somebody who was also kind of policy-oriented and wanting to change the world, and I would say this was a group of us who, I think went to college during the Vietnam era - so did Fitz - and we were all kind of restless, trying to see how we could make a difference in the world and where it was going.   And so he had this vision that he was going to almost develop an army of survivors around the country who were going to stand up and have their voices heard about what was going on. Of course, most people didn't even know they were a survivor. They had cancer treatment, but they didn't think about themselves as a survivor. And so he decided to get some people together in Albuquerque, New Mexico, through a support group that he had worked with when he was in the Indian Health Service in New Mexico. And there were various people from the American Cancer Society, from other support organizations, social workers, and a couple of us who are physicians who came to this meeting, some Hodgkin survivors who had been treated at Stanford and were now, including a lawyer, who were starting to do long term late effects work. And we gathered together, and it was a day and a half, really, just kind of trying to figure out how could a movement or anything get oriented to try and help patients move forward.  So that's how this was founded. And they passed the hat. I put in a check for $100, and that was probably a lot of money at that time, but I thought, well, this is a good investment. I'll help this organization get started. And that was the start. And they kind of ran it out of Living Beyond Cancer in Albuquerque for a few years. But then Fitz, who was in the Washington, DC. area decided they weren't going to be able to get organizations all over the country organized to do this, and they were going to have to do some lobbying. So Ellen Stovall, who was a Hodgkins survivor living in the Washington area, beginning to do policy work in this area, then became the executive director and took the organization forward for many years and championed this, got the Office of Cancer Survivors established at the NCI in the 1990s, and really did a lot of other wonderful work, including a lot of the work at the Institute of Medicine. She was very involved with the first Quality of Care report and then ultimately the survivorship report, the Lost and Transition report in 2005, 2006, I was on that committee. So that was really how things were evolving.  And by that time, I was also on the ASCO board, 2003 to 2006. And so all of these things were kind of coming together. We had 10 million survivors. That was kind of an important note and a lot of diseases now - lymphoma, breast cancer, multi-agent therapy had certain benefits, but obviously toxicities. We lived through the horrible time of high-dose chemotherapy and transplant for breast cancer in the ‘90s, which was a problem, but we saw a lot of toxicities after that. And so there were people living after cancer who now had sequelae, and the children obviously had been leading the way in terms of the large number of childhood cancer survivors. So this was this idea that the children were kind of the canary in the coal mine. We saw them living 20, 30 years later after their cancer diagnosis, and we were now beginning to see adults living 10, 15, 20 years later, and we needed to think about these long-term and late effects for them as well. Dave Johnson: I'm glad you mentioned Fitz's article in the New England Journal that still resonates today, and if listeners have not read it, "Seasons of Survivorship" is a worthwhile five-minute read.  What do you think the most pressing issues and challenges in cancer survivorship care today?  Dr. Patricia Ganz: Many people are cured with very little impact. You can think of somebody with T1 breast cancer maybe needing endocrine therapy for five years, and lumpectomy radiation. That person's probably not going to have a lot that they're going to be worried about. But if they're a young breast cancer patient, say they're 35 or 40, you're going to get five years of ovarian suppression therapy. You're going to be put into acute menopause. You're going to lose bone density. You're going to have cardiac risk acceleration. You may have cognitive changes. You may have also problems with cognitive decline later. I mean, all of these things, the more intense treatments are associated, what we're really thinking about is accelerated aging. And so a lot of what I've been studying the last 20-25 years in terms of fatigue and cognitive difficulties are related to neuroinflammation and what happens when somebody has intensive systemic therapy and that accelerated process that's, again, not everyone, but small numbers of patients, could be 10-15-20%. So I worry a lot about the young patients. So I've been very focused on the young adult population who are treated intensively for lymphoma, leukemia, and breast. And that's, I think, something that we need to be looking out for.  The other thing is with the newer therapies, whether it's immunotherapy or some of the targeted therapies, we just don't know what the late effects are going to be. Where we're very schooled now in what the late effects of radiation, chemo, and surgery could be for patients, we just don't know. And another wonderful part of my career has been to be able to do quality-of-life studies within the Clinical Trials Network. I've been affiliated with NSABP, I was SWOG previously, but NSABP is now NRG Oncology doing patient-reported outcomes and looking at long-term outcomes in clinical trials. And I think we're going to need this for all of these new agents because we have no idea what the long-term toxicities are going to be. And even though it's amazing to have people surviving where they wouldn't have been, we don't know what the off-target long-term effects might be. So that's a real challenge right now for survivorship.  And the primary care doctors who we would want to really be there to orchestrate the coordinated care for patients to specialists, they are a vanishing breed. You could read the New England Journal that I just read about the challenges of the primary care physician right now and the overfilled inbox and low level of esteem that they're given in health systems. Where are we going to take care of people who really shouldn't be still seeing the oncologist? The oncologist is going to be overburdened with new patients because of the aging of the population and the many new diagnoses. So this is our new crisis, and that's why I'm very interested in what we're going to be looking at in terms of a ten-year follow-up report to the 2013 IOM report. Dave Johnson: The industry-based trials now are actually looking at longer-term treatment. And the trials in which interest is cancer, we cut it down from two years of therapy down to nine weeks of therapy, looking at minimizing therapy. Those are difficult trials to do in this climate today, whereas the industry would just as soon have patients on for three to five years worth of therapy as opposed to three to five months. Talk a little about those pressures and what we should be doing as a society to investigate those kinds of therapies and minimizing treatments. Dr. Patricia Ganz: Minimizing treatments, this is the place where the government has to be, because we will not be able to do these de-escalation studies. Otherwise, there will be countries like the UK, they will be able to do these studies, or other countries that have national health systems where they have a dual purpose, if you will, in terms of both financing health care and also doing good science. But I think, as I've seen it, we have a couple of de-escalation trials for breast cancer now in NRG Oncology, which is, again, I think, the role that the NCTN needs to be playing. But it's difficult for patients. We all know that patients come in several breeds, ones who want everything, even if there's a 1% difference in benefit, and others who, “Gee, only 1 out of 100 are going to benefit? I don't want that.” I think that's also the challenge. And people don't want to be denied things, but it's terrible to watch people go through very prolonged treatments when we don't know that they really need it for so long.  Dave Johnson: Pat and I both like to read. I'm wondering if there's something you've read recently that you could recommend to us. Dr. Patricia Ganz: It's called A Gentleman in Moscow by Amor Towles. I do like to read historical fiction. This one is about a count at the time of the Bolshevik Revolution who then gets imprisoned in a hotel in Moscow and how constrained his life becomes, but how enriched it is and follows him over really a 50-year period of time and what was happening in the Soviet Union during that time. And of course, with the war in Ukraine going on, very interesting. Of course, I knew the history, but when you see it through the drama of a personal story, which is fictional, obviously it was so interesting.   My husband escaped from Czechoslovakia. He left in '66, so I had exposure to his family and what it was like for them living under communism. So a lot of that was interesting to me as well.  Dave Johnson: Thank you for joining us. It's been a wonderful interview and you're to be congratulated on your accomplishments and the influence you've had on the oncology world.  We also want to thank our listeners of Oncology, Etc., and ASCO Educational Podcast where we will talk about oncology, medicine and beyond. So if you have an idea for a topic or a guest you'd like us to interview, by all means, email us at education@asco.org. To stay up to date with the latest episodes and explore other ASCO educational content, please visit education.asco.org. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Discussing two important lymphoma studies, POLARIX which led to the approval of Polatuzumab in DLBCL patients and SWOG S1826 comparing Nivolumab vs. BV with AVD in Hodgkin's Lymphoma patients with Dr. Jonathan Friedberg. In discussion with the lead author, Dr. Jonathan Friedberg - Director of Wilmot Cancer Institute, Professor of Medicine at University of Rochester Medical Center, and Editor-in-Chief at Journal of Clinical Oncology (JCO).

Heinz-Josef Lenz, MD, FACP, is a Professor of Medicine and Preventive Medicine, J. Terrence Lanni Chair in Cancer Research, Section Head of GI Oncology and Co-Director of the Colorectal Center at the University of Southern California. He also serves as the Deputy Director for Research at USC Norris Comprehensive Cancer Center. Dr. Lenz is a physician-scientist known for his work on the pharmacogenomics of GI cancers. He is a member of several professional societies, including the AACR & AGA and serves on the National Advisory Board of a number of professional organizations. Dr. Lenz is the Co-Chair of the GI Committee and Correlative Science Committee for SWOG. He has published over 450 peer reviewed manuscripts. He has been listed in the Best Doctors' database since 2003. “You need to be very resilient and always dream big. Don't limit yourself with boundaries.” Why is resilience so important for a physician? Early in his career, Dr. Lenz was told that he cannot make it as a researcher by his superior; the only response Dr. Lenz had was, "I will show you." Looking ahead a few years, Dr. Lenz is now a highly renowned researcher and clinician with many accolades to his name. Join us on another episode of Medicine Mentors where we discuss core values a physician must exhibit, the success factor of effective mentors, and what it means to be an influential physician-leader with Dr. Heinz-Josef Lenz. Pearls of Wisdom:   1. Learn to be open-minded. Always be relentless and resilient in your pursuits. Explore different diversities with the right mindset and maximize your potential. 2. A successful mentor can instill a sense of accountability in their mentees, making sure they know that great things are expected of them. 3. A leader's job is to maximize the existing potential of the group and eliminate the gaps and weak links by recognizing talent and assigning appropriate roles.

Two cracking bladder cancer studies to discuss on GU Cast today (in our brand new GU Cast studio)! We are joined by Dr Sia Daneshmand, Urologist and Director of Urologic Oncology at the University of Southern California, who presented the headline-making Tar-200/SunRIse-1 study at the recent Annual Meeting of the American Urological Association. Not sure what a urological pretzel is and how it can help patients with high-grade non-muscle-invasive bladder cancer? Sia explains all! He was also an investigator on the SWOG 1011 trial presented at the ASCO Annual Meeting recently by Dr Seth Lerner. A practice-changing randomised trial of standard vs extended pelvic lymph node dissection for patents with invasive bladder cancer. These are very significant papers and we really enjoyed having Sia on GU Cast to discuss. Even better on YouTube when you can check out our new studio!

Drs. John Sweetenham and Marc Braunstein discuss advances in hematologic malignancies featured at the 2023 ASCO Annual Meeting, including the potentially practice-changing SWOG-S1826 study in Hodgkin lymphoma, the promise of bispecific antibodies in B-cell malignancies, and a novel approach to deliver vital anti-myeloma medications that could improve patient quality of life and alleviate barriers to care. TRANSCRIPT   Dr. John Sweetenham: Hello, I'm John Sweetenham, the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and the host of the ASCO Daily News Podcast.    The 2023 ASCO Annual Meeting featured some exciting new data on hematologic malignancies. I'm delighted to have Dr. Marc Braunstein return to the podcast to discuss some of these potentially practice-changing studies and new approaches in the heme space. Dr. Braunstein is a hematologist and oncologist at the NYU Perlmutter Cancer Center.    You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.   Marc, it's great to have you back on the podcast, and thanks for being here again.   Dr. Marc Braunstein: Thank you, John. It's great to be back.   Dr. John Sweetenham: Marc, we already mentioned that there are some potentially practice-changing studies that were reported at ASCO this year. And among those, LBA4, which was presented in the Plenary Session, was a study which explored the treatment of advanced Hodgkin lymphoma. This was the Southwest Oncology Group study S1826. Could you give us your insights on this?    Dr. Marc Braunstein: Sure, happy to discuss S1826. So as background, you know, the ECHELON-1 study, which was published in the New England Journal of Medicine in 2022 showed a 40% decrease in the risk of death at six years follow-up by adding brentuximab to AVD compared to bleomycin AVD. And that was in high risk or advanced-stage patients and that led to adoption of brentuximab for upfront use in patients with classical Hodgkin lymphoma in advanced stage.    Also of note, immune checkpoint inhibitors such as pembrolizumab or nivolumab do have activity in the relapse setting. The SWOG S1826 study was a randomized control study looking at the use of the PD-1 inhibitor nivolumab plus AVD versus brentuximab AVD in patients with advanced stage classical Hodgkin lymphoma who are at least twelve years of age. And the primary endpoint in the study was progression-free survival.     It was a large study which enrolled 976 patients and randomized them one to one to either nivo AVD or brentuximab AVD. The median age in the study was 27 and the median follow-up was 12 months. And what the study found, which could be practice-changing, was that the primary endpoint of progression-free survival was superior in the nivolumab arm with a hazard ratio of 0.8 and a one-year PFS of 94% versus 86%, favoring the nivolumab arm. And while there were side effects associated with the class of medications, for example, hypo or hyperthyroidism was more frequent in the nivolumab group, whereas peripheral neuropathy was higher in the brentuximab group, I think that these results are particularly encouraging for how we can continue to improve outcomes for patients with advanced-stage classical Hodgkin lymphoma. And this may be practice-changing in terms of whether we use upfront immune checkpoint inhibitors in combination with our standard chemotherapy backbone.    Dr. John Sweetenham: Yeah, absolutely. There are a couple of things that occur to me. One in particular which is unique about this study, and the fact that it was for patients who are 12 years and older in many respects represents a first because I can't think of another large, randomized study of this type which has attempted to align pediatric and adult care of patients with Hodgkin lymphoma. So, I think it's something of a landmark in that regard. I don't know if you'd agree with that.    Dr. Marc Braunstein: I agree, especially with the range of ages from 12 to 83. It's a pretty broad population by age, but I agree it does kind of reconcile those two groups in a disease that has a bimodal presentation and clearly shows that immune checkpoint inhibitors are both potent and well tolerated in different age groups.    Dr. John Sweetenham: The other question that I have about this study is we haven't seen so far in this study an overall survival benefit to the nivo arm, which is maybe not surprising, but in terms of the practice-changing potential of this study, do you think that will matter?   Dr. Marc Braunstein:  I think that's an excellent question, John. Initially, the ECHELON-1 study only showed progression-free survival, and then the update did show overall survival. And so if we take the lead from that study, we expect to see an overall survival benefit in the SWOG study as well with nivolumab, but it remains to be seen. But I think that the data presented thus far at the Plenary Session is compelling enough to consider using nivolumab upfront.   Dr. John Sweetenham: Yeah, I absolutely agree. And then I guess the other question that we're going to have to wait probably several years to know is what happens in terms of relapse? So, for the minority of these patients who do relapse, how salvageable, if that's the right word, are they going to be with a second- or third-line regimen? But I think that's clearly something for the future, and it's a very interesting, exciting outcome from this study.   Dr. Marc Braunstein: Absolutely.    Dr. John Sweetenham: Let's move on. Marc, again, we're still in the lymphoma world here, but looking at high-risk follicular lymphoma. And this was Abstract 7506, looking at epcoritamab plus the R2 regimen in patients with follicular lymphoma. Could you walk us through this one?    Dr. Marc Braunstein: Yeah, absolutely. Bispecific T-cell engaging antibodies are showing impressive efficacy in relapsed and refractory non-Hodgkin lymphoma. Epcoritamab is a bispecific antibody that binds to CD3 on T-cells and CD20 B-cells. And this antibody is currently approved for diffuse large B-cell lymphoma patients after two or more prior lines of treatment.    In this study presented by Merryman and colleagues, they explored the addition of epcoritamab to standard lenalidomide-rituximab. In 109 patients with relapsed or refractory follicular lymphoma who had at least one prior therapy, and, of note, the study was enriched for high-risk patients for progression, including those who had progression of disease within 24 months of their initial treatment and those patients who had been refractory to prior anti-CD20 treatment. This study enrolled 109 patients with relapsed refractory follicular lymphoma. The median age was 65 and 56% of patients had FLIPI scores on the higher end of the spectrum from three to five, and 61% had stage 4 disease. Also of note, 38% of patients had progression of disease within 24 months of their prior treatment. So at a median follow-up of 8.8 months, the overall response rate was impressive at 97%, and 82% of patients were still on treatment at that time.     Now, of course, with this mechanism of action of bispecific antibodies, there is a risk of both cytokine release syndrome and immune-related neurotoxicity. The rates of CRS were primarily low grade, there were only 2% grade 3, and of note, most occurred after the first dose. And in terms of ICANS or neurological toxicity, there were no grade 3 adverse events, and those occurred in only two patients. Finally, the estimated six months progression-free survival was 93%. So, if we cross-compare these results historically to the R-squared regimen, which was published to be about 80%, just cross comparing, so it's not exactly the same study, this clearly shows high activity on par or better with R-squared alone. Although this study was not a randomized study, I think the addition of epcoritamab certainly shows high overall response rates and we'll need randomized data to confirm the efficacy, but it's definitely encouraging in high-risk follicular lymphoma patients.   Dr. John Sweetenham: Thanks, Marc. I agree. I think these data are really enticing, in as much as the response rates are so high, but of course, it is follicular lymphoma, so we'll have to wait a while. But the thing that it does make me reflect on is that bispecific antibodies really are turning out to be remarkably effective in a range of B cell malignancies, so, it's very interesting to continue to watch this space.    I'm going to change gears now and talk about something completely different for a moment. And this was Abstract 1536. I think that many of us are in a position where we're now looking at how we deliver our clinical services, and particularly inpatient services, to patients with hematologic malignancy. And this study addressed that very specifically. Can I have your thoughts on that?   Dr. Marc Braunstein: Sure. In the context of how our therapies are improving, our approaches to how we manage patients clinically is changing too, in many ways for the better. So, various models exist for, you know, which practitioners manage oncology patients who happen to be admitted to the hospital. This abstract, which was performed by authors at a large medical center in New York, describes the use of a dedicated hematologic malignancy hospitalist for managing medicine-related issues. And the authors did comparisons of that service to a service primarily managed by oncologists. The authors compared things such as length of stay, whether the patients were discharged by noon, which is a hospital metric that's used for facilitating turnover of patients and space availability, as well as 30-day readmission rates among patients cared for by an oncology attending versus this heme malignancy hospitalist between July of 2021 and July 2022.    The outcomes showed that admissions to the heme malignancy hospitalists were, although less because that service was primarily for patients who required medicine-related issues as opposed to primarily oncologic issues, there were 95 admissions to that service versus 669 to the oncology service. There was a significantly shorter length of stay on the heme malignancies hospitalist service by about 2 to 5 days compared to the oncology hospitalist service. The rates of patients who were discharged by noon or the length of stay were similar between the two groups.    So, while this study is confounded by differences in acuity of disease between the services, using a dedicated heme malignancy hospitalist has many benefits, not just to offload the oncology-managed service, which may have a higher level of acuity, but also allow for a deviation of care for medicine-specific issues, to a hospitalist that's specifically trained in managing patients with hematologic malignancies and then dedicating the oncology specialty service to those who need acute oncologic care, such as those with leukemia or other high acuity diseases.    Dr. John Sweetenham: Thanks, Marc. I think it is really interesting to see some outcome data for this model of care. A number of centers I know are looking at an APP-led inpatient service for these types of patients, too, so it's going to be very interesting to see how further studies of these kinds of approaches continue to develop.    And on a related theme of changes in patterns of care, Abstract TPS1609 looked at home infusion and of course, this is something that really started to attract a lot more attention during the COVID-19 pandemic. But I wonder if you could walk us through some of the details of this poster.    Dr. Marc Braunstein: This study was presented as a poster proposing a prospective study looking at home infusion of the anti-CD38 monoclonal antibody daratumumab, which has a vital role in managing patients with newly diagnosed or relapsed multiple myeloma. And monoclonal antibodies have really revolutionized the care of patients with multiple myeloma, but often their infusion schedule is weekly or biweekly, and it does require relatively frequent visits to an infusion center.    So, this single-arm, open-label study is going to examine whether we can provide home administration of subcutaneous daratumumab and assess whether it improves quality of life and assess its safety. So, in this study, a visiting nurse will come and deliver the medication after patients take their pre-medications at home prior to the arrival of the infusion nurse. And then the investigators will provide quality of life questionnaires prior to and after the infusions and at the end of the study, and they'll be looking at any barriers to adherence, any barriers to the logistics of this home infusion arrangement.    And I think that this has a lot of potential not just to improve quality of life, but also to facilitate care to patients who may be frail, who may not have good caregiver support, who may have barriers in traveling to an infusion center or perhaps in places that are more resource-deprived and don't have local infusion centers. This could be a potential approach to delivering vital anti-myeloma medications at home, and I'm looking forward to seeing the results.    Dr. John Sweetenham: Yeah, I agree. I think a lot of us still have anxieties about the safety of this approach, but I think there are increasing data to suggest that home infusion is not only safe but also, as you mentioned, is a big enhancer of the quality of life of these patients. And so, very interesting to see how this plays out in prospective studies.    So, to close out, I wonder if you could walk us through Abstract 7072, a poster looking at the issue of clonal hematopoiesis.    Dr. Marc Braunstein: Clonal hematopoiesis, which is a phenomenon in which the blood cells acquire somatic mutation, is associated with both cardiovascular disease adverse outcomes as well as hematologic malignancy. It's been shown to be a precursor for diseases such as leukemia. So, this relatively small study from MD Anderson Cancer Center examined clonal hematopoiesis in 78 patients with malignancies, 70% of which had a history of cancer, and the authors described outcomes associated with clonal hematopoiesis.    So, again, 78 patients were examined, and 76% of them had a history of malignancy, and 73% had other comorbidities. And the authors demonstrated clonal hematopoiesis by the finding of specific mutations in the blood associated with clonal hematopoiesis. The authors essentially looked at outcomes such as mortality. They noted that only 20% of the patients developed a myeloid neoplasm, and that's relevant because, again, clonal hematopoiesis is a precursor for myeloid neoplasms. They also noted that most patients had died from a primary malignancy rather than a myeloid neoplasm, which is not too surprising considering that most patients with clonal hematopoiesis will not develop a hematologic malignancy, but it is a marker for the potential transformation.    And so, I think the authors conclude that clonal hematopoiesis is important for monitoring patients who are at risk for potential myeloid transformation and hematologic malignancy, but it's not necessarily the case that patients who have a background of malignancy will often develop a myeloid malignancy. I think there are many implications of clonal hematopoiesis for cancer in general in terms of the risk of secondary malignancies in those treated with adjuvant chemotherapy, in terms of how we monitor patients who actually more and more are going to have this detected as we use more next-generation sequencing and liquid biopsies.     So, I look forward to future studies that are exploring how to actually prospectively assess clonal hematopoiesis and use it for clinical stratification for things like adjuvant chemotherapy or monitoring for risks of hematologic malignancy.    Dr. John Sweetenham: Thanks, Marc. I agree. Very important for the future, especially as we gain more and more sequencing data.    So, Marc, in conclusion, I want to thank you very much for sharing your insights with us today on the ASCO Daily News Podcast. It's been great to talk with you again.    Dr. Marc Braunstein: My pleasure. Happy to be back, and I look forward to a future podcast session.  Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstracts discussed today in the transcripts of this episode. Finally, if you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Find out more about today's speakers:   Dr. John Sweetenham   Dr. Marc Braunstein   @docbraunstein      Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn       Disclosures:   Dr. John Sweetenham:   Consulting or Advisory Role: EMA Wellness   Dr. Marc Braunstein:   Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb/Celgene, Adaptive Biotechnologies, GlaxoSmithKline, ADC Therapeutics, Janssen Oncology, Abbvie, Guidepoint Global, Epizyme, Sanofi, CTI BioPharma Corp   Speakers' Bureau: Janssen Oncology   Research Funding (Institution): Janssen, Celgene/BMS        

This week's episode is part 4 of 5 of a joint mini-series with our friends Two Onc Docs. In today's episode, we will be recapping the current treatment of resectable NSCLC and discussing KEYNOTE 671, which was presented at ASCO 2023, looking at neoadjuvant chemo+immunotherapy followed by adjuvant immunotherapy. We also discuss the use of the “interaction test,” “multiplicity,” and it's important role in understanding subgroup analyses. Content: - A quick recap of the current standard of care for resectable lung non-small cell lung cancer - A discussion about KEYNOTE 671 presented at ASCO 2023- We define the "interaction test"- We discuss "multiplicity"Want to read the abstract for yourself? Click here!Episode list: Episode 1 covering covering rectal cancer & the PROSPECT Trial, as well as non-inferiority trials (released by Two Onc Docs): https://podcasts.apple.com/us/podcast/updates-from-asco23-rectal-cancer-the-prospect-trial/id1616541733?i=1000616604349Episode 2 covering classical hodgkin's lymphoma & SWOG 1826 as well as “p-values” and what it means when trials say “the median was not reached.” (released by The Fellow on Call): Episode 061: “Paging Heme/Onc: Updates from ASCO 2023” - Classical Hodgkin's Lymphoma and SWOG 1826Episode 3 covering mRCC & the CONTACT03 Trial, as well as subgroup analysis (released by Two Onc Docs): https://podcasts.apple.com/us/podcast/updates-from-asco23-mrcc-the-contact03-trial/id1616541733?i=1000617519386** Want to review the show notes for this episode and others? Check out our website: https://www.thefellowoncall.com/our-episodesLove what you hear? Tell a friend and leave a review on our podcast streaming platforms!Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google Podcast

This week's episode is part 2 of 5 of a joint mini-series with our friends Two Onc Docs. In today's episode, we recap the current treatment of classical hodgkin's lymphoma and then dive into the the SWOG 1826 plenary session abstract from the ASCO 2023 annual meeting. We also cover the concept of “p-values” and what it means when trials say “the median was not reached.” Content: - A quick recap of the current standard of care for classical hodgkin's lymphoma- A review of the recent SWOG 1826 trial presented at ASCO 2023- A discussion about "p-values"- A discussion about what it means when "the median was not reached" Want to reach the abstract yourself? Click here: https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.17_suppl.LBA4?af=RHave you checked out Episode 1? See link here for this episode released by Two Onc Docs: https://podcasts.apple.com/us/podcast/updates-from-asco23-rectal-cancer-the-prospect-trial/id1616541733?i=1000616604349** Want to review the show notes for this episode and others? Check out our website: https://www.thefellowoncall.com/our-episodesLove what you hear? Tell a friend and leave a review on our podcast streaming platforms!Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google Podcast

Age is a main factor when determining cancer care. In this ASCO Education podcast we speak to one of the top leaders in treatment for older patients who has also credited mentorship as a foundation for his career. Dr. Hyman Muss describes his childhood in Brooklyn, serving as a general physician for troops in Vietnam (6:18), the doctor who influenced his choice of hematology and oncology (7:48) and creating one of the first geriatric oncology fellowships in in the country (21:58).  Speaker Disclosures Dr. David Johnson: Consulting or Advisory Role – Merck, Pfizer, Aileron Therapeutics, Boston University Dr. Patrick Loehrer: Research Funding – Novartis, Lilly Foundation, Taiho Pharmaceutical Dr. Hyman Muss: None More Podcasts with Oncology Leaders  Oncology, Etc. – Devising Medical Standards and Training Master Clinicians with Dr. John Glick Oncology, Etc. – Rediscovering the Joy in Medicine with Dr. Deborah Schrag (Part 1) Oncology, Etc. – In Conversation with Dr. Richard Pazdur (Part 1) If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org. TRANSCRIPT Pat Loehrer: Welcome to Oncology, Etc., an ASCO Education Podcast. I'm Pat Loehrer, director of Global Oncology and Health Equity at Indiana University.  Dave Johnson: And I'm Dave Johnson of Medical Oncology at the University of Texas Southwestern in Dallas, Texas. If you're a regular listener to our podcast, welcome back. If you're new to Oncology, Etc., the purpose of our podcast is to introduce listeners to interesting and inspirational people and topics in and outside the world of Oncology. We have an inspirational guest today. Pat?  Pat Loehrer: If you ask anyone who's achieved any level of success and how they've achieved it, most likely they'll mention a number of people who've influenced them along the way. Quite often, these people reflect on their mentors, and after a certain time of accomplishment and reflection, they begin to mentor others. This is very much what our next guest has done. Dr. Hyman Muss has been a mentor to me and to Dave, and he's one of the most outstanding, wonderful people in the world, and we're so excited to have him today.   Dr. Hyman Muss served in the US Army in Vietnam, where he was awarded the Bronze Star Medal. He's an experienced Clinician Scientist, the Mary Jones Hudson Distinguished Professor of Geriatric Oncology at the University of North Carolina School of Medicine, and the Director of Geriatric Oncology Program at the UNC Lineberger Comprehensive Cancer Center Program. His interest in education and research is focused on cancer and older patients, and he is internationally recognized in this area. He's been the co-chair of the Alliance Committee on Cancer and Older Adults and won the BJ Kennedy Award from ASCO in Geriatric Care. His particular interest in research expertise is in the care of breast cancer patients, with a focus on the management of women who are of older ages. He's had a major interest in breast cancer survivorship and long-term toxicity of treatment and also served as the co-chair of the Breast Committee for the Alliance Group. He serves as a mentor for medical students, medical residents, junior faculty, and more recently, his Geriatric Oncology fellows. He served on the Board of Directors of the ASCO Foundation and on the ABIM, the American Board of Internal Medicine, where both Dave and I were privileged to work with him and witness his leadership and his deep breadth of knowledge.  Dr. Muss, thanks for joining us today. Dr. Hyman Muss: What a pleasure to be here. Thank you so much for inviting me. My mother would have loved the introduction.  Pat Loehrer: Well, speaking of that, tell us a little bit. You grew up in Brooklyn, so tell us a little bit about your parents. Your father was a dentist, I think, and your uncle was a general practitioner. So give us a little bit of the early life of Hy Muss. Dr. Hyman Muss: So I grew up in Brooklyn, New York. I was born and bred there. I went to Brooklyn Technical High School. I almost went to Brooklyn College, but I came back and went to Downstate Medical Center, which was just terrific. My tuition was $600 a year, but that's another story. My parents lived in the same neighborhood. My dad was a dentist, so we knew all the people. My uncle was the GP. You came into their office, sat down, and they saw you anytime, day or night, almost 24/7, something we're probably not going back to, but they had a profound influence on me. My uncle, as a GP, used to take me on house calls in Brooklyn when they were done, and he had an old Buick with MD plates. And I would go into these families, and they loved him, and they would give me ice cream and things. Maybe that's what made me a doctor. But it was a terrific and indelible experience. I had terrific parents. In those days, doctors and medical people usually lived in the same neighborhoods as their patients, so they really knew their people well. It was a terrific upbringing. I got to love medicine and have never had a look back. Dave Johnson: So your inspiration for a career in medicine obviously started at home. Tell us more about your formal education. You mentioned your high school education. What about college? And shortly thereafter?  Dr. Hyman Muss: Yeah, well, I went to Lafayette College. I was not the best high school student, but I had good college board scores or whatever they called them then. And I went to Lafayette and I thought I was going to be a chemist, a chemistry major. But I took enough premed courses and I spent a summer in a lab building cyclic ketones. And everybody was outside sitting on the lawn of the campus. And I was in there with all these distillation apparatus, and I said, “I don't think I can do this the rest of my life.” So I applied to medical school, and I got into several medical schools. But my father at that time was dying of metastatic bladder cancer. He had been a heavy smoker, and he was still working as a dentist. He worked until the day he unfortunately died. But I got into Downstate. We lived in Brooklyn, and my uncle, the GP, said, "Hy, you need to come home and help take care of your dad." I'm an only child, so I did. And I had a wonderful experience at Downstate.   Several years ago, I was listening to NPR and heard that one of my professors had won the Nobel Prize. Dr. Furchgott in physiology, one would have never thought. And I had a wonderful education and subsequently got into what was then Peter Bent Brigham in Boston, did my internship and residency there, joined the army and medical school, so I wasn't drafted, it was a program then. And then after first year of residency, I went to Vietnam, worked with an artillery battalion, a mystical experience, but no regrets. And then subsequently came back and did hematology and oncology at Brigham and at what was then the Jimmy Fund and Sidney Farber Cancer Center. And Tom Frei had just come. And I did hematology with a guy named Bill Moloney in Boston at Harvard. I'll tell you, a wonderful man. He was like a surrogate father. My dad had died by then, and I just feel I've had every opportunity to have a wonderful education and terrific mentors along the way. Dave Johnson: So we want to ask you about both of those gentlemen, but I would like to just, if I may, drop back to your experience in Vietnam. What was that like?  Dr. Hyman Muss: Well, I was 27 years old and I was put as the doctor for 500 men in artillery. My job was to take care of the general health of the troops. Fortunately, we didn't have many casualties. It wasn't a front war like my uncle, who was a GP actually in World War II, landed in Normandy about a week later and went all through World War II as a doctor. But Vietnam was an unusual war, there wasn't really a front. So my experience was I would go out to fire bases, which were units of about 100 men in the jungle, go out three days in a week in a helicopter, do sick call, check people. I dealt with really alcohol problems, unfortunately, a lot of drug problems. You had young people with really not a lot to do during the day, nothing much to do, and no real goal of being there. I did that for a while, and actually, the reason I got the Bronze Star was because I set up– It was nothing like standing in front of a machine gun. I'm not that kind of brave guy, but I set up a drug amnesty program so I got a lot of support from our regular field people to do this, so we didn't have to keep sending kids home with dishonorable discharges. And I learned a lot. I think we were reasonably successful. I learned a lot about artillery. I think overall it was a great experience in my life. Dave Johnson: Tell us how your interest in hematology and oncology originated. Where did that come from?  Dr. Hyman Muss: When I was an intern at the Brigham, Dr. Moloney was a very famous Harvard professor. He had studied war casualties after Hiroshima, he was one of the people that found the Philadelphia chromosome in CML. He was a guy that rounded on every single one of his leukemia patients every day. So I was an intern. So in those days I would go and see all the hematology people rounding because all the acute leukemia patients and all the serious cancer patients were right on the floors, right on the wards. We had 17-bed wards, and then we had some private rooms. And he loved what he did. And before I left for Vietnam, we didn't have Ara C and daunomycin. So every leukemia patient I saw died. This is '68 to '70. Yet we tried all these different regimens. Occasionally you got someone who did well for six months, a year. But his bedside manner was absolutely wonderful to me. He knew all the patients. He'd ask them about where they lived in Boston. His humanism was terrific, and yet I loved the diseases he treated. The stakes were high. We didn't have good treatment, and I decided that that's probably what I want to do.   So when I was in Vietnam, I applied and got back in the Hematology Fellowship and came back and did that. I saw Ara C and daunomycin. I gave the chemotherapy to them, and he'd say, "Go up and treat Harry Smith with Ara C and daunomycin." I had the syringes in my pocket, guys. Forget about hoods and mixing. And I'd go up and treat them and the marrow would be gone within four or five days. I did a bone marrow. They published their regimen in the New England Journal called COD, C-O-D because they also gave vincristine. So it was cytarabine, vincristine, and daunomycin, the COD regimen. It fit Boston. And I saw it was like the emergence of cisplatin after Larry Einhorn. You saw people that never survived going into remission and I saw some remissions in AML and it cemented it.  About my second year of residency, we had a child. I was running out of money. I was being paid $6,000 a year and I had the GI Bill. I went into Dr. Moloney and he talked with Dr. Franny Moore, who was head of surgery at the Brigham, and they made me the Sidney Farber Research Fellow, doubled my salary and I had to go to the Jimmy Fund and see cancer patients. And it so happened that was when Tom Frei came to Dana-Farber. And so I started rounding with Dr. Frei and seeing those patients. And I think the first day I walked in, I knew I wanted to do more than just leukemia because I saw groups of patients with every disease. We treated everybody with CMFEP, it didn't matter what cancer they had. And I just loved it and said, "My God, there's so much we can learn. What a great career." And so that got me into the oncology portion.   And then I was offered to stay at Harvard. They were going to make me an assistant professor, but they wanted me to do lab work. And I knew my personality, it just wasn't for me. I worked with a lovely guy named Frank Bunn, one of the world's great hem guys in his lab, and he's still a close friend in his 80s. And he told me one day, he said, "Hy, I don't think the lab is for you." And he actually helped me get my first job at Wake Forest University, which turned out to be wonderful. So that's how I ended up with my circuitous in HemOnc. And it's really from great mentors, it's from Bill Moloney, it's from Tom Frei, Dave Rosenthal, tons of wonderful people along the way that not only taught me a lot, but they seemed to love what they do, which is a gift in life to love what you do and love the people you're doing it with. They instilled that in me. Pat Loehrer: From there you went to Wake Forest and there's a couple of colleagues down there, I believe, that inspired you, Charlie Spurr and Bill Hazzard, who was the founding founder of geriatrics. Tell us about that experience and how'd that shape your life.  Dr. Hyman Muss: I was looking for a clinical job and I looked at Rochester, and I got snowed in one night in Wake Forest, and I said, “Where's the contract?” And I signed it. And my mother, who was living in New York City, didn't know where North Carolina was. My mother was from a family, was born over a candy store in Greenwich Village, and said, “Where are you going?” And then I showed her where it was, and she says, “They're going to kill you down there.” And it turned out to be one of the best decisions of my life. My wife Loretta, who both of you know so well, we got out of our VW with our dog and our daughter when we moved here, and VW bug, by the way, not a van, and she cried. It turned out it was one of the best opportunities.  Charlie Spurr was an iconic oncology leader. He actually did some of the early work on nitrogen mustard in Chicago during the war, the first chemotherapy drug. He was a terrific leader. He had patients programmed in on those IBM punch cards. He had little cards for the protocols, CMFEP, CMF, AC on little laminated index cards. I learned so much from him, and he was to me, great leaders and great mentors morph from things they do themselves to teaching other people, and whose brains have the ability of having the same dopamine shot when you see one of your fellows or young faculty present a wonderful study as you do. And your brain isn't saying, “I wish I was up there.” It's saying, “Isn't this so cool that this young man or woman or fellow or medical student is doing such a wonderful job?” And I had something to do with providing the soil for this seed to grow. That's the kind of guy he was. And so it was wonderful there.  And as I moved on, we got a new Chief of Medicine, Bill Hazzard. And I still hear from Bill on rare occasions, but Bill was one of the first geriatricians in the United States. He wrote the textbook, and his wish was that all the faculty and all the specialties get involved in a geriatric project. And so I had all those little index cards, and I looked and saw how many older people with metastatic breast cancer we'd given chemotherapy to. And these were little protocols, nothing like the protocols today, no 50-page consent forms, 50 pages of where your data is stored. They were like, here's the treatment, here's the dose mods. And I looked at those 70 patients with one of our residents, Kathy Christman, she may be retired now, but in any event, we wrote a paper and showed the old people did as well as the young with breast cancer. And we published it in JAMA. And it's one of the few papers in my career, I got no reviewers. They accepted the paper. I got no reviewers. So because I'm from Brooklyn, and my English is not what it should be, I had my friends read it to just make sure I didn't say anything egregious. But it got published and the next thing I know, my friends in medical oncology in the state were calling me. They said, “I got a 75-year-old woman here.” I'm saying, “Guys, I just wrote this paper. I really don't know anything about older people.” But slowly, with Bill Hazzard and others, I got more and more interested. I started reading about Geriatrics and I ended up making it a focal point of my career. It was kind of happenstance. And Bill was a wonderful mentor.  And then as I subsequently moved on, I worked with terrific people like Harvey Cohen, Lodovico Balducci, and Martine Extermann, all of them heavily involved with ASCO over the years as well, and B.J. Kennedy. They were wonderful to work with. And BJ was inspirational because BJ would get up at an ASCO meeting and he'd say when he saw the age cut off, he'd say, “How come you didn't let old people on that study? There'd be 1000 people in the audience.” And so he really was a great mentor. And I had the bittersweet opportunity of writing his obit for JCO years ago and kept up with his family a few years, but he was a wonderful man. Dave Johnson: I'm just reflecting on the fact that today, patient registries are sort of mainstream, but certainly in the ‘70s, ‘80s, even into the ‘90s, having a list of patients with a particular disorder seemed almost novel in many respects. And to have that was a godsend.  Dr. Hyman Muss: It was a godsend. I still remember those little file cards. And he called it the Oncology Research Center and it was a godsend. And you've got to remember, this is like ‘74, ‘75, it's a long time ago. Dave Johnson: So many of our listeners may not be as familiar with Wake Forest as they are with Duke and North Carolina, the other medical schools located there. But you were at right at a point where I mean, it was one of the top oncology programs in the country at that time. Still is, I don't mean to diminish it, but there was a who's who of people there at the time. And you were also involved in creating, I think, one of the first cooperative groups of sorts. It was the Piedmont Oncology Group. Tell us about that.  Dr. Hyman Muss: Oh, yeah, well, that brings back memories. So the NCI at that time wanted to get more, I think, rural and other smaller places involved in research. And they put out an RFA to form like regional cooperative groups. And we formed the Piedmont Oncology Association, the POA. We actually did well for a few years. We wrote some really good studies. We got one or two New England Journal articles. I worked with all the people, mainly in the community, community docs who would go on, and put people on the protocol. I mean, I looked at all the X-rays and scans in a lot of these patients myself as part of the studies we did. And it turned out to be a wonderful organization and it's still run today by Bayard Powell, who is one of our terrific fellows who's the head of Oncology at Wake Forest.  But after a while, we just couldn't compete with CALGB, of which I was a member of also, and ECOG and SWOG, even North Central Group, which was kind of formed in a similar venue, eventually merged. So we did a wonderful job for a while but the truth is we just didn't have the manpower to write studies for every disease site. So eventually we kind of petered out as a clinical trials group. But it's been maintained for educational programs and it's really served as a good resource for a lot of good education for the community oncologists who give most of the care in this country in the state. So it's been good. I think Pat kind of exceeded us with HOG, the Hoosier Oncology Group, which was in a similar vein. But it was a great experience and it was all Dr. Spurr, who thought of doing this and built it.  Dave Johnson: Certainly, it was inspirational in many people in and outside of Wake Forest. So with such an idyllic life, what in the world possessed you to move north to Vermont?  Dr. Hyman Muss: Well, you get this urgent life. You want to be a leader, you want to be a chief. Now, I tell younger people, if they love what they do, don't do it. So I got a wonderful opportunity at the University of Vermont to go up there and be Head of HemOnc. Chief of Medicine was a terrific guy, Burt Sobel. The university at that time, at one time it had a wonderful Oncology program. It had a federally funded cancer center with Irwin Krakoff and Jerry Yates, two other iconic guys. I don't know what the politics were but it had lost a tremendous amount of faculty, especially its clinical faculty, and they needed to rebuild it. And I went up and I thought, “Well, I'm in my 50s. This is going to be a great opportunity. If I don't do it now, I may never get the chance.” So I went up there and actually, it was a great opportunity. We hired terrific people. We got CALGB and we participated. We had actually a very good accrual for a small place and we had a very small but very effective cancer center. So it turned out to be a really good experience.  I worked with wonderful people. I recruited some wonderful people. But over time, the issues of the business of medicine, all the issues that happened, I'm saying I'm kind of losing my focus on clinical care and clinical trials, which I love to do. I don't need to tell either of you. I mean, Dave, you've been chief and department chair and Pat has run cancer centers. After a while, the administrative tasks just were so overwhelming and I didn't enjoy them, that I said, “I've got to get back in some type of more clinical focus.” And that's when I decided to look around and fortunately found what's turned out to be a dream job at UNC.  But it was a time of life. Maybe my ego got in the way of my logic. I don't regret it. I met and I think we rebuilt a wonderful clinical program. But you realize some of the resources of big places with-  we never had the research infrastructure to hire a lot of people and get big programs going on and great translational programs, just didn't have the funding. But it was great, and I have no regrets. And I learned how to tolerate the cold weather. And I have a lovely daughter, Sarah, who still lives up there. So we get back occasionally. And I've kept up with a lot of the people there. There are some wonderful people at UVM.  Pat Loehrer: From there, though, you were pulled down to North Carolina, where you've, again, built an incredible breast program there is outstanding. But you've created a Geriatric Oncology program, one of the first geriatric fellowships in oncology in the country. So tell us a little bit about that and what you feel may be your legacy is there at North Carolina.  Dr. Hyman Muss: Well, I had the opportunity over the years when I was at Wake, really, I got to know Shelley Earp, who's our cancer center director. I think maybe you were close to him, Pat. The longest surviving cancer center director on the planet, or among them. And we were good friends. And North Carolina's legislature actually gave the University of North Carolina substantial funding to improve cancer care in North Carolina, not just research. And so I had talked with Shelley about maybe moving, and because of the generosity of the state, really, he was able to really get me going, start a Geriatric Oncology program. And what I wanted to do was develop trials. As Dave says, I built a registry in 2009 here for older cancer patients using geriatric assessment. I have 2000 patients, which has been a resource for all types of faculty and fellows, and students to write papers. But I was able, with the support, to do things like this right from the get-go. And plus, I joined probably one of the best breast groups on the planet with Lisa Carey and Chuck Perou, and Larry, terrific people, Claire Dees. I had great luck in doing this, so I was able to really focus, get great support from my colleagues to build studies focusing on older people.  And then I had the great fortune of meeting Ned Sharpless, our prior NCI director. And Ned is one of the world's great aging biologists. And I don't mean aging as an adjective, he's really been a master on why we age, the biology of aging, cell senescence. So Ned taught me all about cell senescence and the mechanisms, especially the gene expression p16, which is like our own CDK inhibitor. And so I was able to start using his lab, collect samples, treat people with chemotherapy, follow them off with geriatric assessment. It was a great opportunity to do that here, and we got a lot of studies going and we showed what the pediatricians have known for years, that chemotherapy dramatically ages people, not just children, but adults. But it also allowed me to work with my colleagues in lymphoma and lung cancer to do little studies along the way.  And we eventually then built a T32 program. We got a T32, which we're kind of completing now our first five years to train oncology specialists in geriatrics. So the way we do it is they can be surgical oncologists, GU, we had a GYN oncologist, medical. With their HemOnc training, they do a year where they work with the geriatricians, so they go on geriatric inpatient service for a month and they really learn about older people. And part of it is a project. So we've been able to build that and develop a lot of programs with that. And I should say we've been very successful with mentorship and with ASCO support for things like YIAs, the late and great Arti Hurria, who absolutely an amazing woman. Some of her legacy at ASCO, the YIAs, and things. We've been successful in applying for some. So we've been able to build a whole spectrum of med and hematologists. We have an interest in Myeloma and AML focusing on older people. We've been able to build a whole team approach, including translational projects related to older people. And it's just been a great opportunity, and hopefully, my legacy here will be, too, and I'm working on it.  We have a wonderful guy, Bill Wood, who is very effective and has built this incredible coaching program to continue this legacy. Like many of us in this field, we are bothered because we all know the stats, we all know that first slide of the demographics of cancer, and yet it's been very hard in our culture to provide a lot of the services and build the clinical trials we need to best care for older people. It's still a major problem in this country. So as I cut back on my clinical care, I'm going to still advocate to try to improve the care of older people. Do geriatric assessment, build it into your clinical programs, get your hospitals to support you, convince them, build business plans, et cetera. And hopefully, that'll be my ultimate legacy, that we've made greater awareness of the older people, other than the usual stats, and we're really trying to care for them in a much more global sense, in a much more holistic sense than we've done. I hope we'll be successful. It's a slow haul, but we've got lots of great young people coming up through the pipelines, ASCO has been a great player in this. Many of you know people like Supriya Mohile and William Dale, Heidi Klepin, people, the next generation that's going to keep building this. So I hope the legacy will be that we get more buy-in, more interest, more trained people in other oncology-related subspecialties RadOnc, SurgOnc that will really focus on the care of older people. Dave Johnson: I don't think there's any doubt that that will be a part of your legacy Hy, but I think your legacy will be much broader than the world of geriatric oncology. Your mentorship leadership, your clinical skills, your educational capabilities, all of that will certainly last for many, many years in the future.  Well, I don't want to bring up a touchy topic, but you yourself are geriatric and we're wondering what your plans are for your semi-retirement. I recognize you're not retiring, but what do you like to do outside of medicine? Dr. Hyman Muss: I'll tell everybody who's interested in hearing this. On Tuesday, I had my 80th birthday.  Dave Johnson: Congratulations.  Dr. Hyman Muss: And I think I'm one of the most blessed guys. I'm pretty healthy. I married up -  my wife Loretta, who both of you, Pat Loehrer and Dave Johnson, know well.  Dave Johnson: Yeah, you definitely married up.  Dr. Hyman Muss: Yes. It's really carried me most of my life. She's great and so she flew up our three kids and we celebrated and I'm very fortunate. I have the enthusiasm and strength to do more clinical medicine. But I think the time has come for me to cut back my clinical medicine, so I'm going to do that in June. The hardest thing I've done is say goodbye to so many of my patients here.  We've been blessed. We have a lovely family. We're pretty close. I'm never bored, probably you two know well, I love to do things like fishing, outdoor stuff. I've really gotten into woodworking, so I'm not going to be bored. But there will be a small piece out of me when I walk out of that clinic in June. I know that and my two close psychiatry friends think it's going to really be a hard fall, but I don't think so. I still have some grants. In fact, I'm working with a fellow in City of Hope, Mina Sedrak, who's been very involved in ASCO, too. We are hoping to get an R01 looking at senolytic drugs that may prevent aging, and exercise in older women with breast cancer to see if we can reverse the trends of chemo. So my brain is still on that stuff, but the clinical care is going to be tough.  I had a note and for some reason, we talked about so many things. I wanted to mention that one of my great opportunities was joining the CALGB and then the Alliance and getting the support of Dr. Schilsky, Rich Schilsky, who's been one of the icons of ASCO to build cancer in the elderly working group with Dr. Harvey Cohen at Duke. And Harvey is one of the world's great geriatricians. And using that to get studies done, to incorporate studies with Arti Hurria on geriatric assessment, and really have it as a place where a lot of younger investigators could get started on a career in geriatric oncology. And that was really a great opportunity. It was kept on by Dr. Bertagnolli, who now is our NCI director, and I think was really the first group to really give good support for this. Dave Johnson: So we want to thank you very much for being our guest today.  We also want to thank our listeners of Oncology, Etc. This is an ASCO Educational Podcast where we talk about oncology medicine and much more. So if any of our listeners have an idea or a guest they would like for us to interview, please email us at education@asco.org. To stay up to date with the latest episodes and explore other educational content, visit ASCO's website at education.asco.org.   Thanks again for being our guest, Hy.  Dr. Hyman Muss: My pleasure. Thank you so much. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss the CLEAR study in renal cell carcinoma, a new exploratory analysis combining the TheraP and VISION trials in metastatic urothelial cancer, and compelling advances in prostate cancer and across GU oncology in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host for the ASCO Daily News Podcast today. I'm the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to welcome Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical director of the Genitourinary Cancers Program at the Inova Schar Cancer Institute in Virginia.   Today, we'll be discussing some key abstracts in GU oncology that will be featured at the 2023 ASCO Annual Meeting.  Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcript at asco.orgDNpod.   Jeanny, it's great to have you on the podcast today. Dr. Jeanny Aragon-Ching: Thank you so much, Dr. Agarwal, for having me. Dr. Neeraj Agarwal: Jeanny, let's begin with Abstract 4502 regarding long-term updated results on the CLEAR study. The abstract reports the final, prespecified overall survival analysis of the CLEAR trial, a four-year follow-up of lenvatinib plus pembrolizumab versus sunitinib in patients with advanced renal cell carcinoma. Dr. Jeanny Aragon-Ching: Yes, I would be happy to. So, just as a reminder, the combination of lenvatinib and pembrolizumab was initially approved by the FDA in August 2021 for first-line treatment of adult patients with advanced renal cell carcinoma. So, this was based on significant benefits that were seen in progression-free survival, which was a primary endpoint, but also showed improvement in the overall response rates compared with sunitinib in first-line advanced renal cell carcinoma.   So this abstract reports on longer-term follow-up now at a median of 49.8 months, and PFS favored the combination lenvatinib and pembrolizumab compared to sunitinib across all MSKCC risk groups, and PFS benefit versus lenvatinib and pembro compared to sunitinib was maintained with a hazard ratio of 0.47. And even overall survival was also maintained with the combination with a hazard ratio of 0.79, and the overall survival favored the combination across all risk groups. If we look at the CR rate, it was 18.3% for the combination compared to 4.8% with sunitinib, unless patients in the combination arm received subsequent anticancer therapies, and that's intuitive. And the PFS2 was also longer with the combination at 43 months compared to 26 months. Now, it is important to note that grade III or more treatment-related adverse events did occur in about 74% of the patients in the combination of lenvatinib and pembro, compared to 60.3% in patients with sunitinib. Dr. Neeraj Agarwal: Jeanny, this is good news. So the main message from the abstract is that sustained results from this combination of lenvatinib plus pembrolizumab are being seen even after a longer follow-up of more than four years.  Dr. Jeanny Aragon-Ching: Yes, I agree. So now, moving on, Neeraj, to a different setting in the RCC space, let's look at Abstract 4519, which is titled “Efficacy of First-line Immunotherapy-based Regimens in Patients with Sarcomatoid and/or Rhabdoid Metastatic Non-Clear Cell RCC: Results from the IMDC,” which will be discussed by Dr. Chris Labaki. So, Neeraj, based on this abstract, can you tell us a little bit more about the impact of these adverse pathologic risk features in non-clear cell RCC?  Dr. Neeraj Agarwal: Of course. So, using real-world patient data, the IMDC investigators compared the outcomes of patients with metastatic non-clear cell RCC who were treated with immunotherapy-based combination regimens versus those who were treated with VEGF-TKIs alone. They also assessed the impact of sarcomatoid and rhabdoid features on response to IO-based combinations versus VEGF-TKIs. Of 103 patients with metastatic non-clear cell RCC who had rhabdoid or sarcomatoid features, 32% of patients were treated with immunotherapy-based combinations.   After adjusting for confounding factors, the authors show that those treated with a combination of two immune checkpoint inhibitors or an immune checkpoint inhibitor with a VEGF-TKI combination had significantly improved overall survival, which was not reached in the immunotherapy combination group versus seven months within the VEGF-TKI group. Time to treatment failure and objective responses were also prolonged, significantly higher, and better in the immunotherapy groups compared with patients who were treated with VEGF-TKIs alone. Interestingly, if you look at those 430 patients with metastatic non-clear cell RCC who did not have sarcomatoid or rhabdoid features, they didn't seem to benefit with immunotherapy-based combinations.  Dr. Jeanny Aragon-Ching: This is an exciting update, Neeraj. What are the key takeaways from this abstract? Dr. Neeraj Agarwal: So the main takeaway is if you see a patient with advanced non-clear cell RCC who has sarcomatoid and rhabdoid features, there appears to be a rather substantial and selective benefit with IO-based combinations. And in this context, I would like to highlight the ongoing SWOG 2200 trial also known as PAPMET2 trial, which is comparing the combination of cabozantinib plus atezolizumab. So immuno-therapy-based combinations versus cabozantinib alone in advanced papillary renal cell carcinoma setting. So this trial is being led by Dr. Benjamin Maughan and Dr. Monty Pal. And I like to encourage our listeners to consider referring their patients for involvement in this federally funded trial so that we can validate the data from this retrospective study in a prospective way. So, Jeanny, let's now move on to another important disease type which is urothelial carcinoma. There is a very recent accelerated FDA approval of the drug combination of enfortumab vedotin and pembrolizumab for cisplatin-ineligible metastatic urothelial carcinoma patients. This is Abstract 4505, which is being presented by Dr. Shilpa Gupta and colleagues. Can you please tell us more about this update? Dr. Jeanny Aragon-Ching: Yeah, absolutely. So, as you mentioned, Neeraj, the FDA just granted accelerated approval in April 2023 for this combination of enfortumab vedotin or EV, which is and ADC, antibody drug conjugate against nectin-4 and the PD-1 inhibitor pembroluzimab. So it's a combination for patients with locally advanced or metastatic urothelial carcinoma who are considered cisplatin ineligible. So this is nearly a four-year follow-up.   So as a reminder, this was a phase 1b/2 trial that included 45 patients and it had a primary endpoint of safety and tolerability although the key secondary endpoints included confirmed overall responses, duration of response, progression-free survival, and the resist criteria was investigated via investigator and BICRs which is in a blinded independent central review. Even overall survival was a key secondary endpoint.  So, the bottom line was the confirmed overall response by BICR was 73.3%, the disease control rate was about 84%, and the CR rate was 15.6% with a PFS of close to 13 months, and a 12-month overall survival rate of 83%. However, it is important to cite that there were treatment-related adverse events including skin reactions in 66%, neuropathy occurred in 62%, and ocular disorders in 40%. And there was a little bit of pneumonitis in close to 9%, colitis, and hypothyroidism, so there are side effects to watch out for.  Dr. Neeraj Agarwal: So, Jeanny this is great. What is the key takeaway from this trial?  Dr. Jeanny Aragon-Ching: So I think the most important thing is we now have a new combination of EV and pembro which shows very promising responses and survival in part which led to the FDA accelerated approval in the cisplatin-ineligible population of patients. However, we must note that the phase 3 trial of EV302 will ultimately establish which approach is really beneficial for all of our cisplatin-ineligible patients, either a carboplatin-based chemotherapy regimen or a non-platinum-based regimen such as EV and pembro. Dr. Neeraj Agarwal: Thanks Jeanny, would you like to discuss any other study in the bladder cancer space? Dr. Jeanny Aragon-Ching: Absolutely. I think Abstract 4508 from Dr. Seth Lerner and colleagues will be very relevant to our colleagues. This abstract is SWOG S1011, which is a phase 3 surgical trial to evaluate the benefit of a standard versus an extended lymphadenectomy performed at the time of radical cystectomy for muscle-invasive bladder cancer.  Dr. Neeraj Agarwal: Yes. So this trial, as you said, is an important trial which randomized in a one-on-one fashion 618 patients with muscle-invasive bladder cancer undergoing radical cystectomy, and these patients were randomized to either standard lymph node dissection or an extended lymph node dissection. And standard lymph node dissection included, as we know, external and internal iliac and operative lymph node. The extended lymph node dissection included lymph nodes up to aortic bifurcation which included common iliac, presciatic, and presacral lymph nodes. At a median follow-up of approximately 6 years, there was no disease-free survival or overall survival benefit in patients undergoing an extended lymph node dissection compared to standard lymph node dissection. And extended lymph node dissection was also associated with greater morbidity and preoperative mortality. Dr. Jeanny Aragon-Ching: Very interesting data, Neeraj. So these results, I think, will be very useful for a lot of our surgical colleagues in both academia and the community who may still be inclined to perform extended lymphadenectomy during cystectomy. This study shows that it's actually not necessary. Dr. Neeraj Agarwal: Absolutely. So now let's move on to another disease type, which is very important - prostate cancer. There are several practice-informing abstracts that are worthwhile discussing. The first of these involves Abstract 5002, which looks at the impact of the PSA nadir as a prognostic factor after radiation therapy for localized prostate cancer, which will be presented by Dr. Praful Ravi and  colleagues. Jeannie, can you please tell us more about this abstract? Dr. Jeanny Aragon-Ching: Yeah, definitely. So this abstract, as you mentioned, Neeraj, is a prognostic impact of PSA nadir of more than or equal to 0.1 nanogram per ml within six months after completion of radiotherapy for localized prostate cancer - an individual patient data analysis of randomized trials from the ICECaP Collaborative. Basically, it refers to an attempt to evaluate early surrogate measures to predict for long term outcomes such as prostate cancer-specific survival, metastases-free survival, and overall survival. So they looked at a big registry from the ICECaP collaboration that included 10,415 patients across 16 randomized controlled trials. And those men underwent treatment for intermediate risk and high risk prostate cancer treated with either radiation therapy alone in about a quarter of patients, or they got RT with short-term ADT in about 58% of patients, and 17% of them got RT with long-term ADT.  So, after a median follow-up of ten years, what they found was, if you had a PSA nadir that is over or equal to 0.1 nanogram per ml within six months after completion of radiation therapy, it was associated with worse prostate cancer-specific survival, metastases-free survival, and overall survival. For instance, the five-year metastases-free survival for those who achieved a PSA nadir of less than 0.1 was 91% compared to those who did not, which was 79%. Therefore, they concluded that if you achieve a bad PSA of 0.1 or above within six months after you completed radiation, you had worse outcomes.  Dr. Neeraj Agarwal: Jeanny, what is the key takeaway message from this study? Dr. Jeanny Aragon-Ching: The key takeaway from this ICECaP analysis is that this information would be very important to augment a signal-seeking endpoint, especially for clinical trial development, so that we can develop further strategies to de-escalate for those who don't need systemic intensification or therapy intensification versus escalation for those who really do. Dr. Neeraj Agarwal: So, my radiation oncology colleagues need to watch out for those patients who do not achieve a PSA of less than 0.1 nanogram per ml within the first six months of finishing radiation therapy. Very interesting data.  Dr. Jeanny Aragon-Ching: Yes, absolutely. So. Neeraj another important abstract for our fellow clinicians, switching gears a little bit now, is Abstract 5011, which is titled “Do Bone Scans Overstage Disease Compared to PSMA PET?” This was an international, multicenter retrospective study with blinded, independent readers. Can you tell us more about this abstract? Dr. Neeraj Agarwal: Yes, a relatively small retrospective study, but still pertinent to our practice. So I'll summarize it. This study by Dr. Wolfgang Fendler and colleagues evaluated the ability of bone scans to detect osseous metastasis using PSMA PET scan as a reference standard. So in this multicenter retrospective study, 167 patients were included, of which 77 patients were at the initial staging of prostate cancer, 60 had biochemical recurrence after definitive therapy, and 30 patients had CRPC or castor-resistant disease.  These patients had been imaged with a bone scan and a PSMA PET scan within 100 days. And in all patients, the positive predictive value, negative predictive value and specificity for bone scan were evaluated at different time points. They had bone scan and PSMA PET scan and both were compared. And what they found was interesting. All these three values - positive predictive value, negative predictive value, and specificity for bone scan were 0.73, 0.82 and 0.82 in all patients, and in initial staging, it was even lower at 0.43 and 0.94 and 0.80.  So, without getting into too much detail regarding these numbers, I want to highlight the most important part of the study, that at the initial staging, 57% patients who had a positive bone scan had false positive bone scans. The interreader agreement for bone disease was actually moderate for bone scans and quite substantial for the PSMA PET scan.  Dr. Jeanny Aragon-Ching: So, Neeraj, what do you think is the key takeaway message here for our audience?   Dr. Neeraj Agarwal: The key takeaway message is that positive predictive value of bone scan was low in prostate cancer patients at initial staging, with the majority of positive bone scans being false positive. This suggests that a large proportion of patients which we consider to have low-volume metastatic disease by bone scan actually have localized disease. So in the newly diagnosed patients with prostate cancer, patients should ideally have a PSMA PET scan to rule out metastatic disease.   So, let's move on to another abstract I would like to discuss, which has important implications in treatment, especially now that lutetium 177 is approved, but frankly not available widely. Dr. Jeanny Aragon-Ching: Yeah, that's actually very timely. So the abstract you're referring to is 5045, which is being presented by Dr. Yu Yang Sun and colleagues entitled “Effects of Lutetium PSMA 617 on Overall Survival in TheraP Versus VISION Randomized Trials: An Exploratory Analysis.” So, Neeraj, can you tell us more about the relevance of this exploratory analysis? Dr. Neeraj Agarwal: Definitely. In this abstract, Dr. Yang Sun and colleagues assess the effect of lutetium PSMA on overall survival in two different trials, TheraP and VISION trials. So, just for our listeners' recollection, the phase 2 TheraP trial compared lutetium PSMA and cabazitaxel in patients with mCRPC who had progression on docetaxel and had significant PSMA avidity on gallium PSMA pet scan, which was defined as a minimum uptake of SUV max of 20 at least one site of disease and SUV max of more than 10 at all sites of measurable disease.  In this trial, 20 of 101 patients in the cabazitaxel arm crossed over to lutetium PSMA, and 32 of 99 patients in the lutetium PSMA arm crossed over to cabazitaxel. In the VISION trial, patients with mCRPC who previously progressed on at least one ARPI and one taxane-based therapy and had a positive gallium PSMA scan, and here, positivity was not stringently pre-specified as it was done in the context of TheraP trial. So, positive gallium pet scans were randomly assigned in two to one fashion to receive either lutetium PSMA plus best supportive care or standard of care versus standard of care.  And I'd like to highlight that the standard of care comprised ARPIs and bone protecting agents and these patients were not allowed to have cytotoxic chemotherapy such as cabazitaxel in the standard of care arm. Now, overall survival was similar in the lutetium PSMA group regardless of whether they got lutetium PSMA in the VISION trial or TheraP trial. There was no difference in overall survival with lutetium in the lutetium arms of VISION and TheraP trial with a hazard ratio of 0.92. And there was no difference in the overall survival between the lutetium PSMA and the cabazitaxel group in the TheraP trial if you use counterfactual analysis, assuming crossover had not occurred. So, quite interesting in my view. Dr. Jeanny Aragon-Ching: Yeah, thanks Neeraj for that wonderful synopsis and discussion. So, what is the key take home message then? Dr. Neeraj Agarwal: The main message in this new exploratory analysis, which combined both the TheraP and VISION trials, is that lutetium PSMA and cabazitaxel seem to be associated with similar overall survival benefit in these highly selected patients with PSMA positivity. Additionally, the difference in the observed effect of lutetium PSMA and overall survival in the TheraP and VISION trials may be actually better explained by the use of different treatments in the respective control arms of these trials. And these results, in my view, are quite pertinent for those patients and providers who do not have access to lutetium-177 therapy.  Let's go to another abstract that is currently relevant to our practice, given many patients with advanced prostate cancer who have concurrent diabetes; I'm talking about Abstract 5066. Jeanny, can you please tell us more about this abstract?  Dr. Jeanny Aragon-Ching: Certainly, Neeraj. So this abstract will be presented by Dr. Amy Shaver and colleagues. So it's also very relevant, since many men who are diagnosed with prostate cancer frequently also have a concomitant diagnosis of type 2 diabetes mellitus. So, this was a SEER-Medicare population database analysis that looked at men who were treated with either abiraterone or enzalutamide and also had concomitant diagnosis of type 2 diabetes mellitus (DM). And they were identified using ICD-9 and ICD-10 codes and they were all tied in to acute care utilization. So they looked at CMS research data codes and ER hospitalization visits six months after treatment initiation was recorded. So all in all, they took a sample of 11,163 men, of whom close to 62% were treated with abiraterone and about 38% were treated with enzalutamide.  So, of these, about 27% of them had type 2 DM, of whom 59% received abiraterone and about 41% had enzalutamide. So, the bottom line is, compared to those without diabetes mellitus, those who had type 2 diabetes had worse acute care utilization, which was 43% higher than those who got abiraterone compared to enzalutamide, and also had higher overall mortality. Therefore, the bottom line is, having type 2 diabetes mellitus, unfortunately, portends worse outcomes in men with prostate cancer, so careful attention needs to be paid to those who are starting out already with such comorbidities. So Neeraj, any final thoughts you have regarding this abstract and overall before we wrap up on the podcast today?  Dr. Neeraj Agarwal: Absolutely. So it looks like, based on this very important pertinent Abstract 5066, which talks about the impact of diabetes on our patients, I think we need to be very watchful regarding the impact of diabetes on our patients who are being treated with abiraterone or enzalutamide, especially drugs which are known to make the metabolic syndrome and diabetes worse. I think close monitoring and close attention to control of diabetes is very important. So with that, I would urge the listeners to come and join us at the Annual Meeting, not only to celebrate these successes but also to help disseminate this cutting-edge data to practitioners and maximize the benefit to our patients across the globe.   And thank you to our listeners for joining us today. You will find links to the abstracts we discussed today on the transcript of this episode. Finally, if you value the insights that you hear on our ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast.  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:  Dr. Neeraj Agarwal @neerajaiims Dr. Jeanny Aragon-Ching Follow ASCO on social media:   @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn     Disclosures:  Dr. Neeraj Agarwal:   Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences  Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas  Dr. Jeanny Aragon-Ching: Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant,  Exelixis, Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics.

