Podcasts about iiia

Dr. Diwakar Davar and Dr. Jason Luke discuss novel agents in melanoma and other promising new data in the field of immunotherapy that were presented at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Diwakar Davar: Hello. My name is Diwakar Davar, and I am welcoming you to the ASCO Daily News Podcast. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. Today, I'm joined by my colleague and good friend, Dr. Jason Luke. Dr. Luke is a professor of medicine. He is also the associate director of clinical research and the director of the Phase 1 IDDC Program at the University of Pittsburgh's Hillman Cancer Center. He and I are going to be discussing some key advancements in melanoma and skin cancers that were presented at the 2025 ASCO Annual Meeting. Our full disclosures are available in the transcript of this episode.  Jason, it is great to have you back on the podcast. Dr. Jason Luke: Thanks again so much for the opportunity, and I'm really looking forward to it. Dr. Diwakar Davar: Perfect. So we will go ahead and start talking a little bit about a couple of key abstracts in both the drug development immunotherapy space and the melanoma space. The first couple of abstracts, the first two, will cover melanoma. So, the first is LBA9500, which was essentially the primary results of RELATIVITY-098. RELATIVITY-098 was a phase 3 trial that compared nivolumab plus relatlimab in a fixed-dose combination against nivolumab alone for the adjuvant treatment of resected high-risk disease. Jason, do you want to maybe give us a brief context of what this is? Dr. Jason Luke: Yeah, it's great, thanks. So as almost all listeners, of course, will be aware, the use of anti–PD-1 immunotherapies really revolutionized melanoma oncology over the last 10 to 15 years. And it has become a standard of care in the adjuvant setting as well. But to review, in patients with stage III melanoma, treatment can be targeted towards BRAF with BRAF and MEK combination therapy, where that's relevant, or anti–PD-1 with nivolumab or pembrolizumab are a standard of care. And more recently, we've had the development of neoadjuvant approaches for palpable stage III disease. And in that space, if patients present, based on two different studies, either pembrolizumab or nivolumab plus ipilimumab can be given prior to surgery for somewhere in the 6- to 9-week range. And so all of these therapies have improved time-to-event endpoints, such as relapse-free or event-free survival. It's worth noting, however, that despite those advances, we've had a couple different trials now that have actually failed in this adjuvant setting, most high profile being the CheckMate-915 study, which looked at nivolumab plus ipilimumab and unfortunately was a negative study. So, with RELATIVITY-047, which was the trial of nivolumab plus relatlimab that showed an improvement in progression-free survival for metastatic disease, there's a lot of interest, and we've been awaiting these data for a long time for RELATIVITY-098, which, of course, is this adjuvant trial of LAG-3 blockade with relatlimab plus nivolumab. Dr. Diwakar Davar: Great. So with that, let's briefly discuss the trial design and the results. So this was a randomized, phase 3, blinded study, so double-blinded, so neither the investigators knew what the patients were getting, nor did the patients know what they were getting. The treatment investigational arm was nivolumab plus relatlimab in the fixed-dose combination. So that's the nivolumab standard fixed dose with relatlimab that was FDA approved in RELATIVITY-047. And the control arm was nivolumab by itself. The duration of treatment was 1 year. The patient population consisted of resected high-risk stage III or IV patients. The primary endpoint was investigator-assessed RFS. Stage and geography were the standard stratifying factors, and they were included, and most of the criteria were balanced across both arms. What we know at this point is that the 2-year RFS rate was 64% and 62% in the nivolumab and nivolumab-combination arms, respectively. The 2-year DMFS rate was similarly equivalent: 76% with nivolumab monotherapy, 73% with the combination. And similar to what you had talked about with CheckMate 915, unfortunately, the addition of LAG-3 did not appear to improve the RFS or DMFS compared to control in this patient population. So, tell us a little bit about your take on this and what do you think might be the reasons why this trial was negative? Dr. Jason Luke: It's really unfortunate that we have this negative phase 3 trial. There had been a lot of hope that the combination of nivolumab with relatlimab would be a better tolerated combination that increased the efficacy. So in the metastatic setting, we do have 047, the study that demonstrated nivolumab plus relatlimab, but