There is ongoing progress in the urothelial carcinoma treatment landscape, but after radical resection, what adjuvant options are there for your patient? Special guest Shilpa Gupta, MD, joins us to discuss the various ways to individually approach the adjuvant treatment setting for your patients with radically resected urothelial carcinoma along with their multidisciplinary care team. Dr. Gupta is a genitourinary oncologist at the Cleveland Clinic. She has led several investigator-initiated trials in genitourinary cancers, help leadership roles within National Cancer Institute Trials, and is the chair of the Alliance-led phase 3 trial in bladder cancer, co-chair of the Southwest Chemotherapy Study Group (SWOG) S1206 trial in prostate cancer and SWOG champion of the Alliance A031701 trial in bladder cancer.Learn more about an adjuvant treatment option for patients with urothelial carcinoma.https://www.opdivohcp.com/efficacy/uc/adjuvantINDICATIONOPDIVO® (nivolumab), as a single agent, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.IMPORTANT SAFETY INFORMATIONSevere and Fatal Immune-Mediated Adverse ReactionsImmune-mediated adverse reactions listed herein may not include all possible severe and fatal immune- mediated adverse reactions.Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO. Early identification and management are essential to ensure safe use of OPDIVO. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment with OPDIVO. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.Immune-Mediated PneumonitisOPDIVO can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (

Host Dr. John Sweetenham and guests Dr. Karen Reckamp and Dr. Harpreet Singh discuss the S2302 Pragmatica-Lung trial, a streamlined, real-world clinical trial that is poised to simplify and transform the entire clinical trials model as we know it. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast.  Today, we are going to be discussing a streamlined, real-world clinical trial from the Southwest Oncology Group (SWOG), which is S2302, also known as the Pragmatica-Lung trial. This study is poised to simplify and transform the entire clinical trials model as we know it. Joining me for this discussion is the trial's lead investigator, Dr. Karen Reckamp. Dr. Reckamp is a clinical professor, director of the Division of Medical Oncology, and associate director for clinical research at Cedars-Sinai Samuel Oschin Cancer Center. I'm also delighted to welcome Dr. Harpreet Singh, the director of 1 of 3 divisions of oncology at the U.S. Food and Drug Administration. She will discuss the FDA's views on streamlining clinical trials to reach more representative groups of patients and will also more broadly address some of the key questions that regulators consider when deciding on whether real-world data can substitute for randomized controlled trials. Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/DNpod. Dr. Reckamp and Dr. Singh, it's a great pleasure to have you on the podcast today. Dr. Karen Reckamp: Thank you for having us. Dr. John Sweetenham: Dr. Reckamp, I'm going to start with you if I may and ask if you could give us some background on S2302, the Pragmatica-Lung trial for non-small cell lung cancer. Dr. Karen Reckamp: Sure. The Pragmatica-Lung trial really started with the sub-study from Lung-MAP, which was called S1800A, and it was a randomized phase 2 trial that evaluated pembrolizumab and ramucirumab versus standard of care for patients who had previously received chemotherapy and immunotherapy with advanced non-small cell lung cancer and had had disease progression. And in this phase 2 trial, we found that there was an improvement in overall survival with a hazard ratio of 0.69% and survival of 14.5 months for pembrolizumab and ramucirumab, and 11.6 months for standard of care. And with that, we had again a randomized phase 2 trial, but the study was small. And so, trying to think about how to move this to the next level to get phase 3 data, we started thinking about how to do this in a way that would reduce the timelines and potentially move this treatment to patients more quickly than standard registrational, randomized phase 3 trials. And that's kind of where S2302 and Pragmatica-Lung started. Dr. John Sweetenham: So, can you tell us in a little more detail how the dramatically streamlined pragmatic design of this trial is going to hopefully simplify trial design and trial conduct in the future beyond non-small cell lung cancer?  Dr. Karen Reckamp: I think the important piece of this—and we have Dr. Singh here to speak to the FDA part—but this has been a partnership with the FDA and CTEP [NCI's Cancer Therapy Evaluation Program]. Really, our goal was to try and find a way to run trials in a more streamlined way. One of our colleagues at CTEP during this process said, “If this is not making you uncomfortable, then you're not doing it right.” So, the first thing we did was kind of lean into the discomfort because for those of us who have been writing trials and putting trials together for the last 20-plus years, this is dramatically different. And we're really looking at one question, and that is overall survival. We're trying to validate the overall survival we saw in S1800A. And with that, we stripped away all the unnecessary data collection that comes along with other types of registrational issues that come with randomized phase 3 trials. And then, we also looked at patient burden and really opened it up. So, again, pragmatically, making this practical, allowing investigators to be empowered to treat patients how they normally would in their own practice. And so, moving forward, again, for types of trials where we have drugs whose toxicity profiles are well known, they're used in practice but using novel combinations for a subset of patients who have limited treatment options available, this could really change the paradigm moving forward for these types of trials in multiple diseases. Dr. John Sweetenham: Yeah, thanks. And in addition to simplifying the trial design, obviously, one of the goals here is to have a study population which is more representative of the patients who are seen typically in community practice. Hopefully, we'll overcome some of the known disparities that we see in clinical trial accrual. Could you speak just a little bit to how the study design and the organization of the study helps to achieve that? Dr. Karen Reckamp: So, I think it's on several levels, but we are looking to allow this to be more generalizable and allow a more diverse population into this study. First, by again stripping down the eligibility criteria to only the absolute essential criteria for understanding our scientific question. And so, we don't require imaging studies to be uploaded or presented. If the patient has progression, it's based on the investigator's opinion. And so, we don't need to be searching for outside scans or things like that. We don't have tissue requirements, and we don't even actually have lab requirements. If this is a patient, you would treat your standard of care practice with the standard of care regimens; those are the labs that you do. So, it's all based on standard of care. So, by doing this based on standard of care, it really allows almost any patient to enroll. And then we have outreach. We have our DEI group and our community practices very well engaged to make sure that we have broad reach. Having this open through NCTN [NCI's National Clinical Trials Network] will make sure that we get this to multiple practices in far-reaching parts across the United States. Dr. John Sweetenham: Yeah, I think that's excellent. And you've already alluded to the fact that the data collection requirements for the study are going to be kind of pared down to the absolute minimum and that's going to include, I believe, toxicity reporting as well. So, can you comment a little bit on that and, specifically, what your plans are for reporting toxicity in this trial? Dr. Karen Reckamp: Yes, you're correct. This is significantly pared down from what we're used to doing. And so, most clinical trial offices are struggling with staffing and making sure that their patients have enough staff and that they have enough staff to get patients onto trials efficiently, and then getting the data in is always a challenge for sites. So, we have really, again, working with our partners, working with the FDA, and with CTEP, we have minimized what we are going to collect on patients. So, we're collecting survival and vital status on patients. We are collecting the background standard information that we collect on kind of prior therapies, and we are collecting only unexpected grade 3 and higher adverse events. And so, thinking about these drugs—ramucirumab and pembrolizumab—we know how these drugs work, we know the toxicity profile, we're using them in combinations and single agents in multiple tumor types. And so, thinking about most of the immune-related adverse events wouldn't even be reportable because they're expected. And so, a large number of data that is normally collected would not be collected here. And, as noted, we don't collect scans, we don't collect labs, we're not collecting con-meds, start and stop dates. A lot of that burden of data collection, but also data auditing and queries, goes away. It should be a significantly easier trial to perform by sites.  Dr. John Sweetenham: And can you just update us on the status of the trial right now? Dr. Karen Reckamp: We're in the process of pre-activation, and so, if you're an NCTN site, you can actually go in and do some pre-training and take a look at the draft protocol. And we are anticipating approval sometime in early March. Dr. John Sweetenham: Great. Congratulations on getting this trial launched and underway because I know that the word “groundbreaking” is used a lot, but I think that, obviously, if this trial proves to be the success that it looks like it will be, then it's going to have, I think, major implications for study design in the future. And that's going to lead me to ask a couple of questions to Dr. Singh. And the first one of those is the FDA's decision to consider data from a simplified pragmatic trial design like this, which uses more limited clinical information, is really kind of almost revolutionary. And could you comment a little on this from the FDA perspective and how you think it's going to influence the future of clinical trials and the future of cross-trials? Dr. Harpreet Singh: Well, thanks so much for the question, and thanks for having me. I want to push back on that just a little bit because I think, for what it's worth, the FDA has been advocating for trial efficiencies in oncology for many years. And, of course, as you know, our current commissioner, Dr. Robert Califf, is very vested in this concept. And certainly, the idea of pragmatic trial has been there in the field of cardiology for some time.  In terms of this trial, in particular, in coming to oncology, I do think actually putting pen to paper and drafting the protocol, which we did really in cohesion with SWOG and many calls with Karen and others who were a part of this, that collaborative piece, I think, is groundbreaking because what we saw here was a great deal of discomfort, actually around everything that we were stripping down. We sensed a lot of discomfort in terms of including various, like you mentioned, safety issues, safety reporting not being perhaps as rigorous as we're accustomed to seeing at the FDA. And certainly, investigators are accustomed to collecting other endpoints besides overall survival, like time to progression, but the real-world version of that, or time to next therapy. And so, one very difficult lesson that I've had to learn, and we've had to learn, is that you have to really learn to say no to some very interesting trial design elements that are not essential to the big question here, which is, does this combination regimen offer an improvement in survival over the control? So, while I do think the actual organizational and structural piece of this, now that it's actually stood up, is groundbreaking, I think that the idea of pragmatic trials and incorporating clinical care into the idea of answering a clinical question as opposed to the traditional randomized clinical trial is a concept that's been around. I'm just thrilled to see it actually occur in this very, I think, ideal setting for patients with lung cancer. Dr. John Sweetenham: Yeah, absolutely. I want to broaden the scope of what we're discussing here just a little bit, perhaps to talk a little more about the “real world” and “real-world data.” More real-world data is being considered in regulatory decision-making. And one of the questions I have, again, from an FDA perspective, is that everyone still, I think, regards randomized controlled trials as the gold standard for evaluating efficacy if not effectiveness, of various interventions. What are the key questions that you consider when deciding whether any kind of real-world data analysis is a good substitute for a randomized controlled trial?  Dr. Harpreet Singh: Well, thank you for the question about how FDA considers real-world data when we consider this to be appropriate. There are many nuances to this. So, first of all, what is real-world data? And there's actually a distinction between real-world data, which is just simply a source used in observational studies traditionally. But real-world data is not specifically a trial design; it's just data. Whereas real-world evidence, which is evaluating the benefits and risks which are derived from real-world data, may come from things like electronic health records. It's not either-or. So, for example, in a pragmatic trial, you could use a blended approach where you have some components of real-world data or real-world practice, which we may consider kind of part of real-world data, but while retaining some elements of randomized control trials. So, I think when FDA considers real-world evidence, so I'll say that instead of data, it usually would be a source like a very high-quality registry or data obtained through a very well-designed observational study. And this would be in settings of perhaps super rare diseases in which randomization is either not feasible or, in some cases, where you may have preliminary data which suggests that randomization is not ethical. But we agree with the general idea that the gold standard is randomization.  And that's what I love about this pragmatic trial, is that you are retaining the benefit of randomization while bringing pragmatic elements in, bringing the trial to patients and really incorporating clinical practice into the trial, as opposed to the reverse, where you're having patients enrolled on a traditional trial where the visits are outside of routine. Dr. John Sweetenham: Thanks for drawing that distinction between real-world evidence and real-world data because I think the two expressions are sometimes used a little carelessly, as maybe I just did. But certainly, one of the things that I've observed over the last several years since we started to incorporate real-world data or real-world evidence into our kind of oncology lexicon is that real-world data has been used in a fairly relaxed, let's say, way and certainly any relatively small series which has been registry based or retrospective, there's been a tendency to use this term called real-world data, which personally, I've certainly seen applied to patients who are undergoing very intensive therapies such as CAR T. And certainly, when I look at the patient characteristics in those elements of so-called real-world data, it's a long way from the real world that I'm familiar with in my own practice. And so, I do think that the term has been used very loosely. And your point about real-world evidence is an important one, I think. People are still questioning whether real-world evidence in oncology is truly valid. And I think to some extent, you've already answered that question.  Do you think that there are mistakes and pitfalls that investigators can avoid when they're looking at real-world evidence? Dr. Karen Reckamp: Sure. I mean, I think the first point of clarification is, are we looking at this evidence to support use of an oncology drug in clinical practice, or are you an investigator working to bring real-world evidence to the FDA for drug approval? But either way, no matter what scenario you're in, I think the first question you must ask yourself is, is this data fit for purpose? And what does that actually mean, ‘fit for purpose'? And I think it goes to things like, are the patients well-matched? So, there's this very complex process, but the concept is not complex of propensity score matching, which our statisticians do for us beautifully. But this idea of are the patients in this data set that you're looking at, this is just a collection of data, right? How relevant is it to the patient in front of you? Is there some sort of matching that's going on in terms of patient characteristic?  After that, you have to ask yourself about this kind of array of epidemiologic biases that are inherent in non-randomized comparisons. Like, is this contemporaneous data? So, if this data set came from a group of patients who started their therapy—this goes to the idea of the index date, okay, start of therapy—has the standard of care changed? Has supportive care become increasingly better? Obviously, the answer to that is yes. And so, if you have these contemporaneous mismatches, then can you actually really rely on this real-world data or evidence, either one, as you're applying it to your patient? So, I think if it's for regulatory purposes, certainly you could avoid many mistakes by coming to the FDA early and often, which we always recommend. And if it's you as a clinician, as a health care provider, looking at this collection of data, I think you do have to walk yourself through in a really basic kind of logical process of, “how well does this data apply to the scenario in which I want to use this therapy?” So, index date, selection, timing, patient characteristics, things like that. Dr. John Sweetenham: Yeah, great, thanks. And I'd like to maybe ask both of you for your comments on one final question, and this is circling back to the S2302 study. Intrinsic to the study design and the concept is that the population in this study will be truly representative of the “real world.” My two questions to both of you will be, first of all: What is the gold standard for representative? In other words, what does that really mean to have a representative population of patients with advanced non-small cell lung cancer? And secondly, do you have any safeguards in place in the course of the study designed to make sure that that study population doesn't get skewed in some way so that it becomes unrepresentative of the real world? So, Dr. Reckamp, maybe I can start with you and ask you for your comments about that. Dr. Karen Reckamp: Thank you. I think that's a very good question and something that we grappled with as we designed this study and really did keep coming back to that. So, I think when we talk about representation, most randomized trials don't have broad representation. They are very specific populations that we curate in order to take as much variability out of the trial as possible so that we can investigate just the experimental arm versus standard of care or whatever we're evaluating. And here, we've consciously made an effort to say we want to know how this works in a real practice and make this as generalizable as possible while still being safe. So, we have the premise of keeping patients safe as the number one goal of this trial. And then, we want to look at the survival data. So, we actually did lower the bar a bit and changed our hazard ratio. Our hazard ratio was 0.69% for the phase 2 trial. We loosened that a little bit for the phase 3 trial, knowing that the patients that are coming on to trial are not going to be perfect patients, and there may be a little more coming together of those curves. That being said, randomization is what is supposed to wash away all sins, which has been said many times as we put this trial together. And so, the randomization is really the goal, to utilize the randomization process in order to make sure that there is balance and that we are getting representation on both sides that will help us understand how the investigational arm is really doing in this population. It's not going to be perfect, and we are allowing for performance status 2 patients. But I think we all believe that this is really important because there's a large proportion of patients who have performance status 2 who never go on to trials, but in the real world, we treat them generally with the standard of care options that we use. So, I think this is really important for moving things forward, and will be groundbreaking in that way, too. Dr. John Sweetenham: Great, thank you. And Dr. Singh, just to add to that, will the FDA be looking at this from the perspective of making sure that the study population as a whole—accepting that randomization will hopefully cancel out some of the potential pitfalls there—but will the FDA be looking to make sure that the population as a whole is truly representative of what's out there in the real world?  Dr. Harpreet Singh: We always look at the population. We are always hopeful that, in general, the population is reflective of the disease for which—in this case, lung cancer. I think in this case, we were very hands-on with developing the protocol, and it is our hope and it's our expectation, and I think it very much will happen that you are going to see a very diverse and representative, more generalizable population here. I just want to add a piece to this because remember that traditional randomized clinical trials typically do have a more homogeneous patient population because a lot of this is designed around a de-risking strategy when you're bringing new drugs to market. One of the reasons we felt so comfortable stripping away, as Karen mentioned, no lab criteria. If the clinician says, “I think you're fit for this regimen, go ahead and enroll them.” We pushed for inclusion of PS 2 patients. We, the FDA, did. So, yes, we're going to be looking, but we do really hope that these really streamlined inclusion and exclusion criteria allow for that. And so there's other things too, like race, ethnicity, age. And so it starts with not excluding patients based on perhaps unfair or arbitrary cutoffs like labs. Not to say that performance status is arbitrary. But in this case, if the clinician deems you fit for this therapy, that is between the patient and the investigator and their judgment, which is really part of the element of real-world trials and this pragmatic element too.  I also wanted to add on this idea of diverse representation, we expect there to be a lot of extra, for lack of a better term, noise, in this trial, even though it's randomized. And so, part of the negotiation around designing this trial was the need for an increased sample size to try to account for some of what we expect to be perhaps unequal randomization, perhaps in terms of patient characteristics on either side, perhaps patients lost to follow-up, etc. And so, when we talk about pragmatic trials, one element is that you probably often may need an increased sample size to account for the increase in heterogeneity, not only in your patient population but perhaps in monitoring as well. Dr. John Sweetenham: Well, thank you both, Dr. Reckamp and Dr. Singh, for a great discussion today and for sharing your insights on these developing trends in clinical trial design. Dr. Reckamp and Dr. Singh, we'll be watching closely to see how the trial performs in the coming months and advances the concepts of pragmatic trial design that Dr. Singh mentioned earlier within the FDA. We obviously are very excited to see whether this change in trial conduct will enable you to meet new groups of patients and ultimately improve outcomes for them. So, thanks once again for being with us today. Dr. Harpreet Singh: Thanks so much. Dr. John Sweetenham: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers: Dr. John Sweetenham  Dr. Karen Reckamp  @ReckampK  Dr. Harpreet Singh  @harpreet_md Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn  Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Karen Reckamp: Consulting/Advisory Role: Amgen, Takeda, AstraZeneca, Seattle Genetics, Genentech, Blueprint Medicines, Daiichi Sankyo/Lilly, EMD Serono, Janssen Oncology, Merck KGaA, GlaxoSmithKline, Mirati Therapeutics Research Funding (Institution): Genentech/Roche, Janssen Oncology, Calithera Biosciences, Elevation Oncology, Daiichi Sankyo/AstraZeneca, Blueprint Medicines Dr. Harpreet Singh: None Disclosed

Dr. Rachna Shroff, chair-elect of the 2023 ASCO GI Cancers Symposium, and guest host Dr. Shaalan Beg discuss new research presented at GI23, including new data from SWOG 1815 in biliary tract cancers, advances in biomarker studies in mCRC such as the PARADIGM trial, and promising updates in ctDNA technology. She also highlights the exciting potential of AI in oncology. TRANSCRIPT Dr. Shaalan Beg:  Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center and vice president of Oncology at Science 37. Today we'll be discussing key abstracts and other highlights from the 2023 ASCO Gastrointestinal Cancer Symposium, which celebrated 20 years of transformative care in GI cancers. I'm delighted to welcome Dr. Rachna Shroff, the chair-elect of this milestone meeting. Dr. Shroff is the interim division chief of Hematology Oncology at the University of Arizona Cancer Center. She also serves as the associate dean for Clinical and Translational Research and is the chief of GI Medical Oncology. Our full disclosures are available in the transcript of this episode, and disclosures related to all episodes of the podcast are available on our transcripts at ASCO.org/podcasts. Dr. Shroff, it's great to have you back on the ASCO Daily News podcast. Dr. Rachna Shroff: Thank you so much for having me. I'm so excited to be here. Dr. Shaalan Beg: The ASCO GI Cancers Symposium has been heralded as one of the biggest conferences in the GI cancer space and has occupied this space for the past two decades. Some would say that this year's conference was probably the best GI Cancers Symposium to date. Can you comment on the 20th anniversary milestone and the impact of the symposium on GI cancers? Dr. Rachna Shroff: Absolutely, and that's so great to hear that that's the feedback that you've heard. I have to say GI ASCO is absolutely my favorite meeting of the year, so that is my full disclosure. But I think that this was a tremendous meeting, and I think it was so beautiful that it was also coinciding with the 20th anniversary. It meant so much to us to have Dr. Margaret Tempero open the meeting because she really was the impetus for creating a GI cancer-focused meeting that really brought together multidisciplinary expertise. And so to us, that is what this 20th anniversary represented—20 years of multiple different specialties coming together to discuss how to improve cancer care for patients with gastrointestinal malignancies. And it has been a transformative meeting to see the impact of research presented at this meeting and how it has been implemented over the course of 20 years. And I completely agree that this year in and of itself had some incredible pivotal data that there is no doubt will be practice-changing, and that is absolutely the purpose. I also think that the beauty of this meeting is the networking opportunities for all of us to come out of our individual silos, come together, and discuss cross-cutting care across the spectrum of GI malignancies. And I think that this meeting really did that quite well. Dr. Shaalan Beg: There were many practice-changing studies that made headlines this year, and for me, one of the most anticipated studies was a trial that you led for cholangiocarcinoma and much-anticipated results. The study finished enrollment at a record pace. Can you share your key findings of cholangiocarcinoma? And I'd really like to hear your perspective on cholangiocarcinoma studies. Dr. Rachna Shroff: Yes, it was actually a really big year in the hepatobiliary space, and I was proud to present SWOG 1815, LBA 490, which was the pivotal randomized phase 3 trial looking at gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin. This was a study that was opened across the entire NCTN and based on a single-arm phase 2 trial that had shown some promising early efficacy of the triplet chemotherapy regimen. As you mentioned, this study accrued 441 patients in two years. And it's really a testament to the fact that the cooperative group mechanism can and should be asking important questions in large, randomized studies and that it is even possible to do in what are historically thought of as, quote-unquote, “rare tumors.” The study was a randomization of two to one to the triplet chemotherapy versus the standard of care for newly diagnosed biliary tract cancer patients. And the primary endpoint was median overall survival. And while the median OS of the triplet regimen was numerically improved at 14 months compared to 12.7 months, this did not meet statistical significance. Other efficacy endpoints, including median progression-free survival and overall response rate, were also numerically improved but not statistically significant, with an overall response rate of 31% with the triplet regimen versus 22%. There were some prespecified stratification factors, including disease site and disease stage, and there may be some interesting signals that bear out of that in terms of perhaps gallbladder cancer and locally advanced patients may be benefiting from the triplet regimen a little bit more, but these are small numbers, and we would really need to explore that in a more rigorous prospective manner. The toxicities were, not surprisingly, there, especially hematologic toxicities. I will say for those of us that use this regimen in practice, we use it a little bit differently than what was done in SWOG 1815, but you can't deny that there were significantly higher grade 3-5 toxicities with anemia neutropenia and thrombocytopenia, though the treatment discontinuation rate did not differ. I think the next steps are really going to be the ongoing biomarker analyses. The study had archival tissue and prospective blood collection and we know that in the space of cholangiocarcinomas and biliary cancers, molecular complexities absolutely play a role in how patients do and how they respond to therapies. So that's going to be an important next step, I think, for this study. Dr. Shaalan Beg: Speaking of biomarkers and an impact on GI cancers, the other malignancy where biomarkers are having a much greater impact than other GI cancers is colon cancer. Another year where we continue to see advances in our understanding of molecularly targeted treatments for colon cancer. What caught your eye? Dr. Rachna Shroff: Well, there were a lot of really interesting studies happening in this space and as a biliary person, one of the first things I got excited about was seeing Abstract 139 that looked at pemigatinib, which is the drug we are very familiar with in cholangiocarcinoma. This was a single-arm phase two study looking at the use of the FGFR inhibitor pemigatinib in metastatic colorectal cancer patients who had FGFR alterations. And so this was a study that was opened through the ACCRU mechanism. It was multicenter with assignment two-stage design and it was specifically for patients with FGF and FGFR-altered metastatic colorectal cancer who had progressed on standard therapies. There was a prespecified interim analysis for futility after 12 evaluable patients and so 14 patients were enrolled in the first stage of the study and evaluated for the primary endpoint of objective response. What was seen and the study was subsequently stopped is that there was really not much efficacy, there was no evidence of safety signals, but this did not seem to be a very active drug in patients with FGFR alterations with no objective response noted. So, the study was stopped with the recognition that perhaps the FGFR translocation or fusion patient population may be something to explore since they did not look at that in this study. The other kind of study that I think is really important was important work of Dr. Raghav and colleagues through SWOG. This was SWOG 1613 Abstract 140. This was the first real study that was investigating targeting HER-2 overexpressed and amplified metastatic colorectal cancer who had RAS wild-type tumors. And it was based on, obviously, some early signals of the effectiveness of HER-2 targeting in metastatic colorectal cancer. And this was a large study looking at pertuzumab and trastuzumab in these patients. They were compared to cetuximab and irinotecan, and the initial plan was for a much larger study. Unfortunately, accrual was really slow so the study was really kind of reformatted and a total of 54 patients were randomized, 26 to the trastuzumab arm and 28 to the CetIri or cetuximab and irinotecan arm. What was seen was that you can absolutely use HER-2 targeting therapies with trastuzumab and pertuzumab in these patients. It was safe and there were some obvious signs of efficacy in terms of overall response rate with an overall response rate of 31% compared to the CetIri arm. Crossover was allowed from the CetIri arm to trastuzumab and pertuzumab. So just that's important to keep in mind when they start to follow out the survival data. But unfortunately, because this study did not accrue, it was stopped early and it's really hard to understand in terms of power calculations the impact of trastuzumab pertuzumab. Of course, we can't talk about this without recognizing that the FDA approval based on the MOUNTAINEER study for tucatinib and trastuzumab came through during GI ASCO. So clearly HER-2 targeting is here to stay in colorectal cancer. Dr. Shaalan Beg: So technology is advancing every year and it's important that we are aware of these advances and how they impact our patients. Probably one of the most exciting technologies in oncology in general is the evolution of ctDNA. And it's been amazing to watch that field unfold as we understand how to use circulating biomarkers for early detection of cancer, for minimal residual disease detection, even as a biomarker of response. What caught your eye when it comes to the use of ctDNA in GI cancers, and how do you see this space develop in the next couple of years? Dr. Rachna Shroff: I completely agree. I think the technology of ctDNA is so incredibly exciting and as somebody who does not actively see and treat colorectal cancer, I'm a little bit envious of my colleagues in that space because the strides that have been made in terms of understanding the utility of ctDNA, especially in colorectal cancer, has just been tremendous and even for the last two to three years. One perfect example of integrating that sort of technology into treatment paradigms is the PARADIGM trial, Abstract 11, which was looking at the concept of hyperselection of patients with RAS wild-type metastatic colorectal cancer who were on the PARADIGM trial which basically looked at frontline FOLFOX with panitumumab versus bevacizumab in patients with RAS wild type left-sided metastatic colorectal cancer. So, you know, the initial data from PARADIGM had demonstrated a longer median overall survival 37.9 months versus 34.3 months, but very smartly, the investigators had also collected baseline plasma ctDNA in the biomarker component of this study and used a custom panel that looked at gene alterations for hyperselection and that included KRAS, NRAS, PTEN, and extracellular domain EGFR mutations HER-2 and MET amplifications, as well as some fusions like ALK, RET, and NTRK. And so out of the 802 patients in the full set, 91% - 733 patients - actually had pretreatment samples for ctDNA, which is really in and of itself, I think, tremendous. And when you break it down, about 28% had at least one gene alteration, and that was across each of those different genes that they were looking at. In the 72% of patients who were defined as hyperselected without any gene alterations, the OS was actually longer with panitumumab versus bev, and that actually was independent of sidedness with hazard ratios that kind of ranged from 0.76 to 0.82. And OS was similar or inferior with panitumumab versus bevacizumab again, regardless of sidedness in patients with any of these gene alterations. And so I think it's a really interesting concept that you can use ctDNA to define negative hyperselection rather than looking at left sided and right sided to really help select patients with frontline therapy in terms of using panitumumab versus bevacizumab. And with the speed with which ctDNA can be obtained, this actually seems like something that could be implemented into clinical practice, which is, I think, really the important component of that. There were a number of other really interesting abstracts. Abstract 5, presented by Dr. Cohen and colleagues, really looked at the kinetics of circulating cell-free DNA and how that kind of relates to minimal residual disease detection rates. And this was in patients with resected stages one through three colorectal cancer. And so, this was a retrospective study, so we have to keep that in mind. And it was multi-institutional in really over 16,000 patients with stages 1 through 3 colorectal cancer. But the complete dataset had about 417 patients and basically the patients' circulating cell-free DNA levels, the total cfDNA, were compared to the ctDNA MRD positivity rates and they looked at very specific time points after surgery. What the authors generally found was that the postoperative cfDNA correlated well with ctDNA positivity and that there was really the ability to see plasma cfDNA levels kind of track and follow with the very specific MRD windows that were being looked at, which really, again, just kind of talks about leveraging this technology in terms of real-world and real-time application and better understanding and informing us of minimal residual disease post what is thought to be curative resection. The last one that I thought was really interesting in relation to ctDNA was actually looking at anal cancer and following ctDNA in patients who were treated with definitive chemoradiation. This was a study that was looking at 31 patients with anal squamous cell carcinoma who were treated with definitive chemo radiation and underwent ctDNA response. The majority of these patients had stage 3 disease and the majority of them received the standard 5-FU Mitomycin with radiation. The patients had ctDNA testing performed in 25 of these patients at baseline and then a smaller number over the course of time, some during chemoradiation. And then they looked again at 30 days post chemoradiation. And at baseline, 88% of patients had detectable ctDNA with those with stage three disease having numerically higher baseline ctDNA levels. And basically what they found was that over the course of treatment, ctDNA levels decreased among the patients with detectable ctDNA. And then ctDNA that tested during chemo radiation showed a drop in decline and were going into molecular remission at a time point in which it was subsequently confirmed that they had a clinical complete response. So, the suggestion here is that the time to molecular ctDNA remission was significantly shorter than being able to see that clinical complete response, which suggests that using surveillance ctDNA monitoring could be an earlier response assessment for patients with anal squamous cell carcinoma who are undergoing definitive therapy. Now, obviously this needs to be confirmed in a larger manner, but again, really suggests that we could be understanding how we're doing with treatment in more of a real-time fashion, which I just think is incredible for those of us who are making sure that we are doing and taking the right approaches for these patients. Dr. Shaalan Beg: One of the major transformative announcements that took place only a couple of months before the GI Cancer Symposium was the announcement of ChatGPT. And we heard a lot of discussion on how it can be used for improving cancer care, improving drug development, and in general, artificial intelligence and machine learning. We've been hearing these buzzwords for such a long time, to the point that a lot of people are probably just filtering it out and then this tool comes up and it makes it real. And we're seeing different people apply these technologies in different ways. But there is tremendous potential in how this technology can improve clinical trials, drug development, and early diagnosis. And luckily, we had already secured a keynote speaker, Dr. Matthew Lundgren from Nuance Communications, and he was invited to talk about artificial intelligence, machine learning, and how it applies to cancer care. I'm really curious to hear what your highlights were from his address and how you see this impacting your day-to-day, or just the ecosystem of which we're all part of. Dr. Rachna Shroff: Yeah, I will say that his keynote was really one of the highlights of the entire meeting for me. And that is coming from somebody who doesn't really know– I know who I'm speaking to, but somebody who does not truly understand the way AI is moving. And so, I was joking with him that it was like AI 101. And I really, really appreciated the way he was able to kind of speak to a crowd that he doesn't normally speak to and help us really understand the way in which artificial intelligence can be integrated into healthcare, and specifically oncology. To me, I think what were the most salient takeaways from his address was really about how this is just a rapidly evolving field and we need to be a little bit ahead of the eight ball when it comes to thinking how we can smartly leverage artificial intelligence like you mentioned, to improve our clinical research efforts, to improve access, and to improve fully integrating AI into our EMR, so that we can really leverage that technology and ensure that we are capturing every potential patient for a clinical trial and be smarter about how we're even approaching things. I mean, I loved him talking about the prior authorizations and that sort of thing, and the ways in which we can decrease the burden on health care providers and really let us focus on the areas that we need to focus on. The one thing that I thought was a really important point, though, and I think a number of people asked him, was about how using this technology has the potential to create more gaps and disparities and how can we be smart to ensure that we don't broaden those gaps. And I think that is a really important point that we all need to think about because we know that especially when we think through clinical trials, there's already underrepresentation of certain populations and certain geographic regions. And so, I think that was a really important takeaway for me is how can we make sure that we work and partner with those who are creating these technologies to ensure that we aren't taking two steps forward and four steps back. Dr. Shaalan Beg: It really calls into question how we define productivity and what our value in the entire delivery system really is. And I think from people who are in middle school or high school to people who are in college and even folks who are in the field as you and I are, it's forcing us to rethink what we bring to the table in a way that we've never been challenged to ask that question ever before. Dr. Rachna Shroff: Absolutely. Dr. Shaalan Beg: So, thank you very much, Dr. Shroff. This was wonderful. Thank you for sharing your insights with us today. And we thank you and Dr. George Chang, the chair of the ASCO GI Cancers Symposium, and everyone who worked so hard to develop a robust program this year.  Dr. Rachna Shroff: Thank you. It was so wonderful to be able to speak about it. And thank you to all of the attendees for making it such a memorable meeting. Dr. Shaalan Beg: And thank you to all our listeners for your time today. You'll find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Rachna Shroff @rachnatshroff Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn  Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Rachna Shroff: Consulting or Advisory Role: Exelixis, Merck, QED Therapeutics, Incyte, Astra Zeneca, Taiho Pharmaceutical, Boehringer Ingelheim, SERVIER, Genentech, Basilea Research Funding: Pieris Pharmaceuticals, Taiho Pharmaceutical, Merck, Exelixis, QED Therapeutics, Rafael Pharmaceuticals, Bristol-Myers Squibb, Bayer, Immunovaccine, Seagen, Novocure, Nucana, Loxo/Lilly, Faeth Therapeutics        

This episode follows 2 Kidney Cancer expert Urologists in understanding Kidney tumors from diagnosis to treatment options.  Guest:   John L. Gore, M.D. Professor of Urology, Professor of Surgery, Health Services Researcher, University of Washington. Urologist, surgeon, clinician, researcher, educator and expert in clinical care guidelines and outcomes. Dr. Gore is the PI of a large pragmatic trial in bladder cancer, and a quality of care expert. He previously served as the American Urological Association (AUA) representative to the National Quality Forum, which endorses national health care performance measures, and has been on guidelines panels for the National Comprehensive Cancer Network (NCCN) for kidney cancer, and the AUA for bladder cancer.   Brian Shuch, MD is the Director of the Kidney Cancer Program and the Alvin & Carrie Meinhardt Endowed Chair in Kidney Cancer Research. He completed his urology training at UCLA followed by a Urologic Oncology Fellowship at the National Cancer Institute. He is an accomplished surgeon (open/laparoscopic/robotic surgery and percutaneous ablations) and clinical/translational researcher. He serves in leadership positions within various kidney cancer research organizations such as SWOG and the Society of Urologic Oncology. He is recognized as an expert in the genetics of kidney cancer and runs a translational research program with over 140 peers reviewed publications including primary research published in prestigious journals such as Nature, Nature Genetics, Proceedings of the National Academy of Sciences, Journal of Clinical Oncology, and Clinical Cancer Research. He is one of the few clinicians to bring bench science to the bedside in an upcoming therapeutic clinical trial for metastatic kidney cancer.   During This Episode We Discuss: The types of Kidney Cancer   Non cancerous kidney cysts (benign) versus cancerous kidney cysts,   Solid kidney tumors, benign and malignant   Diagnosis of kidney cancers: Imaging and Biopsy   Risk factors for kidney cancers   Genomics of kidney cancer   Treatment of kidney cancer: Localized and Metastatic Quotes (Tweetables) Back in the olden days we used to talk about the triad of three symptoms people associated with kidney cancer. Those three symptoms were hematuria or blood in the urine, palpable mass, and flank pain. Realistically in 2023 this triad happens less than 1% of the time. What has changed is that there is a much higher frequency of use of imaging to diagnose problems in our bodies. Kidney cancer is one of the fastest growing cancer types in terms of it's incidence, because of incidental detection.                                                                                  Dr Gore   Regarding tumor size, it all depends on the scenario.The larger the lesion the more concerning it is for cancer, but even a 1 cm tumor can have some aggressive elements. There is not an absolute size where you say that a tumor below this threshold cannot be a cancer.                                                                                Dr Shuch Most kidney cancers are what we would call sporadic, in that it occurs in the absence of known risk factors. The 2 biggest risk factors that are more behavioral are smoking and obesity.                                                                                 Dr Gore                                                                                Recommended Resources:   KCA: Kidney Cancer Association www.kidneycancer.org   Kidney Can www.kidneycan.org   KC Cure  www.kccure.org   American Cancer Society   Fred Hutchinson   UCLA

Key takeaways: The changing role of the Oncologist - Starting as the Sherpa, transitioning to a mentor, and then breaking up! Awareness of barriers the LGBTQ community faces in accessing healthcare The distinction between addressing reproductive health and sexual health in cancer care About Dr. Don Dizon: Don S. Dizon, MD, FACP, FASCO, is an oncologist who specializes in women's cancers. He is the director of women's cancers at Lifespan Cancer Institute and director of medical oncology at Rhode Island Hospital. He is also a professor of medicine at The Warren Alpert Medical School of Brown University. His research interests are in novel treatments of women's cancers and issues related to survivorship, particularly as they relate to sexual health after cancer for both men and women. He is a prolific researcher and writer, and he has authored hundreds of publications, including peer-reviewed articles, books and book chapters. He is an active member of the American Society of Clinical Oncology, SWOG cancer research network, and the National Consortium of Breast Cancers, of which he has served as both vice president and president. Key moments: 12 minutes 27 seconds That person may be more interested in symptom control, in which case they would find more affinity in a metastatic brain tumor group. But they also may want to see people that look like them, that are like them who are going through this experience because of the threats metastatic brain cancer has on people's sexual health. 14 minutes 35 seconds It's what makes cancer care so multifaceted today. There's no one person who can really manage all the aspects of cancer care. By that, I mean whole-person cancer care. It really brings in the importance of having a team approach. 21 minutes 8 seconds There's a relationship between medical oncologists and their patients that is very difficult to walk away from for a lot of people. It almost feels like severing a relationship and it's quite an unsettling thing. Disclaimer: This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice, and no doctor/patient relationship is formed. The use of information on this podcast or materials linked from this podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard, or delay in obtaining, medical advice for any medical condition they may have, and should seek the assistance of their health care professionals for any such conditions. --- Support this podcast: https://podcasters.spotify.com/pod/show/manta-cares/support

CME credits: 0.75 Valid until: 30-09-2023 Claim your CME credit at https://reachmd.com/programs/cme/neoadjvuant-versus-adjuvant-pembrolizumab-for-resected-stage-iii-iv-melanoma-swog-s1801/14452/ tbd

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In the Research Round Up series, ASCO experts and members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today's episode, our guests will discuss new research in lung cancer, lymphoma, and childhood cancer that was presented at the 2022 ASCO Annual Meeting, held June 3-7 in Chicago, Illinois. First, Dr. Charu Aggarwal will discuss 3 studies looking at treatment options for people with non-small cell lung cancer. Dr. Aggarwal is the Leslye Heisler Associate Professor of Medicine in the Hematology-Oncology Division at the University of Pennsylvania's Perelman School of Medicine in Philadelphia, Pennsylvania. She is also the Cancer.Net Associate Editor for Lung Cancer. You can view Dr. Aggarwal's disclosures at Cancer.Net. Dr. Aggarwal: Hello and welcome to this Cancer.Net podcast. I'm bringing you updates from the Annual Meeting of the American Society of Clinical Oncology, held in Chicago in 2022. I'm Dr. Charu Aggarwal. I'm the Leslye Heisler Associate Professor for Lung Cancer Excellence at the University of Pennsylvania's Abramson Cancer Center. I will be discussing updates on 3 studies today that offer insights and new advances in the management of patients with non-small cell lung cancer. I don't have any direct relationship with any of these companies or studies, and you can view a list of my disclosures on the Cancer.Net website. First off, I would like to talk a little bit about advances in the management of patients with EGFR exon 20 mutations. We know that a lot of advances have been made in the management of patients with non-small cell lung cancer, and much of that has been attributed to the fact that we are now able to deliver targeted therapy for a subset of patients. EGFR mutations form one such subset where we have a lot of oral drugs that are available, and we can offer these that improve survival, and patients can avoid chemotherapy, immunotherapy, and other IV infusional therapies. Within the subset of EGFR mutations lies this unique subset of EGFR exon 20 insertion mutations, which have been historically harder to target with currently available EGFR inhibitors. And over the last 5 years, we have seen tremendous growth of opportunities, targets, and new drugs for this subset of patients. The mutations in this subset forms about 2% to 5% of all non-small cell lung cancers. But now we have 2 FDA-approved drugs in this space, one being intravenously administered, amivantamab, and another that is orally available, mobocertinib. We covered this in a podcast as well as a blog, so please check those out on our Cancer.Net website. But building upon that progress, there is now another drug that was reported at ASCO. This drug is called CLN-081. And we saw preliminary activity in a phase 1 and 2 study of this molecule or this drug in patients with EGFR exon 20 insertion mutations. It's an orally available drug. The top line data is that it is safe, it is effective, it was tested in different doses. It was tested at less than 65 milligrams, 100 milligrams, and 150 milligrams, again, as I mentioned, administered orally, and we saw responses and patients that had previously received other therapies and may have progressed on other therapies. And what we found was that this drug also tends to have activity against brain metastases, which I think is this huge unmet need in the management of such patients. So I think more to come, but again, I think offers us an insight into what may be in the future, an attractive drug for our patients with EGFR exon 20 insertion mutations. So stay tuned, more on that in the future. Shifting gears, I would like to now talk about one of the common mutations. So we talked about EGFR exon 20, which is about only 2% to 5%, but the largest subset of mutations in non-small cell lung cancer really revolves around KRAS mutations, and these form about 30% to 35% of all mutations in non-squamous, non-small cell lung cancer. And amongst this group there is another subset which is KRAS G12C non-small cell lung cancer, that forms about 13% of all lung cancers. We have 1 approved drug already in this space by the name of sotorasib that is FDA approved for the management of patients with this particular mutation after having received 1 prior therapy, be it chemo-immunotherapy or immunotherapy. At this year's ASCO meeting, we heard data from a study called KRYSTAL-1, which looked at the activity and safety of another molecule called adagrasib, which is an orally available drug targeting KRAS G12C, again, in a similar population of patients with advanced and metastatic non-small cell lung cancer harboring a mutation. We found that this drug is again effective, the overall response rate was about 43%, the majority of the patients had stabilization of disease, about 80%, and many patients were able to remain on treatment with stabilization of disease. We found that this drug does have side effects and adverse events and most commonly of this were diarrhea, nausea, vomiting, and fatigue. Many patients did require dose reductions, but the activity of the drug remained despite dose reductions. Now, what would be the advantage of this drug against the currently available sotorasib? In another smaller study reported at ASCO, there seemed to be activity in the brain, including intracranial penetration with the use of this molecule, adagrasib, which has not been demonstrated before with other KRAS G12C inhibitors, so I think that makes it a potentially attractive option. Again, I will say that the report of this intracranial activity was in a very small subgroup of patients, so I think needs to be further corroborated in a larger study. Shifting gears again and talking about our last study, so I would like to highlight what do we do if, in case, patients don't have a targetable mutation. I want to highlight that we do have a lot of available options, and we are continuing to improve upon available options. The way we treat such patients is by using immunotherapy, either alone or in combination with chemotherapy. But what do we do after this treatment stops working? Researchers from the Southwestern Oncology Group, or SWOG, launched a massive national effort called Lung-MAP, which is basically a clinical trial that evaluates several different strategies all at once, either for patients with targetable mutations or for patients without a targetable alteration. And they reported results from a study that evaluated the combination of pembrolizumab with ramucirumab in patients that may have progressed after frontline immunotherapy. Now, pembrolizumab is immunotherapy, so the concept was, can we continue immunotherapy beyond progression and perhaps get some synergistic activity by using ramucirumab, which is a drug that prevents blood vessels from forming in the tumor itself. It's an anti-angiogenic agent, meaning that it is a targeted molecule that prevents blood vessel formation and promotes tumor death. What they found was that patients that received pembrolizumab and ramucirumab were more likely to live longer, so overall survival was longer for patients with this combination compared to a physician investigator discretion choice, such as chemotherapy in combination with ramucirumab or other chemotherapies that are otherwise used in the second line setting. And interestingly, we did not find a significant improvement in shrinkage with this combination of pembrolizumab and ramucirumab or a significant reduction in the time of progression-- or, sorry, prolongation of the time of progression of disease. But the overall survival findings are interesting, and I think that's why we are including them in this podcast because that's one of the approaches that is leading to an improvement in survival and improvement in outcomes. I will point out that this is a phase 2 study. These results would need to be validated in a large prospective phase 3 trial so that we can account for certain confounding factors that may have led to these results. Having said that, I think there's a tremendous excitement, there's tremendous excitement in this field. I gave you examples of, or highlighted, 3 studies: one in patients with EGFR exon 20 insertion mutations, another in KRAS G12C mutations, and the third in patients who may have already received either immunotherapy or chemoimmunotherapy. We will continue to update our Cancer.Net website with updates as they come through, new advances, new studies, so thanks for following, thanks for listening, and more to come. Stay tuned. Thank you. ASCO: Thank you, Dr. Aggarwal. Next, Dr. Christopher Flowers will discuss new research in treating people with different subtypes of lymphoma, including mantle cell lymphoma and diffuse large B-cell lymphoma. Dr. Flowers is the Chair of the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center and was appointed Division Head ad interim of Cancer Medicine in August 2020. He is also the 2022 Cancer.Net Associate Editor for Lymphoma.   You can view Dr. Flowers' disclosures at Cancer.Net. Dr. Flowers: Hello and welcome to this podcast that is a review of late breaking abstracts from the ASCO Meeting and recent updates in lymphoma. I'm Dr. Christopher Flowers, professor and chair of the Department of Lymphoma and Myeloma and Interim Division Head for Cancer Medicine at The University of Texas MD Anderson. And it's my great pleasure to discuss with you some of these late breaking abstracts. I do have some disclosures that are related to the content that I will present from this year's ASCO Meeting and recent studies in lymphomas. Those are available at Cancer.Net. Those relate to my role as a consultant for the development of clinical trials in lymphomas and research funding that MD Anderson has received from companies related to my role in clinical trials in lymphoma and clinical trials across cancers. So, the ASCO Meeting had a host of new information that was presented. Some of that information centers around key clinical trials. One that was a pivotal clinical trial, the SHINE clinical trial, looked at patients with mantle cell lymphoma, a rarer lymphoma subtype, that looked at the combination of bendamustine and rituximab, a standard chemoimmunotherapy combination, compared to that same chemoimmunotherapy combination, bendamustine, rituximab, plus the Bruton's tyrosine kinase inhibitor ibrutinib. Ibrutinib, as some of you may know, is a kind of therapy that is typically used in the relapse setting for patients with mantle cell lymphoma when they have their disease come back. And the SHINE clinical trial was looking at adding it to frontline therapy. What this randomized, controlled trial in the phase 3 setting found was that patients who received the combination of bendamustine, rituximab, plus ibrutinib had improvement in their progression-free survival, meaning that the time that it took for their disease to come back or them to have deaths related to the lymphoma was longer for patients who received this combination. About 2.3 years longer than the group that received bendamustine, rituximab, plus placebo. And in total, that led to a median progression-free survival of 6.7 years. That study has now been published in the New England Journal of Medicine and was led by my colleague Dr. Michael Wong from MD Anderson. Dr. Wong also led another study that was presented at the ASCO Meeting looking at CAR T-cell therapy for patients with mantle cell lymphoma. That study has now been published in the Journal of Clinical Oncology, and it looks at brexucabtagene autoleucel, a kind of CAR T-cell therapy, where that-- the CAR T-cell therapy was successfully manufactured for 71 of the 74 patients in the trial. 68 of those patients received an infusion and the median progression-free survival, so the average amount of time that it took for patients to have progression of their disease, was about 25 months. And so a marked benefit for those patients who were receiving CAR T-cell therapy when their mantle cell lymphoma came back. There also were major breaking abstracts at the ASCO Meeting in the area of diffuse large B-cell lymphoma. As many of you may know, diffuse large B-cell lymphoma is the most common type of lymphoma that occurs in the United States. And there was a breaking trial that was presented in December at the American Society of Hematology Meeting describing polatuzumab, a CD79b antibody drug conjugate, as a new drug in the substitution of frontline therapy for patients with diffuse large B-cell lymphoma in combinations with rituximab, cyclophosphamide, adriamycin, and prednisone, or the pola-R-CHP arm, that compared favorably to rituximab and CHOP chemotherapy, which has been the standard of care for patients with diffuse large B-cell lymphoma. And that trial showed an improvement in progression-free survival. At this year's ASCO Meeting, Franck Morschhauser presented results from looking at subsets of that patient population. Those patients who had BCL2 by immunohistochemistry that was positive or MYC expression by immunohistochemistry that was positive, or both of those, what we call double-expressor lymphomas, those who have poorer risk than standard groups. And those double-expressor lymphomas, treated with pola-R-CHP, had improvement in progression-free survival compared to R-CHOP with a hazard ratio of 0.64 in that group. We also saw in a multitude of analysis that that supported the benefit of pola-R-CHP in patients with both BCL2-positive and MYC-positive diffuse large B-cell lymphoma. Another area that has been very hot in diffuse large B-cell lymphoma clinical trials is the role of bispecific antibodies. Bispecific antibodies are antibodies that bind both to CD20, a marker on the diffuse large B-cell or the lymphoma cells, and to the marker CD3, which is a marker on T-cells which brings the normal T-cells of the immune system in close proximity to the lymphoma cells and then leads to immune-directed killing of lymphoma cells. The agent glofitamab is an agent that was presented by Michael Dickinson at this year's ASCO Meeting in an abstract. And in this study, 107 patients who received more than 1 dose of steady treatment went on to have complete responses in about 35% of patients. And this showed that glofitamab induced durable complete responses and had a very favorable safety profile in patients with relapsed and refractory diffuse large B-cell lymphoma. And in this trial, they compared that also for patients who had prior exposure to CAR T-cells and showed that responses were also good in those patients. Another set of studies has also looked at bispecific antibodies and a whole host of other areas with multitude of other agents. Another study that was presented at this year's ASCO Meeting explored the use of bispecific antibodies in the frontline setting in combination with the R-CHOP regimen that I just discussed. In that study, Lorenzo Falchi presented results of the subcutaneous bispecific antibody epcoritamab in combination with R-CHOP. This was a relatively small study of 33 patients that showed that the combination of epcoritamab plus R-CHOP was something that was safe and tolerable. There were no new treatment emergent adverse events that led to discontinuation of epcoritamab in the study. And there are some adverse events that are of special interest that we see with the bispecific antibodies, and those include the kind of immune-mediated adverse events that we can also see with CAR T-cells, like cytokine release syndrome, or CRS, or neurologic toxicities that we can see there that are also called ICANS. What we've seen in this trial, that about 42% of patients had some form of cytokine release syndrome, but that most severe form of cytokine release syndrome, those that were greater than grade 3 in severity, was only in 3% of patients. And likewise, the neurologic toxicities, or ICANS, that were grade 2 was in only 3% of patients. Relatively few patients completed all therapy by the time that this was presented. Only 10 patients had completed 6 cycles of therapy, but that showed an overall response rate that was quite high in that patient population. There were a whole host of other trials that were presented at this year's ASCO Meeting, and those portend improved kinds of outcomes on the horizon for patients with lymphomas across the spectrum. And I think it's an exciting time moving forward for clinical trials in lymphoma and hopefully, to see new therapies that emerge for the management of this disease. One of those new therapies that happened outside of the ASCO Meeting was the recent FDA approval of CAR T-cell therapy in the relapse setting for follicular lymphoma. And this was based on the ELARA clinical trial. And I think the future is quite bright for therapies and for patients with lymphomas broadly. ASCO: Thank you, Dr. Flowers. Finally, Dr. Daniel Mulrooney will discuss new research in childhood cancers, including a study comparing treatment options for Ewing sarcoma, and several studies on neuroblastoma. Dr. Mulrooney is an Associate Member in the Division of Cancer Survivorship at St. Jude Children's Research Hospital. He is also the Cancer.Net Associate Editor for Pediatric Cancers. You can view Dr. Mulrooney's disclosures at Cancer.Net. Dr. Mulrooney: My name is Dr. Dan Mulrooney from St. Jude Children's Research Hospital. I'm the Deputy Director of the After Completion of Therapy Clinic at St. Jude and primary care for survivors of pediatric solid tumors. The annual ASCO Meeting is typically quite busy and full of research presentations sharing knowledge and advances in cancer treatment and care. Today, I'd like to highlight some of the exciting presentations in pediatric cancer. Please note, I do not have any relationships to disclose related to any of these studies. At this year's meeting, one of the highlights was a European study in patients with relapsed or refractory Ewing sarcoma. Ewing sarcoma is a rare bone cancer that typically occurs in adolescents or young adults. While challenging to treat, it is difficult to cure in patients who have relapsed, and studies are needed to improve the care of these patients. Investigators from 13 European countries and Australia and New Zealand studied the most common relapsed therapies, which include irinotecan and temozolomide, gemcitabine and docetaxel, topotecan and cyclophosphamide, or high-dose ifosfamide. The study enrolled 451 patients between 2014 and 2021 and randomly assigned them to one of these four treatments. Based on response rates, the first 2 arms were dropped and the study was largely a comparison between topotecan cyclophosphamide and high-dose ifosfamide. The main outcome was event-free survival. Event-free survival is a common way in a clinical trial to see how well a treatment works. It measures the time from treatment that the patient remains free of complications, such as return or progression of the cancer. But investigators also looked at overall survival, toxicity, and quality of life. The 6-month event-free survival was better for high-dose ifosfamide at 47% compared to 37% for topotecan cyclophosphamide. The median overall survival was also better for high-dose ifosfamide compared to topotecan cyclophosphamide. The results were best for children younger than 14 years old versus those 14 or greater. Toxicities included fever and neutropenia, nausea, vomiting, and diarrhea. Patients receiving high-dose ifosfamide had more neurologic and kidney toxicities, which might be expected since ifosfamide is known to affect these organ systems, while only descriptive measurements of quality of life appeared higher for those children treated with high-dose ifosfamide compared to topotecan and cyclophosphamide. The strength of this trial is its large size, particularly for a rare cancer, and the fact that it randomized patients to the most commonly used treatment regimens for relapsed Ewing sarcoma. Importantly, data did not previously exist comparing these different treatments. While the results of this study are promising, clearly more needs to be done, and there was a lot of discussion at the ASCO Meeting about how to further improve survival in these patients. This study provides some information for doctors and patients, but importantly, provides data to advance future trials, which will concentrate on incorporating new targeted drugs with high-dose ifosfamide. This study is ongoing and is adding additional arms to continue to improve the outcomes for patients with relapsed or refractory Ewing sarcoma. In addition to this study in Ewing sarcoma, several studies investigating neuroblastoma were presented. Neuroblastoma is the most common extracranial solid tumor in children and for children with high-risk disease requires intensive and prolonged treatment, including chemotherapy, surgery, radiation therapy, and stem cell transplantation. Treatment for these patients has improved since the introduction of immunotherapy, particularly an antibody directed at a particular antigen named GD2 on the neuroblastoma cells. One study showed improvement in outcomes using this antibody for children with relapsed or refractory neuroblastoma, and another study demonstrated feasibility of using this antibody earlier in treatment, which was not previously known to be safe and tolerable. In what is called the BEACON study, investigators tested whether the antibody, called dinutuximab, would be effective when combined with chemotherapy for relapsed or refractory neuroblastoma. They enrolled 65 patients from 2019 to 2021 and randomized these patients to either chemotherapy alone or chemotherapy plus dinutuximab. The median age of these children was 4 years. The overall response rate, which means either a complete or partial response, was 18% for the chemotherapy-only arm but improved to nearly 35% for those treated with chemotherapy and dinutuximab. The progression-free survival was 27% for chemotherapy only and improved to 57% for those treated with chemotherapy and the antibody. There was no change in overall survival, though investigators think this may have been due to some patients who had progressive disease and crossed over to the antibody arm of the study. This presentation was followed by a study from the Children's Oncology Group, which investigated the feasibility of adding antibody treatment earlier in the treatment regimen for neuroblastoma. Prior studies had used antibody later in treatment when the tumor burden is thought to be lower. The endpoint of this study was tolerability measured by toxic deaths or unacceptable toxicities, such as adverse reactions to the medication. For example, sustained low blood pressure requiring a ventilator or breathing machine, or severe neuropathy. 42 high-risk neuroblastoma patients were enrolled from 8 different children's hospitals between 2019 and 2021. 41 of the 42 were able to complete the induction chemotherapy plus the antibody. There were no toxic deaths or unacceptable toxicities. Importantly, 85% were able to complete the next phase of treatment, called the consolidation phase, and 79% were able to complete the following phase after consolidation, called post-consolidation. One-year event-free survival was 83%, and 1-year overall survival was 95%. Now, it's important to know these are still early results, and the trial recently closed, and some of the patients have only completed therapy within the last year. Both of these studies add to the knowledge of chemoimmunotherapy for children with high-risk neuroblastoma. These studies provide a foundation for larger randomized trials that will further advance the care of these children. And finally, another study looked at race, ethnic, and socioeconomic disparities among children treated for high-risk neuroblastoma on Children's Oncology Group studies. There were no differences in event-free survival, but there were differences in overall survival based on ethnicity. The 5-year survival was lowest for Hispanic patients at 47%, 50% for non-Hispanic other ethnicities, which included Asian, Native American, Native Hawaiian, or Pacific Islanders, and 62% for non-Hispanic Black and non-Hispanic White children. Importantly, these investigators also studied household and neighborhood poverty. Overall, survival was lower for children living in poverty, though some of these differences went away when accounting for other factors, such as stage of disease or high-risk features. This study is important because it highlights the increasing need to collect data on clinical trials that may contribute to inequities in outcomes. While most studies collect data on the race and ethnicity of participants, other factors known as social determinants of health, such as income, neighborhood, education, access to health care, and insurance coverage, may also contribute to outcomes in pediatric cancer patients. Overall, the studies highlighted here and presented at this year's ASCO Annual Meeting focused on difficult-to-treat cancers, such as relapse or refractory disease, and they have laid the groundwork for future investigations to continue to improve survival rates for all children diagnosed with a malignancy through improved therapies and by addressing potential social barriers. Thank you for listening to this brief summary of the new research in pediatric oncology presented at the 2022 ASCO Annual Meeting. ASCO: Thank you, Dr. Mulrooney. You can find more research from recent scientific meetings at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

In this episode, we spoke with Dr. Elizabeth Henry, a clinical associate professor at Loyola University Chicago with a clinical focus on GU medical oncology. Before joining the faculty, she completed her hematology/oncology fellowship at Loyola and served as Chief Fellow in her final year of training. Elizabeth is a former heme/onc fellowship program director and has research interests in medical education and utilization of digital technology in training and professional development. She is a 2021-2022 ASCO Education Scholar. As the Medical Director of Oncology with theMednet, she oversees the editorial teams in moderating the high quality physician discussions, as well as expanding engagement through special programming such as the Tumor Board Q&A, ASCO and NEJM Journal Club discussions, SWOG outreach programs, and more. We discuss her many interests, including hematology-oncology and medical education and technology to advance medical knowledge. She explains her role at theMednet as a medical information platform for physicians, highlighting how physicians can have unique roles aside from practicing medicine in the hospital and/or clinic. Dr. Henry also shares her story about pursuing medicine and hematology/oncology specifically, simultaneously while conveying valuable advice to all aspiring physicians. More information about theMednet can be found at: https://www.themednet.org Episode produced by: Emily Hagen, Insup Hong Episode recording date: March 28th, 2022 www.medicuspodcast.com | medicuspodcast@gmail.com | Donate: http://bit.ly/MedicusDonate --- Send in a voice message: https://anchor.fm/medicus/message

Ce septième épisode du podcast Resilience est dédié à Mercedes. Mieux vaut prévenir que guérir est un précepte que Mercedes applique à la lettre. La grand-mère de Mercedes était décédée d'un cancer du sein. En prévention, elle a ainsi pris l'habitude de faire des mammographies chaque année. Et une année, son oncologue a détecté une tumeur, encore petite mais très agressive. Dans la semaine qui suit, Mercedes s'est entourée d'une équipe soignante et s'est faite opérer. Le lundi suivant, retour au travail. Elle devait faire une chimiothérapie mais après avoir posé 4 fois la question à ses médecins, ils optent pour un traitement différent. Ses conseils : poser des questions, demander des conseils et s'entourer. Figure de proue de la publicité, à la tête de la célèbre agence de publicité BETC, Mercedes Erra prend le temps pour nous aujourd'hui, avec une franchise et sincérité déconcertante, de nous raconter son cancer du sein. « J'ai vécu des événements très difficiles, mon cancer n'en fait pas partie. » Loin de minimiser le cancer, les inquiétudes qui peuvent émerger et la multitude d'impacts que celui-ci peut avoir sur une vie, Mercedes lance un message positif : oui, il peut arriver que cette épreuve se traverse sans encombre. Sources : • Can some postmenopausal women with breast cancer skip chemotherapy? By T. Salewa Oseni, MD — https://www.health.harvard.edu/blog/can-some-postmenopausal-women-with-breast-cancer-skip-chemotherapy-2021041522344 • SWOG researchers identify group of breast cancer patients who can skip chemo. EurekAlert! December 1, 2021. Accessed December 2, 2021. https://www.eurekalert.org/news-releases/936214 • Chimiothérapie, INCa — https://www.e-cancer.fr/Patients-et-proches/Les-cancers/Cancer-du-sein/Chimiotherapie

Ce septième épisode du podcast Resilience est dédié à Mercedes. Mieux vaut prévenir que guérir est un précepte que Mercedes applique à la lettre. La grand-mère de Mercedes était décédée d'un cancer du sein. En prévention, elle a ainsi pris l'habitude de faire des mammographies chaque année. Et une année, son oncologue a détecté une tumeur, encore petite mais très agressive. Dans la semaine qui suit, Mercedes s'est entourée d'une équipe soignante et s'est faite opérer. Le lundi suivant, retour au travail. Elle devait faire une chimiothérapie mais après avoir posé 4 fois la question à ses médecins, ils optent pour un traitement différent. Ses conseils : poser des questions, demander des conseils et s'entourer. Figure de proue de la publicité, à la tête de la célèbre agence de publicité BETC, Mercedes Erra prend le temps pour nous aujourd'hui, avec une franchise et sincérité déconcertante, de nous raconter son cancer du sein. « J'ai vécu des événements très difficiles, mon cancer n'en fait pas partie. » Loin de minimiser le cancer, les inquiétudes qui peuvent émerger et la multitude d'impacts que celui-ci peut avoir sur une vie, Mercedes lance un message positif : oui, il peut arriver que cette épreuve se traverse sans encombre. Sources : • Can some postmenopausal women with breast cancer skip chemotherapy? By T. Salewa Oseni, MD — https://www.health.harvard.edu/blog/can-some-postmenopausal-women-with-breast-cancer-skip-chemotherapy-2021041522344 • SWOG researchers identify group of breast cancer patients who can skip chemo. EurekAlert! December 1, 2021. Accessed December 2, 2021. https://www.eurekalert.org/news-releases/936214 • Chimiothérapie, INCa — https://www.e-cancer.fr/Patients-et-proches/Les-cancers/Cancer-du-sein/Chimiotherapie

Hey everyone, I'm sharing some very positive news in this podcast! After 4 1/2 years with multiple recurrences and 9 TURBT surgeries, I finally started on BCG. In this podcast, I'll explain why there was a delay with this important treatment and what my experience has been since starting it last fall. If you're on the fence about beginning BCG treatments, you'll want to hear about my personal experience in this podcast. I also discuss blue light cystoscopy and how it's not only becoming a standard of care among many urologists, but an absolute necessity in my book for those with multiple tumor recurrence or carcinoma in situ. So grab a cup of coffee and settle in as we learn from each other and travel this journey together! Wishing wellness for us all, Cindy P.S. If you'd like to be my guest on Bladder Cancer Patient-to-Patient, please click the voice mail link under one of my podcasts. You can leave me a message about your experiences, diagnosis, emotions, treatments... whatever you'd like to share with others. Interviews are done by phone and the magic of technology! So please reach out and leave me your contact information. I'd love to chat and maybe include your experience in an upcoming episode. Disclaimer: THIS PODCAST IS NOT INTENDED TO BE A MEDICAL ALTERNATIVE FOR PHYSICIAN CARE, NOR TO DIAGNOSE, TREAT, CURE OR PREVENT ANY ILLNESS OR DISEASE. ALWAYS CONSULT WITH A PHYSICIAN FOR PROFESSIONAL MEDICAL ADVICE. #bladdercancer #bladdercancerawareness #bladdercancertreatment #urology #bladdercancersupport #cancerpatient #cancerpodcast #TURBT #BCG #kickcancer #cancersucks #patientadvocacy #cancerresearch #immunotherapy #survivorship Search: BCG intravesical treatment for bladder cancer, bacillus Calmette-Guerin, SWOG schedule, BCG treatments, benefits of BCG for bladder cancer, what is BCG --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app --- Send in a voice message: https://anchor.fm/cindy-lawson8/message Support this podcast: https://anchor.fm/cindy-lawson8/support

Hey everyone! BCG is known as the 'gold standard" for early-stage, non-muscle-invasive bladder cancer treatment. In this episode, I discuss BCG treatment for bladder cancer... What it is; how it works as immunotherapy; its advantages and sometimes side effects, as well as my own experience in receiving BCG treatments and what to expect. You'll learn what I've learned about shortages of BCG and potential alternative treatments that are available. If your doctor has recommended BCG, you'll definitely want to take a listen to this episode! Wishing wellness for us all, Cindy Disclaimer: THIS PODCAST IS NOT INTENDED TO BE A MEDICAL ALTERNATIVE FOR PHYSICIAN CARE, NOR TO DIAGNOSE, TREAT, CURE OR PREVENT ANY ILLNESS OR DISEASE. ALWAYS CONSULT WITH A PHYSICIAN FOR PROFESSIONAL MEDICAL ADVICE. #bladdercancer #bladdercancerawareness #bladdercancertreatment #urology #bladdercancersupport #cancerpatient #cancerpodcast #TURBT #BCG #kickcancer #cancersucks #patientadvocacy #cancerresearch #immunotherapy #survivorship Search: BCG intravesical treatment for bladder cancer, bacillus Calmette-Guerin, SWOG schedule, BCG treatments, benefits of BCG for bladder cancer, what is BCG, non-muscle-invasive bladder cancer, BCG side effects --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app --- Send in a voice message: https://anchor.fm/cindy-lawson8/message Support this podcast: https://anchor.fm/cindy-lawson8/support

Guest host, Dr. Neeraj Agarwal, ASCO Daily News editor-in-chief and director of the Genitourinary Cancers Program at the University of Utah's Huntsman Cancer Institute, discusses the practice-changing KEYNOTE-564 and SWOG 1500 trials with Drs. Toni Choueiri and Sumanta "Monty" Pal. Dr. Choueiri is director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute and Dr. Pal is co-director of City of Hope's Kidney Cancer Program and associate editor of Cancer.Net. (This episode was recorded on 11/18/2021) Transcript Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News podcast. I am Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program, and the professor of Medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to welcome two internationally recognized leaders in the field, Dr. Toni Choueiri and Dr. Sumanta (Monty) Pal, for a discussion about two practice-changing studies in kidney cancer published this year-- KEYNOTE-564 and SWOG 1500. As a quick introduction, Dr. Choueiri is the director of Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute. He's also the Jerome and Nancy Kohlberg Chair, and professor of medicine at the Harvard Medical School. Dr. Sumanta "Monty" Pal is a professor in oncology, and co-director of City of Hope's Kidney Cancer Program, and he is an associate editor of cancer.net of ASCO. Our full disclosures are available in the show notes. And disclosures relating to all episodes of podcasts can be found on our transcripts at ASCO.org/podcast. Toni and Monty, what a day it has been for our patients with kidney cancer. I woke up with the news of the U.S. Food and Drug Administration (FDA) approval of the first ever adjuvant immunotherapy for patients with renal cell carcinoma. It is so great to have you both on the podcast today.   Dr. Monty Pal: Glad to be here. Thanks, Neeraj.   Dr. Toni Choueiri: Thank you, Neeraj. So glad to be here.   Dr. Neeraj Agarwal: So, let me start by asking questions to you first, Toni. So, you recently published the primary results of the phase 3 KEYNOTE-564 study, showing the efficacy of adjuvant therapy with pembrolizumab and immune checkpoint inhibitor in patients with renal cell carcinoma. And this study led to the approval of pembrolizumab this morning. So, please tell us more about the study design and why did you do this study.   Dr. Toni Choueiri: Thank you, Neeraj. And thank you, really, ASCO for this wonderful podcast series. And a big hit, I always listen to them when I'm driving or jogging. And really, thanks for this opportunity because kidney cancer adjuvant therapy has been something like a holy grail we're trying to find for a long, long time. The first adjuvant trial, a randomized trial, in renal cell cancer was in 1973 with radiation therapy. And since that time, all the trials except for one have been a complete failure in a way. And the first adjuvant immunotherapy trial was with old immunotherapy cytokine that we don't use much anymore and was in 1992. I was not done with medical school. I was not actually done with high school at that time, let alone medical school. And now that we have, as we all know, a revolution in the oncology field through these immune checkpoint inhibitors that reinvented immunotherapy in cancer, and now that pembrolizumab has shown activity in patients with more advanced disease, we thought about taking this into the adjuvant setting, a setting of patients where they were subjected to surgery. But on the pathology report, we knew that their risk of this cancer coming back, of recurrence, is somewhat intermediate high or high. These are patients that have stage 2 but grade 4, stage 3, D3, D4. These are patients that had node-positive resected. And we took even patients where the kidney is out, but, also, they had a removal of a metastatic site--let's say a lung metastasis--within a year of removing the kidney. And we know these patients we refer to as M1NED are at quite high risk of recurrence. And we randomly assigned 994 patients to receive pembrolizumab for a year versus placebo. And after a median follow-up of only 2 years--so I want to insist here that this is short for any trial in general--we saw a decrease in the risk of recurrence or death. The hazard ratio for disease-free survival was 0.68. So, a 32% decrease in the risk of recurrence or death. We looked at safety, and we already are familiar in the field of GU oncology with pembrolizumab. And we didn't see when we looked at the safety profile any surprises, any enhanced toxicity. Of course, immune-related adverse events are the number one concern with pembrolizumab. There were no deaths on trial related to pembrolizumab. We saw around 7% of patients needing high dose steroid to medicate these immune-related adverse event, and some patients had to come off therapy for that. We also took a look, Neeraj, an early look, at overall survival. We only had 25% of events, 51 deaths. And we did not meet the very rigorous statistical significance that is needed to say that study is positive for overall survival. But the hazard ratio was 0.54, a 46% decrease in the risk of death, which is kind of encouraging. And after a year, the curve starts to separate. Before a year, they're not separating. And that is consistent with prior studies in general.   Dr. Neeraj Agarwal: This is a very interesting point you just raised, that DFS, disease-free survival, is strongly positive. And even overall survival is trending in the right direction, right?   Dr. Toni Choueiri: Correct.   Dr. Neeraj Agarwal: That's great. So obviously, I would like to raise another point here. When we talk about adjuvant study, we usually think about a localized kidney cancer, which is removed by the surgeon, and then [the] patient is coming to see us for treatment in adjuvant setting. But this study, I would like to highlight, as you said, also included patients who had oligometastatic disease, had successful surgical removal of the oligometastatic disease, and they were also eligible for this trial.   Dr. Toni Choueiri: Yes, absolutely. And I think this is somewhat on the recent side in clinical trials in kidney cancer. The reason for that is that, in practice, we see those patients. And we even had two small trials in the TKI era with sorafenib and pazopanib, small studies, were also completely negative. So, we thought here that we should not exclude these patients. They end up being 6%, 7% of all participants, but this remains an area of unmet medical need.   Dr. Neeraj Agarwal: So, how is the hazard ratio in those patients who had metastatic disease removed and then treated with pembrolizumab?   Dr. Toni Choueiri: Yeah, it was very low. It was 0.2, so 0.29. And this was great to see. I don't want to go into really over-interpreting these results. All the hazard ratio--when you look at subgroup analysis or in the forest plot, all the hazard ratio are less than 1. We didn't see something--let's say 1.5--in favor of pembrolizumab. Now you go into a smaller subgroup, then your confidence intervals are very large and hard to interpret, except that to say, look, on average there could be a significant benefit here, but we can't tell.   Dr. Neeraj Agarwal: Sure, absolutely. I agree with you. So, how this is going to affect the current treatment paradigm, which is for patients with newly diagnosed metastatic RCC, where combination of VEGF-TKI plus immunotherapies (IOs) or IO/IO combinations have become standard of care or treatment paradigm?   Dr. Toni Choueiri: I do believe it will be a standard of care currently in the right population. There are a lot of unanswered questions, but that will be answered hopefully with more follow up. We have already, beside these results, reported--so these results were reported in the plenary session at the 2021 ASCO [Annual Meeting]. But later on, another analysis dealing with patient-reported outcome and quality of life was reported at ESMO and also showed no detriment in quality of life--that's the voice of the patient--no detriment with pembrolizumab (pembro). There is a lot still to do and a lot of unanswered questions, such as the non-clear cell histology, those patients who had surgery of their metastatic disease more than a year. But most important, I think, two questions. One, how can you know from the get-go who are the patients that need adjuvant pembrolizumab? We do not have any valid ctDNA. And I know Dr. Pal was involved with a lot of these type of research. We don't have any ctDNA test that is really that faithful and sensitive in the MRD space in renal cell. Many of us are working, so we don't know. We may end up over-treating patients that need surgery only. And actually, we may end up under-treating patients that need, perhaps, pembro, and another drug. And the second thing in those patients--and I hope it does not happen, but unfortunately, it will to some extent--whose tumor progress on adjuvant pembrolizumab, what do you do? What's the treatment paradigm? And actually, there is no data. This is a data-free zone. And I would think somebody whose tumor progressed, tumor continued to grow or grows, while they're actively on pembrolizumab, on IO, is way different than someone whose tumor comes back after 2 or 3 years from stopping the drug. Should we treat them with the same drug? Should we treat them with the TKI plus IO? Luckily, there are trials that are ongoing in patients whose tumor progressed after PD-1/PD-L1 inhibitor to give them a TKI as a control arm, or a TKI plus an immune checkpoint inhibitor. And I know Dr. Pal is very heavily involved with such trials. So, hopefully, we will answer this question, but not anytime soon.   Dr. Neeraj Agarwal: Very interesting, and definitely new results are posing new challenges in how we practice medicine here in the coming future. So, Monty, you are leading a trial with a very similar trial with atezolizumab. And I'm really hoping, we are all really hoping, that we see the other trial being positive, so we have more treatment options for our patients.   Dr. Monty Pal: I couldn't agree with you more. I mean, I definitely think that Toni's study really adds a lot of fuel to the fire suggesting that this strategy of adjuvant immunotherapy may be successful in localized renal cell.   Dr. Neeraj Agarwal: And I'm not going to really delve into the side effects of pembrolizumab and atezolizumab because these drugs are used quite often. They are in widespread use for different types of cancer. But just a quick question, any safety signal, Toni? Did you see any safety signal with pembrolizumab in this patient population?   Dr. Toni Choueiri: Yeah, this is an excellent question. So, nothing that would be different than using pembrolizumab overall knowing in other diseases as a single agent. So, this drug not first in human, as you know, and it's been approved in combination or as a single agent in many diseases. A tumor that the three of us treat is bladder cancer, and we know from another study how to use pembrolizumab. I think that the use of corticosteroid is somewhat of an objective way, at least to me, in looking at immune-related adverse event. And it has been between 5% to 10%, so we're not way off here. But there is no doubt that there are patients that we had no death on trial attributed to drug that may have, with pembrolizumab, some serious toxicities. We had patients that had autoimmune diabetes, hypophysitis, pneumonitis--quite uncommon, but not impossible.   Dr. Neeraj Agarwal: We'll still need to keep an eye for that, basically.   Dr. Toni Choueiri: No doubt.   Dr. Neeraj Agarwal: Yes. So, changing gears, let's talk to you, Monty. You recently presented the primary results of the SWOG 1500 trial in patients with metastatic non-clear cell renal cell carcinoma. Could you please tell us why you did this study and how this study's design was unique compared to similar studies in this setting?   Dr. Monty Pal: Yeah. No, absolutely. Toni did a great job of outlining areas that are sort of free of data in the adjuvant space, particularly with immunotherapy. I think that data-free area for us in kidney cancer for a long time has been non-clear cell histology. We just don't really know how to treat them. And I actually got advice from Toni when I was devising SWOG 1500. We planned it out as a very simple study comparing sunitinib and cabozantinib. And Toni will remember this history well. It sort of went through several iterations. The study blossomed into a six-arm trial. Ultimately, it turned into a four-arm study, looking at sunitinib versus cabozantinib versus two other MET inhibitors--savolitinib and crizotinib. And ultimately, the study was boiled down to essentially what we'd originally proposed. Two of the MET inhibitors--savolitinib and crizotinib--failed to surpass that initial analysis for PFS. So, ultimately, we demonstrated a superiority with cabozantinib over sunitinib for progression-free survival.   Dr. Neeraj Agarwal: So, what is the current treatment paradigm for patients who have newly diagnosed metastatic papillary RCC now?   Dr. Monty Pal: I think for patients who don't have genomic selection, I think that cabozantinib remains the standard. I really want to champion- and maybe Toni can talk a little bit more about this--a study that Toni is leading called the SAMETA trial, which I think has a really innovative design. And it's going to be genomically characterizing patients and randomizing to savolitinib with durvalumab or sunitinib. Tell me, Toni, if I have the design right there.   Dr. Toni Choueiri: Yes. Actually, this is a specific study in a specific population. It's not in papillary RCC as much as in those 30%, 40% of papillary RCC that have MET-driven tumors, so MET alteration, whether through chromosome 7 duplication, through chromosome 7 trisomy, through mutation or amplification. These patients will get either control arm or they will get savolitinib, which is a pure MET inhibitor that is devoid of VEGF-related toxicities, savolitinib plus durvalumab, or durvalumab alone. So, two experimental arms and one control. And the reason for this is we saw activity and quite a good toxicity profile with savolitinib, a pure MET inhibitor, over sunitinib in an earlier trial that was sunitinib against savolitinib in selected patient populations. The study had to close early. So, despite the numerical difference, this was not statistically significant. And then in another study led by Dr. Powles and colleagues, there was also some interesting activity how durvalumab could augment that activity. So, we're launching a phase 3 trial with three arms that you described very well.   Dr. Neeraj Agarwal: That's wonderful. So, what are the next steps, Monty? I mean, this is amazing to see you designing an investigator-initiated trial. This was your concept. You designed it. You built this to be a huge multicenter trial, which was open across the country, funded by the National Cancer Institute. And congratulations for making that happen. It's rare for us to see these trials going from a concept stage to a national trial, and then changing the standard of care. So, what are the next steps now for you and your team in SWOG for papillary RCC or metastatic papillary RCC? How do you build out further with the backbone of cabozantinib?   Dr. Monty Pal: I really appreciate the question, Neeraj. It's so critical to understand that we're just not quite done yet. Toni's study, as I've mentioned, is incredibly innovative. I'm also really thrilled to be working with someone who you've mentored so well, Ben Maughan, at the Huntsman Cancer Institute in Utah. And he's actually designed a brilliant study, which we're going to be leading together, which looks at cabozantinib with or without atezolizumab. Recently, in a study that you and I and Toni were a part of that we just published in JCO, we actually saw quite impressive response rates with the combination of cabozantinib and atezolizumab in patients with papillary RCC, around 47%. Those response rates were actually replicated in a separate study run by Joe Lee at Memorial Sloan Kettering. In the context of papillary disease response rates were again above a threshold of around 40%. So, I think there's something to it. But until we really subject this to randomization, I think we're not going to know whether or not cabo plus IO is standard. So, I encourage everyone to consider Toni's study. I encourage everyone to look out for our trial of cabo plus or minus atezo, which should be rolling out next year.   Dr. Neeraj Agarwal: What is the name of the trial, or the number, for our audience?   Dr. Monty Pal: Yeah, we lucked out with another great number. We got 1500 for the first trial. This is going to be SWOG 2200. So SWOG 2200, and I think it's due to open maybe in the first quarter of 2022.   Dr. Neeraj Agarwal: That's fantastic news. Any new signal? We know cabozantinib is already approved for our patients with metastatic RCC, courtesy METEOR trial led by Dr. Choueiri. Toni, it's amazing to see how many times you have changed standard of care for our patients with metastatic RCC. So, any new safety signal of cabozantinib in this patient population with metastatic papillary RCC?   Dr. Monty Pal: Nothing that appreciated. The toxicity profile was pretty much on par with what you'd anticipate for cabozantinib in the setting. Major side effects were hypertension, hand-foot syndrome, [and] diarrhea. Nothing that really sort of stood out relative to what we would expect in a clear cell population of patients.   Dr. Neeraj Agarwal: That's great. Any final messages for our patients, for our audience, for our listeners?   Dr. Toni Choueiri: Well, let me start, and maybe Monty can add. It's been, and it hopefully will continue to be, this humbling experience, where median survival from metastatic RCC in mid-2000--not long time ago during our training--has been 1 year. And now in metastatic disease, it's 4 to 5 years. And that is only going to get better. And then it's even more humbling to be in a time where you can talk about adjuvant treatment in this disease, renal cell cancer, that continues every year to kill, unfortunately, 14,000 Americans. That's just in the U.S. alone. So, we have to continue in getting more targets, more drugs, more reasonable combination, and the right patient, whether through specific biomarker that are tissue or blood-based or specific liquid biopsies that can tell you who has and who doesn't have cancer at the microscopic levels.   Dr. Neeraj Agarwal: Thank you. How about you, Monty? Any final message for our audience?   Dr. Monty Pal: I couldn't have summarized it better than Toni, just such a wonderful statement around optimism for what we've achieved so far and what's yet to come. And if I could emphasize to anyone in the audience today the need to keep progressing the field further with clinical trials, I think that would be my underlying message.   Dr. Neeraj Agarwal: Thank you again, Toni, Monty, for your valuable insights and thoughts. Thank you for all the inspiration. This is indeed so inspiring to see your work, which is changing the lives of our patients on a daily basis. Our listeners will find links to your studies in the transcript of this episode. I wish you all the best.   Dr. Toni Choueiri: Thank you.   Dr. Neeraj Agarwal: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you so much.   Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Pfizer, Merck    , Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Foundation Medicine, Gilead Sciences Research Funding (inst.): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas   Dr. Sumanta (Monty) Pal: Consulting or Advisory Role: F. Hoffmann LaRoche, F. Hoffman Research Funding (inst.): Eisai, Genentech, Roche, Exelixis, Pfizer Travel, Accommodations, Expenses: Genentech, Seattle Genetics   Dr. Toni Choueiri: Employment: Dana Farber Cancer Hospital Leadership: Dana Farber Cancer Hospital, NCCN, KidneyCan, ASCO, ESMO Stock and Other Ownership Interests: Pionyr, TEMPEST Honoraria: NCCN, UpToDate, Michael J. Hennessy Associates, ASCO, Harborside Press, Analysis Group,                AstraZeneca, Alexion Pharmaceuticals, Sanofi/Aventis, Bayer, Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck          , Novartis, Peloton Therapeutics , Pfizer, Corvus Pharmaceuticals, Ipsen,                 Foundation Medicine, Eisai, PlatformQ Health, Clinical Care Options, Navinata Healthcare, Kidney Cancer Journal, Exelixis, Prometheus, Lpath, NEJM, Lancet Oncology, Cerulean Pharma, alligent, EMD Serono, HERON, Lilly, Janssen Oncology, IQvia, Aveo, and NCI. Consulting or Advisory Role: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus Laboratories, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Journal, Clinical Care Options, Paltform Q, Navinata Healthcare, Harborside Press, ASCO, NEJM, Lancet Oncology, EMD Serono, HERON, Lilly, ESMO, NiKang Therapeutics, Kanaph Therapeutics, Infinity Pharmaceuticals, and Aravive Research Funding (inst.): Pfizer, Novartis, Merck, Exelixis               , TRACON Pharma, GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca, Peloton Therapeutics, Roche/Genentech, Celldex, Agensys, Eisai, Takeda, Prometheus, Ipsen, Corvus Pharmaceuticals, Cerulean Pharma, Seattle Genetics/Astellas, Bayer, Foundation Medicine, Roche, Calithera Biosciences, Analysis Group, NCI, GATEWAY for Cancer Research, and Congressionally Directed Medical Research Programs (DOD) Patents, Royalties, Other Intellectual Property (inst.): International Patent Application No. PCT/US2018/058430, entitled “Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy, International Patent Application No. PCT/US2018/12209, entitled “PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response Patents, Royalties, Other Intellectual Property: ctDNA technologies Travel, Accommodations, Expenses: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, UpToDate, Peloton Therapeutics, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Journal, Clinical Care Options, PlatformQ Health, Harborside Press, Navinata Healthcare, NEJM, Lancet Oncology, EMD Serono, HERON, Lilly, and ESMO Other Relationship: Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, Parexel   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Journal Review in HPB – Surgical Outcomes of the SWOG S1505 Trial Description: Neoadjuvant chemotherapy remains a controversial topic for resectable pancreatic adenocarcinoma. This randomized trial examines surgical and clinical outcomes from peri-operative regimens, mFOLFIRNOX and gem-Abraxane. The HPB Behind the Knife team dives into the specifics of the trial design and findings, as well as sits down with the Principal Investigator Dr. Syed Ahmad himself to ask about the behind-the-scenes decision-making and the investigations yet to come.  Links to Papers Reviewed in this Episode Surgical Outcome Results from SWOG S1505: A Randomized Clinical Trial of mFOLFIRINOX Versus Gemcitabine/Nab-paclitaxel for Perioperative Treatment of Resectable Pancreatic Ductal Adenocarcinoma Ann Surg. 2020 Sep;272(3):481-486 https://pubmed.ncbi.nlm.nih.gov/32740235/ Efficacy of Periopertive Chemotherapy for Resectable Pancreatic Adenocarcinoma: A Phase 2 Randomized Clinical Trial JAMA Oncol. 2021 Mar;7(3):421-427 https://pubmed.ncbi.nlm.nih.gov/33475684/  Guest:  Syed Ahmad, MD (@SyedAAhmad5) is a Professor of Surgery and Chief of the Division of Surgical Oncology at the University of Cincinnati College of Medicine, and the Director of the UC Cancer Center. He is the surgical chair of SWOG, and a co-Principal Investigator of the SWOG S1505 study in addition to numerous other national trials for pancreatic cancer. Hosts: Timothy Vreeland, MD, FACS (@vreelant) is an Assistant Professor of Surgery at the Uniformed Services University of the Health Sciences and Surgical Oncologist at Brooke Army Medical Center Daniel Nelson, DO, FACS (@usarmydoc24) is an Associate Professor of Surgery at the Uniformed Services University of the Health Sciences and Surgical Oncologist at William Beaumont Army Medical Center Connor Chick, MD (@connor_chick) is a PGY-4 General Surgery resident at Brooke Army Medical Center Lexy (Alexandra) Adams, MD, MPH (@lexyadams16) is a PGY-3 General Surgery resident at Brooke Army Medical Center Other References from this Episode FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer N Engl J Med. 2018 Dec 20;379:2395-2406 https://www.nejm.org/doi/full/10.1056/NEJMoa1809775 APACT: phase III, multicenter, international, open-label, randomized trial of adjuvant nab-paclitaxel plus gemcitabine (nab-P/G) vs gemcitabine (G) for surgically resected pancreatic adenocarcinoma J Clin Oncol. 2019 May 20;37:no. 15 suppl:4000. https://ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.4000 Operative Standards in Cancer Surgery: Pancreatoduodenectomy: Superior Mesenteric Artery Dissection American College of Surgeons. 2020 Jun 18. https://www.facs.org/quality-programs/cancer/acs-crp/oscs https://www.youtube.com/watch?v=bs8xlCr5XyE The AHPBA Podcast  The Americas Hepato-Pancreato-Biliary Association https://podcasts.apple.com/us/podcast/the-ahpba-podcast/id1501441845   Please visit behindtheknife.org to access other high-yield surgical education podcasts, videos and more.  