now we have this negative trial in the adjuvant setting. And so as to why exactly, I think is a complicated scenario. You know, when we look at the hazard ratios for relapse-free survival, the primary endpoint, as well as the secondary endpoints for distant metastasis-free survival, we see that the hazard ratio is approximately 1. So there's basically no difference. And that really suggests that relatlimab in this setting had no impact whatsoever on therapeutic outcomes in terms of efficacy. Now, it's worth noting that there was a biomarker subanalysis that was presented in conjunction with these data that looked at some immunophenotyping, both from circulating T cells, CD8 T cells, as well as from the tumor microenvironment from patients who were treated, both in the previous metastatic trial, the RELATIVITY-047 study, and now in this adjuvant study in the RELATIVITY-098 study. And to briefly summarize those, what was identified was that T cells in advanced melanoma seemed to have higher expression levels of LAG-3 relative to T cells that are circulating in patients that are in the adjuvant setting. In addition to that, there was a suggestion that the magnitude of increase is greater in the advanced setting versus adjuvant. And the overall summary of this is that the suggested rationale for why this was a negative trial may have been that the target of LAG-3 is not expressed as highly in the adjuvant setting as it is in the metastatic setting. And so while the data that were presented, I think, support this kind of an idea, I am a little bit cautious that this is actually the reason for why the trial was negative, however. I would say we're not really sure yet as to why the trial was negative, but the fact that the hazard ratios for the major endpoints were essentially 1 suggests that there was no impact whatsoever from relatlimab. And this really makes one wonder whether or not building on anti–PD-1 in the adjuvant setting is feasible because anti–PD-1 works so well. You would think that even if the levels of LAG-3 expression were slightly different, you would have seen a trend in one direction or another by adding a second drug, relatlimab, in this scenario. So overall, I think it's an unfortunate circumstance that the trial is negative. Clearly there's going to be no role for relatlimab in the adjuvant setting. I think this really makes one wonder about the utility of LAG-3 blockade and how powerful it really can be. I think it's probably worth pointing out there's another adjuvant trial ongoing now of a different PD-1 and LAG-3 combination, and that's cemiplimab plus fianlimab, a LAG-3 antibody that's being dosed from another trial sponsor at a much higher dose, and perhaps that may make some level of difference. But certainly, these are unfortunate results that will not advance the field beyond where we were at already. Dr. Diwakar Davar: And to your point about third-generation checkpoint factors that were negative, I guess it's probably worth noting that a trial that you were involved with, KeyVibe-010, that evaluated the PD-1 TIGIT co-formulation of vibostolimab, MK-4280A, was also, unfortunately, similarly negative. So, to your point, it's not clear that all these third-generation receptors are necessarily going to have the same impact in the adjuvant setting, even if they, you know, for example, like TIGIT, and they sometimes may not even have an effect at all in the advanced cancer setting. So, we'll see what the HARMONY phase 3 trial, that's the Regeneron cemiplimab/fianlimab versus pembrolizumab control with cemiplimab with fianlimab at two different doses, we'll see how that reads out. But certainly, as you've said, LAG-3 does not, unfortunately, appear to have an impact in the adjuvant setting. So let's move on to LBA9501. This is the primary analysis of EORTC-2139-MG or the Columbus-AD trial. This was a randomized trial of encorafenib and binimetinib, which we will abbreviate as enco-bini going forward, compared to placebo in high-risk stage II setting in melanoma in patients with BRAF V600E or K mutant disease. So Jason, you know, you happen to know one or two things about the resected stage II setting, so maybe contextualize the stage II setting for us based on the trials that you've led, KEYNOTE-716, as well as CheckMate-76K, set us up to talk about Columbus-AD. Dr. Jason Luke: Thanks for that introduction, and certainly stage II disease has been something I've worked a lot on. The rationale for that has been that building off of the activity of anti–PD-1 in metastatic melanoma and then seeing the activity in stage III, like we just talked about, it was a curious circumstance that dating back about 7 to 8 years ago, there was no availability to use anti–PD-1 for high-risk stage II patients, even though the risk of recurrence and death from melanoma in the context of stage IIB and IIC melanoma is in fact similar or actually higher than in stage IIIA or IIIB, where anti–PD-1 was approved. And in that context, a couple of different trials that you alluded to, the Keynote-716 study that I led, as well as the CheckMate 76K trial, evaluated pembrolizumab and nivolumab, respectively, showing an improvement in relapse-free and distant metastasis-free survival, and both of those agents have subsequently been approved for use in the adjuvant setting by the US FDA as well as the European Medicines Agency.  