In part one of this two-part ASCO Education Podcast episode, Dr. Sonali Smith (University of Chicago Medicine) and Dr. Paolo Strati (MD Anderson Cancer Center) discuss the application of recently approved therapies for diffuse large B-cell lymphoma through examination of challenging patient cases. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: education.asco.org | Contact Us Air Date: 10/20/21   TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] SONALI SMITH: Hello, and welcome to this episode of the ASCO Education Podcast highlighting new therapies for lymphoma. My name is Dr. Sonali Smith, and I'm a hematologist and medical oncologist specializing in lymphoma and clinical investigation in lymphoma. I'm also the Elwood V. Jensen Professor and chief of the hematology/oncology section at the University of Chicago, and very excited to be joined by my colleague, Dr. Paolo Strati. PAOLO STRATI: Good morning to everybody. My name is Paolo Strati. I'm a hematologist and medical oncologist and an assistant professor in the Department of Lymphoma/Myeloma, and in the Department of Translational Molecular Pathology at MD Anderson Cancer Center, Houston, Texas. And I'm also the clinical director for the Lymphma Tissue Bank. In part one of this podcast episode, we will discuss the adoption of recently approved therapies for diffuse large B-cell lymphoma, such as selinexor, tafasitamab, Liso-Cel, and Lonca-T. These therapies have transformed care for patients with this disease. And we'll start our conversation today with a patient case. SONALI SMITH: Great. Well, I'll go ahead and present a patient to you, Paulo. So this is a 78-year-old man with diffuse large B-cell lymphoma that is the germinal center-derived subtype. It is not double expressor, it is not double-hit. He has advanced stage disease with a high IPI, as well as the high CNS IPI. Luckily, his performance status is zero and he has no significant comorbidities or other health conditions. He received frontline dose-adjusted EPOC-R with intrathecal methotrexate for six cycles. But at the end, he had a partial remission. So how do you select your salvage therapy in this situation? Are you concerned about using agents targeting CD19 in the second line, given the potential need to use anti-CD19 cellular therapy, or CAR-T in the third line? PAOLO STRATI: This is a very interesting and unfortunately not uncommon case. And thank you, Sonali, for asking these very important questions. Technically, a platinum-based regimen followed by autologous transplant will be a standard answer and may be feasible. Because as you mentioned, this patient has a good performance status and non-meaningful comorbid health conditions. However, patients who are refractory to a frontline anthracycline-based regimen, such as in this case, with achievement only of partial remission at the end of frontline dose-adjusted EPOC, can potentially experience a suboptimal outcome following the standard approach with a platinum-based second line regimen. And as such, alternative strategies may be needed. To this regard, the combination of tafasitamab that, as you know, is a monoclonal antibody targeting CD19, and lenalidomide, an oral immunomodulatory agent, a combination which is currently approved by the FDA in the United States as a standard second line option for transplant ineligible patients, would be a great option in this case. Data from the three year follow-up of the phase II study that has brought to the FDA approval this combination, the L-MIND had been recently presented and have showed the complete remission rate of 40% and immediate duration of response of 44 months, including patients who received this regimen as a third line or beyond. So there is, of course, a biological concern by targeting CD19 in second line. These may potentially impact a third line use of an autologous anti-CD19 CAR-T, because CD19 downregulation may potentially be a mechanism of escape to tafasitamab. And recent data has shown the CD19 levels are strongly associated with the efficacy of CAR-T cell therapy in patients with large B-cell lymphoma. Small retrospective studies have shown that autologous anti-CD19 CAR-T can be safely and effectively used after antibodies or antibody drug conjugate targeting CD19. But we need a significantly larger and prospective data, including serial tissue biopsy in these patients before considering this combination as a standard practice in patients for whom we plan to use CAR-T as a third line. Until then, I would be cautious in using second line tafasitamab in patients, again, for whom there is a potential plan for anti-CD19 autologous CAR-T in third line. And if necessary, limited to very selective cases. Finally, recent press releases have anticipated the two autologous anti-CD19 CAR-T products, Axi-Cel and Liso-Cel, are superior to autologous settings transplanted in second line. And so in the near future, CAR-T cell therapy may become a standard second line option. And that would be an ideal option in primary chemorefractory patients as the case that you presented here. SONALI SMITH: Yeah, I agree. There are a tremendous number of options. And having anti-CD19 products as well as autologous stem cell transplant, the sequencing will be an evolution. So going back to this patient, he received tafasitamab and lenalidomide for two cycles with no significant toxicity, but unfortunately, he had further progression after two cycles based on a PET/CT scan. So what are your next steps? Would you move directly to an autologous anti-CD19 CAR-T cell therapy now? Would you re-biopsy before that? And how would you select among the three available CAR-T products? PAOLO STRATI: These are not easy questions, particularly the selection of one out of three available CAR-T products. As you said, there are currently three autologous anti-CD19 CAR-T products approved by the FDA in the United States for the treatment of large B-cell lymphoma in third line or beyond. And these are Axi-Cel, Tisa-Cel, and Liso-Cel. For all of them, the best outcome is observed for patients who have a low turmor burden at time of CAR-T infusion. And they need to either select patients with no bulky disease or to decrease it through bridging therapy. And as we define bridging therapy given between leukapharesis and CAR-T infusion. Unfortunately, there is currently no standard bridging therapy and all FDA products approved in third line can potentially be used in this specific scenario that you described, including polatuzumab with bendamustine/rituximab, selinexor, and Lonca-T, of course, beyond tafasitamab and len that has already been used in this case. Of course, when selecting a bridging therapy, there are many disease-related and patient-related factors to take into consideration, including the need to preserve the host immune microenvironment that we all know is crucial for the subsequent activity of CAR-T cells. And also, we need to give into consideration the need to preserve as much as possible, as we discussed previously, in CD19 expression. To this regard, and going back to one of your questions, I strongly recommend to re-biopsy patients if any bridging therapy is used between bridging therapy and CAR-T infusion in order to document CD19 expression before CAR-T infusion. When it comes to CAR-T product selection, as I said, it's a really difficult decision to do. And we don't have at this time randomized trials in third line. And as such, the decision is really left to the treating physician based on multiple factors. But all of the limitations of inter-study comparison, efficacy seems to be pretty much the same for the two products, maybe slightly higher based on the recent second line data. But Axi-Cel and Liso-Cel as compared to Tisa-Cel, and also as suggested by recent press release. However, due to the fact that Liso-Cel and Tisa-Cel have less potent co-stimulatory domain for 1BB instead of CD28, the rate of CRS and ICANS, the two main toxicities associated with CAR-T cell therapy, is usually lower with this to the point that some centers are able to infuse them in the outpatient setting, whereas Axi-Cel is almost always infused in the inpatient setting so the toxicity can be monitored more closely. So with older patients or those who have comorbid health condition, Tisa-Cel and Liso-Cel may be a safer option, though there's a lot of research going on trying to mitigate toxicities associated with Axi-Cel. Finally, it's important to keep in mind manufacturing time. Axi-Cel is manufactured in an average of 17 days, whereas Tisa-Cel and Liso-Cel take typically longer than three to four weeks. This can be itself a determining factor, particularly for patients who are quickly progressing and where immediate treatment is needed. SONALI SMITH: Yeah, I agree. I think there are going to be many patient product and disease-based factors that will impact both the effectiveness as well as the toxicity. And you did a really great job of explaining the role of the co-stimulatory domain potentially in some of that, as well as all of the products that are out there. It's definitely a complicated area. Going back to our patient, so he did undergo leukapharesis for Liso-Cel and received third line polatuzumab and rituximab without bendamustine. The restaging PET/CT after two cycles showed a PR with a significant decrease in tumor burden, and repeated biopsy showed high expression of CD19 by flow cytometry. He then proceeded with Liso-Cel, which was relatively well tolerated. There was only grade 1 cytokine release syndrome and no ICANS, so no neurotoxicity. And his day 30 PET/CT showed a complete remission. Unfortunately, the 90 day PET/CT showed progression. So Dr. Strati what is the outcome for patients who relapse after CAR-T? Do you recommend to re-biopsy? And what are the efficacy data for FDA approved agents for these patients? And I know this is a long question, but is there any role for repeated CAR-T or allogeneic transplant now? PAOLO STRATI: Unfortunately, currently, the outcome of patients with large B-cell lymphoma relapse or progress after autologous anti-CD19 CAR-T is suboptimal, with a life expectancy, unfortunately, shorter than six months. Hence, the need to be creative and customize treatment based on biological data. To this regard, I think it's crucial to repeat a tissue biopsy to guide subsequent therapy. As mentioned previously, there are currently four products approved by the FDA for patients with large B-cell lymphoma in third line and beyond. Two of these target CD19, tafasitamab plus lenalidomide and Lonca-T One targets CD79B, polatuzumab combined with bendamustine and rituximab. And one is an SPO1 inhibitor, selinexor. While we have no data for selinexor in patients who relapse or progress after CAR-T cell therapy, limited prospective data showed that a progression-free survival in the order of weeks is usually observed for patients who receive polatuzumab with or without bendamustine and rituximab after CAR-T cell therapy. So I would not recommend that. However, there's some interesting activity in the post-CAR-T setting for Lonca-T and for tafasitamab/len is limited to patients who still express CD19 in time of relapse. And of course, it needs to be largely and prospectively further investigated before becoming a standard approach for patients who relapse or progress after CAR-T cell therapy. When it comes to cellular therapy, repeated anti-CD19 CAR-T infusion is not shown to be successful in the original registration studies. So it is not currently something that I would recommend and is not definitely a common practice. And very limited retrospective studies have shown the use of allogeneic stem cell transplants in the post-CAR-T setting may be associated with quite elevated treatment-related mortality. So I don't suggest this as a standard practice in large B-cell lymphoma at this time. This is different from B acute lymphoblastic leukemia, where instead, allogeneic stem cell transplant is becoming progressively a standard approach. And we definitely need more data before using this consistently. While we strive to identify the optimal cell batch therapy for large B-cell lymphoma patients who relapse or progress after CAR-T cell therapy. I think the priority should be given to clinical trials, including CAR-T targeting molecules other than CD19, such as CD20, CD22, CD79B, allogeneic CAR-T there are immediately available, so without the need to wait for manufacturing times. And K-CAR, that may be less toxic than CAR-T and other non-cellular therapy biological agents. So definitely, clinical trials are, at this time, the best approach in patients who relapse after CAR-T cell therapy, as the case that you described. SONALI SMITH: Thank you Dr. Strati. As an update, this patient had repeated biopsy showing a CD19 positive relapse. He consented for a clinical trial with a novel NK-CAR targeting CD19, achieving CR which is still ongoing at nine months. And this case really does represent some of the most exciting advances that we've had for this disease for patients who can tolerate aggressive therapies and have access to clinical trials. PAOLO STRATI: Dr. Smith, I'd like to hear your opinion about another patient with diffuse large B-cell lymphoma. This patient is an 81-year-old man with a history of coronary artery disease and well-controlled diabetes mellitus, who noticed a right cervical lymph node while shaving that seemed to have popped up. He was evaluated by his primary care physician and given a course of antimicrobials. 10 days later, the lymphoma seems to be enlarging and he is referred to ENT pharyngeal biopsy. The specimen is small but shows follicular lymphoma in a portion of the sample. However, there is also concern for larger cells and possible transformation. The patient is also beginning to note night sweats and a decreased appetite. And labs are notable for elevated LDH, 500, and thrombocytopenia with a platelet count of 110. So Dr. Smith, in your opinion, is this specimen sufficient to start treatment? Or should treatment be delayed to get a larger and maybe excisional biopsy? SONALI SMITH: Yeah, thank you for this question. I think this is a challenge we have in the clinic all the time, which is what is a sufficient biopsy specimen to make a diagnosis that allows us to subtype lymphoma? As we know, every lymphoma subtype, the treatment is really guided by the histology and not so much the stage or some other factors. So having a needle biopsy is unfortunately often insufficient. In this case, we have a very strong concern for a possible transformation. And as we know, both follicular lymphoma and diffuse large B-cell lymphoma can mark very similarly when it comes to immunophenotype. Certainly, the germinal center type of diffuse large B-cell lymphoma or any transformed follicular lymphoma will be CD20 positive, CD10 positive, and it really requires architecture to be able to tell whether or not there are sheets of large cells. So the ideal outcome for this patient would be to have a biopsy that is done promptly that allows us not only to confirm whether or not there is histologic evidence of transformation, but also to conduct FISH studies to determine if there's acquisition of a MYC rearrangement. At its core, all follicular lymphoma patients essentially have a transformation of 14;18, leading to BCL2 rearrangement and BCL2 overexpression. During the transformation process, there can be an acquisition of a MYC rearrangement, which would then make this a double-hit lymphoma and certainly has a much worse prognosis and may also prompt a change in treatment if the patient can tolerate more intensive therapy. So my recommendation would be to have a biopsy. Now one other aspect is that sometimes, we don't really have the time to proceed with a biopsy, or the lymph node may be in an inaccessible area. And in that case, there are some other criteria that we can use to assume that somebody has a transformation. Symptoms such as profound B symptoms and elevated LDH, and sometimes, a PET scan with multiple areas of very high avidity, can lead you to feel or suggest that this person has a transformation. There is some controversy over the use of PET and we know it does not confirm a diagnosis of transformation. But in my opinion, this is very suggestive if there are many areas of high SUV. PAOLO STRATI: Thank you, Dr. Smith. I agree completely about the importance, when time allows, to perform either a larger core biopsy or an excisional biopsy, because as you very well-outlined, this has not just a mere diagnostic purpose, but can meaningfully affect treatment planning for patients. And actually, in this case, as you suggested, the patient eventually had multiple core biopsy that showed transformed follicular lymphoma with very evident areas of diffuse large B-cell lymphoma. FISH, as expected for follicular lymphoma, was positive for translocation for TN18, but luckily negative for MYC rearrangement. So fortunately, we didn't have to deal with a double-hit lymphoma. The remainder of his staging showed he had diffuse lymphadenopathy. And PET scan, as you mentioned, has a controversial role in the diagnosis of transformation. So there's some areas that had high avidity with an uptake with an SUV of 1215, whereas other areas were less intense with SUV 618. And usually, heterogeneity in SUV actually helps further supporting diagnosis or transformation. While meta-maps showed follicular lymphoma, no large cells. So movement was isolated in the B-cell lymphoma. So Dr. Smith, at this point, based on the provided information, what's your treatment approach in this older patient and also a patient with comorbid health conditions, but with diffuse large B-cell lymphoma? SONALI SMITH: Yes. The goal of treating any aggressive lymphoma is to obtain remission, and if the remission lasts, to hopefully offer cure to the patient. And when somebody has a transformed lymphoma, of course, there is a dual concern, which is that the aggressive component can potentially be put into remission in a durable way achieving cure. But the indolent component will always need to be monitored, although hopefully, will not be life threatening the way the aggressive component can be. Treating an octogenarian is really challenging, particularly due to comorbidities in this age group and the potential toxicity of chemotherapy. So the standard of care for diffuse large B-cell lymphoma is anthracycline-based chemotherapy. But this, of course, can have significant toxicity in older patients. And in addition, the vincristine can aggravate neuropathy. And I've personally found that the high dose steroids that are part of CHOP can also cause toxicity in older patients and patients who are frail. So unfortunately, the literature is somewhat sparse. But we do have several data sets that can guide management in this particular patient situation. The French published, over a decade ago, the development of R mini CHOP, that includes an attenuated dose of cyclophosphamide, doxorubicin, and vincristine, and leads to some durable remissions and cure. Unfortunately, the long-term overall survival is less than 50% with R mini CHOP. And so although this is an appropriate backbone, there's certainly a lot of room for improvement. And there's also toxicity even with R mini CHOP. So in their initial phase II trial, there was actual deaths related to the R mini CHOP, particularly in the first cycle or two, really necessitating some type of pre-phase help ease patients into the chemotherapy. One of the challenges that we face in the clinic is that when we meet an older patient, we both want to maximize our chance for cure, but also minimize the toxicity that is particularly pronounced. And there is very little data in terms of how to guide this at the bedside. I'm excited that SWOG, with the US Intergroup, is conducting a trial, S1918, which prospectively includes a frailty assessment tool that was developed by the Italian group in lymphoma, and then also includes serial comprehensive geriatric assessment so that we can get a better idea about quality of life both during and after treatment. So there is no great standard of care right now, but I would say that R mini CHOP, outside of a trial, is a very reasonable way to proceed. PAOLO STRATI: Dr. Smith, thank you for outlining so well what we can do to minimize toxicity and to better select patients for this type of treatment. And as an Italian practitioner in the United States, I am very excited that the Italian frailty tool will be used in this SWOG trial. Are there any other ways to further improve safety when we use chemo immunotherapy in older patients or patients with comorbid health conditions? In particular, there is a lot of concern about potentially infectious complications in these patients. And so I'm wondering if there's any routine antimicrobial prophylaxis that you recommend. SONALI SMITH: Yes. I think it's really important to maximize supportive care for our older patients with aggressive lymphomas getting intensive therapy. I did mention the pre-phase, and I would just like to mention that one more time because I do think there's data that providing a brief pre-phase can minimize toxicity with the first cycle. And how this pre-phase is given is highly variable. Again, the data is somewhat limited, but it typically includes steroids given for five to seven days with or without a dose of vincristine. And steroids themselves can have toxicity. And the dose of the steroids, I think, is somewhat controversial. In my personal practice, I use somewhere between 40 to 60 milligrams per day for five to seven days. And I do not typically use vincristine, although a prospective French trial recently did and showed that this significantly improved toxicity. Other complications that can occur really are related to infection. And so, of course, all patients should have growth factor support as per ASCO guidelines. But I also routinely give VZV prophylaxis with acyclovir or valacyclovir. And for the first cycle in particular, I have patients come back to clinic after the first dose one week later to ensure that the counts are stable and that they are doing well. This is really where our team of nurses and other providers who are part of the care team are so important and communication is also very important. PAOLO STRATI: So Dr. Smith, as you suggested, also, this patient actually received mini R-CHOP without any complications. And end-of-treatment PET/CT can showed a VL score of 3, so a complete metabolic remission, potentially. How do you interpret these findings? SONALI SMITH: So response criteria in clinical trials, and then of course, extrapolated to the clinic, have evolved in lymphoma. And the Deauville or the International Prognostic Scoring System that has been used typically defines a uptake relative to liver and mediastinal blood pool. And those patients who have a Deauville 1 to 2, which is less than that bar, is considered negative. And 4 to 5 is positive, with five being the emergence of new sites of adenopathy. The interpretation of a Deauville 3 can be somewhat more complicated, but this really outlines the limitations of just using the SUV or the PET scan uptake to measure response. For my patient and for this patient, the lymph nodes all substantially decreased in size. And having some type of combined interpretation of the uptake, as well as the size that has decreased, I think is going to be a very important part of how we approach patients going forward. So for this patient, I opted for close observation after the completion of therapy and felt that his Deauville 3, along with the decrease in the size of the lymph nodes, was very significant. PAOLO STRATI: I completely agree with that. Where PET scan is an extremely helpful tool, particularly for the management of aggressive B-cell lymphoma, can also become a major challenge when it comes to its interpretation for these borderline scenarios. And as you said, it's very important to add into the equation multiple parameters, including CT findings and overall patient performance status symptoms. So that's all we have for today. Thank you, Dr. Smith. This was a great conversation. We have learned and discussed a lot about diffuse large B-cell lymphoma, including novel biological agents, CAR-T cell therapy, management of elderly patients, and patients with comorbid health conditions and interpretation of PET/CT scan. I think this will be very helpful. And the conversation will continue beyond this podcast. In part 2 of this episode, airing in November, we will discuss new therapies for mantle cell lymphoma and for follicular lymphoma. Thank you so much to all the listeners tuning into this episode of the ASCO Educational Podcast. SONALI SMITH: Thank you. It's been a pleasure to speak with you today. [MUSIC PLAYING] SPEAKER: Thank you for listening to this week's episode of the ASCO e-learning weekly podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive e-learning center at elearning.asco.org.

Dr. Gabrielle Rocque, chair of the 2021 ASCO Quality Care Symposium, breast oncologist and health services researcher at the University of Alabama at Birmingham, and symposium chair-elect, Dr. Stephanie Wheeler, professor in the Department of Health Policy and Management at the University of North Carolina at Chapel Hill, discuss key interventions in quality care and compelling patient perspectives presented at #ASCOQLTY21. Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. On today's episode, we'll discuss promising interventions to improve the quality of care for patients and survivors and other key takeaways from the 2021 ASCO Quality Care Symposium. I'm delighted to welcome the chair and chair-elect of the [ASCO Quality Care] Symposium, Dr. Gabrielle Rocque and Dr. Stephanie Wheeler, for this discussion. Dr. Rocque is a breast oncologist and health services researcher. She is also associate professor of medicine in the Division of Hematology and Oncology and Gerontology, Geriatrics, and Palliative Care at the University of Alabama at Birmingham. Dr. Wheeler is a professor in the Department of Health Policy and Management at the University of North Carolina at Chapel Hill. She also serves as associate director of community outreach and engagement at the UNC Lineberger Comprehensive Cancer Center. My guests' full disclosures are available in our show notes, and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/podcasts. Dr. Rocque and Dr. Wheeler, thanks for being on the podcast today. Dr. Gabrielle Rocque: Thank you for having us. ASCO Daily News: Dr. Wheeler, it was wonderful to have a hybrid event this year, with people participating in person in Boston and virtually. This is surely a sign of things to come. Can you tell us about some of the most important interventions in quality improvement that were presented at the [ASCO Quality Care] Symposium? Dr. Stephanie Wheeler: Absolutely, and thank you so much for hosting us. It was a really terrific [ASCO Quality Care] Symposium. And the fact that we had hybrid engagement from investigators all over the country and internationally was really exciting. There's a couple of intervention classes, if you want to call it that, that I think were particularly inspiring and interesting to me. The first were sets of interventions that focused on strategies to improve goals of care conversations and advanced care planning directives for patients with cancer or people with terminal illness in particular. And I just wanted to highlight a couple of those that I thought were particularly innovative. One was Abstract 8, which focused on using computer modeling and care coaches to increase advanced care planning conversations for people with advanced cancer. And this was presented by Dr. Divya Gupta. And it was just a wonderful example of how we can utilize technology and also care coaches. And in many cases, these don't necessarily have to be clinicians. They sometimes can be community health workers and others who can help direct those conversations and make it more comfortable for people living with advanced disease, and also their families, to consider next steps. In a similar vein, there were two other presentations--Abstract 1 delivered by Dr. Manali Patel and Abstract 2 delivered by Dr. Divya Parikh--that also utilized a similar model in a different care setting. And in those cases, the care settings ranged from VA to integrated health care settings. And we even had a conversation about how to do this work in community rural oncology practices. And I think that this kind of intervention has the potential for translation across a variety of settings. And the next steps are going to be figuring out exactly how to implement it in these settings. So, that's one class that I thought was particularly interesting. And I just want to highlight another group of interventions and studies that I found really innovative. And those were the presentations about hospital at-home models and how we can better deliver oncology care in the comfort of individuals' homes. And I thought Dr. Cardinale Smith did a great job from Mount Sinai describing the landscape of those interventions and the future for this kind of care delivery (“Overview of Programs and Ethics”). ASCO Daily News: Excellent. Great to hear about those promising new approaches. Dr. Rocque, the [ASCO Quality Care] Symposium captured many trends in quality care, including patient-reported outcomes measurement as an important way to monitor quality of care and patients' experiences. Can you highlight the studies that will help inform our listeners about how to integrate patient-reported outcomes into real-world settings? Dr. Gabrielle Rocque: Yeah. This was a major topic of the conference this year to think about how patient-reported outcomes are informative both in traditional research settings and in real-world settings. So, I was really intrigued by the Abstract 154 by Joy Jarnagin. And that abstract talked about how the changes in patient-reported outcomes actually had a very strong association with patients' treatment response, and in fact, was even more informative than those patients' tumor markers and I think show a novel way that patient-reported outcomes can be used. We also saw some more traditional abstracts on patient-reported outcomes. I'd like to highlight Abstract 152 by Valerie Lawhon, which really used patient-reported outcomes to identify patients' experience and their mental health outcomes during the COVID-19 pandemic, and I think provided us some really important insight into the experiences of our patients. And then as you mentioned, there is a lot of focus on real-world settings and how to transition from typical research patient-reported outcomes to a more broad scale implementation. And the session implementing PROs in oncology practice was really outstanding in terms of considering how this can be done. So, Dr. Terry Mulvey from Massachusetts General Hospital presented their experience on how to get these patient-reported outcomes into routine care, and what are some of the challenges associated with that, and how did they have to adapt to make sure that this was doable in real-world settings (“Challenges to Getting Started in a Practice Setting”). I was also impressed with the study by Dr. Raymond Osarogiagbon on the potential populations where there can be barriers of care and their study looking at an intervention in which they're implementing patient-reported outcomes over a wide variety of different practice types across the country (“Potential Populations Where This Can Be a Barrier to Care”). And I think these early insights also pointed us to future questions. Dr. Wynne Norton did a wonderful job of outlining some of the future questions that are likely to come up as we move into an era where patient-reported outcomes are a part of standard of care, and really think about how do we refine these for maximal benefit (“Overview of Current Strategies”). So, I think all of these sessions were highlighting the promise of patient-reported outcomes, as well as the future questions in this space. ASCO Daily News: Excellent. As a specialist in gerontology, geriatrics, and palliative care, please tell us about new approaches that oncologists should be aware of as they strive to provide high quality care for older patients and those receiving palliative care. Dr. Gabrielle Rocque: Absolutely. So, we've talked a bit about the patient-reported outcomes. And I think we'd be remiss in not highlighting the presentation on geriatric assessment--the presentations on the geriatric assessments into clinical practice by Dr. [Rawad] Elias (“Incorporating Geriatric Assessments Into Practice”). And I think this highlights another opportunity for us to move the field forward and take better care of our older adults. In terms of palliative care, there were multiple very informative abstracts. Dr. Wheeler has highlighted a few in the space of care guides or lay health coaches providing support in advanced care planning. In addition, we saw an interesting discussion of caregiver interventions for patients that are receiving--with cancer treatment by Dr. Nick Dionne-Odom (“Caregiver Interventions”). And I think it's important that we remember both the patients and the caregivers who are affected by cancer and by the amount of work that has to be done to support a patient with cancer going through their journey. ASCO Daily News: Absolutely, so important to remember caregivers and their needs and resources that could be available to them as well. Dr. Wheeler, financial toxicity is an enormous concern for many patients and their families, and the oncology care community has been trying for some time to figure out how best to address the concerns of patients and the health care system. Are there any new interventions that we should be aware of? Dr. Stephanie Wheeler: Yes, and I think that the [ASCO Quality Care] Symposium was an opportunity to hear about several of those. And some of them didn't make it onto the main stage but were featured in abstract sessions and poster sessions. So, as we're all well aware, financial toxicity is a multidimensional set of constructs that includes patients and their family's material out-of-pocket burden, as well as the psychological distress and potentially harmful care altering behaviors that financial hardship induces. And so, we continue to hear at the [ASCO Quality Care] Symposium multiple talks about the strain that patients are undergoing, including the non-medical hardship that's introduced by a cancer diagnosis. And that was really interesting, and I think important to document. But I think that where the field is moving is more towards interventions, both behavioral interventions and systems interventions, multilevel approaches to dealing with the hardship itself as well as the importance of policy. So, there were several abstracts that talked about the introduction of biosimilars and generics and how that affected price of many of the oncologic drugs available on the market. And frankly, the message is a bit discouraging. Prices continue to rise. And in some cases, the price increases are not limited to pharmacologic products. In some cases, we saw abstracts presenting the increased cost of surgery, of outpatient care appointments, and things like that as well. So, we're not going to fix the problem by managing drug pricing alone. In terms of patient and family-directed interventions, I thought that there were some interesting abstracts. I want to highlight a number 53--or excuse me, Abstract 43 by Melissa Beauchemin that focused on the existence of hospital specialty pharmacies and partnering with freestanding care coordination organizations to improve access to oncology medications, as well as Abstract 96 presented by Ms. Rachel Marquez which was focused on resolving transportation disparities and access to cancer treatments. These kinds of interventions are obviously patient directed but have tremendous potential. And then I also want to just note a couple of additional studies that are ongoing that are important to recognize in this field. There are at least five National Cancer Institute (NCI)-funded R01 trials underway right now investigating the role of financial navigation and various iterations of it in different care settings. So, I think we will want to look to this meeting as an opportunity to hear about that work as it moves forward. And how that work is implemented is going to be vital, because the types of care settings where it's being done--ranging from AYA populations in Utah, to urban populations in Washington state, to integrated care organizations in Northern California, all the way to parts of rural North Carolina--we're going to see a diversity of outcomes and different ways in which those types of interventions can manifest in those different studies. I also want to note that the NCI has funded a series of supplements through its Cancer Center Core Grant Initiative that are all focused on identification, timely identification of financial toxicity in practice. And many of the investigators leading that work were attending the [ASCO Quality Care] Symposium, and so that will be important to keep an eye on as we move forward as well. ASCO Daily News: Excellent. Dr. Rocque, let's focus on health equity and access. I'd like to ask you about the session on eliminating barriers to clinical trial access. The presenters of this session shared strategies to directly address inclusion and diversity in cancer care. Can you tell us about approaches that caught your attention? Dr. Gabrielle Rocque: Absolutely. So, this was a really great session talking about clinical trial access and barriers, and particularly as it relates to health equity. And so, in Abstract 74, Dr. Joe Unger presented a really interesting conceptual model that highlighted that the barriers to clinical trial access are not necessarily always at the patient level, but they are at the system level, the provider level. And this framework for considering how do we target in the future our ability to engage patients in clinical trials was really important, and I think was complemented well by the patient perspective from Rick Bangs, who's worked closely with SWOG, in thinking about how do patients view clinical trials and how can we better engage them. And I think folding together these different experiences and models to develop future interventions. I also thought the Abstract 75 looking at survival in the real-world analysis was noteworthy. And in particular, the ability to consider patients who are typically excluded from clinical trials based on their laboratory criteria and potentially having something like chronic kidney disease, and how little data there is on those patients who actually, in this study, had different outcomes after chemotherapy for breast cancer. I think when you think about clinical trial access and inclusion, I also think you need to think about how we collect our data and how we consider race and other social determinants of health. So, there were a few other abstracts that, although not in this session, I think were incredibly important for us to consider. The first is Abstract 78 by Ms. Niveditta Ramkumar that talked about the association between rurality and race and surgical treatment and outcomes for non-metastatic colon cancer. And so, she talked a bit about the intersectionality between race and rurality, and I think brings up an important topic that we need to think about these constructs, not only as individual constructs but how they impact each other as we consider analysis in the future. And also Abstract 80 by Dr. Kekoa Taparra, which was a really interesting abstract that talked about the disaggregation of Pacific Islanders in major Asian subpopulations to reveal hidden cancer disparities. So, in this abstract, he discussed how we often lump together different populations, potentially because of small numbers, who really may have very different experiences and characteristics. And I think challenges us to move the field forward by identifying populations in groups that are, in fact, very similar to each other and not just pulling this together. And I think that will have an impact on how we view engaging patients in clinical trials, as well as reporting those clinical trial results that allows our providers to understand how the trial results fit for the patient that is sitting in their clinic for whom they're making their decisions. ASCO Daily News: Indeed. Dr. Wheeler, is there anything that you'd like to add on the issue of access to clinical trials? Dr. Stephanie Wheeler: So, there was an abstract that particularly sparked my attention, [Abstract] 79 presented by Dr. Jenny Xiang about the VA Connecticut Cancer Experience, where universal pre-screening and using computer algorithms to identify patients who might be eligible for clinical trials was used. And I think that this is an important approach that can help us rely less on the assumptions and the biases that exist in clinical care practice about whether a patient may or may not participate in a clinical trial, and instead use the vast amounts of information that we know about them in their electronic health record to try to preemptively identify them and approach them. We know that when patients are asked and invited to be part of trials, they are much more likely to say yes than people assume. And this could be a more unbiased way of assessing that eligibility, and then proactively identifying people, ideally, with a trial navigator. I think that would enable us to potentially overcome some of the barriers that exist and that are, frankly, institutionally biased in many cases. ASCO Daily News: Thank you, Dr. Wheeler. Dr. Rocque, the [ASCO Quality Care] Symposium featured an excellent keynote address by Dr. Ben Corn of Hebrew University of Jerusalem (“Integrating Hope – Real Hope! – Into Clinical Oncology”) and a wonderful lecture by Dr. John Cox, who was honored with the Joseph V. Simone award for advancing quality cancer care (“Reshaping Practice: Necessary Trouble”). Can you share some highlights from their talks? Dr. Gabrielle Rocque: Definitely. So, the keynote address by Dr. Ben Corn was perfectly timed for this meeting. I think everyone has had a difficult past 2 years with the pandemic. And his message of the importance of hope really struck a chord with me and many of the attendees, and how this is something that we can strategically work to improve, and that hope is something we can modify and train for. And so, I'm really excited to both hear this lecture and then also see what's to come in the future in this domain of hope-related research. Another session that I would like to highlight as well is Dr. Cox's talk after receiving the Joe Simone Achievement Award. And his lecture highlighted that change is coming. And he emphasized the importance of changing payment structures to be able to improve the quality of care that patients receive and to be able to leverage those changes for infrastructure that allows us to enable our health system to have a more patient-centered approach with many of the types of interventions that we've been talking about here today. So, I think both of those sessions are really must-watch sessions that I would like to highlight today. ASCO Daily News: Excellent. Well, the [ASCO Quality Care] Symposium also heard some compelling patient perspectives. Dr. Wheeler, can you share some of these messages with us? Dr. Stephanie Wheeler: One of the most powerful sessions in the entire meeting was the very first one, which was focused on the metavivor experience (“The Patient Voice: “Metavivors” and Long-Term Survivorship Care”). And I think because part of the intention of the planning committee was to proactively feature patients' voices at this meeting, this particular session was almost entirely comprised of patients and survivors. And living with advanced disease, as we know now, is very different than it was in the past. And we know that patients living with incurable disease may sometimes go on to live 15, 20, 25 years. And their needs are quite different than patients who have early-stage cancer. And so, this session was impactful because it represented a range of experiences. We heard from a caregiver. We heard from a young woman who's living with stage four melanoma, Dr. Tarlise Townsend (“An AYA Perspective”). And one of the things that I took away from this session in particular was that our approaches in the way that we talk to metavivors has to be fundamentally different, that they want providers to be truthful, they want providers to acknowledge the uncertainty and prognosis and the sometimes complex and rapidly changing regimens that may be available for them in terms of dealing with their disease. But they don't want to be condescended to, they don't want to feel like there's information that is being withheld. One of the things that Dr. Townsend shared that was very powerful was that she talked about how her providers, in many cases, outlined an optimistic future for her and would give her maybe unfair expectations about what the future might hold and think about it in terms of the outlier effect. But that's not the case for many people with her condition. And so, she talked about having to do her own death work--and that's her term--and how much time she spent really trying to understand for herself what the future looked like. And it just resonated so much with me. And everybody on this panel had similar stories to share about their experiences. And it reminded me that at the end of the day, we're all human. None of us deal with uncertainty well. None of us deal with death well, or the prospect of death. But the best that we can do in these situations is to be open and honest and straightforward and recognize the fear and the hope and all of that being intermingled, and really respect the person's autonomy and the person's experience and their ability to make plans for themselves going forward. ASCO Daily News: Thank you, Dr. Wheeler. We will have links to these important patient perspectives in the transcript of this episode, as well as the other abstracts discussed today. Dr. Rocque and Dr. Wheeler, thank you very much for sharing these important highlights from the 2021 ASCO Quality Care Symposium. Dr. Stephanie Wheeler: Thank you for having us. Dr. Gabrielle Rocque: Thank you so much. ASCO Daily News: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclosures: Dr. Gabrielle Rocque: Consulting or Advisory Role: Pfizer, Flatiron Research Funding: Carevive Systems, Genentech, Pfizer Travel, Accommodations, Expenses: Carevive (an immediate family member) Dr. Stephanie Wheeler: Research Funding (institution): Pfizer Foundation Travel, Accommodations, Expenses: Pfizer Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Hayes interviews Dr. Sarah Donaldson and her pioneering work in pediatric radiation oncology.   TRANSCRIPT SPEAKER 1: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] DANIEL HAYES: Welcome to JCO'S Cancer Stories: The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insights into the world of cancer care. You can find all of these shows, including this one, at podcast.asco.org. Today my guest on this podcast is Dr. Sarah Donaldson. Dr. Donaldson has really been instrumental in much of the development of both, in my opinion, modern radiation oncology and especially related to pediatric radiation oncology. Dr. Donaldson was raised in Portland, Oregon. She received an initial undergraduate and nursing degree at the University of Oregon in Eugene and ultimately in Portland. After a few years working as a nurse with Dr. William Fletcher, who I hope we'll get a chance to talk about later, she elected to go to medical school and spend her first two years at Dartmouth and then finished with an MD from Harvard. She was planning to do a surgery residency at the Brigham Women's in Boston but then elected to do an internal medicine internship at the University of Washington and ultimately then a residency in radiation oncology at Stanford. After a residency and a few side trips along the way, she joined the faculty at Stanford and has remained there since. Dr. Donaldson has authored nearly 300 peer-reviewed papers, probably more than that by now. That was when I last looked at her CV a couple of weeks ago, and it seems like she brings them out every week. She has served as president of the American Board of Radiology, the Radiology Society of North America, and the American Society of Therapeutic Radiation Oncology, ASCO's sister organization, of course-- ASTRO. And she also served on the board of ASCO, the board of directors, from 1994 to 1997 and, in my opinion, perhaps as importantly, on the board of directors of the ASCO Foundation for over a decade. She has way too many honors for me to lay out here, but a few that caught my eye. Named after a distinguished scientist in the past, the Marie Curie award for the American Association of Women Radiologists, the Janeway Award from the American Radiation Society, and the Henry Kaplan Award for Teaching from Stanford. And she was the inaugural recipient of the Women Who Conquer Cancer Award from our own Foundation, the Conquer Cancer Foundation. Dr. Donaldson, welcome to our program. SARAH DONALDSON: Thanks so much, Dan. It's a privilege to be talking with you today. DANIEL HAYES: I hope I got all that right. It's pretty tough to cram the distinguished career you've had into about a minute. [LAUGHS] Anyway, I'm going to start out. So I've interviewed a lot of the luminaries and the people who really started our fields or even the subfield within our field, and you yourself had quite a journey. I know you started out as a nurse. Can you just give us some background about going to nursing school and then who and what influenced your decision to become a physician? SARAH DONALDSON: Yes, I did. I can, Dan, and it's an interesting story. Because when I grew up, girls that wanted to go on to college-- and it wasn't all girls didn't go to college, but I did. The three areas that one could do in that era were become a teacher or maybe a librarian or a nurse. And so I elected to become a nurse, and I went to nursing school. And I loved nursing school. I had a terrific time in nursing school, and along the line, I met the house officers and such and ultimately got to know a surgical oncologist. That was before surgical oncology was a field, but a young man from the Boston City Hospital training program, which was a very good surgical training program at the time, who was recruited to the University of Oregon to start a cancer program. His name was Bill Fletcher-- William S. Fletcher. And when I graduated from nursing school, Bill Fletcher was looking for a right arm assistant. He was looking for somebody to help him develop a cancer program. And he offered me a job, and the job was to work with him in the operating room, either scrubbing or circulating, to run his tumor board-- and that meant just scheduling it and taking notes and such-- and working with him in his tumor clinic. And in the tumor clinic, he was at that time beginning clinical trials, and Oregon was part of something that was called the Western Cancer Chemotherapy Group, which ultimately merged with SWOG. But at that time, his helper-- me-- filled out the forms, and we sent them to patients that were entered onto the study and got consents and measured lesions and that sort of thing. And I worked hand in hand with him. In addition to working with him in those clinical parameters, he gave me a little laboratory project, and so I worked with him in the lab and learned a little bit about small animal oncologic research, et cetera. And after a couple of years working with him, he suggested that I would be a better employee if I took some additional courses, and he suggested that maybe I should take physics because at that time he was doing isolation perfusion. I was running his pump oxygenator. He asked me what I would do if there was a pump failure. I didn't know. And he said, well, I think it would be good if you took physics. Well, the prerequisite to physics was organic. I hadn't had organic, and he was also working with radioisotopes in the lab. And he said, you could really be more helpful to me if you could work in the lab. That meant I had to take organic, and the prerequisite to organic was inorganic. To make a long story short, I took these series of classes in night school while I was working for Dr. Fletcher in the daytime. And then one night, I was working on my hamster project, and he said, I think you should go to medical school. I said, I can't go to medical school. And the long and the short of it was Dr. Fletcher thought I should go to medical school, and he made that possible for me. It's a very, very interesting story, but what it means is that I was mentored by somebody who was a visionary, and he could see a lot more than I could see. And he got me excited about medical school and everything that I knew about medical school is what he had taught me, so I of course wanted to be a cancer surgeon. And then after I went to medical school and I went to the same medical school he did, I just followed his advice. Every time I needed some guidance along the way, I asked Dr. Fletcher what I should do, and he told me what I should do, and I applied. And that's what I did. And so when I came time to choosing a specialty, I decided I would train in surgery, and I applied at the Brigham and was accepted into their surgical program. It was run by Francis Moore at the time. And that was a big deal because they hadn't had women in their surgical field, and I was very excited about all of that but feeling totally inadequate because I didn't think I knew enough medicine. And so I went to Dr. Moore and said, I think I'd be a better house officer if I knew some medicine. He says, OK, well, go take a medical internship, and we'll hold you a spot. So I went to the University of Washington and took general medicine, which was a very vibrant program, a really exciting program, and I just came alive in my internship. I loved everything about it. And then I decided I wanted to be an internist. So at this point, I was offered a position in Washington, and I had already accepted Dr. Moore in Boston. And I didn't know what to do, and I asked Dr. Fletcher what I should do. And he said, Sarah, the world of-- he called it radiotherapy at the time, but what we would call radiation oncology-- needs more surgically oriented physicians. I think you should go down and talk to my friends at Stanford. So I came down to Stanford. I met Henry Kaplan and Malcolm Bagshaw and the leaderships in the department, and including Saul Rosenberg, who was one of the people who interviewed me, and I left that day visiting at Stanford making a commitment that I would come to Stanford as a radiation oncologist. So I wanted to do everything, and I met some very inspiring people along the way, perhaps like you have in your own career. And it's for that reason that I am now excited about mentoring because it's a little bit of payback because somebody opened the door for me and made it possible for me to have a most gratifying professional career, and I would like to do that for as many people as I could. DANIEL HAYES: I love that story. And there were two things about it that came out. One is I normally don't like people who namedrop, but when you can namedrop the names you just dropped-- Bill Fletcher, who I consider really one of the early surgical oncologists, Henry Kaplan, Saul Rosenberg, Franny Moore. I was in Boston of 15 years, and he was a legend. He was not the chair anymore by any means. In fact, he passed away. But it was legendary. You should be doing these interviews instead of me. [LAUGHS] You've been there. SARAH DONALDSON: Well, it's all about where you are at the time you are and meeting the right people. I think so much of my gratifying career is just because I happened to be at the right place at the right time and met the right people. DANIEL HAYES: Well, the other thing I want to say is I always believed I don't trust people I interview who say they know exactly what they want to do. And the reason I say it that way is I have a young woman who's been a technician in my lab that just got into med school, and she sat with me and said, now, when I go there, should I tell them I know exactly what I want to do? Because she's interested in the oncology. Or should I go through my rotations and see what I like? And I said, I forbid you from going there knowing what you want to do. Go to your rotation. See what you like. You're going to run into somebody who just inspires you beyond words who-- I don't know-- maybe selling shoes. But whatever it is, become like her, and you'll be extraordinarily successful. So if there are young people listening to this, I think that your story, Dr. Donaldson, is a classic for that, the way you kicked around. And actually, you didn't tell us, but I'm going to have you tell us about your trip to Paris and that experience too and how that influenced you. SARAH DONALDSON: Oh, that was another wonderful opportunity. When I finished my training, it was 1972, and that's when America was in the Vietnam War. All of my classmates were being recruited to a mandatory draft and were having to go to Vietnam, and I felt like I too should be just like all of my best friends and I too should join the military and go to Vietnam. But that wasn't possible. Women couldn't do that. So I looked for things that I could do where I could do something useful, and I thought about joining the ship Hope and all sorts of fanciful things, but basically I was lost, and I didn't know what I wanted to do. And at that time, there wasn't a carve-out of pediatric oncology as a specialty. It hadn't been defined, but there were people that were doing pediatrics. And as a resident, I had had a little rotation at the M.D. Anderson, and when I was in medical school, I had spent a fair amount of time at the Boston Children's, so I kind of knew a little bit about those institutions. But the thing was at Stanford, I knew that I wanted to be at Stanford. But Stanford didn't have a cancer program either. And so again, I went to Henry Kaplan and Malcolm Bagshaw-- at that point, Kaplan was head of the department, and Malcolm was his associate director. But they changed positions about a year after that. So I trained under both of them, really, but I went to Dr. Kaplan and said, I'm interested in pediatrics. And I said that because we didn't have a program at Stanford and that was like a carve out that nobody had addressed yet. And he said, oh, well, if you want to study pediatric cancer, you have to go to the Institute Gustavo Roussy and train under Odile Schweisguth. And I said, no, I don't speak French. I can't do that. I'd like to go to London because I like the theater. And he said, no, no, no, no, no, that's not the way it is. If you want to be a pediatric doctor, you have to go learn pediatrics and learn to think like a pediatrician, and that means you have to go and train under Odile Schweisguth. She was at the Grand Dame of pediatric oncology. She took care of all the children in Western Europe. And so I went to Institute Gustavo Roussy to be a fellow in pediatric oncology, although I did spend some time on the radiotherapy unit as well. But that's where I learned pediatric cancer because I learned from Odile. And in French, there's a formal and an informal, and I never understood the formal because when you talk to kids, you talk in the familiar form. So I was just talking to and not [SPEAKING FRENCH]. I would just say, [SPEAKING FRENCH] and such. [INAUDIBLE] French. And that's how I learned French. More importantly, I learned the biology of cancer from Odile. It was largely observational. And I learned a lot of late effects of children who were cancer survivors. So when I came back to Stanford, at that time Mal Bagshaw was chair, and he said, well, why don't you work on starting a cancer program? We'd like to have a cancer program. So I worked with the pediatric cancer doctor at Stanford. His name was Dan Wilber, and he had just come from the M.D. Anderson. And the two of us started a cancer program at Stanford. And so I've been kind of doing that ever since, of doing pediatric cancer. So I would say my skill set came along just because the right people told me where to go at the right time. DANIEL HAYES: Were the pediatricians welcoming, or did they resent the fact that you'd never been a pediatrician? SARAH DONALDSON: Malcolm Bagshaw gave me the clue to that by saying the only way the pediatricians will accept you is by having them accept you is one of their own. So you have to learn to think like a pediatrician, and then they will accept you onto their team as one of theirs because pediatric doctors are very possessive about their patients, and pediatric cancer doctors are possessive about their patients. So it worked for me. But it worked because I had had this special training under Odile Schweisguth, who was a general pediatrician, and so I was accepted because I was at that point thinking like Odile thought because that's what she taught me how to do. So I always felt like I was accepted by the pediatric cancer doctors who then became the pediatric oncologists because that field didn't really open up for a couple of years later. DANIEL HAYES: For our listeners, Dr. Donaldson and I have not met before, and I certainly have never worked with her. But she's talking, she's glossed over that when you work with the French, you really have to speak French. When you work with the pediatricians, you really have to speak pediatrician. And you've managed to do both of those. I don't know anybody who's been that successful. I should take a sabbatical and come work with you. [LAUGHS] SARAH DONALDSON: Well, I'll tell you, Dan, there was one wonderful thing that happened because shortly after I was working at Stanford doing pediatrics, our dean wanted to recruit some more people and buff up our pediatric cancer unit. And he recruited Michael Link, who had just come out of his training at the Dana Farber. And so Michael and I started working together his first day as an assistant professor at Stanford, and pediatric oncology is a team sport. Pediatric radiation oncology is a team sport. And I had a wonderful teammate, Michael Link, with whom I worked very well, and we became very fast friends. And we did pediatric lymphoma and sarcoma, bone sarcoma, and soft tissue sarcoma, and all sorts of stuff. And I had a wonderful, wonderful colleague working with Michael Link. So one of the keys to my most gratifying part of my career at Stanford has been working with Michael Link and his associates. DANIEL HAYES: As an aside, by the way, Michael and I overlapped just a little bit at Harvard, but then he proceeded me as president of ASCO by two years, and we got to be pretty close friends during that period of time. And I echo your fondness for him. He's just an amazing human being, as far as I was concerned. And he's one of the-- he may be-- I'm trying to think, has there other pediatricians that have been president of ASCO? I'm not-- SARAH DONALDSON: No, he was the first. Yeah, he's the only one to date. DANIEL HAYES: Yeah. And he left a big stamp on the society in terms of-- we always had some pediatrics involved-- you, especially-- during the years, but as president, he was able to leave a big footprint of what we do. So he was terrific. I'd also like you to talk a little bit about the early days of the co-operative groups. You threw out that you were in the Western Group that became part of SWOG, and what were the hurdles and obstacles to getting all these folks to work together? And what do you see the pros and cons of the cooperative groups in the country? SARAH DONALDSON: I know the cooperative groups mainly through the lens of the pediatric cooperative groups. I mean, I can tell you about the adult ones, but I really know the pediatric ones. And at the beginning, there was one, and then there were two. And we worked competitively, and then ultimately the pediatric doctors learned early on that the children they took care of had rare tumors, and no one physician had a whole lot of experience with any cancer. For example, this tells the story well. When Hal Maurer was chairman of Pediatrics at Virginia, he had a child with rhabdomyosarcoma. And he called his friend Ruth Hein, who was at Michigan, and said, Ruth, I've got this child with rhabdomyosarcoma. Have you ever treated a child like this? And Ruth said, oh, I had one patient, but I think you should call Teresa because Teresa, I think, had a patient. And so Teresa Vietti was at Washington University, and so Hal Maurer and Teresa Vietti and Ruth Hein and a few other really, really pioneers started to throw their lot together and decided that the way they could answer a question about these rare tumors is by deciding what was the question of the day and working collaboratively. And then Hal Maurer became the first chair of what was then called the Innergroup Rhabdomyosarcoma Study, which has now been merged into the other pediatric groups. But that same process that worked for rhabdomyosarcoma was then employed for Wilms tumor, and then subsequently down the line, brain tumors and all the other solid tumors. And of course, St. Jude was doing this with their leukemia studies and Dan Finkel, and then Joe Simone did it with leukemia. They got everybody to join in on their team, decide together around the table by consensus what is the question that we want to have an answer for, and then just treat all the patients in a consecutive fashion, analyze those, and then take that step and go on and build to the next step. That's how the pediatricians have done it because their cancers are so rare that one person doesn't have very much experience. They have to throw their lot together and work collaboratively. So they don't work competitively. They work collaboratively. DANIEL HAYES: This is very similar to the stories I of course heard from Drs. Frei and Holland that they came ultimately to CALGB to be after a couple of mis-starts. But it's one of the things I worry about COVID. It's not the same Zooming with somebody or talking on the phone as it is sitting around dinner and just saying, maybe we could do this and make it work. So I'm hoping young people are listening to this and saying, OK, maybe we can start something new that a bunch of us work together and get things done. That's a really great story. You were early on and ended up taking both diagnostic and therapeutic radiology boards, correct? When they were combined? SARAH DONALDSON: No, no I didn't. Radiology was combined at that time, but Stanford was one of the few institutions that had a carve-out for radiation oncology without diagnostic training, and I wasn't in the first class. I was in the fourth or fifth class, so my formal training was only in what was called radiation therapy, now called radiation oncology. So it was one department, and I worked collaboratively with a diagnostic radiologist because I knew nothing about image interpretation-- nothing at all. So I'd see an X-ray. I didn't know how to interpret it, and I'd have to go and ask for some help. But they were like our best friends. But the diagnostic people could take the picture, but the therapists had access to the patients. So that made all the difference in the world because we really had access to the material, the clinical material or the blood or the bone marrow or the biopsy specimens or whatever it was, and allowed us to do studies. But to clarify, no, I was not. I do not have formal training in diagnostic radiology, although I have worked with them so closely now that I feel like they're all my brothers because you cannot do radiation oncology without collaborating closely with the imagers. DANIEL HAYES: And my first interview was with Sam Helman. This has been three or four years ago. And he was still lamenting the split because he thought it was to learn both-- and for the reasons you just said. If you don't know where it is to shoot your bean, you can't shoot your bean. That's not exactly what he said but something like that. On our side, they team hematology and oncology. Like you, I never got trained in hematology. I only trained in solid tumor oncology, which has not hurt me in any way. In fact, in many respects, I focus my efforts on things I seem to know about and let somebody else worry about blood clotting. Of all the things you're well known for-- and again, it was hard for me to get it all into a minute or two, but probably teaching and mentoring. And in this conversation, I see why. Tell me how you think that's evolved in your field, especially in radiation oncology, teaching and mentoring, and the importance of the things you've done-- and perhaps some of the people you have trained yourself and you're proud of. SARAH DONALDSON: Well, when I think of all the things that I love about my professional career, I love taking care of patients. And I've had very joyous experiences of watching pediatric cancer patients grow up and watching them in their process and treating them when they're toddlers and then getting invitations to graduations and wedding invitations and baby announcements and following through that. That's very, very gratifying. But the single most important and most gratifying part of what I do is the volumetric feedback and gratification from training residents because one patient is one patient, but one trainee then goes into academic medicine and that person has 30 or 300 or 3,000 trainees. And you see your impact is just explosive. And Stanford has had a training program in radiation oncology from the very, very beginning. It was one of the first programs that did train in radiation oncology, so a lot of talented people have come through Stanford. They need to have what Bill Fletcher did for me, which was open doors and help them with networking and giving them an opportunity and giving them some guidance and being their new best friend. When your trainees trust you like that, then you can really, really have a relationship, and you can really help them. And so I am very, very, very proud of our trainees that are now all over the place as cancer center directors or directors of departments or divisions that are doing what they're doing. You just meet the best of the best. That is the most gratifying part of-- maybe it's because that's what I'm doing now, but it's the most gratifying part of medicine that I've experienced. DANIEL HAYES: This is the third time I've said this on this call-- I hope there are young people listening, and I hope they're looking for a mentor and they can find someone as generous and trusting and helpful as you have been. SARAH DONALDSON: Dan, let me just say one little thing. DANIEL HAYES: Yeah. SARAH DONALDSON: It was extremely helpful to me-- and wonderful recognition for ASCO-- to provide the opportunity that I received the Women Who Conquer Cancer Mentoring Award. Because when I won that award, I was the inaugural-- but when I won that, all of a sudden people thought that I knew something about mentoring. I'm not certain I did know anything about mentoring, but I was asked to talk about it and asked to give advice, et cetera. And it gave me a carve out that was quite novel at the time, and now, of course, it's a mandated requirement in every training program, et cetera, but it wasn't then. And for me, it was just to return what Bill Fletcher did for me. The only way I can say is that it's a pay out, and it's so gratifying. It just makes you happy to get out of bed every morning and interact with the people you do interact with. DANIEL HAYES: He was pretty young when he began to mentor you. And I think having seen and been mentored and mentored other people, I always worry about a young person trying to mentor because you've got your own career to worry about, and it's hard not to be selfish when you're building a career in academics. He must have been a remarkable-- is he still active? Is he still around? He must have been a remarkable guy. SARAH DONALDSON: He was a remarkable guy, and no, he passed away. But that was true. And that is true because junior faculty are busy making their own professional career, and they don't have time. They're busy on their own path, and it's a hard path to go on. So most junior faculty don't really have very much time to do formal mentoring. But in Bill Fletcher's case, we worked hand in hand as sort of partners. And so I think, in some ways, I was helpful to him because I could do literature searches for him. I could write the first draft of his paper. I could write the first draft of his grant. I filled out the forms. I did a lot of things that were labor saving for him, but for me, what was he doing for me? He was teaching me to suture. He was teaching me how to resect normal [INAUDIBLE]. He was teaching me lymph node drainage from cancers. He was teaching me about drug metabolism, methotrexate, and phenylalanine mustard. And 5-FU was an experimental agent. So was vincristine-- those kinds of things. So I learned a lot from him just in the ordinary practice of taking care of the patients. DANIEL HAYES: By the way, two stories I read about you-- one is how you met Henry Kaplan, and the second is the first paper you wrote with him. Can you give us those two? And then I think we've got to sign off. SARAH DONALDSON: Well, let me tell you about the first paper I wrote with him because the other one is too funny. Everybody will laugh at me. The first paper I wrote with Henry Kaplan, I worked really, really hard on it. It had to do with bacterial infections in patients with Hodgkin's disease because we were doing splenectomies on everybody, and they were getting pneumococcal bacteremias and meningitis. And I was running the ward at that time. I was taking care of a lot of patients that were sick. So I was writing up this experience. And I wrote what I thought was the perfect paper because, see, Kaplan had a high bar, and you didn't want to disappoint him. So I wrote the paper that I thought was perfection. I had gone through a lot of drafts. And I gave it to him, and he returned it to me the next day. He read it that night. But I only looked at the first page because the first page looked like a blood bath. Everything he wrote, he wrote with a red pen. And there was red writing all over the first page. I couldn't see any white paper. It was all red comments. DANIEL HAYES: [LAUGHS] SARAH DONALDSON: And I went through-- I don't know-- 24 different drafts of that paper finally being published. And so one of the things I try to do with residents now is to teach them, you have to have a hypothesis. You have to make certain you have a database. You have to have a long term follow up. You have to understand statistics, and you have to write a paper knowing what you're doing. You don't just start writing. You do a section and a section and you build it with evidence. So I enjoy doing editing, and I think I can help some trainees focus their thinking in terms of writing a grant proposal or a manuscript that's worthwhile publishing. My introduction to Henry Kaplan-- there are many, many funny stories about them, but to end them all, I will have to say that he was very, very, very good to me. He provided a lot of opportunities and was a huge role model. He taught by scarification. We were all scared to death of him, but he was absolutely a wonderful, wonderful huggable person, if you felt like you could hug him. We didn't do that very often. We might have hugged Saul Rosenberg, but we didn't hug Henry Kaplan. But they were both helpful to me, especially in understanding lymphomas. DANIEL HAYES: For those of you listening who don't know who Henry Kaplan was, I think it's fair to say he was one of the first people to prove you could cure Hodgkin's disease with radiation. Do you agree? Is that a fair statement? SARAH DONALDSON: Yes, that's where his name came. But of course, what Kaplan did was he recruited Saul Rosenberg, and the two of those worked hand in hand, and they brought to Stanford what we call the Lymphoma Staging Conference, which was a combined modality conference where we talked together over each patient. And together, they wrote clinical trials that were institution-based clinical trials. So what Kaplan did was he did a lot of technical work with the linear accelerator, but that was just a tool. My way of thinking is his most important contribution was the importance of combined modality therapy and understanding what your colleagues can contribute and what you can contribute in doing it as a team. DANIEL HAYES: And I will encourage anyone who's listening to this to go back to the website and listen to my interview with Dr. Rosenberg who laid that out in spades. And the first few patients he treated, he had a chair outside his exam room. He would examine the patient, take them out, put them in the chair, start the IV himself, go mix the chemotherapy, hang it up, and then see the next patient in the room while the first patient was getting chemotherapy. It's a little different now. [LAUGHS] Anyway, thank you so much. By the way, I have a copy of Dr. Kaplan's book on Hodgkin's disease, which was the Bible when we were training. You can't see it because it's on my bookshelf behind my camera, but I still open it up quite a while, even for a breast cancer guy. It was a classic. I also want to say, it's very clear to me you're a nurse at heart. You've been a fabulous physician and researcher and mentor, but your love for people shines through, so congratulations. I think that's terrific. SARAH DONALDSON: Thank you so much. DANIEL HAYES: Thanks for taking your time to speak with me today. I'm sure people are going to be thrilled to listen to this, and thanks for all you've done to feel. It's just really remarkable-- and what you've done for ASCO and the Foundation, which is a big, big, payback. Thanks for everything. SARAH DONALDSON: Thank you. DANIEL HAYES: Until next time, thank you for listening to this JCO's Cancer Stories: The Art of Oncology Podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories: The Art of Oncology Podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.asco.org. [MUSIC PLAYING]

Dr. Ben Corn, professor of Oncology at Hebrew University of Jerusalem Medical School, and deputy director of the Shaare Zedek Medical Center, discusses his current research with NRG Oncology and SWOG on the study of the science of hope, and it's role as a mediator in well-being and health care improvement. Dr. Corn is co-founder and CEO of the NGO, Life's Door, which teaches health professionals, patients and others strategies for hope, meaning and well-being throughout illness and at the end-of-life.   Transcript ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. Our guest today is Dr. Benjamin Corn, a professor of oncology at the Hebrew University of Jerusalem Medical School and deputy director of the Shaare Zedek Medical Center. Dr. Corn is the co-founder and chairman of the nonprofit organization Life's Door, which teaches health professionals, patients, and caregivers strategies for hope, meaning, and well-being throughout illness and at the end of life. Dr. Corn was honored with the 2021 ASCO Humanitarian Award and joins me to discuss his work, including his current research on the study of the science of hope and its role as a mediator in well-being and health care improvement. Dr. Corn's full disclosures are available in our show notes, and transcripts for all episodes are available at asco.org/podcasts. Dr. Corn, it's great to have you on the podcast. Dr. Benjamin Corn: It's a pleasure to be here, and thank you very much, Geraldine. ASCO Daily News: Dr. Corn, can you tell us about the experiences early on in your personal life and then your medical training that prompted your interest in helping patients find hope and meaning while navigating cancer treatment? Dr. Benjamin Corn: Sure. I think everyone has a story that sent them on their way for a career in medicine, which for many of us is not a job. It's not a career. It's a mission. My personal story had to do with losing a parent, my dad, at a very young age. He died of prostate cancer, left behind three young children and a lovely widow, who was my mom. And I was quite disappointed with the way the system tried to cope with the reality that was now forced upon us. There were no viable options for somebody with metastatic prostate cancer then. But yet, there was not a cognizance of some of the psychological trauma that we would all have in trying to navigate our daily lives. And I was very surprised also the way my dad's death was communicated to the family. And I've spoken about this in a variety of podcast settings and written a piece for the JCO narrative section about 10 years ago on that, some of what I found to be harshness, coldness of telling us that our dad was not going to make it and how the bad news was conveyed (PMID: 24733795). And so, with that, I was an 11-year-old child, and I very much was intent on curing this thing called prostate cancer to make sure other middle-aged men wouldn't suffer from it, and their families wouldn't have to pick up the pieces. And I went to medical school. I entered my residency in oncology at University of Pennsylvania, thinking that that was my destiny. And when I got to the wards, I was quite disillusioned because I saw a variety of scenarios that told me things hadn't changed drastically in 7 or 8 years since losing my dad and initiating my medical studies. I saw many cases of senior attending physicians, who were fantastic scientists, brilliant researchers, and yet didn't seem to pay enough attention to the subtleties of making sure that a family was whole, bringing in other resources. This was right before what I would call a palliative care revolution. We didn't have the Tamil paper, the Zimmermann paper, the Bakitas paper. And we didn't really know the value of early interventions with teams that included not only oncologists but also nurses and psychologists, chaplains, who could help navigate such a difficult period for patients and for the people in the concentric circles around those patients. So it was very important for me to begin to explore those issues. I never found it to be a conflict for pursuing an academic career that asks bread-and-butter questions about disease, areas of interest. I published a lot in gynecologic malignancy, in prostate cancer itself, and in central nervous system tumors. But by the same token, I thought it was very important to be looking at the psychosocial dynamics that are involved. And that's pretty much the genesis of how I got interested in this area. ASCO Daily News: Well, your work integrating hopefulness into cancer care has had an important impact even on communities beyond the medical setting. Can you tell us about this work, about the hope enhancement model, and how you've used this approach to train medical professionals, patients, and caregivers? Dr. Benjamin Corn: Well, first of all, I want to say that, in many ways, even though I've been blessed with having terrific education at outstanding institutions of higher learning, my greatest teachers have really been the patients, and I'll bet you most colleagues would say the same thing. And I noticed there was a subset of patients who were very intuitively aware of what was important to them, patients for whom the prognosis was very bleak and yet managed to maintain hopefulness. And I saw that the common thread for these patients was that, even though they couldn't be hopeful for cure, they could still find other goals, other objectives that they could pursue. And that sent me on a quest of sorts to see if anybody had formally tried teaching people how to become more hopeful. And with not too much effort, I found literature of Professor Rick Snyder from University of Kansas. It basically modeled this notion of hope theory. And without turning this into a lecture, very briefly, Snyder said that there are three conditions that will allow hopefulness to thrive. The first is defining a goal. And by that, he meant some kind of an objective that was not only plausible but also that could provide meaning in one's life. So it would be a good goal in hope theory if I said my goal is to win the lottery tomorrow because that's really not anything I can have an impact on, so it's not really statistically plausible. But likewise, if I took a goal that was just very mundane and didn't add that much purpose to my life, it would be out there, and I'd be interested in pursuing it. But I probably wouldn't have the same degree of motivation if I thought about something that, without too much effort, could really make my day or make the day of the people around me. So, the first thing was the goals that have these two criteria--plausibility and meaning. The second is a pathway to get to the goal. And when Snyder discusses pathways of thinking, he's supposedly speaking to a mature audience and saying none of us were born yesterday. We all realize that on almost every path that we travel on during our lifetimes, we see that there are obstacles. The question is, how do we manage and circumvent those obstacles, or how do we dance with those obstacles if, in fact, it's something very much within me, an obstacle such as anger, an obstacle such as jealousy? How do I deal with those particular factors? A hopeful person is a creative person, is a resourceful person, who finds a way to sally forth even when these obstacles are out there. So we have goals. We have pathways. And finally, the other secret sauce that I mentioned before is motivation. The word that Snyder used for motivation is called "agency." Agentic thinking, like almost an agent that might represent an NBA basketball player or a Hollywood movie star. That agent will do everything on behalf of his or her colleague so that they'll succeed. And so to the person who has an agentic way of seeing the world is going to be an activist, is going to want to set out on those trails, those pathways, to reach those goals. So those are the three components. And what we found is that--and this is based on some work that was done by one of Snyder's proteges, Dr. David Feldman, who's at Santa Clara University--one could actually construct workshops that are very palatable, that take less than 2 hours to conduct, in which a tool called hope mapping is used. Hope maps are basically dependent on those three components. So you can actually sit there in dyads, buddying up with people in this workshop, people who you know before the workshop, or people who you meet in the workshop, because there's a similarity, a selection for those who attend such workshops. People want to work together. And it's a wonderful energy, because let's say, as I said before, I have a goal, and I have a pathway. But there's a big, bad obstacle there, and I don't know how to get around it. What could be that my buddy in the workshop is going to say, "You know what, Ben? Here's a great way. You might not have thought about this. Why don't we contemplate creating a workaround?" And they're very, very instructive. And we've done some of these workshops now, both in Israel, where I practice, as you mentioned at the opening, and with colleagues at Johns Hopkins in Baltimore with really thought leaders in hopefulness--Tom Smith, who has for many years written the ASCO guidelines on palliative care, and Anna Ferguson, who is the coordinator of the hope enhancement program at Hopkins. And together, we've proven, especially in a population of women suffering from stage IV breast cancer, that we really can invest 2 hours or less and make them much more hopeful. Now, you mentioned in your question that some of this has an impact on communities beyond the medical setting, and that's exactly what's been happening. As the word has trickled out, especially during the COVID pandemic, we've been approached by a variety of communities on the international level--communities in London, communities in Athens, communities in South Africa, communities in the Pacific Rim--who are very interested in bringing together different strata within those communities, perhaps people who have recently become married or people who have recently become parents, who have a similar set of struggles, and to help us help them become more hopeful, especially when you add on to that a little something called COVID-19. So I'm an oncologist. I think there's tremendous upside for this in the setting of cancer care for patients and for the health care professionals who have the privilege of treating these patients. But the spillover phenomenon has really been marvelous to behold, especially during 2020. ASCO Daily News: Well, you're also collaborating with the National Cancer Institute groups of NRG Oncology and the Southwest Oncology Group to study the science of hope and its role as a mediator in well-being and health care improvement. Can you tell us about this research? Dr. Benjamin Corn: Sure. So in the context of NRG Oncology, there are two protocols. One is called CC003 (NCT02635009). That's a protocol for patients with small cell lung cancer. And another one is a protocol called BN005, which is a protocol for individuals with, I guess, what we want to call low-grade gliomas, to look at neuroanatomic loci that could constitute a source for hopefulness (NCT03180502). I'll just give you one example, which is from the small cell lung cancer study I mentioned before. So in years past, at least, it's been a standard of care to provide prophylactic cranial irradiation--that is, prevention with radiation--where there's a tumor, small cell lung cancer, that has a proclivity to spread to the brain. And so one of the hot areas that has emerged in radiation research over the last decade is hippocampal avoidance. It seems trivial, but it took us a while to understand how to protect concentric circles, such as, let's say, the spinal cord when treating the vertebral body or to protect the hippocampus when treating the whole brain. So in prophylactic cranial irradiation, we typically treat the whole brain. And a randomized trial was developed by NRG investigators, where the randomization was between prophylactic cranial irradiation itself to 25 Gray in 10 fractions versus that same regimen with hippocampal avoidance. Now, when I saw that study design, I actually put forward the idea that this could be a wonderful model to study the neuroanatomic correlative hopefulness because there are several candidate anatomic structures in the brain, which are thought to be associated with hopefulness. No one, by the way, is saying that the circuitry is so primitive that all of hopefulness resides in one structure. But if I had to say that there's a lead candidate that's been identified in the literature, it's exactly the hippocampus. So the proposal to the NRG committee and to the PI of the protocol, Dr. Vinai Gondi, and the head of the brain tumor committee, Dr. Minesh Mehta, was, could we very simply administer one of the validated scales for hopefulness that was built by Snyder. It has all of 12 questions. It takes about 5 minutes to complete. Give that to a patient at baseline, then have them randomly assigned to either prophylactic cranial irradiation of the whole brain or the same treatment wherein the hippocampus is protected. Re-challenge the patients 6 months after the irradiation is completed, and see if there is less of a decrement in hopefulness on these validated scales among the group that had the hippocampus protected. When you compare the hopefulness among the groups that didn't have the hippocampus protected, that would offer some interesting, at least circumstantial, evidence that the hippocampus is implicated in the hope pathways. And so this has been very interesting to NRG Oncology. We've enrolled now over 250 patients en route to 300 patients. We have very meticulous quality assurance, where the co-investigators sit down once a month and make sure that the hippocampus was properly contoured and protected. And in the other study, we're looking at particular dosimetric analyses in case someone thinks that 25 Gray might be, for instance, below the threshold of hippocampal tolerance. There, we'll look at a variety of doses to see where we might see the correlation with hippocampal toxicity and decrements in hopefulness. So those are two variations of ideas that are on burners in NRG Oncology. SWOG has taken a different tack. And here, I want to truly applaud SWOG leadership, the group chair of SWOG, Dr. Charles Blanke, as well as the leaders in the palliative care movement at SWOG, including Mark O'Rourke, Marie Bakitas, and Ishwaria Subbiah, who have said, "Look, we know that you've got some preliminary pilot data on the impact of a hope workshop for patients with cancer. Can we, first of all, look at this now among the SWOG investigators?" That had never been done before. In other words, we talk all the time about levels of burnout among health care providers who are treating a patient with cancer. It's very gratifying on the one hand, but it's very challenging on the other hand. It can even be demoralizing for some, and as you know, there are very high rates of burnout. So they've been very interested, first of all, in meticulously establishing levels of hopefulness at baseline and correlating that with levels of burnout among SWOG investigators. So by "investigators," I'm talking about physicians, nursing professionals, even patient advocates. And we have some data that were just recently published in JCO Oncology Practice (DOI: 10.1200/OP.20.00990). In addition, we've been very interested in offering now these hope enhancement workshops that I told you about before to the SWOG investigators. So in the month of May, we got together every Monday night--at least for me, it was Monday night at midnight, I have to say, which was about 5:00 PM Eastern time. And we did these 2-hour workshops every week for about a dozen SWOG investigators. And we actually have some data right now that we just submitted to the ASCO Quality Conference, showing the feedback we got from the SWOG investigators. And to me, the most encouraging part was that these investigators were so enamored of these techniques and found them to be so useful that they--almost all wanted to find ways to bring them into their own clinical environment to share them with their patients, wanted to learn how to become facilitators of such workshops to also help prophylax burnout and increase hopefulness among their colleagues. So SWOG has taken the tack of using this intervention to help providers. We're soon going to be trying to do it among the patients and roll it on to our protocols. And there, what we want to do is take meaty, challenging questions. Let's say the question of adherence, a situation where perhaps women who need endocrine therapy are somewhat--want to take the endocrine therapy but are somewhat reluctant to be adherent to the regimen because of all the hormonal side effects. So we want to see if we can use our workshop to align this value of a patient and this motivation with the patient to help them, in fact, become very adherent, because as I'm sure you know, upwards of 40% of these patients just don't want to take these therapies. So we're interested in using this for adherence. And we're also interested in using it as a tool for medical decision making. We give a lot of lip service to the idea of shared decision making between provider and patient, but most of us haven't really been trained in how to have a robust experience that helps me as a provider understanding what my patient wants. When I counsel patients with prostate cancer, it's almost impossible for me to do such a consultation in less than 90 minutes because there's such a range of options. And before I can really get to understanding which of those options might be most appropriate for a patient, I have to really know the patient. I have to know, in the case of prostate cancer, what makes him tick. And so I think there's going to be tremendous upside for these hope enhancement techniques, not just using it for hope's sake but also for these other epiphenomenon in medicine, like adherence and like decision making, that we speak about all the time, but I wonder to what extent we're really committed to doing a better job on those parameters. ASCO Daily News: Right. Do you see a role for technology to grow hope enhancement workshops, to make them accessible to more people in other parts of the world, in other medical settings? How do you think technology has changed the way people confront the experience of illness? And what role do you think you can play in this? Dr. Benjamin Corn: Yeah. Well, I guess all of us were brought in very rapidly, sometimes kicking and screaming, into this new era. And health care providers are smart, and they're resourceful, and they've figured out a way to ride this challenging wave that COVID has brought into our lives, this tsunami, if you will. So COVID has pushed us all into digital health. My organization, Life's Door, which developed an application, a smartphone app, called Hopetimize--kind of a  play on the words "hope" and "optimize"--in other words, the idea is to optimize your life with using these hope techniques I described before. So we had a game plan to get to digital work in the year 2022. That was a strategy that we basically developed about 5 years ago. When COVID came along, we realized that we had this wonderful product called hope enhancement workshops that we thought could really help oncologists who we thought could help their patients. But we couldn't get people together because of the new criteria for social distancing. So what was once a tailor-made concept for intimate settings with 15 people, I can tell you that even in our IRB-approved protocol--and people can see this on nih.gov, clinicaltrials.gov--our protocol specifies the kind of environment one has to have to conduct these workshops when you're doing it face to face. But that just couldn't happen for a full year, maybe a little bit more than that. So we very quickly developed the smartphone app, and we found a way to move our entire workshop to a Zoom platform. And we'll have some data that we'll be sharing that basically says that we can do it just as well with the Zoom platform as doing it face to face. And what's more, it gives more people access to the technology. It allows for more sustainability because we're not only using Zoom, we're using different social media outlets. Most of the literature on hope enhancement--it's sometimes called hope augmentation--can demonstrate a spike in hopefulness after such an intervention. But the challenge then becomes how to sustain that hopefulness, and that's not easy. Well, by creating these digital communities of hopefulness, with the aid of different social media, we think that maybe this is exactly how we can deal with the sustainability question. And finally, this kind of technology gives us scalability. I mentioned before that we've been approached by groups around the world, throughout Europe, now throughout Asia, parts of Africa, not to mention North America. Haven't heard much from South America and Antarctica now that I'm thinking about it, so we're waiting for you guys. But we could never--all of us--I'm a busy physician as well. So there's a limit to how many times my colleagues would have to cover me when I say, "Oh, I'm off on another trip, teaching these hope techniques to people." But once we have it on Zoom platform, and we can bring, let's say, 15 to 20 people into the experience by bringing them into a Zoom room, I don't have to go anywhere. I can do it right from my living room, just like they're in their living room. And it sounds very simple, but I don't think anybody would have really imagined that we could be on our way like this if you sat down to contemplate this upside of 2019. ASCO Daily News: Right. And do you feel the response from the oncology community, from your peers across the world, has been quite positive? Scientists are sometimes skeptical about things such as hope enhancement techniques. Or have you found that not to be the case? Dr. Benjamin Corn: Yeah. That--so there's another example. I think that a barrier is the working assumptions of, let's say, my colleagues--let's say, me myself before I got into it. I mean, we're trained in a truly biological, scientific model. We talk about a biopsychosocial model, sometimes a biopsychosocial narrative model, but at its core, we pride ourselves as being scientists, and this kind of an idea was very off-putting to a lot of people. When we started publishing on this and the word got out that there were actually reproducible results showing that we can enhance hopefulness, people said, "Wait a second. I'm having a problem myself with patients who are just not hopeful." "Wait a second. I'm having a problem myself with my own burnout and my own compassion fatigue." And these colleagues have been seeking this out now in droves. And what our challenge has been right now is to be training facilitators so that we can really fan out and make sure that we answer this need of people saying, "I want to learn these techniques." Again, not just hope for hope's sake--I mean, I'm for hope. But for all the other upsides that we mentioned before--anti-burnout, increased adherence, probably bettered medical decision making--I think these are the motivators for people as opposed to just saying, "Make me more hopeful." So whatever gets you to the workshop, I couldn't care less. Everybody comes with their own reasons. That's always quite fascinating to hear why somebody decided to enroll in one of our workshops. But once people are there, most of them find that they really benefited from it. Typically, if we do a workshop with 20 people, the next day, we'll get a third to 40% of the participants saying, "You know what? I love this so much. I took these techniques, and I called in my children after dinner, and we talked about their goals and what struggles they're having in trying to reach the goals." So to me, that's very touching. And to get through your earlier question about the impact of this thing in communities outside of medicine, I think we're really on the cusp of forming what I like to describe as communities of hopefulness. And I think, again, we saw that in the COVID era. There was, in particular, a community in London that was very interested and brought us in also for a series of four workshops. And one of the things that we're working on right now in a hospital setting is what we call the seal of hopefulness. And that's based on, when I was growing up, this notion of the Good Housekeeping Seal of Approval. Well, we want to be able to approach hospitals and to say, "Just like you like to go through the accreditation process, perhaps you want to go through this process of making your staff more hopeful." Patients pick up on these things. So imagine, Geraldine, a world in which the physicians were taking care of you and the people you love, the nurses, the orderlies who bring them down to CT scans and the MRI. There's a lot of time that a patient in a hospital spends outside his or her bed. Imagine if en route to having a study, which you're very anxious about, you have somebody who's been trained and knows how to speak to you about your goals and your value. I think that would be the kind of environment I'd want to be taken care of in. I mean, of course I want to know that the knowledge base is top shelf. But could you imagine if there was this hope seal on the door that said, "People here really give a damn. They care about you, not just your tumor, and that is their commitment." I think that can be very reassuring. And we've begun to pitch that idea to hospital administrators, both in Israel, where I'm based, and in large-scale hospitals both on the community level and the academic level in the U.S. and Canada. ASCO Daily News: Excellent. Thank you so much, Dr. Corn, for telling us about your innovative work today. You really seem to be having a great impact. And I thank you very much for taking the time today. Dr. Benjamin Corn: Thank you. It was a pleasure. ASCO Daily News: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Ben Corn: None disclosed.  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

El Dr. Jerónimo Rodríguez Cid, oncólogo médico adscrito al Instituto Nacional de Enfermedades Respiratorias en la Ciudad de México, México, junto al Dr. Luis Ubillos, oncólogo médico subdirector del Insituto Nacional del Cáncer INCA-ASSE en Montevideo, Uruguay, nos comentan sobre lo más destacado en melanoma presentado en ASCO 2021, resaltando los siguientes estudios: Melanoma (adyuvancia): KEYNOTE 054: Estudio fase III, aleatorizado, doble ciego el cual evaluó a 1019 pacientes con melanoma. Su objetivo primario fue comparar el tratamiento de inmunoterapia adyuvante con un anticuerpo monoclonal anti-PD-1 (pembrolizumab) vs. placebo después de la resección completa de un melanoma en estadio III de alto riesgo. SWOG 1404: Estudio fase III, doble ciego el cual evaluó a 1378 pacientes con melanoma resecado de alto riesgo y que comparó el tratamiento con interferón de dosis altas o ipilimumab vs. pembrolizumab. Melanoma (metastásico): RELATIVITY 047: Estudio fase II/III, doble ciego, aleatorizado el cuál evaluó a 700 pacientes con melanoma metastásico o irresecable no tratado previamente. Este comparó el tratamiento de relatlimab combinado con nivolumab vs. nivolumab solo. CHECKMATE 064: Estudio fase II, aleatorizado, de etiqueta abierta con 138 pacientes inscritos con melanoma avanzado o metastásico, el cual evaluó el tratamiento de nivolumab administrado secuencialmente con ipilimumab. ABC: Estudio fase II, aleatorizado, de etiqueta abierta el cual evaluó a 76 pacientes con melanoma con metástasis cerebrales y que comparó el tratamiento de nivolumab vs. nivolumab + ipilimumab. COLUMBUS: Estudio fase III multicéntrico, abierto, aleatorizado, el cual comparó dos partes de LGX818 + MEK162 vs. la monoterapia con vemurafenib + LGX818 en 907 pacientes con melanoma BRAF V600 mutado irresecable o metastásico. Pembrolizumab + lenvatinib: Estudio que evaluó la combinación de pembrolizumab + lenvatinib en pacientes con melanoma que hayan progresado a un tratamiento anti-PD-1 o anti-PD-L1 previo. Abstract “Eficacia de la inhibición de los puntos de control en el melanoma acral avanzado”: La población de este estudio consistió en pacientes del Registro Holandés de Tratamiento del Melanoma prospectivo a nivel nacional entre 2014 - 2020, y la tasa de respuesta objetiva fue calculada en todos los pacientes con melanoma acral no resecable en estadio III y IV y con melanoma cutáneo, los cuales fueron tratados con anti-PD1 y con la combinación anti-PD1 + anti-CTLA4.

ASCO: You’re listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world’s leading professional organization for doctors who care for people with cancer. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so clinical trials described here may no longer be enrolling patients, and final results are not yet available.  Before any new cancer treatment can be approved for general use, it must be studied in a clinical trial in order to prove it is safe and effective. In today’s podcast, members of the Cancer.Net Editorial Board discuss 3 clinical trials that are exploring new treatment options across kidney, bladder, and prostate cancer. This podcast will be led by Dr. Timothy Gilligan, Dr. Tian Zhang, Dr. Petros Grivas, and Dr. Neeraj Agarwal. Dr. Gilligan is an Associate Professor and Medical Oncologist at the Cleveland Clinic Taussig Cancer Institute. He has no relevant relationships to disclose. Dr. Zhang is an associate professor of medicine at Duke University School of Medicine and is a medical oncologist at Duke Cancer Institute. She has served in a consulting or advisory role for Bristol-Myers Squibb and Merck, and has received research funding from Astellas Pharma. Dr. Grivas is the clinical director of the Genitourinary Cancers Program at University of Washington Medicine. He is also an associate member of the clinical research division at the Fred Hutchinson Cancer Research Center. He has served in a consulting or advisory role for Bristol-Myers Squibb and Merck. Dr. Agarwal directs the Genitourinary Oncology Program at the Huntsman Cancer Institute at the University of Utah. He has served in a consulting or advisory role for Bristol-Myers Squibb, Merck, and Astellas Pharma. View full disclosures for Dr. Gilligan, Dr. Zhang, Dr. Grivas, and Dr. Agarwal at Cancer.Net. Dr. Gilligan: Hi. I'm Dr. Timothy Gilligan from the Cleveland Clinic Taussig Cancer Institute. I'm joined today by Dr. Tian Zhang from the Duke Cancer Institute, Dr. Petros Grivas from the University of Washington and Fred Hutchinson Cancer Research Center, and Dr. Neeraj Agarwal from the Huntsman Cancer Institute and University of Utah. Today, we're going to discuss 3 ongoing clinical trials in kidney, bladder, and prostate cancer. As you may know, clinical trials are the main way that doctors are able to find better treatment for diseases like cancer. Patient participation is vital for clinical trials. By participating in the clinical trial, you can directly help researchers develop better treatment, reduce side effects, or even reduce the risk of cancer altogether. The 3 trials we'll discuss today were chosen by members of the Cancer.Net Editorial Board Genitourinary Cancers panel from the Trials in Progress abstracts that were presented at ASCO's 2020 Annual Meeting. Because these are ongoing clinical trials, final results from these studies are not available yet. I'd like to note that none of us have any direct involvement with any of these trials. To view our full disclosures, please view the show notes for this episode on Cancer.Net. We're going to start with Dr. Zhang discussing the trial CheckMate 914. Why don't we begin with who the study is designed for? CheckMate 914 is a study in the adjuvant setting, so it's a study after patients have had their primary kidney cancers removed, and everybody needs to have a kidney tumor that's either 7 centimeters or larger or have extension beyond the kidney or any nodal involvement. So after their kidney tumors have been removed, this study really is in that timeframe after nephrectomy or after surgery with complete resection of their tumor. Dr. Gilligan: What's the current standard of care for these patients if they're not on a trial like this? Dr. Zhang: We often will compare against that standard which currently in the adjuvant setting we either do observation until disease recurrence or there is 1 oral treatment that's approved called sunitinib. But sunitinib really has some controversial data around it, and so it's not often used. And so currently, many patients are still observed as standard of care in the setting. Dr. Gilligan: And so if a patient goes on this trial, what can they expect?   Dr. Zhang: So patients who are enrolled to CheckMate 914 are randomized to either a combination immunotherapy called ipilimumab with nivolumab, which is approved in the metastatic setting for kidney cancer, or they're placed on placebo for these 2 treatments, or there is a third cohort that receives nivolumab alone with a placebo of ipilimumab. And so these patients are receiving either active immunotherapies or a placebo, which would be our current standard of care, sort of observation until disease recurrence. Dr. Gilligan: So patients will either get the current standard, which is observation, or else they'll have 1 drug or 2 drugs if I'm understanding correctly? Dr. Zhang: That's right. Dr. Gilligan: What is the hope of this study? What is the outcome that we're hoping to see? Dr. Zhang: The primary outcome of this study is disease-free survival, so that means time until disease recurrence for all comers. And we're really trying to prolong time until disease recurrence or time until metastasis for these patients. There are some secondary outcomes that are very important as well, so prolonging overall survival as well as the incidence of adverse events that are seen from these treatments. And then there is an independent radiographic assessment to look for disease-free survival intervals as well. Dr. Gilligan: And the hope is that these treatments will prevent recurrence or at least delay recurrence then? Dr. Zhang: That's absolutely correct, yes. And we have had 2 other adjuvant trials with immunotherapies in this space of atezolizumab and pembrolizumab, but those trials have finished accruing. And so this is the main ongoing and accruing trial that's looking at active immunotherapy options in this space. Dr. Gilligan: What risks should patients be aware of that they might encounter if they go on this treatment? Dr. Zhang: So with all immunotherapies, we talk a lot about the immune mediated adverse events and just the usual rundown of those. And in my clinic, we talk a lot about the common rashes. In the GI tract, it can cause some inflammation or colitis. Very rarely, it can cause some inflammation in the lungs or liver and then very commonly, endocrine dysfunction. So we watch pituitary, thyroid, adrenal, and pancreas function very carefully. But all of these side effects are well described for the ipilimumab, nivolumab combinations as well as nivolumab on its own in the metastatic setting. So most people should know what to monitor for and what we're looking out for and how to manage these toxicities. Dr. Gilligan: Right. So these are drugs that have been in wide use for some years now, so we have significant experience managing the side effects is what I'm hearing you say. Dr. Zhang: That's right. Dr. Gilligan: Is this trial still open to patients? Dr. Zhang: Yes. This trial is still accruing. It's a global study about to enroll up to 1,600 patients. So it's a very large global trial that is still active and still accruing patients. So I would encourage people and also oncologists to refer patients for the trial at a center close to them if possible. Dr. Gilligan: And when might we expect results for a study like this? Dr. Zhang: These adjuvant studies take a while to finish accruing and then it takes a while to finish seeing the data. So I would hazard a guess that we're still years away from seeing the data from this trial. Dr. Gilligan: So once again, this is for people who have had surgery to remove a kidney cancer and looking at ways to reduce the risk of subsequent relapse. Well, thank you for summarizing that so coherently and succinctly. Let's move on now, and we're going to talk about the trial KEYNOTE-992 with Dr. Grivas. Dr. Grivas, who is this study designed for? Dr. Grivas: So this is a clinical trial, a phase III clinical trial that applies to patients who opt to pursue what we call bladder preservation, which is an attempt to keep the bladder intact and still try to treat bladder cancer with concurrent use of chemotherapy and radiation. And this bladder preservation approach applies to a proportion of patients with bladder cancer still in the bladder but not spread. And as I mentioned before, the decision to pursue that strategy depends on particular patient characteristics, how the cancer looks on the CAT scans, and also how it looks under the microscope. Dr. Gilligan: What is the current standard of care for these patients? Dr. Grivas: So patients who are characterized as great candidates for this bladder preservation approach, because this does not apply to everybody with bladder cancer, the standard of care right now is patients undergo what we call a transurethral bladder tumor resection, which means that the urologists go through the urethra and they resect or remove or scrape, remove the visible bladder tumor, and then the patients undergo concurrent, meaning at the same time, chemotherapy and radiation. Dr. Gilligan: How does the study aim to improve or change the standard of care? What would be different as a result of the study if it's successful? Dr. Grivas: So this particular clinical trial, the KEYNOTE-992, is asking the question whether the addition of immunotherapy with 1 of those immune checkpoint inhibitors that activates the immune system, does this addition add value in the combination of chemotherapy and radiation? So the patients are being randomized by a computer system to either getting chemotherapy-radiation, as is the standard of care that we just discussed, or chemotherapy plus radiation which is standard of care, plus the addition of this drug called pembrolizumab, which is an immunotherapy aiming to activate the immune system. Dr. Gilligan: And it's given at the same time as the chemotherapy and radiation on the study? Dr. Grivas: That is correct. It's given at the same time. And then there is also some—what we call continuation of pembrolizumab for some time after the end of chemotherapy and radiation, and pembrolizumab in this study is given every 6 weeks. Dr. Gilligan: And what makes people think that this might be helpful to add this additional treatment? Dr. Grivas: The notion is that the addition of immunotherapy to chemotherapy-radiation therapy has the potential to make the chemotherapy, radiation therapy work better. What happens sometimes when you give chemotherapy-radiation, this can actually result in a killing of some cancer cells and the contents of those cancer cells can be released, and they may be recognized by the immune system and stimulate the immune response. So if you combine that chemotherapy and radiation with immunotherapy with this agent that stimulates the immune system, the assumption is that this may work better compared to chemotherapy and radiation alone. But we have to do this trial to confirm whether this is true or not. Dr. Gilligan: So patients going on the study, basically, either they'll get the standard of care, which is the chemotherapy and radiation, or the standard of care plus the addition of immunotherapy to see if that results in better outcomes. Am I understanding that correctly? Dr. Grivas: That's exactly right. And the outcomes are being measured by how many patients maintain the bladder intact, in place without the need to remove it, without the need for cystectomy. And also, at the same time, we want to see if those patients can maintain a cancer-free status, so whether the treatment results in a cancer-free state and whether we are measuring a recurrence as Dr. Zhang mentioned before, if the cancer comes back. And also, of course, we measure how many patients are alive over time. So the goal is to see if we can improve upon the rate of patients with no cancer coming back, no recurrence, and being able to keep the bladder intact if possible. Dr. Gilligan: So for both of these trials, the question seems to be if we intensify treatment, can we increase the cure rate and keep patients cancer-free longer? Dr. Grivas: That's exactly right, and that's the promise or the assumption of this trial, whether the addition of immunotherapy to chemotherapy and radiation can improve those chances. Dr. Gilligan: What are the known risks that patients should be aware of? Dr. Grivas: As Dr. Zhang mentioned before, every time we have the immunotherapy in clinical trials or in clinical practice, we have to do a good job educating, of course, all the medical providers, team members, and the patients for early recognition and reporting of what we call immunotherapy-related potential side effects. And as we discussed earlier, any organ of the immune system could be a target of an activated immune system. The reality is that if the side effects from immunotherapy happens, usually it's a mild to moderate degree and usually can be managed by holding of the immunotherapy drug and maybe sometimes give some steroids to cool down the immune system. Obviously, we need to be extra vigilant, and I always err on the caution of overeducated patients to avoid underreporting so we make sure we know ahead of time if a side effect happens. Dr. Gilligan: Is there any reason to be worried that immunotherapy could make the side effects of chemotherapy and radiation worse? Dr. Grivas: It's a great question, and we have to look in that during the course of the trial. The notion is so far, based on the available data, that it's safe to combine chemotherapy, radiation, and immunotherapy. There have been some early data suggesting that, and this is reassuring. At the same time, we need, again, to be extra vigilant, again, over-educating our patients to report any changes so we can be able to compare the potential side effects in the 2 groups. But so far, it seems to be a feasible strategy. Dr. Gilligan: Good. And is this trial still open for patients? Dr. Grivas: Yes, it is open and accruing patients actively, and I think it's a great opportunity for patients to discuss with their providers, urological oncologists, medical oncologists, radiation oncologists, whether they could be good candidates for this bladder preservation approach, if that's a good fit for them and the particular cancer at hand, and if so, whether they can be candidates for this trial or another trial called SWOG 1806, which is in the same space and setting. Dr. Gilligan: And when might we expect results from the study? Dr. Grivas: It may take time because this trial is still early in the accrual process. It may take a few years. The current estimate is probably 2026, so 5 years from now. However, the faster these trials accrue, maybe the faster is to have the results. So this might have been overestimation, but it depends with how quickly the study will accrue patients. It's a very exciting study and definitely, I encourage patients to discuss this and the SWOG 1806 with their providers. Dr. Gilligan: Thank you very much. We're going to move on now, and Dr. Agarwal will tell us about the KEYNOTE-991 study. Dr. Agarwal, who is this study designed for? Dr. Agarwal: This is a study which is designed for patients with newly diagnosed metastatic castration-sensitive prostate cancer. In simple words, this is for those patients who have been diagnosed to have a prostate cancer which has gone to different parts of the body. Dr. Gilligan: And what's the current standard of care for these patients if they don't go on the study? Dr. Agarwal: Fortunately, the current standard of care has gone through a paradigm shift in the last 5 to 6 years. It started with chemotherapy with docetaxel being approved for these patients in 2014 with 2 positive clinical trials showing benefit for docetaxel chemotherapy as far as improvement of survival is concerned. After that, 3 more drugs known as novel androgen axis inhibitors, so deeper blockade of androgen pathway, which is a driver behind prostate cancer progression. So these 3 drugs, abiraterone, or also known as Zytiga, enzalutamide, also known as Xtandi, and apalutamide, also known as Erleada. These 3 drugs and chemotherapy are currently approved agents for our patients with newly diagnosed metastatic prostate cancer. Dr. Gilligan: And what is this study looking at to potentially change that or to add another option? Dr. Agarwal: So this study is using the backbone of androgen deprivation therapy, which is standard testosterone suppression therapy, plus enzalutamide or Xtandi. And then patients who are receiving the standard of care therapy with standard testosterone suppression therapy, plus enzalutamide, they will be randomized to pembrolizumab versus placebo. Pembrolizumab is an approved immunotherapy for multiple cancer types and pembrolizumab, also known as Keytruda, works by activating our immune system to fight against cancer cells. In a way, this study is actually testing whether addition of this novel immunotherapy pembrolizumab to existing regimen of androgen deprivation therapy plus enzalutamide is going to improve survival outcomes. Dr. Gilligan: What do we know about immunotherapy and prostate cancer? Dr. Agarwal: So far, immunotherapy, as we call them, immune checkpoint inhibitors, many of them are approved for multiple cancer types. They have not been successful as single agents in the context of advanced prostate cancer. So this is a trial which is testing whether immunotherapy, the pembrolizumab is going to be effective in combination with enzalutamide and testosterone suppression therapy. Dr. Gilligan: So patients will get the standard of care therapy either way. And then the question is, does adding immunotherapy make it even more effective than it is without it? Is that correct? Dr. Agarwal: That's true. The primary end points of the trial are overall survival and radiographic progression-free survival, which basically means the investigators are going to look for improved survival, overall survival, and delaying of disease progression by adding pembrolizumab. Dr. Gilligan: And we've already discussed the risks of immunotherapy on the previous 2 trials, but can you tell us again for patients who are particularly interested in this study what risks should they be aware of? Dr. Agarwal: So pembrolizumab belongs to a class of drugs known as PD-1 or programmed death 1 receptor inhibitor. Usually, this class of drug, as a class, these are highly well-tolerated drugs and only a small number of patients, I would say less than 5% of patients, would develop grade 3 or 4 side effects which will require treatment with corticosteroids like prednisone. And those side effects usually happen when these immune checkpoint inhibitors are able to activate the immune system beyond desired limits. And when the immune system is activated to very high levels, the immune system can attack our own body and can result in diarrhea, skin rashes, liver enzyme abnormalities, and if not controlled in time can lead to hepatitis, which is inflammation of the liver, inflammation of the lungs causing pneumonitis or cough, dry cough mostly. So these are the common grade 3, 4 side effects which happen in up to 5% of patients with pembrolizumab.   Dr. Gilligan: Just for our listeners in case they're not familiar, when you talk about grades 3 and 4 toxicities, what should they understand that to mean? Dr. Agarwal: In simple words, I would say grade 1 and 2 side effects are the ones which do not require any systemic therapy with steroids. Patients can go on with their daily activities without much problems. And mostly, these are controlled with medications which are over-the-counter. Even if we use prescription medicines, they're usually not able to affect the patient's overall lifestyle or quality of life. So these are the side effects which are pretty easily manageable mostly with over-the-counter drugs, symptomatic drugs, and patients lifestyle and quality of life are usually not affected by the side effects. And grade 3 and 4 side effects are those which require intensive therapy, in this context, with prednisone or corticosteroids sometimes requiring hospitalization and requiring multidisciplinary care with other specialists who are specializing in gastroenterology or pulmonology or on many other specialties. So that's how I would like to simplify the definition of grade 1, 2 versus grade 3, 4 side effects. Dr. Gilligan: That's great. Thank you very much. Is the trial still open for accrual? Can patients still go on it? Dr. Agarwal: Yes. Yes. Trial actually just opened for accrual, which is good news for our patients. And I would like to highlight that patients who have been diagnosed with newly diagnosed metastatic prostate cancer and they have started hormonal therapy like androgen suppression therapy, they still have 3 months to enroll in the trial. So if you have been diagnosed with metastatic prostate cancer and if you have started the treatment with testosterone blockade therapy, you can still go on the trial. You have 3 months to go on this clinical trial. And if you have started chemotherapy with docetaxel, which is a standard of care for our patients with this diagnosis, you can still go on the trial after receiving up to 6 cycles of chemotherapy with docetaxel. So this trial allows actually patients to go on the trial for up to 3 to 6 months after being diagnosed with metastatic prostate cancer. Dr. Gilligan: So that's very helpful to know. At the conclusion of chemotherapy, they would then start the enzalutamide and either the pembrolizumab or placebo? Dr. Agarwal: That's correct. Dr. Gilligan: Well, great. And when do we expect to see results from the study? Dr. Agarwal: So as we know this, which is great news for our patients, survival has gone up by almost 2 to 3 fourths over the last 10, 15 years, and in this disease setting, any trial takes up to 5 to 6 years to show results. So I estimate based on the available information on the ClinicalTrials.Gov website, the trial is scheduled to finish in 2026. Dr. Gilligan: I see. Well, great. So thank you very much. Thank you all 3. That's hopefully a helpful summary of these 3 important new trials. Dr. Agarwal: Yes, it's a pleasure to be here, Tim. Dr. Grivas: Thank you so much. Dr. Gilligan: Thank you. Thank you for listening to this podcast. There are many different clinical trials currently enrolling people with genitourinary cancers. If you're wondering whether participating in a clinical trial might be right for you, please talk to your health care team. ASCO: Thank you, Drs. Gilligan, Zhang, Grivas, and Agarwal. Visit www.cancer.net/clinicaltrials to learn more about participating in clinical trials. All treatments have side effects—please talk to your health care team about possible side effects to watch out for. And if this podcast was useful, please take a minute to subscribe, rate, and review the show on Apple Podcasts or Google Play.