So bringing then to this abstract, throughout melanoma oncology, we've seen that the impact of anti–PD-1 immunotherapy versus BRAF and MEK-targeted therapy have had very similar outcomes on a sort of comparison basis, both in frontline metastatic and then in adjuvant setting. So it was a totally reasonable question to ask: Could we use adjuvant BRAF and MEK inhibitor therapy? And I think all of us expected the answer would be yes. As we get into the discussion of the trial, I think the unfortunate circumstance was that the timing of this clinical trial being delayed somewhat, unfortunately, made it very difficult to accrue the trial, and so we're going to have to try to read through the tea leaves sort of, based on only a partially complete data set. Dr. Diwakar Davar: So, in terms of the results, they wanted to enroll 815 patients, they only enrolled 110. The RFS and DMFS were marginally improved in the treatment arm but certainly not significantly, which is not surprising because the trial had only accrued 16% to 18% of its complete accrual. As such, we really can't abstract from the stage III COMBI-AD data to stage II patients. And certainly in this setting, one would argue that the primary treatment options certainly remain either anti–PD-1 monotherapy, either with pembrolizumab or nivolumab, based on 716 or 76K, or potentially active surveillance for the patients who are not inclined to get treated.  Can you tell us a little bit about how you foresee drug development going forward in this space because, you know, for example, with HARMONY, certainly IIC disease is a part of HARMONY. We will know at least a little bit about that in this space. So what do you think about the stage IIB/C patient population? Is this a patient population in which future combinations are going to be helpful, and how would you think about where we can go forward from here? Dr. Jason Luke: It is an unfortunate circumstance that this trial could not be accrued at the pace that was necessary. I think all of us believe that the results would have been positive if they'd been able to accrue the trial. In the preliminary data set that they did disclose of that 110 patients, you know, it's clear there is a difference at a, you know, a landmark at a year. They showed a 16% difference, and that would be in line with what has been seen in stage III. And so, you know, I think it's really kind of too bad. There's really going to be no regulatory approach for this consideration. So using BRAF and MEK inhibition in stage II is not going to be part of standard practice moving into the future. To your point, though, about where will the field go? I think what we're already realizing is that in the adjuvant setting, we're really overtreating the total population. And so beyond merely staging by AJCC criteria, we need to move to biomarker selection to help inform which patients truly need the treatment. And in that regard, I don't think we've crystallized together as a field as yet, but the kinds of things that people are thinking about are the integration of molecular biomarkers like ctDNA. When it's positive, it can be very helpful, but in melanoma, we found that, unfortunately, the rates are quite low, you know, in the 10% to 15% range in the adjuvant setting. So then another consideration would be factors in the primary tumor, such as gene expression profiling or other considerations.  And so I think the future of adjuvant clinical trials will be an integration of both the standard AJCC staging system as well as some kind of overlaid molecular biomarker that helps to enrich for a higher-risk population of patients because on a high level, when you abstract out, it's just clearly the case that we're rather substantially overtreating the totality of the population, especially given that in all of our adjuvant studies to date for anti–PD-1, we have not yet shown that there's an overall survival advantage. And so some are even arguing perhaps we should even reserve treatment until patients progress. I think that's a complicated subject, and standard of care at this point is to offer adjuvant therapy, but certainly a lot more to do because many patients, you know, unfortunately, still do progress and move on to metastatic disease. Dr. Diwakar Davar: Let's transition to Abstract 2508. So we're moving on from the melanoma to the novel immunotherapy abstracts. And this is a very, very, very fascinating drug. It's IMA203. So Abstract 2508 is a phase 1 clinical update of IMA203. IMA203 is an autologous TCR-T construct targeting PRAME in patients with heavily pretreated PD-1-refractory metastatic melanoma. So Jason, in the PD-1 and CTLA-4-refractory settings, treatment options are either autologous TIL, response rate, you know, ballpark 29% to 31%, oncolytic viral therapy, RP1 with nivolumab, ORR about 30-ish percent. So new options are needed. Can you tell us a little bit about IMA203? Perhaps tell us for the audience, what is the difference between a TCR-T and traditional autologous TIL? And a little bit about this drug, IMA203, and how it distinguishes itself from the competing TIL products in the landscape. Dr. Jason Luke: I'm extremely enthusiastic about IMA203. I think that it really has transformative potential based on these results and hopefully from the phase 3 trial that's open to accrual now. So, what is IMA203? We said it's a TCR-T cell product. So what that means is that T cells are removed from a patient, and then they can be transduced through various technologies, but inserted into those T cells, we can then add a T-cell receptor that's very specific to a single antigen, and in this case, it's PRAME. So that then is contrasted quite a bit from the TIL process, which includes a surgical resection of a tumor where T cells are removed, but they're not specific necessarily to the cancer, and they're grown up in the lab and then given to the patient. They're both adoptive cell transfer products, but they're very different. One is genetically modified, and the other one is not. And so the process for generating a TCR-T cell is that patients are required to have a new biomarker that some may not be familiar with, which is HLA profiling. So the T-cell receptor requires matching to the concomitant HLA for which the peptide is bound in. And so the classic one that is used in most oncology practices is A*02:01 because approximately 48% of Caucasians have A*02:01, and the frequency of HLA in other ethnicities starts to become highly variable. But in patients who are identified to have A*02:01 genotype, we can then remove blood via leukapheresis or an apheresis product, and then insert via lentiviral transduction this T-cell receptor targeting PRAME. Patients are then brought back to the hospital where they can receive lymphodepleting chemotherapy and then receive the reinfusion of the TCR-T cells. Again, in contrast with the TIL process, however, these T cells are extremely potent, and we do not need to give high-dose interleukin-2, which is administered in the context of TIL. Given that process, we have this clinical trial in front of us now, and at ASCO, the update was from the phase 1 study, which was looking at IMA203 in an efficacy population of melanoma patients who were refractory at checkpoint blockade and actually multiple lines of therapy. So here, there were 33 patients and a response rate of approximately 50% was observed in this population of patients, notably with a duration of response approximately a year in that treatment group. And I realize that these were heavily pretreated patients who had a range of very high-risk features. And approximately half the population had uveal melanoma, which people may be aware is a generally speaking more difficult-to-treat subtype of melanoma that metastasizes to the liver, which again has been a site of resistance to cancer immunotherapy. So these results are extremely promising. To summarize them from what I said, it's easier to make TCR-T cells because we can remove blood from the patient to transduce the T cells, and we don't have to put them through surgery. We can then infuse them, and based on these results, it looks like the response rate to IMA203 is a little bit more than double what we expect from lifileucel. And then, whereas with lifileucel or TILs, we have to give high-dose IL-2, here we do not have to give high-dose IL-2. And so that's pretty promising. And a clinical trial is ongoing now called the SUPREME phase 3 clinical trial, which is hoping to validate these results in a randomized global study. Dr. Diwakar Davar: Now, one thing that I wanted to go over with you, because you know this trial particularly well, is what you think of the likelihood of success, and then we'll talk a little bit about the trial design. But in your mind, do you think that this is a trial that has got a reasonable likelihood of success, maybe even a high likelihood of success? And maybe let's contextualize that to say an alternative trial, such as, for example, the TebeAM trial, which is essentially