Confira neste episódio, sob a apresentação do Dr. Daniel Vargas, oncologista clínico do Grupo Oncoclínicas de Brasília, comentários sobre os estudos de maior relevância na área de Câncer de Rim apresentados durante a ASCO GU 2021. O primeiro trabalho comentado (CLEAR) avaliou a combinação de lenvatinibe + pembrolizumabe versus lenvatinibe + everolimus versus tratamento padrão com sunitinibe isolado na primeira linha do carcinoma renal de células claras metastático. O segundo estudo em destaque (SWOG 1500) avaliou a eficácia de cabozantinibe, crizotinibe e savolitinibe versus sunitinibe na primeira ou segunda linha do carcinoma papilífero de células renais, demonstrando o papel de cabozantinibe como opção terapêutica ativa para essa população. O último trabalho em destaque é um estudo fase II que avaliou a atividade do inibidor do fator induzido por hipóxia 2α belzutifan combinado a cabozantinibe no tratamento de pacientes com carcinoma renal de células claras expostos até dois regimes sistêmicos prévios, reforçando o papel da via da hipóxia como importante alvo terapêutico no tratamento do carcinoma de células renais. Confira o episódio.

In today’s episode, Dr. Neeraj Agarwal, medical oncologist and director of the Genitourinary Oncology Program at the University of Utah’s Huntsman Cancer Institute, discusses the SWOG 1500 trial and a potential new standard of care for patients with metastatic papillary renal cell carcinoma.

Retiring ASCO Chief Medical Officer Dr. Richard L Schilsky gives a far-reaching interview with ASCO in Action podcast host ASCO CEO Dr. Clifford A. Hudis, who examines Dr. Schilsky’s trailblazing medical career, his leadership in ASCO and indelible mark on its research enterprise, and what he sees for the future of oncology. ASCO’s first-ever Chief Medical Officer even offers some friendly advice for Dr Julie Gralow, who starts as ASCO’s next CMO on February 15, 2021. In a touching tribute, Dr. Hudis also shares what Dr. Schilsky’s friendship and mentorship has meant to him personally, and suggests that Rich will still be supporting ASCO on critical priorities moving forward. Don’t miss this exchange with one of oncology’s greats! Transcript DISCLAIMER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. CLIFFORD HUDIS: Welcome to this ASCO in Action podcast brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insights into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org. The ASCO in Action podcast is a series where we explore the policy and practice issues that impact oncologists, the entire cancer care delivery team, and the individuals we care for-- people with cancer. My name is Dr. Clifford Hudis. And I'm the CEO of ASCO and the host of the ASCO in Action podcast series. For today's podcast, I am especially pleased to have as my guest my friend, colleague, and mentor Dr. Richard Schilsky, ASCO's chief medical officer. Now, I am sure that many of our listeners have already heard that Dr. Schilsky will be leaving ASCO in February of 2021, retiring. However, I want to reassure everybody that even in retirement, he will continue to make contributions and provide leadership to all of us. And his illustrious and path-blazing career in oncology spanning more than four decades is not quite over thankfully. Rich is ASCO's first chief medical officer. And as such, he has made a truly indelible mark on all of us. He started with a proverbial blank piece of paper. The position had no precedent. It had no budget. It had no staff. But now after just eight years in the role, he has helped make the CMO a critically important position at the society. And I have to say that success is more than anything due to Rich's vision and his leadership. And that's some of what we'll be talking about today. So Rich, thank you very much for joining me today for what I hope is going to be a great casual but informative conversation about your amazing career, your unique role at ASCO, and maybe most importantly in the end what you see for the future of oncology not just in the United States, but around the world. Thanks for coming on, Rich. RICHARD SCHILSKY: Thanks, Cliff. It's great to be here today. CLIFFORD HUDIS: So with that, let's just dive right in and start at the very beginning. Rich, tell everybody why you decided to become an oncologist and maybe share a little bit about what those early days looked like for you and, in that context, what it was like to have cancer at the beginning of your career. RICHARD SCHILSKY: Well, I knew from an early age that I wanted to be a doctor. And in fact, I had written a little essay when I was in sixth grade as a homework assignment called My Ambition. And my mother had tucked that away in a scrapbook. And I found it a number of years ago. And on rereading it, it was quite amazing to me to see what I was thinking about even then. Because I said not only did I want to be a doctor, but I didn't think that was enough, that I wanted to be a medical researcher because I wanted to discover new information that would help people heal from whatever their diseases might be. And so it was never really any doubt in my mind that I would be a physician. I went to medical school at the University of Chicago. But I was living in New York City at the time having grown up in Manhattan. And the only year we had off in medical school, the only time we had off in medical school, was the summer between the end of the first year and the beginning of the second year. So during that time, I went back to Manhattan. And I was able to get a fellowship from the American College of Radiology that allowed me to essentially hang out in the radiation therapy department at New York University Medical Center, which was within walking distance of where I grew up. And so I would go over there every day. And I was taken under the wing of a young radiation oncologist. And of course, I wasn't really qualified to do anything at that point except to follow him around, talk and listen to the patients. But that turned out to be a really formative experience for me because we saw the whole gamut of cancer. We saw head and neck cancers. We saw lung cancer. We saw patients with breast cancer and prostate cancer. And in those years-- this is the early 1970s-- many of these patients have fairly locally far advanced disease and were quite debilitated by it. But listening to their stories, hearing about their hopes and their struggles, really demonstrated to me the human side of cancer. So I went back to school and thought about this in the context of my own personal experience, which dated back to when I was in college when my mother's mother, my maternal grandmother, was diagnosed with breast cancer. This was 1968. And as you well know, there were very few therapies available for breast cancer in the late 1960s, mostly hormone therapies. And my grandmother had the treatment that was considered standard of care at that time, which was extended radical mastectomy followed by chest wall radiation. And some years after that first mastectomy, she had a breast cancer that developed in the opposite breast and had a second extended radical mastectomy and chest wall radiation. And these were very traumatic and disfiguring procedures for her to go through. Anyway, long story short is after another few years, she developed bone metastases and then brain metastases. And there was really very little that could be done for her other than hormone therapies. And having observed her go through that illness and realizing how limited our treatment options were and then having the experience after my first year in medical school pretty well cemented for me that I wanted to be an oncologist. I thought actually about being a radiation oncologist. But then I did my internal medicine rotation in medical school, fell in love with internal medicine. And that sort of put me on the path to be a medical oncologist. The clinical challenge of caring for cancer patients, the emotional attachment to those patients, and, of course, even then, the unfolding biology of cancer was so intellectually captivating that I actually applied for oncology fellowship when I was a senior medical student. So even before going off to do my medical residency, I had already been accepted as a clinical associate at the National Cancer Institute to start two years hence. And that's how I became an oncologist. CLIFFORD HUDIS: So it's so interesting. Because, of course, the story I'm sure for many people interested not just in oncology, but even medical education, there are little things that don't happen nowadays that happened with you like that last little vignette about the early acceptance into an advanced training program before your fellowship among other things. Can you remind us about the timeline? Because I think one of the things that many of our listeners often can lose sight of is just how new oncology really is as a specialty. ASCO itself founded in 1964. And the first medical oncology boards were mid-'70s, right? So you were in med school just before that second landmark, right? RICHARD SCHILSKY: That's right. I graduated from medical school in 1975. I started my oncology fellowship in 1977. And I got board-certified in medical oncology and joined ASCO in 1980. And so that was the time frame at that point. CLIFFORD HUDIS: So the internal medicine was actually, if I heard you right, just two years, not the now traditional four. RICHARD SCHILSKY: Yeah. I was a short tracker. I did only two years of internal medicine training rather than three. I did my training at Parkland Hospital and University of Texas Southwestern in Dallas with at that time a legendary chair of medicine, Don Seldin, who I had to get permission from him to leave the program prior to completing the third year of residency because I had already been accepted into fellowship at NCI. And he, Seldin, who was a brilliant chairman and a brilliant nephrologist, was not at all interested in cancer. And it took a bit of-- I was going to say arm twisting, but it really took bleeding on my part to get him to agree to allow me to leave the residency program to go to the NCI. But he eventually agreed. And in those years, the first-year clinical fellowship at the NCI was like being an intern all over again. There were about 15 of us. We were on call overnight in the clinical center once every two weeks. We cared for all of our inpatients as well as had a cadre of outpatients. We did all of our own procedures. We had no intensive care unit. So patients who were sick enough to require ventilator support, we cared on the floor in the inpatient service on our own with guidance from senior oncologists. It was a bit different from the way it is now. But, of course, it was fantastic on-the-job training because we just learned a ton and had to learn it very quickly. CLIFFORD HUDIS: So that's actually a great segue to the advances because there was a lot to learn then. But, wow, there's a lot more to learn, I think, now. And I have real sympathy for trainees and younger oncologists for the breadth of what they need to learn. Again, just testing your memory, but platinum came along pretty much in the mid-'70s as well, right? That was a pivotal expansion of the armamentarium for us. So what do you see-- when you summarize progress in cancer research and care over these decades, what do you think are the most pivotal or revolutionary milestones that you identify over the span of your career? RICHARD SCHILSKY: Yeah. It's really interesting to think about it historically. There were the early years of discovery in oncology from the 1950s to the 1970s when we really had the introduction of the first chemotherapy drugs and the miraculous observation that people with advanced cancer could actually obtain a remission and, in some cases, a complete remission with chemotherapy and combination chemotherapy in particular. And so that was the formative years of oncology as a medical specialty and really proof of concept that cancer could be controlled with drugs. When we got into the 1980s, the 1980s in many respects were the doldrums of progress in clinical oncology. There really was not a lot of innovation in the clinic. But what was happening and what was invisible to many of us, of course, was that was the decade of discovery of the fundamental biology of cancer. That's when oncogenes were discovered, when tumor suppressor genes were discovered, when it became clear that cancer was really a genetic disease. And that is what transformed the field and put us on the path to targeted therapy and precision medicine as we think of it today. So I think that clearly understanding the biology of cancer as we do now and all that it took to lead us to that point, which was a combination of understanding biology, developing appropriate technology that would, for example, enable the sequencing of the human genome and then the cancer genome. And the other formative technology in my opinion that really changed the way we care for cancer patients was the introduction of CT scanning. When I was still a fellow at the NCI, we did not have a CT scanner. If we needed to get detailed imaging of a patient, we did tomography. And if you remember what tomograms looked like, they were really blurry images that you could get some depth perception about what was going on in the patient's chest or abdomen. But they really weren't very precise. When CT scanning came along, it really revolutionized our ability to evaluate patients, assess the extent of disease, stage them in a much more precise way, which then allowed for better patient selection for curative surgery, better radiation therapy planning. So we don't often point to imaging advances as some of the transformative things that paved the way in oncology, but I think imaging is really overlooked to some extent. So I think the technology advances, the biological advances, are the things that really allowed the field to move forward very quickly. And by the time we got into the mid-1990s, we were beginning to see the introduction of the targeted therapies that have now become commonplace today. And then it was around 2000, I think, that we saw the introduction of Gleevec. And I'm reminded always about an editorial written by Dan Longo in The New England Journal a few years ago. And Dan and I were fellows together. We worked side by side on the wards at the clinical center and became very good friends. And Dan in his role as a deputy editor of The New England Journal wrote an editorial a few years ago that was titled "Gleevec Changed Everything." And Gleevec did change everything. It changed our entire perception of what were the drivers of cancer and how we might be able to control cancer very effectively and potentially put it into long-term remission. Now, of course, we know now that the whole Gleevec story is more of an exception than a rule in targeted therapy. And, of course, we know that tumors become resistant to targeted therapies. But we couldn't have known any of this back in the early years of oncology because we had no real insight into what caused cancer to grow or progress. And the notion of drug resistance, while we realized that it occurred, we had no idea what the mechanisms were. So it's such a different landscape now than what it used to be. It's quite remarkable. CLIFFORD HUDIS: So as you tell the story, there's, of course, a lot of focus on technology, whether it's biology and understanding the key features of malignancy or imaging or more. But what I also note in your story and I want to come back to is the people. And I can't help but reflect on where we are in this moment of the COVID-19 pandemic. Yes, we've moved to telemedicine. Everything can be accomplished via technology. And, yet, the human touch is so important. When we think about being in the room with people, when we think about face to face from the context of career development and your own career, you touched on Dr. Seldin, I think, already from the perspective of internal medicine training. But are there are other mentors or important shapers of your career that you think we should know about? RICHARD SCHILSKY: Well, probably, the most influential person early in my career in medical school was John Altman. John, you may know, was the inaugural director of the University of Chicago's NCI-designated Cancer Center, which was one of the very first NCI-designated cancer centers in 1973 after the National Cancer Act of 1971 created the cancer centers program. And John, who was a leading oncologist studying Hodgkin and non-Hodgkin's lymphoma, was a faculty member there. He was the director of our cancer center as I said. He took me under his wing even when I was in medical school and served as a real role model and mentor to me. When I was in my internal medicine training as I mentioned earlier, Don Seldin, the chair of medicine, was never particularly interested in oncology. So, to some extent, I didn't have-- I had great internal medicine training. But I did not have good mentorship in oncology. When I got to the NCI, then my whole world really opened up. And the two pivotal people there in my career were Bob Young, who was chief of the medicine branch and was my clinical mentor and remains a mentor and friend to this day, and then, of course, Bruce Chabner, who was the chief of the clinical pharmacology branch. And in my second year of fellowship when we all went into the laboratory, I went into Bruce's lab. And that's where I really got interested in the mechanism of action of anti-cancer drugs and ultimately in drug development and early phase clinical trials. And both Bob and Bruce remain very close to me even today. CLIFFORD HUDIS: So I'm concerned about time on our call today on our discussion. Because we could obviously fill lots of hours on all of these remarkable experiences and amazing people you worked with. But I'm going to ask that we fast forward a little bit. You and I share, I think, passion and love for ASCO. So I think that it's reasonable for us to focus a little bit on that for the time we have left here. You didn't start out obviously as chief medical officer at ASCO. But you were a really active ASCO volunteer and leader. Maybe tell us a little bit about some of the ASCO volunteer roles that you engaged in and what that meant to you at the time and how that led to this role. RICHARD SCHILSKY: Well, I'll be brief. I joined ASCO in 1980 at the first moment that I was eligible to join ASCO. I had attended my first ASCO meeting the year before, 1979, when I was still in my fellowship training. And it was clear to me even then when the whole annual meeting was about 2,500 people in two ballrooms in a hotel in New Orleans that that was a community of scholars and physicians that I wanted to be a part of. And so, over the years, I did what people do even today. I volunteered to participate in whatever ASCO activity I could get involved with. Over the years-- I think I counted it up not too long ago-- I think I served or chaired 10 different ASCO committees, more often serving as a member, but in a number of those committees also serving as the chair over many years. And as I became more deeply involved in ASCO and saw other opportunities to engage, I had the opportunity to run for election to the board and was-- after a couple of tries was elected to serve on the board and then eventually elected to serve as ASCO president in 2008-2009. But the attraction of ASCO in many ways was a community of diverse but, in many ways, like-minded people, people who had similar passion and drive and focus. But I think what you get at ASCO in many ways is the wonderful diversity of our field. If you work in a single institution for much of your career as I did and as you did, you get to know that institution pretty well. You get to know its perspectives and its biases and its strengths and its weaknesses. But there's a whole world of oncology out there. And you can get exposed to that at ASCO because you meet and work with colleagues from every clinical setting, every research setting, people who have remarkable skills and interests and passions. And it's just a wonderful environment to help develop your career. So I consider myself to be extremely fortunate to have had the journey in ASCO that I've had culminating, of course, with ultimately my coming on the staff as ASCO's first chief medical officer. CLIFFORD HUDIS: We often joke about that blank sheet of paper. But in retrospect, it's very obvious that you had built up that collection of LEGO blocks, and then you assembled them all into the ASCO Research Enterprise, a name you gave it. And it really, in retrospect, builds, I think, very cleanly upon all of your prior experience, but also the vision that you developed based on that experience for how research should be conducted. Can you maybe share with everybody the scope and vision for the ASCO Research Enterprise, what the intent was, and where you see it going, and what it includes today? RICHARD SCHILSKY: Sure. I won't claim that I came to ASCO with the whole thing fully developed in my mind. As you said, when I came, I literally did have a blank slate. Allen Lichter, who hired me, said, come on board and help me make ASCO better. And so I, in a sense, reverted to what I knew best how to do, which was clinical research. And having in my career been a cancer center director, a hem-onc division chief, a cooperative group chair, I had a lot of experience to draw on. And it was obvious to me that ASCO was fundamentally an organization that took in information from various sources, evaluated it, vetted it, collated it, and then disseminated it through our various channels, most notably our meetings and our journals. But ASCO itself did not contribute to the research enterprise. And that seemed to me to be a lost opportunity. We knew that ASCO had lots of data assets that could be of interest to our members and to the broader cancer community. But they were scattered all around the organization and not particularly well annotated or organized. So we began to collate those. And they are now available to ASCO members on the ASCO data library. I recognized that we did not have an organized unit in ASCO to support or facilitate or conduct research. So, in 2017, we formed the Center for Research and Analytics and brought together staff who were already working at ASCO but scattered in different departments but all people who had an interest in clinical research or research policy and brought them into this new unit, which has really become the focal point for research work at ASCO. We recognized that ASCO members for many years were interested in surveying their colleagues, surveying other ASCO members, to help advance research questions. But ASCO actually had a policy that prohibited that. So that never really made good sense to me. It seemed like a lost opportunity. And we were able to create a program and have the ASCO board approve it whereby any ASCO member could opt in to participate in what we now call the Research Survey Pool. And in doing so, they are essentially agreeing to participate in research surveys conducted by their colleagues. So that program is now up and running. There are, I think, eight surveys that have been completed or are currently in the field. And this is now a service that ASCO provides through CENTRA to its members to enable them to survey their colleagues for research purposes. Most importantly, I think we saw an opportunity back in 2014 or 2015 to begin to learn from what our colleagues were doing in clinical practice as they began to deploy precision medicine. And there was a lot of genomic profiling that was going on at that time. It was revealing actionable alterations in roughly 30% or so of the tumors that were profiled. But there was a lot of difficulty in doctors and patients obtaining the drugs that were thought to be appropriate to treat the cancer at that particular time because most of those drugs would have to be prescribed off label. And there was not a sufficient evidence base to get them reimbursed. And, moreover, even if they could be reimbursed, there was no organized way to collect the patient outcomes and learn from their experiences. So that led to us developing ASCO's first prospective clinical trial, TAPUR, which really solves both of those problems. Through the participation of the eight pharmaceutical companies that are engaged with us in the study, we are providing-- at one point, it was up to 19 different treatments free of charge to patients. These are all marketed drugs but used outside of their FDA-approved indications. And we were collecting data on the patients, the genomic profile of cancer, the treatment they received, and their outcomes in a highly organized way. And so now this is a study that we launched in 2016. We're now almost to 2021. We have more than 3,000 patients who have been registered on the study, meaning consented to participate, more than 2,000 who have been treated on the study. And we are churning out results as quickly as we can about which drugs are used or not useful in the off-label setting for patients whose tumors have a specific genomic profile. So we built all this infrastructure. And having this in place has also then allowed us to respond rapidly to unmet needs. So when the COVID-19 pandemic overwhelmed all of us, and when our members were looking for information about what was the impact of COVID-19 on their patients, one of the things we were able to do because we had CENTRA, because we had a skilled staff and an infrastructure, was to very quickly stand up the ASCO COVID-19 registry, which we launched in April of this year. And there are now about 1,000 patients who've enrolled in the registry from around 60 practices that are participating. And we will follow these patients now longitudinally and learn from their experiences what has been the impact of the COVID-19 illness on them and their outcomes, how has it disrupted their cancer care, and ultimately how that impacts their overall cancer treatment outcomes. So as I now contemplate leaving ASCO after eight years having started with a blank slate, I'm very proud of the fact that I think I'm leaving us with a remarkable infrastructure. We now have a clinical trials network of 124 sites around the country participating in TAPUR that we never had before. We have through the work of CancerLinQ a real-world evidence data generator that is beginning to churn out valuable insights. We have a capacity to survey ASCO members for research purposes. We have an ability to stand up prospective observational registries to gather information longitudinally about patients and their outcomes. We have a core facility in CENTRA with highly skilled data analysts and statisticians that can support these various research activities. So ASCO is now primed, I think, to really contribute in a very meaningful way to the gaps in knowledge that will forever exist in oncology just because of the complexity of all the diseases we call cancer. And that's what I mean by the ASCO Research Enterprise. It is in fact remarkable and, I think, powerful enterprise if we continue to use it effectively. CLIFFORD HUDIS: Well, that's an interesting segue to my next thought, which is really about what comes next. I'll talk about you. But let's start with ASCO first. Your successor, Dr. Julie Gralow, obviously has been announced publicly. She's an accomplished clinician and researcher. She has a known recognized passion for patients, patient advocacy, clinical research through her leadership at SWOG but also health care equity and global oncology. So from your perspective, having created all of these assets and resources, what advice would you give Dr. Gralow publicly on how to make the position hers, what to take us to next? And I do want to acknowledge for everybody listening that the hints I've been making up until now are that Rich has agreed that he will continue to contribute as a leader to TAPUR for the short term, at least, at least the next year helping Julie get fully oriented to this program and others. So what will your advice be to Julie? RICHARD SCHILSKY: That's a great question. She's a great selection. And congratulations on hiring her. I think there are two key issues, I think, maybe three. One is to have a broad scope and cast a wide net. Oncology care and cancer research and cancer biology are incredibly complicated and nuanced and broad in scope. And although Julie is an accomplished breast cancer clinician and researcher, in this role at ASCO, you have to be very broad. You have to understand all of cancer care, all of cancer research, all of policy and advocacy not as an expert in necessarily in any one aspect of ASCO's work, but you have to understand the impact of all of those things on cancer care providers and on cancer patients. And it's important to always be looking to the future. The future is going to be here before you know it. And we as a professional society have to prepare our members for that future. So that leads me to the second point, which is listen to the members. The members are the people on the front lines who are delivering care to patients every day. And, fundamentally, ASCO's job is to be sure that our members have all the tools and knowledge and resources that they need to deliver the highest quality care to patients every day. So listening to what they need, what their struggles are, what their burdens are, is extremely important. And then the third thing I would recommend to her is that she get to know the staff and colleagues that she'll be working with. ASCO has a remarkably accomplished, skilled, motivated, passionate staff, many of whom have been with the organization for years, if not decades, who understand what ASCO can and cannot do and who understand what our members need. And she will be well advised to spend a good portion of her first few months on the job just listening and learning from her colleagues. CLIFFORD HUDIS: That's always good advice for anybody making a big career move. But, of course, the wisdom you bring to it is palpable and much appreciated. And I'm sure Julie will be taking your advice. And, by the way, so will I continue to do that even after you make your move. So speaking of your retirement, can you share with us a little bit about what it's actually going to look like for you? Is it about family? Or are you still going to have some professional engagement? Again, I suggest that there might be some already, but maybe you could expand on it. RICHARD SCHILSKY: Yeah. I'm still fully focused on my work at ASCO. And, of course, as you know, when I wake up on February 15, I will no longer be ASCO's chief medical officer. And it's going to be a bit of a rude awakening. Fortunately, I will be able to continue my engagement with ASCO through the TAPUR study as you mentioned. I will, of course, forever be at ASCO member and a donor to Conquer Cancer and be willing to serve the society in any way. I have a number of activities that I've been involved with even throughout my time at ASCO. Not-for-profit boards, for example-- I'm on the board of directors of Friends of Cancer Research. I'm on the board of directors for the Reagan-Udall Foundation for FDA. I plan to continue with those activities as long as they'll have me. I've been serving the last few years on the board also of the EORTC, the large European cooperative clinical research group. And I expect to continue in that role. Beyond that, I will see what opportunities come my way. I think one of the things about retirement if you will that I'm looking forward to is the opportunity to pick and choose what to work on based on what interests me without having the burdens of having a full-time job. On the personal front, of course, we're all looking forward to crawling out from the pandemic. I've basically been locked in my home outside Chicago since March. And I'm looking forward to getting back out to a little bit of a social life. As you know, I have two grown daughters and now three grandchildren, two of whom are in Atlanta, one of whom is near by us in the Chicago area. So looking forward to spending time with them as well. So it will be a change for me to be sure after working as hard as-- I feel like I've worked for really now 45 years since I graduated from medical school. But I also feel like I'm not quite done yet and that I still have ways in which I can contribute. I just feel like at this point, maybe it's time for me to choose how I want to make those contributions and spend a little bit more time doing some other things. CLIFFORD HUDIS: Well, both you and my predecessor, Allen Lichter, are modeling something, have modeled something, that I think is not often discussed but can be very important. For people and for institutions, change is not a bad thing. And setting the expectation that you will pour your heart and soul into something but not necessarily do it alone or forever and not prevent others from taking that role at some point, that's a really-- I think it's a selfless kind of sacrifice in a way. Because, of course, you could stay and do what you're doing for longer. But as you and I have discussed, there is a value for all of us collectively in having fresh eyes and new people take organizations in a new direction. That's how I ended up here frankly. And I think that's the kind of opportunity you're creating right now, something that should be celebrated in my opinion. RICHARD SCHILSKY: Well, thanks. And I couldn't agree more. When I look back at the arc of my career and having all the different kinds of leadership roles that I've had, I basically have made a job change every 8 to 10 years. I was the director of our cancer center for nearly 10 years. I was associate dean for clinical research at the University of Chicago for eight years, another position that I created from a blank slate at that institution. The exception was serving 15 years as a CALGB group chair. But that was a position I really loved and enjoyed and felt like at the end of the first 10 I hadn't quite accomplished everything I wanted to accomplish. But the point is that I think it is both necessary for organizations to have regular leadership change. And it's also refreshing for us as individuals. There gets to a point where you feel like you can do your job in your sleep. And I actually think that's a good time to make a change. Because if that's the way you feel, you're not being sufficiently challenged. And you're probably not being sufficiently creative. And so it's a good time to move on and refresh your own activities and give your organization a chance to bring in someone to hopefully build on whatever you've created and bring it to the next level. CLIFFORD HUDIS: Well, I agree with all that, although I think your comment there about doing the job in your sleep would not apply because I'm pretty confident that the environment and opportunities have continued to evolve in a way that has made it interesting from beginning to end. But you don't have to rebut me on that. I just want to thank you very, very much, Rich. As we set up this podcast, I expected that we would have a really fun and enlightening conversation. And, of course, you did not disappoint. We could talk for much, much longer if we only had the time. On a personal note to you and for the benefit of our listeners, I want to share that Rich has been for me a remarkable friend and mentor and colleague. I first met Rich at the very beginning of my career when my mentor, Larry Norton, pushed me out from Memorial into the larger world. And he did that first and primarily through ASCO and the Cancer and Leukemia Group. Those are really the two places where I was exposed to the world. And through the CALGB, Rich really began to offer me and others, many others, opportunities that shaped careers plural, mine and others. So when I got to ASCO as CEO, Rich was there. And I knew I could always depend on you to be clearheaded, intellectually precise, constructive, visionary. And the thing about you, Rich, is that you never would say yes to anything unless you knew for sure you could do it and indeed, I think, how you could do it. I always share this story which your staff at CENTRA pointed out to me. And I have to admit that I hadn't picked it up myself. But in all the years of now working down the hall from Rich, probably hundreds and hundreds of hours of meetings, he never has taken a note in front of me. And, yet, everything we talk about, every action item we conclude to pursue, they all get done. So I don't know, Rich. You have a remarkable way of organizing your thoughts and your plans, keeping it together, and getting things done. And I'm going to miss that tremendously in the years ahead. So, Rich, I want to say congratulations. Congratulations on reaching this really important milestone in your life. Thank you on behalf of ASCO and the broader oncology community and the patients we care for and their families for making the world a better place. And just as a small thing, thank you for joining me today for this ASCO in Action podcast. RICHARD SCHILSKY: Thank you, Cliff. It's been great. CLIFFORD HUDIS: And, for all of you, if you enjoyed what you heard today, don't forget to give us a rating or a review on Apple Podcasts or wherever you listen. And, while you're there, be sure to subscribe so you never miss an episode. The ASCO in Action podcast is just one of ASCO's many podcasts. You can find all of the shows at podcast.asco.org. Until next time, thank you for listening to this ASCO in Action podcast.

Dr Hayes interviews Dr Ganz on pioneering quality of life studies. PRESENTER 1: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. PRESENTER 2: Welcome to JCO's Cancer Stories: The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the role of cancer care. You can find all of the shows, including this one, at podcast.asco.org. DANIEL HAYES: Today, my guest on the podcast is Dr. Patricia A., Patti Ganz. Dr. Ganz has been a pioneer in establishing an entire field in our discipline, the discipline of survivorship. And really, this has been based on studies of quality of life and toxicities of therapy in patients with established active cancers that Dr. Ganz was involved with for really, the last four decades. Dr. Ganz was born and raised in Los Angeles. She received her undergraduate degree at Radcliffe, graduating in 1969. And correct if I'm wrong, Patti, I understand you were in the last class before the merger with Harvard. But I see you got your degree from Radcliffe and Harvard. So she received her medical degree and completed her residency and incidentally was chief resident and then medical oncology fellowship, all at UCLA. She then joined the faculty at UCLA and spent much of the early part of her career at the UCLA associated VA hospital. In 1992, she moved back to the mothership where she is now professor of medicine in the David Geffen School of Medicine, a professor of health policy and management in the Fielding School of Public Health, a distinguished professor of medicine and health policy and management, and the associate director for population science research in the Johnson Scott Comprehensive Cancer Center, again, all at UCLA. Dr. Ganz has authored over 400 peer reviewed papers, way too many chapters and reviews for me to recount here. And since 2017, she served as editor-in-chief of the Journal of the National Cancer Institute, one of the leading journals in oncology. She has an enormous list of honors that, again, is too long for me to go through today, except for a few I'd like to highlight. She's received two of ASCO's highest honors, the American Cancer Society award in 2008, and the Joseph B. Simone award for excellence in quality and safety in the care of patients with cancer in 2016. She was also the recipient of the Ellen L. Stovall award for the advancement of cancer survivorship care. She was a founding member of the National Coalition of Cancer Survivorship, and she was inducted into the Institute of Medicine, now designated the National Academy of Medicine, in 2007. And she's really played a major role in the efforts of the Academy to improve quality of care in medicine and particularly in oncology. Dr. Ganz, welcome to our program. PATRICIA GANZ: Thanks, Dan. It's great to be with you. DANIEL HAYES: So just to start out, there are so many things I'd like to talk to you about. One of those, in my opinion, you've been the epitome of role models for women in academics. And a lot of this series has mostly been men, because it was mostly men who started a lot of what we do way back 40, 50, 60 years ago. I know you grew up in LA. What shaped your decision to go into medicine in the first place, and then to stay in academics? PATRICIA GANZ: I went through college at Harvard and Radcliffe in a very turbulent time, in the late 1960s. Social issues were very important to us then, political issues just as they are now. And I was a biology major. And I was thinking about what I would be doing in the future. And for me, I really felt that I had to do something connected with people. And that was part of my decision. But of course, I had a major influence from my father, who was a physician. He actually went to the University of Michigan. And he always encouraged me to think about medicine, although he said ophthalmology, radiology, those are good careers for women. So you know, I had this lurking in the background. I didn't want to necessarily do exactly what my parents said to me. My mother was someone who also had been working in a family business for many years. So I had them behind me saying it was possible to have a career and to move forward in medicine. And of course, summers, doing various kinds of research that was involved with a potential career in medicine. So it wasn't a big surprise. Now why did I come back to LA? I guess that's a good question. Nowadays, when people actually are applying to medical school, I think they apply to 20, 30, 40. In those days, I think I only applied to six, if you can believe it. And three of them were UCs, and three or four of them I guess where on the east coast, or Northwestern with another one. It was a tough time. It was just on the feminist movement, also social change in terms of more African-Americans being admitted to medical school. And it was a tough time for those who were underrepresented, such as women. And in fact, at Harvard Medical School, I think family took 10 women. UCSF maybe took seven or eight women, where I'd gotten accepted there. And when I finally went back to school at UCLA, there were only three women in my class. So again, quite a striking difference than the way things are now. But I did come back to LA because UCLA was pass/fail. Having heard about the competition and medical school people being pretty cutthroat, I said, mm, probably good to go to a place where that wasn't the big issue. In addition, I actually met my future husband in a lab, working in a lab before my senior year in college. And I guess that might have been a motivation as well. DANIEL HAYES: And have you seen major change in attitudes regarding sex/gender in academics now? Do you feel that we've really made advances, or is it all just covering of a system that still exists? PATRICIA GANZ: I could speak for an hour on that, so I'm not going to do that. But I have to say that being a minority in the class was not unusual. Because at Harvard and Radcliffe, there were 300 women in my class at Radcliffe, and 1,200 men. And obviously, in the science classes I took, the women were in the minorities as well. But for women at that time, getting into medical school, they were actually a lot smarter and a lot better than the men because we were highly selected. However, my class, the three women-- one was me coming from an elite Ivy League school. One was a blonde valley girl who was coming from a California State University and another was a Korean immigrant. So we were all quite diverse-- yeah, even then. But by the time I graduated, we had a few women who transferred in. And actually, my husband who was a physicist at that time, went to medical school at UCLA five years later, and his class had about 25% women. So things were rapidly changing then. DANIEL HAYES: So I understand you really started doing hospice care when you were at the VA initially. And how has that colored what you ended up doing in terms of your career? I mean, in the 1980s, there wasn't a lot of hospice care. It must have made you think about and led to what you're doing now, what you've done. PATRICIA GANZ: That's an excellent question, Dan. And it was actually the late-- 1978, where I joined the faculty. And the chief of medicine said, you know, we have this kind of intermediate care unit. We'd like you to start a hospice for our oncology service, et cetera, et cetera. And there was actually a national hospice randomized trial that was going on at one of the other VAs here in Los Angeles. And having come out of my oncology training and thinking about it, I really thought well, you know, lot of those things that we're offering people at the end of life, like pain control and psychosocial support and things like that, we should really be doing that earlier for people. Because why should it just be reserved for those last few weeks? And so as I develop my unit at the VA, I actually called it a palliative care unit, a palliative care ward. Because at the VA I worked at, we had patients who actually often were in the hospital for five or six weeks getting their radiation, traveling by bus to the radiation facility. So they would be in for five days a week and then go home on the weekends. And these-- again, this was 1978, what were we seeing? We were seeing lung cancer. We had men with widespread prostate cancer who needed palliative radiation to the bones. We had a lot of colon cancers. So I was taking care of those patients. And while they weren't in imminent need of end-of-life care, they had trajectories which clearly were not good if they had advanced cancer. And it seemed reasonable-- I had a wonderful team, a physiatris, a psychologist, a social worker, even the pharmacist made rounds with us. It was just wonderful. And I essentially took all of the things that the palliative care end-of-life focus that hospice used and brought it up to the earlier part for some of these patients who, in fact, could be cured. I can think of someone who had localized small cell carcinoma who I took care of for many, many years. He was in getting chest radiation and whole brain. And you know, he lived a long time but he got all the tender, loving care that our nurses and our team were able to provide early in his course. DANIEL HAYES: You know, it segues really into my next question, which is in my own training, in the early 1980s at the Dana-Farber, especially led by Dr. Fry, Tom Fry, who's one of the fathers of medical oncology. We were really trained to learn how to treat and hopefully cure cancer. And there was very little regard to the toxicities. Dr. Fry used to tell us, cure the cancer first, we'll figure out the toxicities later. And at least the shackles begin to fall from my eyes as I began to see what you and others started to say. Well, you know, these people are going to survive. We need to worry about that. And personally, I think you almost-- not quite, but almost single-handedly taken our field beyond just treating the cancer, but worrying about the quality of life of survivorship. When you were starting that, either at the Bay area or when you went back to the main campus, what were the hurdles? Were there people who told you, you were wasting your time? Most have been told this is a fool's errand. You'll never get promoted by doing this kind of research. And you have done OK, I think. PATRICIA GANZ: Yeah. You know, I actually wanted to even go back to my training, you know? Because in the late '70s, there was actually-- in my heme/onc division, it was mostly liquid hematologists who were the leaders. And there were one or two solid tumor oncologists. And because I was interested in medical oncology primarily, I was the mentee of this person in his clinic. And essentially, what happened-- this was in the early days of adjuvant TMF chemotherapy. And you know, I was giving women chemotherapy for 12 months. And they didn't want to take it. They wanted to stop because of the toxicities of treatment. And he typically had me see those patients who needed that kind of support and symptom management and things like that, which were rather primitive, obviously, at that time. Because he was very technocrat in terms of knowing the literature and making those kind of decisions about therapy, but not managing all of this. So because of this collaborative relationship in his clinic for a couple of years, that's essentially where I began to see these issues because patients felt comfortable talking to me about it. Early on actually, at the VA, I was very fortunate, first of all, just to say I was a biology major in college. I never took a psychology class, ever. I took maybe a sociology class, which was on China at the time, but really wasn't trained in behavioral science. And I was very fortunate because there was a psychiatrist who was very interested in understanding the impact of cancer and its treatment on patients. And again, mind you, the five year survival was less than 50% at that time. And certainly, for the patients we saw with lung, colon, prostate that was metastatic, very much shorter. And he got a grant from the VA to do an intervention trial in the veterans and their spouses. But in order to be able to understand what patients were experiencing, Ian, the psychologist he hired as a project director, said, well, we've really got to interview patients and talk to them and find out what they're dealing with. And the psychological or psychosocial literature at that time was rife with issues related to coping. And coping is a concept that is not easy to explain to people. And certainly, it isn't necessarily universal in terms of many cultures. So it was difficult, then, to kind of operationalize this. And again, because I work with this great team, they began to interview our patients in clinic, and really, in detail, understood the day-to-day things that people were dealing with in terms of their cancer and the side effects from the treatment and their social relationships. And then we, all of a sudden, began to think of ourselves as a multidisciplinary team. And in fact, the person, Joe Collin, who was the associate director for population science at the Cancer Center at that time at UCLA, kind of said, gee, you make the ideal multidisciplinary team, you know-- a psychiatrist, a psychologist, and some medical oncologists. And it was from that time forward, that we began working together and I got my first grant. And really, they taught me so much about measurement, reliability, and validity. And in fact, we published our first paper together in JCO the second volume, which was on the Karnofsky performance status we visited, where they compared their ratings of the Karnofsky with my ratings of the Karnofsky for the clinic patients. And because they did a systematic interview about what patients were experiencing, noted that the function of patients was much worse than what I as even a sympathetic clinician would rate them. So that was really so important for me and working with them. And again, I think that's been the hallmark of my career to have had so many psychologists and psychiatrists, behavioral scientists, who embraced working with me, partly because I gave them access to patients if they wanted to study them, but I was also interested in really understanding, in a very rigorous way, how we could measure some of these things. DANIEL HAYES: Yeah, that raises another issue. In my career as a clinical investigator and translational investigator, pretty much inherited the tools to do what I want to do, how to do a clinical trial. It's always struck me that you, and I guess, Charles McKinsey and others had to make up your own tools, basically, to get it out of the realm of touchy-feely, if you will, and into the realm of true quantitative science so you could describe what you've done and how you've done it. How did you go about building those tools? PATRICIA GANZ: So again, a lot of these strategies or approaches to measurement were available in the social science literature. And they were just beginning to be translated into medicine. And again, this goes back to when I was training at UCLA. The Rand Health Insurance Experiment was going on in the '70s. My attendings in clinic were all involved in that. And John Ware, who was a great psychologist/methodologist, developed huge measures to look at patient outcomes in that big insurance experiment trial, which then got adapted into many other instruments that are widely used, such as the SF-36, and more recently, the Promise measures, which are publicly available. So I kind of was-- again, I had these kind of parallel streams of exposure. Health services research was very prominent at UCLA. These were my clinic attendings. And there was a very robust community of health services and health outcomes researchers. So I saw myself as kind of being an oncologist who could use those methods and apply them to the cancer problem. And there certainly weren't too many people out there. In addition, I had good fortune to begin to work in the cooperative groups, Ware and SWOG, with someone like Carol Moinpour, who led the efforts there in terms of patient-reported outcomes for many years, and then actually had a sabbatical in Switzerland, working with some of the IBCSG people and really having a time to just self-educate myself about this methodology. So I'm really self-educated, but have had wonderful collaborators who have kind of held my feet to the fire and said, you know, that's not rigorous enough, on occasion, certainly. DANIEL HAYES: So you were doing team science before the word came up, before the term. PATRICIA GANZ: Yeah, exactly. Certainly, when you have certain gaps in your knowledge, you need those collaborators. DANIEL HAYES: You know, this brings up-- I alluded to her just a moment ago. But when I think of cancer survivorship and quality of life, I think of you. But I think a lot of the late Jimmie Holland, who sadly passed away before I was able to interview her for this series. Can you just-- I think maybe some of our listeners don't know of her, haven't heard of her. We've got a lot of people young people listening to this. Can you just give a little background about Dr. Holland and the things she did? PATRICIA GANZ: Sure. Dr. Holland was a psychiatrist who really invented the field of psycho-oncology. And really, because she was working almost always in a cancer hospital, cancer setting-- I believe first at Roswell Park with her husband, James Holland-- she began to notice the neglect, if you will, of the impact of the cancer on the whole person and on the psychological aspects of cancer. And because of her being within a cancer hospital setting and then later moving to New York and obviously leading this effort at Memorial Sloan Kettering-- and really being very involved with CALGB and now the Alliance-- was able to introduce very early into the cooperative groups, the need for not just looking at the disease and its treatment, but to look at the after effects or show what were going on in the patient and how they were dealing with the illness. And she actually developed one of the first collaborative groups in psycho-oncology, which had people like Gary Morrow, who's at Rochester and who's had one of the big ENCORE research bases and has really continued to carry on a lot of psycho-oncology research across the country. Following what was really an early innovative approach, she developed a whole training program at Memorial. She trained many outstanding psychologists, psychiatrists working in this field and textbooks. I had the good fortune to work with Julia Rowland for a number of years. Julia was a direct descendant, if you will, Dr. Holland, having been at Memorial working with her and leading some of their early survivorship work. But she just trained probably more than a generation of people to take this seriously. As I kind of mentioned in an email to you, just as I would go to the ASCO meeting to listen to what Dr. Fisher or Dr. Bonadonna had to say, because I was interested in breast cancer and it was very exciting to hear the new reports of adjuvant therapy, I would also go to hear her and to Barry Castle, who was another leader in the field at the University of Pennsylvania, who basically were bringing rigor and clinical expertise to characterizing the patient experience, and publishing papers often in high profile journals like the New England Journal. So they were really role models for people who wanted to go into this field, although they weren't oncologists. And I think that's where I had kind of a double opportunity. Number one, I was perceived as a card-carrying oncologist. I was treating patients. I was in a cooperative groups. I was involved in trials, but I was also saying what about this secondary objective to our trial to look at the experience of the patients? So having entree to the patients, being perceived as one of the oncology community was, again, a really good thing to do. Although I must say that there were dozens and dozens of conferences where I was the last speaker on the program because quality of life was down there at the bottom-- not so much anymore. DANIEL HAYES: Your stories are great. I have one brief anecdote again, for the younger listeners. Jim and Jimmie Holland where as different as night and day. And Jim Holland, who was one of the three guys with Dr. Fry and Dr. Freireich-- who decided to put two drugs together and suddenly, we were able to cure some cancers-- was blustery. You might even call him a blowhard. I loved him, but I will never forget as a very junior person in CALGB, and I was appointed to be chair of a committee. And I was running my first committee meeting-- and needless to say, I was nervous anyway. And all of a sudden in the back of the room, Jim Holland, without a microphone, screams out something about, Hayes, if this is the way you think it's sounding, when I'm reading to you now, duh, duh-- so I went ahead and got through the reading. And later, Jimmie walked up to me and said, you know, he really loves you. His bark is much worse than his bite. PATRICIA GANZ: No, and you know, I think the early days of oncology were so much like that. Because again, we would have these wonderful people come to the microphone and ask a question. In the case of Dr. James Holland, he didn't need a microphone. But the point is, that we actually saw these people in real life, posing questions, challenging sometimes what was presented in a meeting, but also being very collaborative. And I think it was wonderful. And I think it's good that we have-- you know, our meetings today, obviously, are quite different because of the pandemic. But in our large meetings, we have scheduled discussions which is good, but it doesn't have the same spontaneity that we obviously were fortunate to experience in an earlier time. DANIEL HAYES: Yeah, I agree. You know, I think probably, of the many, many contributions and things you're known for, I believe your role in the Institute of Medicine then, now the National Academy of Medicine, regarding survivorship may be your greatest impact on what we do. How do you think that's translating now, to use the word translational science, which it really is? And when I was present, I was struck. There are probably 15 million cancer survivors in the United States right now. Have we really changed how they do based on your report, or is that falling on deaf ears? What do you think's going on with that? PATRICIA GANZ: Well, you know, there's several things that have happened. So the report that was in 2006 was led-- actually, Ellen Stovall was actually one of the co-leads of that committee. And you know, that was very seminal in that it was-- it's called the lost in transition report. And it really called out-- at that time, there were 10 million survivors, and that this whole large body of the population didn't really know, didn't have much direction about what to do after treatment and were kind of lost, because the oncology care system didn't really give them any guidance. And if somebody went to their primary care doctor, they would say, uh-oh. I don't know what that's about. You go talk to your oncologist. And then the oncologist would say, oh, that's a weird symptom, but it's not-- you know, you don't have any evidence of disease. That would be the typical thing. But it was usually an ongoing long-term effect of the treatment or possibly a late effect that was emerging, you know, such as a cardiac problem or a neurological problem that might be a secondary to previous treatment. And so the patients really weren't getting good care. And they kind of said we need there to be a group of people-- whether it's an oncologist or someone else-- who will take an interest and really tell us what do we need to be on the lookout for. And that was kind of a way to say, we need an end-of-treatment discharge summary. And it became actually very apparent. I was on the ASCO board actually during that time with the NICCQ report. I don't know if you remember that, but it was a report that ASCO did looking at the quality of care for breast and colorectal cancer patients. And what they found was you could find the op report from the surgeon. You could find the radiation therapist's summary note. But the chemotherapy flow sheets-- and this is, again, before electronic records-- were the only way you could even find out if somebody a series of treatments. And that went on, sometimes, over several years. So there was kind of no summary after the medical oncologists finished their treatment. So they try and figure out, even if you were the treating physician many years later and you needed to retreat someone, it was hard to know what was happening. So in some ways, the treatment summary and care plan had two roles. One was to say, well, what did they actually get? And the patient should know what they got in case many years later, you find out there's the late effects. But also, what do we need to look out for? And so really, again, building on what the childhood cancer survivor people had been doing for many, many years in terms of long term and late effects, this became an issue. Now Ellen Stovall, who was really focused on quality of care for cancer patients, and again, unfortunately, passed away a few years ago from complications of her Hodgkin's disease, really wanted there to be treatment planning and not just the treatment summary and care plan at the end of treatment. So I was actually fortunate in 2013 to lead another-- to lead, at this time, a report on quality of care and quality of care for cancer patients. Because Joe Simone had done one in the late '90s, and this was kind of a catch-up report. But it was also focused on the large and growing number of cancer patients, and many of them older. And with the baby boomers going into an age where cancer is very common, you know, how was our health care system going to approach this? And so we were, in that report, in many ways, echoing what had come about in the earlier survivor report, but saying you need to do this right from the very beginning. And it is very important for survivors. If we're going to be worried about fertility preservation, we need to do it right upfront. If we're going to be worried about potential complications in terms of cardiac toxicity occurring later, we need to be thinking about it in terms of planning the treatment for patients so that maybe they don't need to get chest radiation if they're a lymphoma patient. But chemotherapy and the very targeted therapies and the sensitive PET scans might help us avoid using unnecessary radiation to those individuals. So it has to be upfront thinking about what's going to have happen afterwards. And as part of the 2013 IOM report, we basically had many different recommendations which were kind of, I would say-- I kind of want to say pie in the sky, but futuristic. And one of them was that the insurers-- primarily Medicare, but other insurers-- should insist on patients having a treatment plan at the time of diagnosis, that their needs should be met, that they should have an understanding of the financial impact of the treatment decisions they're making, and that this should be part of a quality of care assessment strategy. And again, the thought was OK, maybe three, four, or five years from now, that will come about. But lo and behold, a year later, CMS picked this up and we had the development of the oncology care model, which in essence, took from our report the 10 or 13 point items that need to be part of initial coordinated care, which also included our survivorship care plan and treatment summary at the end of treatments. So I think to me, actually, that's one of the most significant accomplishments because now I see there's going to be a second version of the oncology care model, that many practices across the country have adopted these things. And as they've been part of the oncology care model, they're delivering this care to everyone, whether patients are insured by CMS or a private insurer. So I think this is an example of how long it takes to implement anything. Again, part of what I see our role, or my role as a health services researcher, is implementation science. If we know what works and what's important, it may take 15 years before it happens, but you need something like CMS to have a bundled payment plan. Or in the case of the treatment summaries and care plans, we have the American College of Surgeons who have championed that. And without these external regulatory policymaking organizations and payers, we don't get a lot of change. A long-winded answer, but to me, that's where the rubber hits the road. DANIEL HAYES: Well, I agree completely. I think that'll be your legacy, among many things. I mean, isn't it also part of the QOPI designation for QOPI accreditation in ASCO, isn't the survivorship plan? PATRICIA GANZ: Yes, the treatment summaries and care plans. I don't know-- I haven't seen any data. Recently, when I was more involved with the ASCO quality care committee, I saw some of those results. I don't know how compliant or adherent people are. But actually, part of the complaints that people have had has been, oh, it's hard to do this treatment summary. But if you actually start out with your initial treatment plan-- and we're actually doing this now on our Epic system at UCLA. There's something called the oncology history. And if you actually begin documenting from the beginning of treatment, you can actually move toward a treatment summary that's easily generated from the electronic record. But it's hard when you have to go back and do it retrospective. DANIEL HAYES: I was going to say, for all the young people who, at the end of a very long day, find themselves also having to do this long-term care plan for their patients, you could blame Patti Ganz for the work she started 30 years ago. PATRICIA GANZ: Yeah, OK. DANIEL HAYES: Actually, in the few remaining moments we've got, I want to bring up your new role as editor-in-chief of JNCI, the Journal of National Cancer Institute. I believe that you and Dr. Disis are the first women who have been editors-in-chief for major oncology journals. In fact, I don't believe it, I know it. You've been in the role now about three years. JNCI has always sort of had a niche that the other journals don't cover very well, in my opinion, and that they do. In taking it over, what are you keeping and what's your vision for the way you'll mold it in new ways and take it in new ways? PATRICIA GANZ: So I've been very fortunate, I was-- you know, I actually had a lot of experience at JCO as an associate editor for many years. And then I was also on the editorial board, and then deputy editor or associate editor and deputy editor of JNCI for quite a while as well. And Carmen Allegra took it over when Barry Kramer stepped down seven, eight years ago. And I knew Carmen from NSABP and RG. We had worked together closely. And I was kind of amazed when he took it over with all the obligations that he had as head of a heme/onc division and other roles, both leading gastrointestinal cancers at the NCI and NSABP Foundation. So he was doing a lot, and I thought, oh my gosh, you know? This is a difficult job to do as well. He basically moved the Journal a bit more towards a clinical perspective. And again, the history really is that JNCI was one of the first cancer journals. And maybe there was cancer research, but it was one of the first journals. And it essentially covered everything from soup to nuts, a lot of basic science. If you go back and see some of the highest cited papers, many different fundamental assays and so forth were published in JNCI. But if you look at the space in oncology, now there are 240-250 cancer journals so that we have many more outlets where some of the more basic science and translational science-- certainly, AACR has many wonderful journals-- so that we actually moved away, I think with Carmen's tenure, from the more basic work. And we really are taking almost no basic work. Things have to be clinical, in a sense that there has to be a translational component, cell line studies. And in vitro and animal models are not something that we're covering anymore. And again, that's a transition that I think occurred in prior years. I'm certainly continuing that. But I think because of my interest in breast cancer, obviously, and outcomes research in psychosocial work, we get more of those papers than perhaps when Carmen was the JNCI editor. But it's stiff competition, you know. We've had a strong epidemiological bent. We still get a lot of epidemiological and genetics papers. And I guess when I think about what I'm doing, it's really cancer prevention and control. That's what I've been doing for over 25 years, both in my academic research leadership position at UCLA, in my own research, and it's very broad. It's really applying all of the disciplines, if you will, of public health to the cancer problem, which means epidemiology, biostatistics, behavioral science, health outcomes research, you know, all of these things-- environmental science. All of these things are very important in both the etiology of cancer, the prevention of cancer, as well as the management of cancer. And so it's this cancer prevention and control swath that I think is our niche, if you will. So it's not as narrow as some journals. We're not just doing clinical trials, although we have them. But we're trying to have the broad scope of cancer prevention and control. That's pretty much how I see it. DANIEL HAYES: OK, thank you so much. Our time has come to an end. I can't tell you how much I appreciate your taking time to talk with us today. But more importantly, taking time to change the field of oncology in the way you have over the last 40 years. I think a lot of the things that our doctors are doing in clinic every day are a direct result of one person, and that's you. And there aren't many people who can say that. So thanks for all you do. Thanks for all your contributions, and I very much appreciate your sharing your history with us today. PATRICIA GANZ: Thanks so much, Dan. It was really a pleasure to speak with you and share what I've learned over time. Thanks so much. PRESENTER 2: Until next time, thank you for listening to this JCO's Cancer Stories: The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts, or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories: The Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.asco.org.