a T-cell bispecific targeting GP100. It's being compared against SOC, investigator's choice control, also in a similarly heavily pretreated patient population. Dr. Jason Luke: So both trials, I think, have a strong chance of success. They are very different kinds of agents. And so the CD3 bispecific that you referred to, tebentafusp, likely has an effect of delaying progression, which in patients with advanced disease could have a value that might manifest as overall survival. With TCR-T cells, by contrast, we see a very high response rate with some of the patients going into very durable long-term benefit. And so I do think that the SUPREME clinical trial has a very high chance of success. It will be the first clinical trial in solid tumor oncology randomizing patients to receive a cell therapy as compared with a standard of care. And within that standard of care control arm, TILs are allowed as a treatment. And so it will also be the first study that will compare TCR-T cells against TILs in a randomized phase 3. But going back to the data that we've seen in the phase 1 trial, what we observe is that the duration of response is really connected to the quality of the response, meaning if you have more than a 50% tumor shrinkage, those patients do very, very well. But even in patients who have less than 50% tumor shrinkage, the median progression-free survival right now is about 4.5 months. And again, as we think about trial design, standard of care options for patients who are in this situation are unfortunately very bad. And the progression-free survival in that population is probably more like 2 months. So this is a trial that has a very high likelihood of being positive because the possibility of long-term response is there, but even for patients who don't get a durable response, they're likely going to benefit more than they would have based on standard chemotherapy or retreatment with an anti–PD-1 agent. Dr. Diwakar Davar: Really, a very important trial to enroll, a trial that is first in many ways. First of a new generation of TCR-T agents, first trial to look at cell therapy in the control arm, a new standard of efficacy, but potentially also if this trial is successful, it will also be a new standard of trial conduct, a new kind of trial, of a set of trials that will be done in the second-line immunotherapy-refractory space. So let's pivot to the last trial that we were going to discuss, which was Abstract 2501. Abstract 2501 is a first-in-human phase 1/2 trial evaluating BNT142, which is the first-in-class mRNA-encoded bispecific targeting Claudin-6 and CD3 in patients with Claudin-positive tumors. We'll talk a little bit about this, but maybe let's start by talking a little bit about Claudin-6. So Claudin-6 is a very interesting new target. It's a target that's highly expressed in GI and ovarian tumors. There are a whole plethora of Claudin-6-targeting agents, including T-cell bispecifics and Claudin-6-directed CAR-Ts that are being developed. But BNT142 is novel. It's a novel lipid nanoparticle LNP-encapsulated mRNA. The mRNA encodes an anti–Claudin-6 CD3 bispecific termed RiboMAB-021. And it then is administered to the patient. The BNT142-encoding mRNA LNPs are taken up by the liver and translated into the active drug. So Jason, tell us a little bit about this agent. Why you think it's novel, if you think it's novel, and let's talk a little bit then about the results. Dr. Jason Luke: So I certainly think this is a novel agent, and I think this is just the first of what will probably become a new paradigm in oncology drug development. And so you alluded to this, but just to rehash it quickly, the drug is encoded as genetic information that's placed in the lipid nanoparticle and then is infused into the patient. And after the lipid nanoparticles are taken up by the liver, which is the most common place that LNPs are usually taken up, that genetic material in the mRNA starts to be translated into the actual protein, and that protein is the drug. So this is in vivo generation, so the patient is making their own drug inside their body. I think it's a really, really interesting approach. So for any drug that could be encoded as a genetic sequence, and in this case, it's a bispecific, as you mentioned, CD3-Claudin-6 engager, this could have a tremendous impact on how we think about pharmacology and novel drug development moving into the future in oncology. So I think it's an extremely interesting drug, the like of which we'll probably see only more moving forward. Dr. Diwakar Davar: Let's maybe briefly talk about the results. You know, the patient population was heavily pretreated, 65 or so patients, mostly ovarian cancer. Two-thirds of the patients were ovarian cancer, the rest were germ cell and lung cancer patients. But let's talk a little bit about the efficacy. The disease control rate was about 58% in the phase 1 population as a whole, but 75% in the ovarian patient population. Now tell us a little bit about the interesting things about the drug in terms of the pharmacokinetics, and also then maybe we can pivot to the clinical activity by dose level. Dr. Jason Luke: Well, so they did present in their presentation at ASCO a proportionality showing that as higher doses were administered, that greater amounts of the drug were being made inside the patient. And so that's an interesting observation, and it's an important one, right? Suggesting that the pharmacology that we classically think of by administering drugs by IV, for example, would still be in play. And that did translate into some level of efficacy, particularly at the higher dose levels. Now, the caveat that I'll make a note of is that disease control rate is an endpoint that I think we have to be careful about because what that really means is sometimes a little bit unclear. Sometimes patients have slowly growing tumors and so on and so forth. And the clinical relevance of disease control, if it doesn't last at least 6 months, I think is probably pretty questionable. So I think these are extremely interesting data, and there's some preliminary sense that getting the dose up is going to matter because the treatment responses were mostly observed at the highest dose levels. There's also a caveat, however, that across the field of CD3 bispecific molecules like this, there's been quite a bit of heterogeneity in terms of the response rate, with some of them only really generating stable disease responses and other ones having more robust responses. And so I think this is a really interesting initial foray into this space. My best understanding is this molecule is not moving forward further after this, but I think that this really does set it up to be able to chase after multiple different drug targets on a CD3 bispecific backbone, both in ovarian cancer, but then basically across all of oncology. Dr. Diwakar Davar: Perfect. This is a very new sort of exciting arena where we're going to be looking at, in many ways, these programmable constructs, whether we're looking at in vivo-generated, in this case, a T-cell bispecific, but we've also got newer drugs where we are essentially giving drugs where people are generating in vivo CAR T, and also potentially even in vivo TCR-T. But certainly lots of new excitement around this entire class of drugs. And so, what we'd like to do at this point in time is switch to essentially the fact that we've got a very, very exciting set of data at ASCO 2025. You've heard from Dr. Luke regarding the advances in both early drug development but also in advanced cutaneous melanoma. And Jason, as always, thank you so much for sharing your very valuable and great, fantastic insights with us on the ASCO Daily News Podcast. Dr. Jason Luke: Well, thanks again for the opportunity. Dr. Diwakar Davar: And thank you to our listeners for taking your time to listen today. You will find the links to the abstracts that we discussed today in the transcript of this episode. And 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 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 Bluesky   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. Vamsi Velcheti and Dr. Nate Pennell discuss novel treatment approaches in small cell and non-small cell lung cancer that were featured at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host of the ASCO Daily News Podcast. I'm a professor of medicine and chief of hematology and oncology at the Mayo Clinic in Jacksonville, Florida. The 2025 ASCO Annual Meeting featured some exciting advancements in small cell lung cancer, targeted therapies for non-small cell lung cancer, and other novel [treatment] approaches. Today, I'm delighted to be joined by Dr. Nate Pennell to discuss some of the key abstracts that are advancing the lung cancer field. Dr. Pennell is the co-director of the Cleveland Clinic Lung Cancer Program and also the vice chair of clinical research at the Taussig Cancer Institute. Our full disclosures are available in the transcript of this episode. Nate, it's great to have you back on the podcast. Thanks so much for being here. Dr. Nate Pennell: Thanks, Vamsi. Always a pleasure. Dr. Vamsi Velcheti: Let's get started, and I think the first abstract that really caught my attention was Abstract 8516, “The Randomized Trial of Relevance of Time of Day of Immunotherapy for Progression-Free and Overall Survival in Patients With Non-Small Cell Lung Cancer.” What are your thoughts about this, Nate? Dr. Nate Pennell: I agree. I thought this was one of the most discussed abstracts, certainly in the lung cancer session, but I think even outside of lung cancer, it