Dr. Hayes interviews Dr. Lawrence Baker on his early involvement with SWOG ANNOUNCER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. DANIEL HAYES: Welcome to JCO's Cancer Stories-- The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org. Today, my guest on the podcast is Dr. Laurence H. "Barry" Baker. Dr. Baker has a long and distinguished career in oncology. It dates back to the early 1970s, when he was intimately involved in new drug development, including doxirubicin or adriamycin, as we know it. He's also led early studies in preoperative chemotherapy in anal cancers. He was instrumental in advances in sarcoma research, and he led the Southwest Oncology Group-- now designated SWOG-- for eight years in the last decade. Dr. Baker was raised in Brooklyn, and since this interview is taking place just a week after the sad loss of Supreme Court Justice Ruth Bader Ginsburg, Dr. Baker informed me that he and his wife Maxine were married in 1964 in the Midwood Jewish Center, Justice Ginsburg's home synagogue. He received his undergraduate degree from the Brooklyn College at the University of New York, and then he graduated from Des Moines University of Osteopathic Medicine in Iowa. He completed a residency in internal medicine at Flint Osteopathic Hospital in Flint, Michigan, and then he has a curious two-year break in his curriculum vitae during which he was on active duty in Vietnam. Upon discharge from the Army, he returned to Michigan, and he served a three year fellowship at Wayne State University, where he stayed on faculty from 1972 to 1994, serving at various times as the chief of the Division of Hematology and Oncology, the chair of the Department of Medicine, and director of the Cancer Center. In 1994, he moved west about 30 miles to Ann Arbor, where he served as the director for the Clinical Research and Translational and Clinical Research Program for the UM Comprehensive Cancer Center, now called the Rogel Cancer Center. And he was also the associate chief of the Division of Hematology and Oncology and currently is the Laurence H. Baker Collegiate Professor in developmental therapeutics. Dr. Baker has authored hundreds of peer-reviewed papers, and like so many of our guests on this program, he has a list of honors that are just, frankly, too long to recite, except two that I want to highlight. He received the ASCO Distinguished Service Award for Scientific Leadership in 2007, and he was named an ASCO Statesman, now designated as a fellow of ASCO in 2010, for his many services to our society. Dr. Baker, welcome to our program. LAURENCE H. BAKER: Thank you. Nice to be here. DANIEL HAYES: Well, it's really great to have you. A lot of questions, but I want to start out, I just can't help but ask you, to be trite, how does a nice boy from Brooklyn end up in the Midwest for the rest of his life? Can you give us some stories about how you got there? LAURENCE H. BAKER: I graduated high school at 15 and went into what some know-- but not everyone knows-- was a very competitive college. Brooklyn College accepted-- was a free school. The grades used in the New York City school system were numerical. They weren't letters. And you had to have a 90 average on high school and certain scores on the state, New York State examinations to get in. And that was it. It didn't matter where your parents went to school. It didn't matter if you had money. And so it was a school largely of relatively low-income families. But that's the one who took me, and I guess they accepted me at 15. To not make this into a long story, but to drag it out a little bit, I was fascinated that I was 15 and I could date 18-year-old girls, and they didn't know it. So that's how I spent the first two years of college. And my grades showed that that was my focus of attention. I did pretty well on the MCAT examination. I would not have gotten into a medical school in this country, and I didn't speak a language that would be sufficient for me to go to Europe, for example, to school. So osteopathy he was where I went. I went to Iowa, but their admitting question to me is, do you have $2,000 a year tuition? To which, of course, I lied. And that's how I ended up being a DO, and that's how I came to the Midwest. And I actually got to like the-- I didn't know anybody from Iowa, as you make reference to my Brooklyn background, but I actually came to really appreciate the Iowa people, and particularly the community people that I came to know. At the time there were-- the really good programs in residency in medicine were in Michigan. That's the direct answer to your question. That's how I came to Michigan. Just about then, just about could have gone to California and gotten an M.D. degree just by taking the licensure examination. And then, that closed. That opportunity closed. So a long story to your question. So I came to Detroit, into Flint, and then returned back to Detroit, and I've been in Michigan ever since. DANIEL HAYES: Now, that raises the second issue I talked about a minute ago. And that is, many of our guests were so-called Yellow Berets at the NIH in the late 1960s and really changed our practice. But you actually ended up in the Evacuation Hospital at Cu Chi in Vietnam. And I've heard horror stories about this. How did that happen? What did you do there? Enlighten me. LAURENCE H. BAKER: Well, there were good and bad things about being an osteopath. The American Osteopathic Association was always in conflict, was always trying to defend itself. And at the time that the Vietnam War was going on, the DOs were not eligible for military service as an officer. You could go in as an enlisted man, but not as an officer. But there was a great need for primary care physicians in Vietnam, and the understanding of the military physicians was that all DOs were primary care physicians. So a deal was struck between the AMA and the Department of Defense that led to the drafting of everyone in my medical school class. Every one of the men-- not women. Every one of the men was drafted. There was a universal draft. I then-- I was given a choice. I could volunteer for the Army or go to jail. Those were the choices. And I had, at the time, two little children with Maxine, and I was not-- you might guess-- not a big fan of the Vietnam War. The alternative was to go to Canada, and I wasn't secure enough to consider that I could actually practice medicine. It was uncertain. So I went in. When I got there, they asked me, did I have any interest in anesthesiology or radiology, because they were really short of those two. And of course, being who I am, I said, if you need a radiologist or an anesthesiologist, why don't you go draft one and let me go home? That didn't work, and so I became-- I was assigned to radiology. DANIEL HAYES: [LAUGHS] LAURENCE H. BAKER: They sent me to Fort Jackson, where-- no, that was actually a good experience then, because I learned a lot about imaging, and I still have interest in imaging, but I don't qualify anymore. This is before CAT scans and MRIs. This is IDPs and upper GIs, right? So anyhow, barium lower bowel examinations. So I was trained for six months, and I stayed on for another few months on staff there and then, lo and behold, was sent to Vietnam. I was sent for a year, but I volunteered to stay an extra month so that I could return without any further obligation to the military and begin my fellowship on July 1, which I had actually secured before I went to Vietnam. So that's the gory details of that. I was elevated to Major about, oh, a few months before I was discharged. And then, because they weren't nasty enough to me when I got home, into my fellowship, I then got a letter congratulating me on being in the active reserve. So I had to go two weeks every summer. That was my summer vacation during fellowship and beginning of faculty. And I had to go once a month for a weekend to play soldier with a bunch of guys who were lucky enough that they didn't have to go to Vietnam. And now we're even, I think. So it was an interesting experience, as I've shared some of it with you. It still is a painful experience in some ways. I was out the busy [INAUDIBLE]. DANIEL HAYES: If you don't mind, a quick story you've told me before about the child with leukemia. LAURENCE H. BAKER: Yes. So they made me a radiologist. I'm not a great-- it doesn't matter where you call me. I am who I am, and I'm really interested in patient care. And there were already five internists, and there was only so much gonorrhea that the troops could acquire. So I volunteered to open a pediatric clinic. And the Army thought that was a good thing for publicity. They did stories about it. Anyway, I opened the clinic for pediatrics. I knew nothing about pediatrics. I mean, the truth is, I had a month of rotation. My wife sent me my textbook. It was Nelson's Textbook of Pediatrics. Nothing I ever saw in Vietnam was ever in Nelson's Textbook. But I did what I could of trying to treat the children as best I could. And along came a young girl, eight years old, who had acute lymphacytic leukemia. I had a wonderful pathologist who was my hoochmate. "Hooch" is translated, there were eight guys who lived in a place. That was called a hooch. And he was a pathologist, and he made the diagnosis of ALL. I had my books from my mentor teaching me about chemotherapy. So even though I hadn't started the fellowship, I had some resources about chemotherapy. And now I had to find chemotherapy. Treated her with-- I started with steroids and penicillin, and then I went to find drugs. I was able to-- I won't tell all the details, but I was able to get drugs at an old French hospital in Saigon. And so I would visit that hospital pretending great interest in the pharmacy, but of course, I stole whatever drug I could steal when the pharmacy wasn't looking. And that included some alkylating agents, methotrexate, 6MP. And so I tell Jay [INAUDIBLE]-- to get to where you want to be, perhaps-- that I invented the bicycle therapy, which was every month, you changed the drug to try to avoid resistance. So that's what I did by necessity. [LAUGHS] And I actually-- there was a second child that I also treated. When I left, they were both in complete remission. And I think that that's what you're asking me. I was lucky that I didn't get shot or thrown in jail for many of these escapades. But I look back and think that at least I did somebody some good. So-- DANIEL HAYES: Kind of makes the current generation who complains about work hours look in a different light, I think. LAURENCE H. BAKER: Yeah, we worked every day. We worked seven days a week with-- there was no such thing as time off. This was the busiest American hospital, certainly in Vietnam, and some think the busiest hospital since the Atlanta train station in the Civil War. It was in Cu Chi, which was on the way to Cambodia, which is, of course, where the North Vietnamese troops would enter into South Vietnam. So it was a major, major place. It was about an hour, an hour and a half west of Saigon. DANIEL HAYES: Let's move on to the rest of your career. You come back, then, and trained at Wayne State, and at the time, [INAUDIBLE]-- and I can never pronounce his name. I'll have you do it. Dr. Venutius Vicevicius-- I always heard him Dr. V.-- who was, I think, a real character and really was one of the first chemotherapy pioneers. Can you tell us more about him? Because we've heard a lot about the folks on the East Coast and the folks in Texas, but not so much what was going on in the middle of the country at the time. LAURENCE H. BAKER: Yeah, Dr. V, or Dr. Vicevicius, who was Lithuanian, he has a story of his life that certainly makes me look like a slump. He was a guest of the Nazis, and then he was a guest of the Russians when Auschwitz was freed. So this was as a child. He grew up in a very educated and somewhat affluent family in Vilnius. And when he got out of these camps, he actually got to medical school in Frankfurt, Goethe Medical School in Frankfurt. He had major interest in biochemistry and, without speaking more than three words of English, chose to come to the United States. And he landed-- I don't really know why; I've heard so many different versions-- but he landed in Detroit and showed up at the Detroit Receiving Hospital-- this would be like LA County or Bellevue in New York, that sort of thing, knife and gun club-- not speaking any English but wanting to do training. And somebody was smart enough to accept him. And so he did his training. He also trained-- after medicine, he trained with Mike Brennan-- that's another name from the past who is a past president of ASCO, by the way, the second or third person, perhaps. Mike was present of the Michigan Cancer Foundation and was the card-carrying medical oncologist in the Detroit area. He trained Dr. V., and he trained another man named Bob Tally, who had a great deal of history to contribute to oncology. And then, V was recruited by Wayne to come there and started a program. He was an extraordinary person. English was the eighth language he learned, and he actually taught me how to write. I flunked college English. I had to take it twice. But he taught me how to write and, I think, made me a better writer. He certainly was an inspiration. His devotion to patients was extraordinary. His knowledge was extraordinary. And so he was a great, great teacher. And one of his major early contributions was the recognition that you could make the drug float-- they had four drugs or five drugs at this time-- but one of them was 5-fluorouracil, that was developed by Fred Ansfield in Minnesota. The drug was given for five days and then every other day until their mouth fell out or their white count got to zero. And maybe that's a little of an exaggeration, but not much. At any rate, he figured out if you gave the drug by continuous infusion-- because it had a rather short half-life-- you could avoid a great deal of the toxicity. And that's how infusion of fluorouracil got its start. He then went on to combine it with other drugs and with radiation, and that was the backbone of this anal canal achievement that you mentioned in the introduction. I had very little to do with it, but I was a cheerleader. It was a rectal surgeon who came to us at the time, and those familiar with that disease-- which we now know is a virus disease that could be prevented, but at that time, nobody had any of that-- the treatment was abdominal perineal resection, and it had to be among the most horrible things we did to people. And the surgeon came to us and said, listen, you guys always squirt those drugs in after they relapse, and I'm really tired of this. Maybe you could give those drugs first, OK? And that's how neoadjuvant chemotherapy got started. It wasn't our idea. It was a surgeon's idea. That story gets repeated again in orthopedics, but that's how it began in anal canal tumors. And so we gave 5FU infusion, and mitomycin, and radiation preoperatively. That almost always shrunk the tumor, by the way-- almost always significantly shrunk the tumor. The patient then once they went through that operation but was cured. And so you took a horrible disease and changed its natural history with that development. If it works once, you know, in oncology, then you try it a second and third time. And I had very shortly thereafter the opportunity to work with a wonderful Japanese pediatric oncologist in Houston, Watsu Tao. He was looking for a partner because he was tired of seeing osteosarcoma patients die. Cure rate at the time was around 20%, 30%, and the surgery that was done for osteosarcoma was amputation, usually of the lower extremities. So 2/3 of osteosarcomas occur around the knee, and the orthopedics really dislike the idea of taking a child's leg off. Every teenager and child wants to be exactly like every other teenager and child, so you can imagine how disruptive it is to have a high amputation of your leg. It took about three months to make a prosthesis, and everyone knew that you didn't really have to do an amputation. You could just cut out the bad bone and replace it with a prosthetic device. But it took three months to make it, because they were handmade at the time. And so the idea came to several people-- Jim Holland was involved in this; Tom Frei was involved in this as well. Different cities were approaching it in this way. And we all ended up giving chemotherapy to these young people-- children, teenagers-- and then having the operation. And osteosarcoma went a cure rate of 20% to 30% to 70% or 80%. And they didn't lose their legs. DANIEL HAYES: I have two personal comments on this. One is you mentioned Dr. Brennan and the Michigan Cancer Foundation. Just for our listeners, Michigan Cancer Foundation is MCF. And if you've done any breast cancer work at all, you've worked with MCF-7 cells or MCF-10 cells [INAUDIBLE], which came from that organization. I think people have forgotten what MCF stands for, except for you and me. LAURENCE H. BAKER: That cell line that you talked about, MCF-7, that was developed by a man with, I think, a high school degree who just had a green thumb at that growing cells-- a wonderful man. And that came from a patient of ours. When I say "ours," I mean Dr. V. I was just the flunky, but it was his patient. And she had ascites from breast cancer. And we would tap ascites, in those days, with some frequency. And the cells for MCF-7 came out of that patient. That's its actual origins, and more papers have been written about MCF-7 than even you and I could count. DANIEL HAYES: Including by me. LAURENCE H. BAKER: I understand. No, it was incredibly useful. I mean, we learned about hormone receptors from this [INAUDIBLE]. DANIEL HAYES: Yep, that's [INAUDIBLE]. LAURENCE H. BAKER: It's was incredible. DANIEL HAYES: My other personal story related to your stories is, as a fellow at the then Sidney Farber Cancer Institute, Dr. Frei was my boss. And he, as you mentioned, was starting to work with Holland and others that had already worked with neoadjuvants. And he would cite your data all the time. Now, I didn't know Larry Baker for us from all the tea in China, but we heard a lot about the Wayne State experience when we were fellows. I don't know if that would have [INAUDIBLE] or not, but people definitely-- LAURENCE H. BAKER: No, I came to SWOG-- which is really why you wanted, I think, to talk to me-- in '70 or '71, I can't remember exactly. And Dr. V, it was an incredible experience. He took me with him. You ran into Tom Frei. They knew each other. And he said, Tom, I want you to meet my colleague, Larry Baker. I just had never been introduced like that. DANIEL HAYES: [LAUGHS] LAURENCE H. BAKER: And Tom was the friendliest person I think I've ever met in oncology. He had a wonderful smile. He clearly-- I was always paranoid that I'm a osteopath. Maybe I went on too long about that story. But when they tell you in school you're just as good as the MDs, you can quickly figure out if you were just as good, they wouldn't keep saying it, right? So that's socially accepted paranoia, and that's how I was brought up. So here is the wonderful, famous Tom Frei being nice to me! I was just amazed. DANIEL HAYES: He used to come to the lunch room in the Dana Farber two or three times a week and would just sit with us, and was constantly thinking of new stuff. This is not an interview with me, but someday, I'd like to tell the stories he told us. He was really just a fabulous man. I want to segway into your work with adriamycin, which is now, of course, also one of the workhorses of oncology. We've all used it. And I believe you were an author on either the first or one of the first phase II trials of adriamycin in Cancer in 1973. Is that an outgrowth of that introduction you just told us? LAURENCE H. BAKER: Yes. That study-- it's in Cancer, I think, not-- I don't think JCO existed. But that study didn't distinguish what the primary was. So it was a phase II study of cancer. And so there was, I don't know, 800 patients. I worked with Bob or Brian on that study. Bob was at Henry Ford, and there was a student of Bob Tally that I had mentioned, and I was the student of V. And the two of us were basically the schleppers for them. And so it had hundreds of patients in it. And in that study, we recognized that it worked in breast cancer, that it worked in lymphoma, and it worked in sarcoma-- and nothing worked in sarcoma. So that was the study. It's often quoted by Jim Dorshow because he said, we do everything that's disease-specific, but look what came out of one study that, by the way, accrued, as I say, 600 or 700 patients in 18 months. And this is before computers, so you can imagine how much work was done to evaluate the flow sheets. It was an incredible opportunity here to work. But it was an amazing paper, and it changed my life, of course. That's how [INAUDIBLE] and other things. DANIEL HAYES: So at the time, you recognized that this was not just another drug off the shelf, that it really was going to be a game-changer? LAURENCE H. BAKER: Absolutely, absolutely. You saw people getting better. And my experiences were mostly in breast cancer patients getting better, and some lymphoma patients that were refractory. First time I saw solid tumor patients dramatically improve. DANIEL HAYES: So I saw that your name is before another giant in the field who was a young Italian investigator who spent time in the United States named Johnny [INAUDIBLE]. LAURENCE H. BAKER: Yeah, that's how I first met him. I don't know that this story's been told. We were trying to make some level of peace with the Russians, and the Russians, of course, claimed that they discovered adriamycin. I don't know, but if you don't know this, I'll continue. DANIEL HAYES: Please go. LAURENCE H. BAKER: OK, but we all-- everyone knew, and certainly [INAUDIBLE] knew, this was an Italian drug, OK? "Adriamycin" is for the Adriatic Sea. As far as I know, you can't see the Adriatic Sea from Russia. But this was a time when our government wanted to be nice. They cared more about building a relationship with the Soviet Union than they did continuing a friendship with the Italians. Jim Holland was then sent to Moscow to negotiate this. That's where the name doxirubicin came from. In other words, we didn't know generic names, trade names. This didn't exist in the early '70s. So we called it adriamycin, which was not only the generic name, it was the trade name, right? Made by adria-- I think far Pharmitalia is the name of the company, right? And as a result of Jim Holland's diplomacy, it became doxirubicin as the generic name. It's a true story. DANIEL HAYES: Yeah. I know that "adria--" came from the Adriatic Sea, but I've not heard that's where "doxi-" came from. That's a good story. That segways into the next segment of your life that fascinates me, and this is your work in SWOG. When I moved here to the University of Michigan, you were on your way to becoming the chair of SWOG, which you did. And it occurred to me that University of Michigan wasn't even in Southwest Michigan, let alone the Southwest of the United States. Just reminisce a little bit about Dr. Coltman, who ran SWOG, the beginnings of SWOG, even before that, and where you see the [INAUDIBLE] groups now. LAURENCE H. BAKER: So Dr. V brought me to a SWOG meeting in San Antonio, Texas, as you said, in 1970 or '71. At the time, Tom Frei was running the group. J. Freireich was chairman of the Leukemia Committee. Chuck Coltman was chairman of the Lymphoma Committee. V specifically chose to work with this group because of those people. You're right, Michigan is not in the Southwest, obviously, and, there were other groups that wanted-- we had a large population of patients we treated, so there was actually some competition, if you will, for us to join other groups. V was adamant that we would be SWOG and that was it, for reasons that I told you. Tom Frei then was invited to go back to Boston. That's how you came to know him. And there was an election for a replacement. And J. Freireich was somebody that we clearly supported. There was no doubt that J. an absolutely brilliant man-- he still is-- and taught a lot of people, trained a lot of people, and taught us a great deal. But he had one flaw. He could not control his ability to saw inappropriate things. If you knew him, you loved him. If you didn't know him, you were like your reaction to the debate, OK? That's how he ground on people. I grew up with the respect for J., as I told you, as I was introduced to him, and he was always incredibly kind to me. Anyway, so we were actively supporting J. To be the replacement. There were some other people that did not want Freireich. So you had some people who didn't have the same feeling. And that's how Boris Hoogstraten became chairman. Boris Hoogstraten was a hematologist from the University of Kansas. And I remember-- and you'll be very proud of me, Dan-- one of my colleagues from Wayne wanted to do a study of this new drug called tamoxifen-- DANIEL HAYES: [LAUGHS] LAURENCE H. BAKER: --for breast cancer, OK? [LAUGHS] And Hoogstraten said, don't you get it, Baker? We're a chemotherapy group. What's with this hormone stuff? I don't have to tell another story, but that one is true. So SWOG didn't study tamoxifen for a long time. Any rate, Boris was an interesting man. I don't want to cut him short. But there came a time when it was clear that SWOG needed to go in a different direction. And we all thought that the right person for that was Chuck Colton. At the time, I have to tell you, there was two things relevant to this. There were lots of regional cooperative groups that don't exist anymore. I led a revolt-- that's what Colton said-- that included the University of Indiana-- Larry Einhorn was in Detroit plotting against Hoogstraten-- along with the University of Michigan. Al Labulio was in Detroit doing that. So you got the idea. So it was a group of institutions, if you want, that were geographically somehow related to the Great Lakes in some way. There were seven or eight of us. And we represented probably 40% of the [INAUDIBLE] of SWOG. And Coltman came to me and said, listen, stay with the group. Don't do this. Stay with the group. And I said, I can't stand this nonsense. I mean, we're not working anymore. We're just-- Anyway, he said, please stay. And he ended up becoming the chairman. And then he turned to me and he said, listen, Larry, I want you to be the deputy. I don't need a title. I don't want a title. He said, no, no, no, I don't care what you need or what you want. I need you right next to me, because if you led a revolt once, I don't want to see it happen again. DANIEL HAYES: [LAUGHS] LAURENCE H. BAKER: Absolutely true story. And so we abandoned the idea of a regional group. I still think that may have been a dynamite group, by the way. But we all stayed-- Indiana was not [INAUDIBLE] SWOG, so let me be clear. That was ECOG, I think. I think that's right. Anyway, so that's how I came to know Chuck, and I was his deputy for 25 years. I had the best job as deputy, because I had nothing to do. He just wanted me sitting there, and that's what we wanted. Then there was some push from the NCI that maybe to 25 years of being chair is a long time, and maybe there's a reason to move on. From that team the suggestion from Bob Livingston and John Crowley, that I was the natural person to do that. I really didn't want it, to be honest. I still maintain that. But there was a good deal of pressure exerted, both from within the group and from the NCI, for me to do that. So I became the chairman, I think, for a couple of terms. I made some changes in the group. I think as groups go on, institutions either get better or they get worse. I think that's true. And we made a number of different ways of appointing disease chairs and things like that, that the group did get better and started on a better path. But I really didn't want to continue it, and there was a time when I was not only running SWOG, but I was also running this sarcoma group called SARC. And it became overwhelming to me. I was working literally 80 hours a week there. So I gave up SARC first. That really-- University of Michigan was thrilled that I did that-- and stayed with SWOG another year or two. But I knew that I wasn't going to stay at that. And so after two terms, I thought I would set the precedent that, maybe, group chairs should have two terms and move on. Witshoski had two two terms. [LAUGHS] But anyway, being serious, I really think there should be a limited amount of time. There's so many talented people in our field that it's silly to think that one person has to stay in these jobs. And so that's-- I think I answered your question. I'm not sure my [INAUDIBLE]. DANIEL HAYES: I have to tell just a brief-- Nobel laureate Bruce Beutler was my intern when I was a resident at UT-Southwestern. After he won the prize, he came up here as a visiting professor, and we went to dinner. And I said, Bruce, I kind of lost track. I know you did an internship with us, but I never heard if you finished your clinical training. And he said, no, I went-- I loved the lab and went back into it. I never did go back and finish my training [INAUDIBLE]. And then he looked at me and said, but I think I worked down all right, don't you? LAURENCE H. BAKER: [LAUGHS] DANIEL HAYES: And in a similar manner, I would say, for all your humility that you've laid out, I think it worked out all right. SWOG is a powerhouse and has changed practice in so many ways. And part of that, a lot of that, was your doing. So we've actually run out of time. I had hoped, actually, to-- you've done too much in your lifetime, Larry. I was hoping to get into the sarcoma work, but we've run out of time. I think everybody who's listening to this who knows about the work you've done in sarcoma-- and lord knows there's plenty of work to do in sarcoma, so-- LAURENCE H. BAKER: Can I give you just one more anecdote, and you can cut it, and I'll try to be very [INAUDIBLE]? DANIEL HAYES: No, no. Please do, please do. LAURENCE H. BAKER: Remember I told you I became chair of the Sarcoma Committee of SWOG? The man I replaced was a man named Jeff Gottlieb. Jeff was a pediatric oncologist-- little did people know-- who was a student of J and Tom at the NCI. Jeff died in his mid-30s of cancer, by the way, but he was the most brilliant medical oncologist I ever met. He was the originator of combination chemotherapy that became popular in breast cancer, and he was involved in sarcomas in combinations as well. I was handpicked by Jeff to be his replacement, which was probably the nicest thing that ever happened to me. And during that period when Jeff died, I went to Houston to his funeral. And I can give you one-sentence description of J. Freireich going to speak at Jeff's funeral. He stood up, and he said, Jeff-- and he broke down and cried for minutes. And that was his talk. When anyone says something to me critical of J. Freireich, I remember that love he showed to his colleague. So that's worth [INAUDIBLE]. DANIEL HAYES: No, that's-- LAURENCE H. BAKER: Not many people were at that funeral. DANIEL HAYES: --very touching. He also gave Dr. Frei's eulogy in Boston, and he got through it, but just barely. It was very similar. These are the kinds of stories I'm hoping to capture in this series. Larry, I'd really like to thank you for taking time to be on. I'd also like to thank you for all you've done for the field, for me personally, frankly, with my time here in Michigan the last 20 years, and most importantly, for our patients who have benefited from all your contributions, your training of-- we could go on about all the people you've trained. So anyway, thanks a lot. We appreciate it. LAURENCE H. BAKER: Thank you. DANIEL HAYES: And have a nice day. LAURENCE H. BAKER: Thank you very much. I appreciate your kind words. DANIEL HAYES: Until next time, thank you for listening to this JCO's Cancer Stories-- The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts, or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories-- The Art of Oncology podcast is just one ASCO's many podcasts. You can find all the shows at podcast.asco.org

ntermountain Healthcare in Utah. He received his medical degree, completed his internal medicine residency, and served as chief resident at Baylor College of Medicine in Houston, Texas. After completing a hematology/oncology fellowship at the Mayo Clinic in Rochester, Minnesota, he returned to Houston to work at the MD Anderson Cancer Center for four years, with a dual appointment in general & gastrointestinal medical oncology. He is also the co-chair of adolescent & young adult (AYA) oncology in the SWOG cooperative group, currently serving a five-year term in that position. During his training he self-diagnosed with multiple endocrine neoplasia type 1 (MEN1) and thus has a particular & deeply personal interest in hereditary tumor syndromes. Additionally, he is passionate about advocacy & research for GI cancer, social media in oncology, and patient-clinician communication.

This episode features Dr. Richard LeBlanc, Dr. Darrell White, and Dr. Julie Stakiw. This program was made possible by unrestricted sponsorship support from Amgen. Trials Discussed: 1. First-line for transplant-eligible myeloma: STaMINA & GMMG-HD6: 00:02:02 2. First-line for non-transplant-eligible (or transplant-deferred) myeloma: ENDURANCE, SWOG 1211 & TOURMALINE-MM4: 00:11:42 3. First-line for transplant and non-transplant eligible myeloma: GMMG-CONCEPT: 00:23:04 4. Relapsed refractory multiple myeloma: BOSTON, IKEMA & CC-92480: 00:29:17 5. CAR-T anti-BCMA: KarMMa, CARTITUDE-1 & EVOLVE: 00:44:10 6. TCE anti-BCMA: TECLISTAMAB Phase I & TCE 2+1 (CC-93269): 00:55:20

During the 25th Congress of the European Hematology Association (EHA), the Multiple Myeloma Hub was pleased to speak to Saad Usmani, Levine Cancer Institute, Atrium Health, Charlotte, US. In this podcast he discusses data from three clinical trials, which address the use of quadruplet treatments and anti-BCMA therapy for multiple myeloma.He describes the progression free survival, overall survival and safety profile of the 100 patients that were evaluable from the SWOG 1211 trial. This was a randomized, phase II trial, which evaluated lenalidomide, bortezomib and dexamethasone (RVd) induction followed by dose-attenuated RVd maintenance until disease progression with or without elotuzumab, in patients with high risk, newly diagnosed multiple myeloma.He then talks about the dose escalation results of first-in-human trial of teclistamab, a BCMA bispecific antibody, in terms of overall response rates and safety profile. He then mentions the randomized phase III study looking at belantamab mafodotin in combination with RVd in patients with transplant ineligible newly diagnosed multiple myeloma. Hosted on Acast. See acast.com/privacy for more information.

Dr. Jason Luke, associate professor and the director of the Cancer Immunotherapeutics Center at the UPMC Hillman Cancer Center, discusses new advances in immunotherapy that were discussed at the #ASCO20 Virtual Scientific Program.   TRANSCRIPT ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. Joining me today is Dr. Jason Luke, associate professor and director of the Cancer Immunotherapeutics Center, at the UPMC Hillman Cancer Center.   His clinical focus is on immunotherapy for advanced solid tumors, as well as cutaneous malignancies and melanoma. Dr. Luke will discuss key abstracts in the immunotherapy field that were featured at the ASCO20 Virtual Scientific Program, including Abstract 3004, the study of an agent called MGD013, which Dr. Luke presented during the meeting. Dr. Luke, it's great to have you on the podcast today.   Dr. Jason Luke: Thank you very much.   ASCO Daily News: Do you have any conflicts of interest to disclose that are relevant to the issues we'll discuss in this podcast?   Dr. Jason Luke: Thanks. I would like to disclose a few things. I'll note that as a phase I clinical trialist, I try to work with every company in the field. But relevant to the abstracts, I have been a consultant to most of the big pharmas that have advanced these. So specifically, EMD Serono, Genentech, EMS, Merck, and some others.   ASCO Daily News: Dr. Luke, are there any advancements in the immunotherapy field that will likely support new standards of care?   Dr. Jason Luke: So thank you. Yes. In fact, this was a big year for immunotherapy. I think ranging from abstracts with a high immediate impact on the standard of care all the way to -- or earlier truly -- research studies that I think we'll look back on and realize this was the year when that technology started to mature.   So when thinking about abstracts-- presentations that are going to have an immediate impact on the standard of care, there are really two that I would highlight. One of them was called the JAVELIN Bladder 100 trial (Abstract LBA1). And the second one was a clinical trial called KEYNOTE 177 (Abstract LBA4). So I'll talk about them individually at first. And I think they introduce ideas about using immunotherapy you should be cognizant of to inform your practice.   So for the first one, the JAVELIN Bladder 100 trial, is a clinical trial in advanced urothelial cancer, in which patients were treated in the frontline setting, albeit for that first treatment and the standard of care setting, with cisplatin-based chemotherapy. And as they completed their cisplatin-based chemotherapy, they were randomized to either get the anti-PD-L1 antibody, avelumab in a maintenance sort of approach, or waiting until they had progression and going on to standard therapy with second line chemotherapy, as would be commonly done.   So the clinical trial showed an overall survival advantage to the maintenance approach of giving avelumab or anti-PD-L1 in that setting. And this is a pretty big deal because this is really the first maintenance approach that really has been associated with an overall survival advantage in solid tumors in general, but specifically a bladder cancer.   Now obviously the context for such an approval is the activity of PD-1 or PD-L1 blocking agents in urothelial cancer. And probably everyone who is listening is aware that multiple checkpoint inhibitors are approved for second line usage in bladder cancer. And all of you listening are probably also aware that there's been a lot of discussion in the field of urothelial cancer about moving checkpoint inhibitors into the frontline setting.   And the FDA had to release a guidance that that should not be done without the obvious presence of PD-L1 positivity. So a very interesting thing from the JAVELIN Bladder Trial was that the benefit to maintenance avelumab appeared to be independent of PD-L1 status. So in other words, everyone, or the total population of patients, benefited from getting that chemotherapy and then going on to get avelumab, whether PD-L1 positive or negative.   So I think that's a big deal. So based on these data my read of it and the conversations that I've had with other experts in the field of GU malignancies aren't to suggest that this is a new standard of care, that patients should after completing initial chemotherapy go on to get a PD-1 or PD-L1 agent.   Now that being said, it isn't without some controversy. These maintenance approaches have been criticized over time about cherry picking patients and discontinuing chemotherapy that might otherwise be active. One can't really know here how many patients would have done well without the avelumab for a long time.   It's also obviously the case that patients could go on to get second line PD-1 or PD-L1 agents on label. So again pembro, nivo, atezo, durva, avelumab, these are all approved for second line therapy. And in this clinical trial, because it was done ex-US, only about 40% of the patients who were on the placebo-matched arm actually went on to second line PD-1.   So this trial definitely did not test the question of maintenance PD-1, PD-L1 versus giving it in the second line after an initial progression event in the front line. And that is obviously a criticism of these data. Now that being said, all of you who have treated patients with urothelial cancer realize what an aggressive malignancy this can be and how these patients can sometimes be rather frail.   And what we can run into is that at the time of progression after frontline chemotherapy performance statuses just dwindle very rapidly, such that you can't really, fully give them a shot to get the second line PD-1 immunotherapy. So here, though, by giving the therapy immediately after the initial chemotherapy without waiting for progression, we make sure that all patients get access to that therapy.   So despite the controversy around subsequent lines of therapy, et cetera, I think most people who view this data really do find it to be practice changing. And moving forward we really should be considering immediate initiation of anti PD-L1, or PD-1 I suppose, after chemotherapy. So that was the first abstract to highlight in that space, the JAVELIN Bladder 100 study.   The second study was the KEYNOTE 177 study (Abstract LBA4). This was a randomized phase III trial in the frontline setting for MSI-- or MicroSatellite Instable-- colorectal cancer for the use of immunotherapy with pembrolizumab, as opposed to chemotherapy. And so again oncologists listening will be very well aware that MSI status has become an important biomarker in our field, selecting out patients, especially with colorectal cancer but actually any cancer type, who if they have MSI status can be treated in this integrative care setting with the anti-PD-1 or pembrolizumab.   One of the questions that has been looming and seemed like had an obvious answer, and, in fact, this trial supports, was whether that biomarker would be strong enough to move that immunotherapy into a prechemotherapy setting. So to date the use of the MSI biomarker has been to select patients after they failed standard therapies to go on to get immunotherapy.   So in colorectal cancer, patients would get FOLFOX/FOLFIRI as per standard. And if they were MSI, they would be treated thereafter with pembrolizumab. So in this study, they moved that biomarker selection into the frontline, looking at MSI high patients and randomizing them to either get pembrolizumab or standard chemotherapy.   And the answer here, as was expected, was that patients who are MSI high in their tumor who got immunotherapy in the frontline, in fact, did better than those patients who got chemotherapy in the frontline. And so I think that's an important clinical practice changing algorithm. So we should be testing all our patients upfront for MSI with colorectal cancer, and one might even argue actually other tumor types, because we find that the patients who have that phenotype, their rates of response approach 50%.   And those responses tend to be very durable with the median not being reached in these kinds of trials. So that quality of immunotherapy response, I personally think that's the thing that we all really like about immunotherapy, is that for the small patients where they get that benefit from immunotherapy, it can sometimes be long lasting-- and even life lasting-- kind of benefit. I think these data are very important, again, to move this biomarker selection of patients for colorectal cancer by MSI high status into the front line and give them immunotherapy if we find that.   These data don't come as much of a surprise given that we know in the adjuvant setting, in fact, the MSI high patients do worse with chemotherapy in the stage two setting. So again, these data don't come as a big surprise. But they do support a change in practice to move immunotherapy into that frontline setting.   And I would say as a sort of forward-looking discussion point, given the broad approval across cancer types for MSI high tumors to get pembrolizumab, one wonders whether or not this phenomenon will begin to come forward and other tumor types where we know MSI could be present, such as gynecological cancers and some others. We'll watch the field. But I think that that's something to be excited about for immunotherapy coming forward and potentially displacing chemotherapy in the front line for different cancer types.   ASCO Daily News: Dr. Luke, what are the other studies that really stood out for you this year?   Dr. Jason Luke: There were three other big trials I think that generated a lot of buzz that I think I should be highlighted. They don't quite change standard of care at this time. But they do influence standard of care.   And so there are three of them. One of them was the CHECKMATE-9LA study of lung cancer (Abstract 9501). There was a second phase 2 study called the CITYSCAPE study (Abstract 9503), also in lung cancer. And a third study in bladder cancer called the IMvigor010 (Abstract 5000) or 10 study.   So just to discuss them-- so CHECKMATE-9LA in fact did lead to an FDA approval of the combination of nivolumab and ipilibumab or PD-1 CTLA-4 in combination with chemotherapy for the frontline management of non small cell lung cancer. So this regimen is somewhat different than the chemo I-O combo that people will be cognizant of right now. So the standard of care now, there's an approval for chemotherapy with platinum-based chemotherapy and a second agent, such as pemetrexed, with pembrolizumab in the front line.   This trial took a different tact. And they randomized patients to either get regular chemotherapy, platinum-based chemotherapy, or they would get the combination of ipi and nivo with two cycles only of platinum-based chemo. So you could refer to this as some sort of platinum sparing approach. And the rationale for this was that perhaps because patients with lung cancer can have a very aggressive course, having that immunotherapy onboard up front might allow a space for immunotherapy then to kick in and have a longer term benefit.   So this trial is a positive Phase III clinical trial. And actually just before the ASCO virtual meeting, the FDA approved this regimen for the use in patients with lung cancer. Now you might be listening and thinking, well, wait a minute. You just told me about their new standards of care. And you're telling me this is approved. So what's the deal?   And so what the deal is is that it's not completely clear at this time that this sort of an approach would be better than using the chemo pembro combination that's already approved. And the toxicity profile using doublet checkpoint blockade with PD-1 and CTLA-4 is not insignificant. Sorry for the double negative there. But in other words, you're generating a lot of immune-related side effects for patients by giving them ipi/nivo and chemotherapy.   So the question then becomes, so which patients then should you give chemo pembro to versus giving chemo ipi/nivo to? And unfortunately at this time, we don't really know the answer to that question. So that then sets us up with a tough spot to sit in, that we don't really know how to use these regimens either way. And we know one of them causes more side effects.   So what I would say right now is that it's not clear that this advances the field in terms of changing the standard of care. But I'll be very interested to see the long-term outlays in terms of overall survival in this clinical trial. So the trial we would want to see would be chemo pembro versus chemo plus ipi/nivo.   But these trials were done chronologically at similar times. And the standard of care had not switched to chemo pembro yet when they had started this trial. So certainly that's a future trial we would look forward to. I think it is possible that the chemo ipi/nivo trial might have the potential to have better overall survival over a long period of time, relative to chemo pembro.   And the reason I say that is we can see that in melanoma where giving ipi and nivo does appear to give better longer overall survival, but you don't see that effect until about two to three years after you start ipi/nivo relative to starting nivo monotherapy. So we're not really going to know whether or not the long term survival of this quadruplet regimen of platinum doublet plus ipi/nivo is actually better than the triplet of platinum doublet plus pembro.   We're not really going to know that in a head-to-head trial for a long time. And even just comparing two trials head-to-head, we're not really going to know that again for at least a couple of years. So I don't know whether or not that trial really changes practice yet. But it'll be very interesting to watch it over time.   The second trial I wanted to talk about that really stood out was the CITYSCAPE trial (Abstract 9503). And so this is a nice name for a clinical trial. Essentially what it is is looking at a combination immunotherapy in the PD-L1 high subset of non small cell lung cancer. So in patients with greater than 50% TPS In lung cancer, the molecule, the PD-L1 antibody atezolizumab, was combined with an anti-tigit antibody in that population and randomized against atezolizumab plus a placebo.   And the idea here would be to look for a second combination checkpoint that's not CTLA-4 and see if that could have more activity relative to a PD-1 PD-L1 monotherapy in that PD-L1 high population. So again, all of you are aware that PD-1 monotherapy is approved in that setting. PD-1 and PD-L1 are both approved for PD-L1 high patients in frontline lung cancer.   And what they observed in this CITYSCAPE study was an improvement in the response rate for the combination immunotherapy relative to the PD-L1 plus placebo. And that was statistically significant. And it was of substantial interest.   So I think that's very interesting. And based on those data, in fact, the company advancing this tigit antibody that makes atezolizumab has rushed forward into a series of randomized Phase III clinical trials, where they're combining atezolizumab with this tigit antibody across a number of diseases. The first two trials will be a non small cell lung cancer as well as small cell lung cancer with the idea that this new PD-L1 plus tigit regiment essentially is going to replace a PD-1 or PD-L1 monotherapy either as-- oh, sorry, either as monotherapy or in combination with chemotherapy and various different indications.   So this is really interesting because the toxicity profile of this combination regimen was quite modest and in fact look mostly like a PD-1 PD-L1 monotherapy. So this wouldn't be the addition of a second checkpoint that actually doesn't increase the toxicity, but might amplify the benefit. And so why would that be the case?   Well the checkpoint tigit we know from basic biology is also associated with the T cell activation state in the tumor microenvironment. And it may very well be that this is yet another checkpoint that's important in the tumor, that by blocking it we might not increase the overall toxicity because where the tumor is where the action is at. And it might increase the benefit.   And that would be different than CTLA-4 or ipi, where the effect is broadly throughout the whole body and not localized in the tumor microenvironment. So that's a very interesting molecule, this tigit molecule to keep your eyes on, because I think there will be a number of Phase III trials coming forward the next few years It'll be very interesting to see if we can find other combination immunotherapies.   The third abstract that I wanted to dwell on quickly that stood out-- again, doesn't change practice, but it's important to be cognizant-- was IMvigor 10 or 010 (Abstract 5000). And this was a bladder cancer randomized Phase III adjuvant clinical trial. And the idea was high risk patients with bladder cancer are randomized to either get atezolizumab or to get placebo in the adjuvant setting.   And really as, I have to say, a shock to most of the people in the field, there was no difference in rates of relapse or overall survival in high risk urothelial cancer for patients who got adjuvant PD-L1 relative to those who got placebo. And this is one of those things where don't count your checks before they're cashed, or don't count your eggs before they're cracked, or whatever the euphemism goes. Everyone assumed this would be a positive clinical trial.   In melanoma when we moved PD-1 antibodies from the metastatic setting into the stage three setting, it was a slam dunk. It was fabulous, unbelievable-- hazard ratio of 0.5. Yet here we see in another disease, which is responsive to immunotherapy in the refractory disease setting, we see no difference in the adjuvant setting. So I think that's really an eye opener and, again, just suggests why we have to do these trials.   My dad used to like to say, that's why they play the games. Let's talk about sporting events with atypical outcomes, things you didn't expect. So that's again what we saw here. So adjuvant PD-1 or PD-L1 is not a standard in bladder cancer. There are some other clinical trials that are ongoing to look at other PD-1 agents that have slightly different designs. And we'll be very interested to see what the results of those kinds of clinical trials look like over time.   ASCO Daily News: Are there any other clinical trials that our listeners should be aware of?   Dr. Jason Luke: Yes, so there are also a whole handful of trials that I think are worth quickly pointing out because I think they give us indications around better using agents that we already have. So in melanoma there were a couple of abstracts presented that looked at the use of CTLA-4 with a PD-1 in second-line melanoma. So in patients who got a frontline PD-1 an open question is, should you give them ipi as the second line, so PD-1 followed by CTLA-4? Or what about the idea of continuing the PD-1 and adding the CTLA-4 antibody on top of it?   And so there were two abstracts. There was a prospective open label Phase II study, in fact, that I designed. It was our study (Abstract 10004). And what that showed was that where we would expect a response rate of about 13% to ipilimumab in the second line as a monotherapy, in our Phase II study of 70 patients, we got a 27% response rate. And that trial was augmented by another abstract from the Melanoma Institute of Australia, who aggregated their experience of what they had done in their standard practice in the second line.   And in the patients who had gotten ipilimumab plus nivolumab after a PD-1 (Abstract 10003), they observed a 32% response rate. So if you put these two studies together, you're now up about 250 patients between both series. And you get a response rate between both of them around 30%. And that looks to be about a doubling of what we would expect in standard care setting of just getting ipi monotherapy after PD-1.   So I think that's a really interesting thing to be aware of. In my practice I tend to give that combination regimen after initial PD-1. And I think we'll look forward to a study from SWOG, which is actually randomized patients to get ipi/nivo versus just ipi after a frontline PD-1. So I think that's a really important abstract to be aware of.   The other study that I'll be-- but I'll just share, however, was that in contrast to that, there was a series of studies presented in renal cell carcinoma, where this paradigm did not appear to be true. So there was an abstract called the FRACTION study in renal cell carcinoma (Abstract 5007), as well as the Hoosier Oncology Group GU16-260 (Abstract 5006). In both of those studies, there did not appear to be a big benefit to adding ipi after a patient had progressed on PD-1.   And that was interesting because in the FRACTION study (Abstract 5007), they used ipi/nivo. And they got responses in the second line. But in the Hoosier study, it was less clear. And so I think the renal guys feel like if you're going to use ipi/nivo, you need to do it right away upfront. And you shouldn't do the sequential approach of giving a PD-1 and then adding on ipi later.   And it's interesting to contrast those two things because that's a difference between tumor types, where we think there might be more benefit to giving that combination or waiting for the combination of melanoma, whereas in renal, if you're going to use it, you should really come in guns blazing both checkpoints at the same time.   One other study I want to do just highlight quickly was also in melanoma, where the group from Sloan Kettering did a study looking at two doses of ipi/nivo versus four doses of ipi/nivo. And not to dwell on it too long, but what they observed was essentially all of the benefit and all of the toxicity appeared to be associated with just the first two doses of ipi/nivo.   In other words, when they looked at an early CT scan to look for responders, all the responding patients had already basically had their benefit after the first two doses. And none of the patients who hadn't already benefited by two doses actually went on to benefit at four. So this was a pretty small study. It was upwards about 25 or 30 patients. But I think this really deserves further follow up.   And I think it emphasizes, however, that in clinical practice, there is no need to really push the envelope in giving more ipi/nivo, especially if patients have toxicity. So if patients get a couple of doses and they get toxicity, you do not need to go back to pushing them to get more doses. We'll be very excited to look for future data to really look into this so we can really optimize the use of combination immunotherapy in the broader population.   ASCO Daily News: Dr. Luke, are there new treatment approaches or agents in development that you are particularly excited about this year?   Dr. Jason Luke: Yes, so there were, as I mentioned, a couple of abstracts around adoptive cell therapies in solid tumors that I think we're going to look back on this year's ASCO and say, wow, this is the year when these things really started coming to the forefront. And there were three of them that I'll highlight quickly.   One of them is a drug called lifileucel. In fact, that is a tumor-infiltrating lymphocyte product. And in melanoma, an updated data series was presented on a group of about 70 patients who had undergone tumor excision and then harvesting of TIL. And then a TIL product was made. Patients were given lymphodepleting chemotherapy and were reinfused their TIL . (Abstract 10006)   And what was exciting about it was the stability of these results over time. So in these patients, a response rate in 70 patients was observed at 36%. And realize that these are patients who already had PD-1. They had CTLA-4. They had BRAF. These were refractory patients. So a 36% response rate-- quite impressive.   The other thing that was very interesting to be observe was that the duration of those responses in the refractory disease setting was not reached. So in other words, the patients who responded did very well. And then the final thing on that one to be aware of was it looked like patients who would benefit from that therapy were disproportionately those who had not benefited from previous PD-1 therapy.   And certainly, that's a big unmet need in melanoma. And in the melanoma field, we're fairly confident that this therapy is going to be approved by the FDA either later this year or next year. So being cognizant of cell therapy for solid tumors, at least in terms of TIL for melanoma, is going to be important.   The other two abstracts I'm going to put together quickly. One of them was about SPEAR MAGE-A4 TCR transduced T cells (Abstract 102), as well as a second abstract about HPV E6/E7 TCR transduced T cells (Abstract 101). So what are TCR transduced T cells, you might ask?   What this is, is taking a patient's own lymphocytes and then ex vivo transducing them with a lentiviral vector most commonly to express a T cell receptor that's been identified from a different patient. So that T cell receptor can be specific for a certain antigen. So you'll have heard-- I mentioned MAGE-A4-- as well as HPV E6/E7.   So these are antigens that we know can be expressed to certain degrees in certain tumor types. For example, MAGE-A4 is highly expressed in sarcomas as well as some esophageal cancers. And HPV is obviously highly expressed in HPV-associated cancers, such as cervical cancer and others-- head and neck, et cetera. And so these studies were very interesting because obviously this is a somewhat complicated process, sort of like the TILs I told you about before, but it adds an extra layer of genetically modifying the product.   But, again, they saw high levels of response in tumor types that had these antigens. And those responses tended to be durable over time. So there are randomized trials coming forward now to look at these agents. And I'm very excited that over the next couple of years, we're really going to see a movement of cell therapies to the prime time and maybe even in the standard of care setting for patients with multiple solid tumors.   ASCO Daily News: Absolutely. Can you tell us about new agents that will likely move the field forward or have already done so?   Dr. Jason Luke: Yes, so there were a handful of abstracts here. But I think there are two conceptual things that I'm going to highlight. It isn't so much the individual agents, I would say, but rather the concepts around them. I'll give you the names of the agents so you can look them up.   But one of them was an agent called MGD013 (Abstract 3004). But the reason it's of interest is that it's a bispecific antibody. So disclosure, I was the presenter of this abstract. But I think it's very interesting because what it gets at is a future of using antibody engineering technology to bring forward novel agents. So MGD013 is a bispecific PD-1 and LAG-3 inhibitor.   So those are two immune checkpoints that are being investigated separately with monoclonal antibodies. But here we have one drug that can hit both of those. And so what was interesting was the drug was safe. And the response was seen across a host of different diseases.   But perhaps most interestingly in the trial, we combined MGD013 with the HER-2 antibody margetuximab. And margetuximab is an FC-modified and optimized HER-2 antibody. And in patients who had refractory HER-2-positive tumors that were PD-L1 and LAG-3 low, the combination of MGD013 with margetuximab generated more than 40% treatment responses.   So this really fits the paradigm of what we were hoping to do. And you may have heard of this-- "turning cold tumors hot" is how we sometimes talk about this. In other words, we can identify a biomarker, target that with the margetuximab in HER-2, and then come in with immunotherapy. And because the first therapy was successful, it makes the second therapy likely to be successful as well.   So I would be aware of these bispecific approaches. Some of them have come forward from leukemias already. And I think in solid tumors, it will be interesting as well.   And the final one I'll note were the combinations of VEGF or VEGFR inhibitors with PD-1s or PD-L1s. And in fact there were so many of these combinations presented that I don't really have time to go over all of them. The listenership will be cognizant that the standard of care has changed in kidney cancer and recently in hepatocellular carcinoma in the front line to include these kinds of combinations.   But there were data presented for endometrial cancer (Abstract 6083), mucosal melanoma (Abstract 10040), colorectal (Abstract 4019), bladder (Abstract 5013), prostate (Abstract 5564), lung (Abstract 9610), more, that these combinations look to be quite active in the PD-1 progressed setting. And in fact clinical trials are now starting to move these combinations into earlier lines of therapy as well. So I think this combination of VEGF blockade with PD-1 is really going to be something to be on the lookout for because I think this is going to expand the horizon of immunotherapy within and across multiple solid tumors.   ASCO Daily News: Excellent. Thank you, Dr. Luke. So I'd like to let our listeners know that the abstract numbers relating to all of the studies Dr. Luke discussed today are on the transcript, which is published with this episode. Dr. Luke, thanks again for your insights on these incredible developments in the immunotherapy field.   Dr. Jason Luke: Thank you very much for having me, Geraldine.   ASCO Daily News: Thanks to our listeners for joining us today. If you're enjoying the content on the podcast, please take a moment to rate and review us on Apple Podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. Mitul Gandhi, a medical oncologist specializing in hematologic malignancies at Virginia Cancer Specialists, which is part of the US Oncology Network, highlights key abstracts from the #ASCO20 Virtual Scientific Program that aim to improve outcomes for patients with multiple myeloma. Transcript ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. I'm delighted to welcome Dr. Mitul Gandhi, a medical oncologist with Virginia Cancer Specialists, which is part of the US Oncology Network. Dr. Gandhi's clinical and research focus is in malignant hematology.   Today he will highlight key abstracts featured at the ASCO20 Virtual Scientific Program and discuss the potential of new agents and treatment approaches to improve outcomes for patients with multiple myeloma. Dr. Gandhi reports no financial conflicts of interest relating to the issues discussed in this podcast. Full disclosure is relating to all daily news podcasts can be found on our episode pages.   Dr. Gandhi, welcome to the ASCO Daily News Podcast.   Dr. Mitul Gandhi: Thank you for having me. I really appreciate the opportunity to review the abstracts from this year's meeting.   ASCO Daily News: Can you tell us about the abstracts that will likely support new standards of care?   Dr. Mitul Gandhi: So within the world of multiple myeloma, there were several exciting studies that were conducted with investigational agents that are new, and then repurposing existing agents in different lines of therapy. When reviewing this, while it may not change how we practice tomorrow, it certainly informs what may be in the very near future.   I think a representative abstract is 8500, presented by Dr. Richardson and his colleagues, and involved a novel compound CC-92480 in relapsed refractory myeloma. And this is an interesting compound, which is a Cereblon ligase modulator and a next iteration of agent based on the Revlimid and, rather, lenalidomide and pomalidomide mechanism acting on Cereblon and degrading Ikaros and Aiolos.   And this was a phase I study with a phase II expansion based on the maximally tolerated dose. And what they found were that this agent studied in heavily pretreated myeloma patients, all refractory lenalidomide, pomalidomide in the majority refractory to anti-CD38 antibodies. This drug was still able to achieve a response across several dosing cohorts.   They had a complex study design involving twice daily along with once daily dosing, and a 1.0 milligram-per-day dose was identified as a MTD. And at that dose, they found 48% of patients achieved a response, with correlative studies demonstrating degradation in Ikaros and Aiolos consistent with the mechanism of action.    And so what it tells us is that this mechanism still remains a potent avenue for exploitation in spite of progression on first- and second-rate generation compounds like lenalidomide and pomalidomide. So this informs possible changes in the future, where we would continue to use a compound like CC-92480 in spite of progression on the existing agents.   And we can see itself working in earlier lines of study and complexing with other compounds to the increased response rate. So this is something that we think will be relevant in the future if not relevant tomorrow in terms of standard of care.   ASCO Daily News: There have been substantial improvements in survival for patients with multiple myeloma in recent years, thanks to the introduction and widespread use of multiple novel agents and regimens. Are there new treatment approaches or agents in development that people should be aware of?   Dr. Mitul Gandhi: Absolutely. I think this can be viewed in a few ways. As all the listeners are well aware of and have experience with, the monoclonal antibodies on top of the existing backbone of treatment that has led to significant improvement and outcomes with relapsed refractory patients, both with daratumumab and elotuzumab.   Daratumumab, of course, being in an anti-CD38 antibody and elotuzumab targeting SLAMF7. There are next-generation antibodies on the anti-CD38 backbone, such as isatuximab. And that was studied in abstract 8508 in high-risk multiple myeloma by Dr. Weisel and colleagues from Germany.   So this particular study kind of captures what the goal is, which are moving these monoclonal antibodies higher up in the lines of therapy. So this particular trial looked at higher risk multiple myeloma, defined by chromosomal aberrations, such as deletion 17p, translocation (4;14) or (14;16), or excess copies of 1q21.   These patients received isatuximab on top of the KRd backbone, with an option for pursuing stem cell transplantation. There were 50 patients in the initially presented data -- 46 in the transplant eligible; 4 in the transplant ineligible. And one of the striking things that was identified was a 46% complete response rate in a otherwise high-risk cohort.   So this is emblematic of what the field is moving towards, which is incorporating these novel antibodies on top of an established backbone and seeing better response rate that were initially met. And as an increasing amount of data identifies achieving lower and lower myeloma burden and hopefully MRD negativity, minimal residual disease negativity, earlier on, pretending long-term, better outcomes, incorporation of these novel antibodies is one - exciting, and two - it will hopefully help inform the next generation of therapy.   Notably, these results are still preliminary phase II studies. And longer term follow up will be needed to identify if they are better than the existing outcome. Another study in that same vein is abstract 8507, presented by Dr. Zafar and his colleagues from SWOG, incorporating elotuzumab with the RVd backbone for, again, newly diagnosed, high-risk multiple myeloma.   They define high risk in a similar vein as a German group with translocation (14;16), (14;20), 17 p or gain of 1q21. And they took 103 patients, randomized them to RVd or RVd plus elotuzumab. They found at 53 months median follow up, a relative similarity in the progression-free survival. 31 months for RVd and 34 months for elo RVd with a P value of 0.449.   And there was no overall survival observed, albeit that truncated follow up. Notably, there were higher rates of response with the incorporation of elotuzumab. And so what this study validated is it's certainly using the proteasome inhibitor backbone. But maybe switching the antibody to increase response rates has, at least at this first analysis, there was no improvement in PFS.   Nonetheless, I think it's an important study, as the goal seems to be incorporating novel compounds on top of an existing backbone to improve depth of response. So these are two representative abstracts, which shows where the field is moving. And the patients that are relapsed and refractory, a slew of other studies targeting anti-BCMA are particularly exciting and relevant.   The DREAMM-6 study, abstract 8502, presented by Dr. Nooka,  used belantamab, which is an antibody drug conjugate targeting the BCMA B-cell maturation antigen conjugated to a cytotoxic payload. And in heavily pre-treated penta-refractory patients, they achieved an impressive response rate, with a clinical benefit rate of almost 80%, which is exciting, as these are patients with limited treatment options.   This is a novel mechanism of action with evidence of excellent responses, many that seem to be durable. It did have a unique toxicity profile, which is increasingly being recognized with cutaneous toxicity. So incorporation of opthalmology and identification of mitigation strategies are going to be important as more familiarity is gained.   But there are a number of further studies that are being pursued with belantamab. In context of this, there were three cellular therapy protocols also presented -- abstract 8503 by Dr. Munshi and colleagues, and abstract 8504 by Dr. Mailankody and colleagues, and abstract 8505 by Dr. Berdeja and colleagues. All three were abstracts around cellular therapy using a CAR T construct targeting BCMA with three different compounds.   And all three looked at similar patient populations with heavily pretreated patients. Abstract 8503 by Dr. Munshi looked at 140 patients penta-refractory and triple-class refractory that were treated with this compound in escalating doses. They found at the highest dose cohort at 450 times 10 to the 6 cells, an overall response rate of almost 82%, many of them durable with durability at median of 11 months.   This was associated with cytokine release storm along with some neurotoxicity, both at night, rather, at 96% and 20%, respectively-- but well managed. Similar findings were found on the other cellular products. Orvacabtagene presented by Dr. Mailankody on abstract 8504 and a Juno product in abstract 8505 by Dr. Berdeja. There was evidence of cytokine release and neurotoxicity in both. But again, with significant response rates in heavily treated patients, many of them durable. So altogether, it shows that an  extension beyond what we discussed initially, where there is next generation of compounds on existing mechanism of actions, these series of abstracts are looking at incorporation of monoclonal antibodies, improving on outcomes in first-line therapy, along with targeting BCMA through either an antibody drug conjugate or through cellular therapy, eliciting responses in very heavily pre-treated patients. Many of them are durable. But with a unique set of toxicities ranging from cutaneous to cytokine release storm.   ASCO Daily News: Dr. Gandhi, are there any other clinical trials that really stood out for you this year?   Dr. Mitul Gandhi: So a few other abstracts I think that are worth noting, with respect to the clinical trials question, I think with the data that's been presented in the abstracts we've talked about, they inform the next generation of studies as we build upon the outcomes that were presented for more mature data, longer term data, and novel combinations.   A few other studies that I think were informative -- abstract 8509, presented by Dr. Kumar and colleagues, involving venetoclax plus bortezomib and dexamethasone in relapsed refractory myeloma. This was interesting because we know that venetoclax seems to have preferential sensitivity and rearranged (11;14) patients for BCL-2 high.   And what the study found in a randomized fashion of 291 patients-- 194 to the venetoclax arm and 97 of the placebo-- in the patients that had a rearranged (11;14) translocation were felt to have BCL-2 high, median duration of PFS was not reached compared to 9.9 months in the placebo arm.   So this is an impressive targeted therapy in a subset of patients. It seems to enjoy very long-term responses in spite of being heavily pretreated with venetoclax, which is a drug that's increasingly gaining experience across a wide swath of hematologic malignancies. And so it speaks to the heterogeneity of this disease and perhaps targeting on a more genomically stratified approach with these targeted compounds.   There are a few other studies I think might be relevant for practical matters on a day-to-day basis in the clinic. One of them was 8518, presented by Dr. Ailawadhi and colleagues, regarding the use of RVd in newly diagnosed myeloma with renal impairment. As we know, many of our patients can present with myeloma-associated kidney dysfunction, whether through light-chain deposition disease or a cast nephropathy with high light-chain levels.   And there sometimes is a bit of a trepidation in administering Revlimid in this setting out of concern for toxicity in the setting of depressed GFR. They performed a retrospective analysis and found that even in patients with baseline depressed GFR ranging from less than 30 or between 30 and 60, the incorporation of lenalidomide helped achieve almost equivalent outcomes in patients compared to patients who had a preserved GFR greater than 60.   So in their transplant-ineligible patients, for example, they found a median PFS of 36 months compared to 30 months in people with and without creatinine clearance less than 60. In their transplant-eligible patients, interestingly, they found a PFS of 48 months versus 43 months in the same cohort. So this speaks to the ability to safely administer this drug in achieving nearly equivalent outcomes compared to the people who have baseline intact kidney function.   So with appropriate monitoring, modification of dosing, and attention to myelosuppression, it seems as though we should be using lenalidomide-based induction therapy, which we would otherwise would if the patient's GFR was preserved and still able to achieve long-term durable responses.   A couple of other smaller studies that I think are worth mentioning include abstract 8515, presented by Dr. Cornell and colleagues, regarding bortezomib induction in light-chain amyloidosis prior to autologous stem cell transplant. There has been some question regarding what the best induction strategy is in patients who presented with light-chain amyloid.   And so this was a retrospective analysis of the CIBMTR database. We're looking at patients who had received a bortezomib-based induction versus no induction prior to proceeding with a stem cell transplant using high-dose melphalan. And it was fairly clear in their followup that a bortezomib-based induction was associated with decreased risk of relapse within two years -- 13% in the bortezomib arm versus 22% in the patients that presented directly to transplant -- and translated into overall longer PFS as well.   So this validates the use of bortezomib in patients prior to stem cell transplantation in a niche population with amyloid. Similarly, abstract 8516, presented by Dr. Zhang and colleagues, questioned whether the incorporation of an alkyqlating agent on top of this proteasome inhibitor backbone would help in these patients with light-chain amyloid.   There has been an increased use of cyclophosphamide, bortezomib, dexamethasone induction based on smaller phase II studies. So this group looked at retrospectively a bortezomib plus an alkylating backbone versus one with bortezomib alone. And found that the overall hematologic response rate was fairly similar -- 73% in the patients that received bortezomib plus an alkylator versus 85% that did not, which was not statistically significant.   So it seems as though while there is a temptation to use the alkylator, it may not be necessary. And bortezomib alone may be sufficient. But of course, it would be on a case-by-case basis. But it adds to the body of literature regarding how to treat these patients with amyloid. So I thought those were helpful analyses in a smaller population but which may be relevant tomorrow in clinic.   ASCO Daily News: Well, thank you, Dr. Gandhi, for sharing your valuable insights on these promising developments in this field.   Dr. Mitul Gandhi: Thank you for the opportunity. I appreciate it.   ASCO Daily News: And thank you to our listeners for joining us today. If you're enjoying the content on the podcast, please take a moment to rate and review us on Apple Podcast.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

A combinação de anticorpos monoclonais com quimioterapia oferece benefícios para pacientes com tumores avançados ou metastáticos. HOWEVER qual deles tem maior eficiência em pacientes não tratados previamente? Estamos falando do cetuximab e bevacizumab novamente! Estamos quase lá! O objetivo é fazer um “background” sobre o assunto e discutirmos em breve a questão da lateralidade para câncer colorretal (ccr). O SWOG Trial, publicado no JAMA em 2017, teve o objetivo comparar a combinação de cetuximab vs. bevacizuma com FOLFIRI ou FOLFOX no tratamento de pacientes com ccr “KRAS wyld-type”. Siga-nos nas redes sociais e faça seus comentários! Sejam muito bem vindo a mais um episódio do Clinical Papers Podcast! Para saber mais sobre esse paper, acesse o link abaixo e tenha acesso grátis na íntegra! https://www.ncbi.nlm.nih.gov/pubmed/28632865

Tramo de 04:00 a 05:00 de In Sessions

This JCO Podcast provides observations and commentary on the JCO article “Dose-Adjusted EPOCH-R Compared to R-CHOP as Frontline Therapy for Diffuse Large B Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial CALGB 50303 (Alliance)” by Bartlett et al. My name is Patrick Stiff, and I am Division Director of Hematology-Oncology at Loyola University Stritch School of Medicine in Maywood, Illinois. My oncologic specialty is hematologic malignancies and stem cell transplantation.     CHOP has remained the chemotherapy backbone of choice for the treatment of diffuse aggressive non-Hodgkin lymphoma since the 4 arm randomized SWOG study was performed 25 years ago1. Since then, only the addition of rituximab has improved patients' outcome2.   Investigators have tried to improve outcomes by employing other strategies like increasing drug intensity, shortening the interval between cycles, adding newer agents, changing the method of administration, and adding transplantation, but none clearly demonstrated a survival advantage. Among these strategies is an infusional one designed to increase apoptosis and inhibit BCL6 and p-glycoprotein in resistant cells.  While SWOG tested infusional CHOP in 2001 and found no difference in outcomes, compared to bolus CHOP3, the NCI group has explored a modified CHOP infusional regimen known as EPOCH consisting of etoposide, vincristine, and doxorubicin given simultaneously as a continuous 4 day infusion with a bolus dose of cyclophosphamide at the end of the 4 days along with daily oral prednisone Combined with aggressive dose escalations based on nadir myelosuppression, they tested this regimen with rituximab, EPOCH-R, reporting an impressive 5 year PFS of 79% in an unselected study of 72 patients from 3 centers4.  Based on this, 18 CALGB institutions treated 69 patients with dose adjusted EPOCH-R, demonstrating a similar 62 month TTP of 81%, with an impressive 100% TTP for the germinal center B cell subgroup as defined by the Hans algorithm, all seemingly superior to R-CHOP5.  Equally impressive was a Phase II study in mediastinal B cell NHL with a 5-yr EFS of 93% administered without consolidative radiotherapy, added frequently to R-CHOP6.  Therefore, a head-to-head comparison was the natural next step.   The trial that accompanies this podcast was designed to compare the PFS and OS at 3 years between patients treated with 6 cycles of dose adjusted EPOCH-R to the standard R-CHOP.  The trial opened in 2005 and enrolled 524 patients with either DLBCL, primary mediastinal BCL or intravascular large cell NHL over an 8+ year period to its close in 2013.  Seventy-four % had stage III/IV disease and 12% high IPI disease.   Eighty-eight percent of the R-CHOP and 82% of the dose adjusted EPOCH-R cycles were administered with 75% of the dose adjusted EPOCH-R patients receiving initial dose escalations per protocol. At a median follow-up of 5.2 years the 5 year PFS and OS were 66 and 85% for the R-CHOP treated patients no different from the 68 and 77.5% for the dose adjusted EPOCH-R  patients.  Prognostic factors for PFS were age > 60, IPI, and double expressers (15.6% of the 270 with complete data) for MYC, BCL-2 and BCl-6.  There were a number of post hoc subgroup analyses performed. Of these, the PFS for the combined High and High intermediate IPI group was higher for the dose adjusted EPOCH-R group (p = 0.041) but no difference in OS was noted.  In none of the other subgroups was a benefit seen for dose adjusted EPOCH-R including CNS relapses, mediastinal B cell NHL, double expressors or those with MYC positivity although percentages of these subgroups were small.  There were however significantly increased grade III-IV myelotoxic and non-myelotoxic complications for the infusional regimen. Should we take these results as the final word on the lack of a benefit of dose adjusted EPOCH-R in the treatment of DLBCL?  In other words is this a case of "déjà vu all over again"?.  This trial recruited slowly, 524 patients over more than 8 years, with < 5% of US eligible patient enrolled. The reasons seem obvious.  Encouraging enrollment on a trial comparing a familiar outpatient regimen administered over hours, versus a 4+ day in-patient regimen was at best difficult. Recall also that this trial took place during the Great Recession, with patients/families fearful of losing their jobs dealing with an in-pt regimen. Slow accrual in and of itself should not have been impacted outcome. But these were not a unselected group as the authors concluded. First by design, all who had an ECOG PS of > 2 (20% of the phase II study5) were excluded.  Second there was the requirement for submission of fresh/frozen material including a second biopsy if needed thereby likely eliminating mostly patients with rapidly progressing disease.  Together possibly with some investigator bias, given the promising Phase II data, there was a decrease in High IPI enrollment of only 12% versus the 20% in the Phase II study, which extended to other high risk patients including double expressors, C-Myc positive, and mediastinal B cell disease. Combined these led to the 3 year PFS for R-CHOP of 72%, 17% better than the planned outcome. However, considering the trial exclusions, and ultimately a PFS similar to that of other recent R-CHOP experiences7,8 one could argue that the 3-yr 55% PFS endpoint for this trial was far too conservative.  While the R-CHOP PFS was 17% better than planned, the dose adjusted EPOCH-R 5-yr PFS was 7% worse than the Phase II results, which is difficult to explain considering the earlier studies, in which the more favorable patients did better5. A lower administered dose intensity compared to prior studies4,5 was not apparent with the incidence of grade III/IV febrile neutropenia and neurotoxicity similar to the Phase II trial.  However 82%  vs 91% of those in the Phase II study completed all dose adjusted EPOCH-R cycles with the decrease mostly due to on treatment deaths and AEs, suggesting that when used in a more 'real world setting' this regimen is more toxic than initially seen.  Might those who completed therapy also have had dose reductions or delays that could also have impacted PFS?  Finally, this report does not include PFS based on cell of origin(COO), which for patients with  germinal center B cell of origin in the Phase II study was 100%.  Perhaps the germinal B cell percentage was lower than in the Phase II studies as well. So what can be concluded about these negative results?  The authors conclude that there was a "potential patient selection bias", at least partially explainable by trial design, and that this "may preclude generalizibility….to specific subgroups".  I would conclude that given the outcome and toxicity data, for the low and low intermediate IPI patient, R-CHOP remains the treatment of choice.  The post hoc PFS improvement for the high risk subgroup might argue for dose adjusted EPOCH-R, but the lack of an OS advantage in this subgroup needs to be acknowledged. However, other compelling phase II studies in high risk subsets, e.g double hit, underrepresented in this trial, still makes the efficacy of dose adjusted EPOCH-R in certain circumstances an open question.  This concludes this JCO Podcast. Thank you for listening.

Dr. Jack West speaks with thoracic oncology global leader, Dr. David Gandara, on his role in mentoring junior colleagues, the evolution of clinical trials under his leadership of the Lung Cancer Committee of SWOG, & the new opportunities presented by blood-based testing for biomarkers.

Ally connects with her inner Poppy while her husband serves nog. Dani asserts dominance while Michael loses points. Tanis is along for the ride to Mars. ​Timestamps ​​ 1:47  Poppy Is 4:26  Grimes, Musk, and Mars 13:12  Mike vs. Dani 15:36  Poppy-bot 24:27  Santa-bot 28:55  Best Frans 30:18  Bob Lazar 36:04  Shared Consciousness 38:15  Storytime with Joel 42:07  Mandela Effect 47:28  Swog on da Nog

William Zellmer speaks with author Daniel L. Hertz about drug interaction screening in SWOG clinical trials and with author Susan Goodin about points she raises in an accompanying editorial. Recorded March 26, 2018. AJHP is the official journal of the American Society of Health-System Pharmacists. www.ajhpvoices.org

steve larsen: All right everybody, hey. I'm super excited for today. This is the first interview that I've actually done on, Sales Funnel Radio. It's actually one of the main reasons that I started this podcast. There's so many cool, silent, unspoken entrepreneurial heroes out there. I really, I just wanted to go expose a lot of those stories and share with you guys how possible it is to make a profitable sales funnel. Today, I have, actually one of my good friends, Ben Wilson, on the phone here recording. Ben and I actually have quite a history together. I'd say that I first got into sales funnels online with him, doing products with him. Anyway, I'm excited. We want to go through our story a little bit and share with you guys things you guys can do in your own business. Ben, how's it going? ben wilson: Absolutely good, man. Great to be here. steve larsen: Awesome, awesome. I was thinking back to the time when you and I first met. That was ... We were in college, that was back, what class was that? ben wilson: I think we were probably, Marketing 101, something wasting our time. steve larsen: Yeah. ben wilson: I remember leaning over and you were looking at Stripe, and I was like, "Most kids aren't looking at Stripe in class. Why is this kid looking at Stripe?" Then I leaned over and I was like, "Hey man, we should totally set up an API for you. We could get that going." You're like, "What do you know about Stripe?" I was like, "Yeah, man, I've set up Stripe." That was the start. steve larsen: That was the start right there. I remember I was making an e-book. ben wilson: Yeah. steve larsen: Yeah. That was my first attempt ever at making a landing page on WordPress, and I had spent two days trying to get this stupid theme to do what I wanted it to do. Yeah. That was funny. That project, I think I've sold two copies of that thing. It's on Amazon. ben wilson: That was a good book though. steve larsen: How did we get together after that though? What did we do? I actually can't remember. I just remember... ben wilson: I think we started bouncing ideas off as to what had done in the past. You started sharing to me about, I don't think you called it funnels at the time, you really started looking at affiliate marketing, and how to push products online without necessarily being attached. I think, I don't know if it was a clash, or some type of beautiful art piece. I always got attached, like, "Well, we have to brand it. We have to be attached to some level at what we're doing." You're like, "It doesn't matter what it is. Let's do it and we're moving forward." Just like a rubber band. Sometimes we'd have the snap, but the snap wasn't a bad thing. The snap was like, okay, I'll give up that I don't have to be that attached. You're like, "Okay, we can kind of brand it," and something would actually happen. Then we convinced our teachers. steve larsen: Yeah, yeah, yeah. ben wilson: I was describing this to someone yesterday. We convinced our teachers that what we were doing was a lot more beneficial. steve larsen: Than in class. ben wilson: Yes! steve larsen: I remember that. That was our internet marketing class itself, man. ben wilson: We missed ... I mean, we convinced several teachers... steve larsen: To not go to class anymore. ben wilson: To [call up the class 00:03:52] the class, and they're ... Oh man. I can't believe we actually pulled that off. steve larsen: Me neither. I was thinking about it. We drew up that plan. We got in our internet marketing and they were doing that stupid, SEO old school stuff. We both wanted to shoot ourselves. I noticed you were the other kid in the class that was just pounding their head on the wall. Like, "Oh this crap is so old. It doesn't work." ben wilson: Yes. I remember they were trying to teach WordPress, and they were like, "How do you do such and such?" I was like, every answer, both of us just raising our hands. steve larsen: Yeah. ben wilson: I was like, "Do we really have to sit here the entire time and build you a website? Can't we go build ourselves a website?" steve larsen: Yeah. That's funny. Then we wrote up that plan. It was basically a flow chart for pages. ben wilson: Yes! steve larsen: He said, "Yeah, go for it. Just bring a deliverable." Then we started meeting every morning for two or three hours. Way more than the other kids in class were doing it. I remember we made that first affiliate product. I think it was, Click Bank. Right? ben wilson: [inaudible 00:05:00] was it? Was our first one the weight loss supplements? steve larsen: It was something like ... No, no, it was the social media producer thing. We put a landing page together using some guys weird generator and put 50 bucks on it and woke up the next morning, saw that 50 bucks had come back, and I was like, "Holy crap! We didn't lose money!" We got 17 people to opt in, and we sold it. ben wilson: I was so stoked the moment we didn't lose money. That was the first accomplishments of, like, no way! steve larsen: How did we get with Paul Mitchell after that though? ben wilson: I think he was assigned to our class, and I had to go over ... steve larsen: That's right, you closed him. ben wilson: He was trying to do something with Facebook, and I noticed he had a lot more other issues than trying to do Facebook advertising through our class. Then we had an assignment that was to get 10 people to fill out the survey. You and I looked at each other like, "We could get a lot more than 10 people, but I'm not calling anyone." Right? Let's think hard of a way to get a lot more people. I think there ended up being, was there 1100 people we got to take the survey? steve larsen: Yeah. Everyone else got 100 or something. ben wilson: Yeah. I think they called their 10 people. steve larsen: Yep. ben wilson: Yeah. steve larsen: That was hilarious. Then we started driving traffic for them. Which, I can't believe we did that. Oh, and then the [Arhenis 00:06:32] Project. ben wilson: Arhenis. You and I were out for what, 72 hours straight building a website, and then come to find out, the guy didn't even mention his website that we had built for him after being asked by him to build this website. steve larsen: Gosh, that whole thing was so weird. ben wilson: We were like, "There's a million people watching right now, and the only way you're going to further your career is by sending people to this website, and you got 2 hours to do it." We sat, I sat, we sat there and even Paul Mitchell watching. They're like, "Okay, any time now, any time now." steve larsen: Mention, just say the URL, just say, and he never did. ben wilson: We're like, "We do not have to run any type of funnels. If you just by chance mention this email address that you paid $1800 for, if you could just mention it once." steve larsen: It would be great. Those of you who are listening, Paul Mitchell asked us to come build out ... They basically said, "Hey, we're getting on tv in 2 days, we need a website people can go to, and we need a lead capture system and all this stuff." This was ... Just mapping the same time, this was when ClickFunnels was still in beta. It was a while ago. It was way longer than that ago. Man, how long ago was that? That was 2 or 3 years ago now wasn't it? ben wilson: We're coming up on ... I mean, it's been 18 months since I graduated, and that was before my last semester. Yeah, at least 2 years. steve larsen: Yeah, yeah. Paul Mitchell, they hired us ... I think we're okay. I'm going to say names. This is a while ago now. They wouldn't pay us, and this is what I love about Ben. Ben looked over at me, and I can't remember the exact phrase. You know, I won't say the phrase he said, but you had this crazy look in your eye. You're like, "Dude, I'm going to go put one period in their code." I was like, "What?" I remember just watching you, and we were in the library on campus. You opened up the back end code, and you put one period in their PHP, in their code, and it white screened the entire website. I was like, "This kids a cowboy. This is awesome!" ben wilson: Like, that's it. Your website's done. You're not paying us, you don't get our benefit. Then, we set out to make Beauty School Index. steve larsen: Yeah. ben wilson: Do you remember that? steve larsen: Yeah. ben wilson: We were like, "We're just going to just give out free leads to every other beauty school for free, and not Paul Mitchell." steve larsen: We scraped 100, what was it like, 1,000 email addresses for them? ben wilson: A thousand email addresses. We ran a campaign to get beauty schools on board with us of how we were going to give them free leads. Our open rate was through the roof. steve larsen: We did a 77% open rate. ben wilson: Yeah, and we had a really big return. We asked people to fill out questions. I don't even remember the questions. I remember you coming back and being like, "We got to get them involved and we need their feedback. That way they're contributing and they're loyal to whatever we're going to do for them. That way they value the leads that we give them." I think one of them was, How is it, or what are you struggling with and how can we help you? steve larsen: Yeah. ben wilson: That's everything we have been doing, and everything I do now always stem from that question that you ask them. We've got to provide a value, so if we listen to them, they're a lot more loyal. We're like, if that's what you want, let's give it to you. steve larsen: Yeah, yeah, yeah. ben wilson: It started from there, and then I moved to Colorado, and it seemed out of sight and out of mind. That's where my life got dark Steven. No longer with you. steve larsen: I got obsessed with sales funnels at that time, and I started dueling for different companies in the area. That was good times man. Talk about a walk down memory lane there. That's awesome. Now you, I mean, it's funny. I can't remember, you sent a message over to [inaudible 00:11:04], would you look at this site. I was wondering if you could just tell everyone who's listening right now a little bit about your website, and what is it you do, and how you came about with that. It's pretty genius. At first, it was like, I had never heard of it, and then you were like, "Oh I have 2,000 subscribers a week later." Oh, now we've made a butt load of money already and not spend a dollar on ads. It's like, what the heck. I thought it would be kind of cool if you want, this is totally your brag moment. Just tell what happened. ben wilson: No, you're good. It's similar, I guess backtrack a bit. Steven and I also once ... Remember when we launcHed [SWOG 00:11:38]? Some of it stemmed from that. There's this new concept of Trilify stemmed from what we were doing at SWOG when you and I came up with a business, entered into a business competition, and we've really been doing it for a week and half. A lot of it was just driving traffic and getting, running people through a certain type of funnel which is so funny because it wasn't ... Neither of us knew what ClickFunnels, at least I didn't and I didn't never think of it necessarily like ClickFunnels, but everything at the time was exactly what is going on at ClickFunnels. We were running people through a certain cycle getting a certain amount of information each time. That way there was creating this loyalty. Similar process as to what you and I were doing with SWOG, is running through certain sales cycles. The concept is only running through affiliates. Affiliates, typically there is the affiliate program that you send out, and anyone can join and sign up. steve larsen: Mm-hmm (affirmative)- ben wilson: Where as, what we're doing is approaching... steve larsen: Like, specific ones? ben wilson: Very specific people who have followers already. Right? When they send out a tweet, they've already gained a genuine sincere following. We don't have to worry about traffic when they send out tweets, or a Facebook post, or making a YouTube video, or anything of that nature because they already have the followers. There's a certain amount of followers that we're trying to gather as well as a certain age group of people who haven't done affiliate marketing, they're not seeking to only do affiliate marketing. We're looking at it at a more of a, how do we provide value to them? They don't recognize how much value they can provide. Millennials are a perfect target because a lot of them are seeking more fame and if they can get fame and money without having to go through the typical college and Corporate America, and they can continue doing and being famous, even it's to several thousand people, they still consider themselves like a taste-maker. We look at those people, try to run some ways of how can we provide value. A lot of it is creating a brand for them or running through certain memorabilia designs that they don't have to worry about their backend. It's like an agency coming to a talent and saying, you keep doing you, and send people to your new "Websites." This is what's going to drive a lot of traffic. We just launched on June 9th. steve larsen: Just a month ago? ben wilson: Just a month ago. Came up with a concept and 3 weeks later we just threw together a Shopify because we didn't have to deal with PCI compliance. steve larsen: Sure, sure. ben wilson: Or any of the other reasons of our design. Easily threw it together, found a bunch of products that we could have drop shipped that looked pretty cool that we didn't have to necessarily have any products on hand. We weren't going to lose out on any up-front costs. It was simply, "Hey, it's brand new. It's going to take 3 weeks to get to you, and we're sending it to you from our Chinese suppliers." steve larsen: Right. ben wilson: Which was the beauty behind it. Suddenly everyone didn't have to care about Trilify, they cared about the person, and the person who had a brand within Trilify. steve larsen: You effectively have gone, and you created an e-commerce store, based around clothing that is totally outsourced to China? ben wilson: Completely. steve larsen: That's amazing, dude. ben wilson: Completely. We've got no products on hand, and we don't have any storage cost. We're not shipping anything, we're not wasting our time. steve larsen: So it's a huge drop ship operation basically? ben wilson: Completely. Now, we could definitely make a lot more money per product if we were to buy upfront. However, we also had, we wanted to come out with a hundred products and then start narrowing down, and then selecting which products are being purchased and obviously moving forward looking at finding a new fulfillment service that we could buy in bulk and then have someone else fulfill it. We're run ... We'll scale it as it needs to be but, we had a hypothesis of how much traffic would come, and our traffic was a lot more than we thought we had. We ended up doing 50,000 by the end of the month. steve larsen: 50,000 people? ben wilson: 50,000 people off of 1 tweet and 1 Instagram post. That was simply it. steve larsen: Wow. ben wilson: From there, all we were doing was, we needed ways to capture peoples information, filled up a MailChimp account within a week. That was when I called you. I didn't actually ever run into that issue before of not necessarily ... We had a lot of names before, we had a lot of information. We just had it on hand and we had scraped it and stuff. steve larsen: Right. ben wilson: More so of, I've got to now start dumping names out of this because I'm not, I don't want to start paying for MailChimp quite yet. steve larsen: Right. ben wilson: I was just exporting names so that I could continuing running a map free account. We're up to 10,000 names at the moment of emails, of people who've opted in. steve larsen: 10,000? Dude, a few weeks ago, you were like, "Dude, we're already at 2,000 subscribers." You've grabbed 8 more thousand subscribers in the past 2 weeks, or whatever? ben wilson: Correct, yeah. steve larsen: Oh my gosh. Man, that's amazing. Okay, so you're "attracting," people through authority figures. Pulling them in and then ... What's causing someone to subscribe? ben wilson: We want all of our, I'm going to call them a brand ambassador, that's probably the best way to say it. We want all of our brand ambassadors to take ownership of what they're doing. That way it's not a 26 year old guy behind the computer who's actually running. I got 2 other guys that are running this with me, and one's in production, and the other is an actual talent agent so it's a lot easier to contact a lot of these people because he's got the experience. steve larsen: Right. ben wilson: He knows what to say. We run through and have all of them take full ownership. This is something that they created, therefore, when they send people over to the sites, and there's this taste of that person. Right? This goes back to that branding. It's got to be branded. steve larsen: Right. ben wilson: Everything comes back to how this person is perceived by their audience and not how they think they are perceived. steve larsen: Interesting. ben wilson: It might be a little confusing so we look at, what is this person actually wearing in their posts? What is that they are into? Then, find similar pictures that we can gather to create the same aura, so it's another, on the social media means to finding more information about this person, or how this person that they already admire, that they can further their knowledge of someone that they look up to. That's kind of the approach behind it. steve larsen: You go and you ... What are you asking for, I guess what are you giving for someone to subscribe. You know what I mean? What's causing them to subscribe. From the 50,000 that have hit so far, I'm sure it's way more than that now and 10,000 subscribe, what's causing them to do that? Just to follow you? ben wilson: Literally, yeah. 10% off, and it says something quirky that probably a millennial would be really attracted to. Right? They're looking at this thinking, "This person I admire who's 18 years old, what's their lingo?" The lingo that pops up right away is, we've got an A/B split test. One of them is, "Let's be BFF's. Sign up here and we'll shoot you a 10% off discount on your purchase." The other one, a little more risque, but I like it. Which is working is, it pops up and says, "Let's be friends with benefits." It also has a 10% off discount. That one is killing it. steve larsen: These people are signing up for a 10% discount. That's not only saying, A: Follow us and we'll give you cool stuff. A 10% discount is implying that they're going to make a purchase in the future obviously, very near future. You're really knocking out more than one bird with the same stone. That's amazing. ben wilson: Yeah. They've all got on a drip campaign. We've got a ... Shopify is really nice, and I know ClickFunnels does a lot of similar things where you can do other affiliates, or similar products, or similar brands, and you can keep sending people to where they want to go. Right? Listen to where people want, follow their clicks, understand your analytics. We set up cross sales and up-sales where people are purchasing certain products with, and they're looking at other products. steve larsen: Right. ben wilson: Everything is an up-sale and that's really where we're making a lot of headway is it's all in the up-seller, it's moving people through a funnel. steve larsen: Yep. ben wilson: If they have a ... In a cart, we send out an abandoned cart. If they didn't do it from there, I would figure out what products that they had. All of this, there's a lot of programs out there that can help you understand what your customers want, and you just have to listen and find out ways to remind them as to what they came for initially. steve larsen: Absolutely. There's a, I can't remember if it's called the secret formula or what Russell Brunson calls it, but he said, "Basically all you need to do is find a raving niche who is willing and able to make purchases and then just give them that thing." It's as simple as that. It's not that hard, especially online. You create these virtual pieces of real estate and they just work for you. That's amazing. Do you mind, if I ask sales? Things like that, like numbers? ben wilson: Yeah, go for it. steve larsen: Of the people that are coming in, what percent are opting in right now? ben wilson: Percentage wise, it's low. steve larsen: Okay. ben wilson: Which is the humble pie I'm eating at the moment. I know it should be a lot better. We've had ... Dealing with Chinese manufacturers is a lot more time consuming than I initially thought. That's where I've got a lot of time. In this regard, out of ... Boy, percentage is dramatically low. If we've had 10,000 people who have opted in, we've had 50,000 to the site. steve larsen: So, 20%? ben wilson: 20% which... steve larsen: That's awesome. ben wilson: That should be better, Steven. steve larsen: I mean, it should be, but when you think about other industries and ... People get stoked. Most people have a 5% off on their rate, 20% is crushing it dude. I mean that really is awesome. ben wilson: I appreciate the lift up, I need that. Definitely, I know ... You know when you are doing something, and you're like, man, there's so much more I could be doing? steve larsen: Yes. ben wilson: That's I guess where the justification comes from. Definitely, 20%'s a good number in looking at what the [inaudible 00:24:13] rate is, but it's always that inner feeling. You've definitely got to trust that movement of flight. I could be doing more to convert. steve larsen: How many customers, purchasing customers have you had? ben wilson: We've had 175 as of yesterday. steve larsen: 175 customers purchased ... I'm pulling out my calculator on the phone because my brain doesn't do all those numbers. ben wilson: That's okay. steve larsen: Here we go. That's awesome. From all the subscribers, the people that actually do subscribe, you have about a 2% conversion rate. That's good. ben wilson: Yeah. steve larsen: I know you look at it and say, we need to do better, but you're not even paying for traffic, man. That's amazing. That's what blows my mind about this. You have a 10,000 person list. I mean, you go drop an email to those people, 2% go and purchase, and you make all this money on the backend also after you acquire the customer. That's amazing. ben wilson: I appreciate it. Yeah. We're starting to run some more campaigns on testing single products as oppose to just sending people to the whole store itself. steve larsen: Yeah. ben wilson: Which we're really excited about launching. We've got something coming out this Thursday, which is more of this memorabilia take on the individual, like you would going to a concert. Right? steve larsen: Right. ben wilson: We're testing out the single product that's more branded and specifically to the person with their name on it. We're excited to see if that changes anything. If the name now suddenly on the clothing as oppose to just similar items of clothing that the person wears. steve larsen: Yeah. ben wilson: We may have to do a round 2, Steven. steve larsen: Yeah. ben wilson: Thursday. steve larsen: That would be awesome. That would be awesome. It's trilify.com, right? ben wilson: Trilify with one L. T-R-I-L-I-F-Y. steve larsen: Okay. ben wilson: .com. steve larsen: Trilify.com. ben wilson: At the moment it's just at an MVP. It's just testing out for our, I guess our test run of an individual person, and then we've got a lot more affiliates in the pipeline who are watching what we're doing. We're keeping them up-to-date as to how we're doing it, and that gets them excited. They can see that we, that their influence is going to provide them with a lot more sustainable of a future with the amount of followers and they can continue doing what they love doing with us basically running the show. steve larsen: Yeah. ben wilson: Yeah. steve larsen: That's amazing. I'm looking at the site right now. I mean, this is fantastic. It looks really good. Yeah, definitely applies to or appeals to millennials and what they love and stuff also. Do you know what the average cart value is for someone who purchases? ben wilson: We're running an average of $40 a purchase. steve larsen: Oh my gosh. That's so cool. ben wilson: Our hypothesis, or our reasoning I guess, within our justification of why we think it's 40 is we set free shipping at $35. steve larsen: Okay. ben wilson: Which is pretty low, but yet again, our average purchase is $40. We think a lot of people are taking advantage. We're going to start creeping that number up and seeing if that actually changes and test the hypothesis that, that is the reason why the average is up. I mean, it can really only benefit us if we can average each purchase to $45 or even 50 and start seeing if that's going to move any further purchases. steve larsen: That's awesome. That'd be an interesting split test and this is super cool. I just want to recap just in case, because I get close to projects and I forget the coolness of them or something like that. You got 50,000 people by asking 2 people to drop a tweet and something else, right? ben wilson: The same person. steve larsen: The same person? You're out there tweeting people. ben wilson: An Instagram post, yeah. steve larsen: 10,000 opt in, you get a 175 purchase, average cart value of 40 bucks, so you've pulled around 7 grand for this thing and you haven't paid a dime in advertising. This is the classic awesome story. It's cool. ben wilson: I appreciate that. We're excited. we're testing each social media to see what kind of pull. Learning Instagram, at least of what we've seen is that there's not as much traffic. We've got a speculation it's because there isn't a link. Sometimes, or link in each picture. It's in the bio. Then at the same time, we also figured out that there isn't as much text that goes below. If you're describing the pictures that you have posted, we've learned put it in the first sentence, in the first line if you're going to try to get someone to do something. Below that, they typically won't see it in their feed. Twitter has driven most of our traffic which was more surprising than we initially thought. We're excited to, like I said, we're also dropping a vine and a YouTube to see how that affects our traffic as well. steve larsen: That's awesome. Hey, I don't want to take all your time. I just want to thank you for this. This is fantastic. Guys, this is Ben Wilson. After one month, one month! People try forever to get profitable, and after one month he's got this awesome result and awesome site. I guess, where can people head? It's trilify.com. Go ahead and opt in and you can see his sales process. Ben, I want to thank you for this. This has been awesome. ben wilson: Absolutely, man. Glad I could come chat and reminisce about the good ole times, man. Definitely miss those time for sure. steve larsen: I look forward to seeing your face all over The Wall Street Journal, soon. ben wilson: It'll be the millennial Journal. steve larsen: Awesome, man. Thanks so much. We'll talk to you later. ben wilson: Absolutely, dude. Bye.

Tracklist: 1) Mark Morris - Insane Rytmica (original mix) Ketra Records 2) A Thousand Details / Solar Debris - Dextrum Mors (original mix) Wretched Recs 3) Bryan Chapman - Valley of the Troodon (original mix) Amazone Record 4) Raize - Sonar (original mix) Shout Records 5) B R 1 0 0 2 - Kill Hetrz (original mix) Monolith Records 6) A-909 - Swog (original mix) Dark & Sonorous 7) Victor Martinez - Foucault's Pendulum (rraph remix) More than Less 8 )Alavux - Witchcraft Sex (original mix) mk Recordings 9) Electrorites - The Head Crusher (Hans Bouffmyhre Remix) Nightmare Factory Records 10) Gønzalo - Pilaf (original mix) Concepto Hipnotico Rec 11) 88uw - Paradigm Intruder (original mix) Heaven to Hell Records 12) Davide Mancini - Marine (original mix) Moderate Records 13) Kalter Ende - Prototype V (Orphx Remix) Concerns Music

Dr. Jack West reviews the Lung Cancer Master Protocol for second line treatment of patients with advanced squamous NSCLC, an "umbrella protocol" in which all patients undergo molecular testing and have treatment assigned by the results.

Dr. Jack West reviews the Lung Cancer Master Protocol for second line treatment of patients with advanced squamous NSCLC, an "umbrella protocol" in which all patients undergo molecular testing and have treatment assigned by the results.

Dr. Jack West reviews the Lung Cancer Master Protocol for second line treatment of patients with advanced squamous NSCLC, an "umbrella protocol" in which all patients undergo molecular testing and have treatment assigned by the results.

Will the success seen for stage IV patients receiving targeted therapies translate into cure for stage III patients? Dr. Daniel Morgensztern of the Washington University School of Medicine talks about what research is ongoing to answer that question.