got some discussion. So, just to put this in perspective, there have been a number of publications that have all been remarkably consistent, and not just in lung cancer but across multiple cancer types, that immunotherapy, immune checkpoint inhibitors, are commonly used. And all of them have suggested, when looking at retrospective cohorts, that patients who receive immune checkpoint inhibitors earlier in the day – so in the morning or before the early afternoon – for whatever reason, appear to have better outcomes than those who get it later in the day, and this has been repeated. And I think many people just sort of assumed that this was some sort of strange association and that there was something fundamentally different from a prognostic standpoint in people who came in in the morning to get their treatment versus those who came later in the afternoon, and that was probably the explanation. The authors of this randomized trial actually decided to test this concept. And so, about 210 patients with previously untreated advanced non-small cell lung cancer were randomly assigned to get chemo and immune checkpoint inhibitor – either pembrolizumab or sintilimab – and half of them were randomly assigned to get the treatment before 3 PM in the afternoon, and half of them were assigned to get it after 3 PM in the afternoon. And it almost completely recapitulated what was seen in the retrospective cohorts. So, the median progression-free survival in those who got earlier treatment was 13.2 months versus only 6.5 months in those who got it later in the day. So, really enormous difference with a hazard ratio of 0.43, which was statistically significant. And perhaps even more striking, the median overall survival was not reached in the early group versus 17.8 months in the late group with a hazard ratio of 0.43, also highly statistically significant. Even the response rate was 20% higher in the early patients; 75% response rate compared to 56% in the late-time-of-day patients. So very consistent across all measures of efficacy with pretty good matched characteristics across the different groups. And so, I have to tell you, I don't know what to make of this. I certainly was a skeptic about the retrospective series, but now we have a prospective randomized trial that shows essentially the same thing. So, maybe there is a difference between getting treated in the morning, although I have yet to hear someone give a very good mechanistic explanation as to why this would be. What were your thoughts on this? Dr. Vamsi Velcheti: It's indeed fascinating, Nate, and I actually think this was a very interesting abstract. Really, I was caught off guard looking at the data. I mean, if it were a drug, we would be so excited, right? I mean, with those kind of survival benefits. I don't know. I think circadian rhythm probably has something to do with it, like different cytokine profiles at the time of administration. I mean, who knows? But I think it's a randomized trial, and I think I would expect to see a mad rush for treatment appointments early in the morning given this, and at least I want my patients to come in first thing in the morning. It'll be interesting to see. Dr. Nate Pennell: It's important to point out that in this study, everyone got chemo and immunotherapy. And, at least in our cancer center, most patients who are getting platinum-doublet chemotherapy and immunotherapy actually do get treated earlier in the day already, just because of the length of the infusion appointment that's needed. So it really is oftentimes people getting single-agent immunotherapy who are often getting the later, shorter visits. But if you have a choice, I think it would be very reasonable to have people treated earlier in the day. And I do think most of the impressions that I got from people about this is that they would like to see it reproduced but certainly well worth further investigation. And I personally would like to see more investigation into what the rationale would be for this because I still can't quite figure out, yes, if you got it at, say, you know, 5 PM, that's later in the day and I can understand that maybe your immune system is somewhat less receptive at that point than it would be in the morning. But because these checkpoint inhibitors have such long half-lives, it's still in your system the next morning when your immune system is supposedly more receptive. So I don't quite understand why that would be the case. Well, let's move on to the next study. I would like to hear your thoughts on Abstract 8515, “Plasma-Guided, Adaptive First-Line Chemoimmunotherapy for Non-Small Cell Lung Cancer.” Dr. Vamsi Velcheti: Yeah, this was another abstract that seems to be really interesting in my opinion. I think there's kind of a lot of emphasis lately on ctDNA and MRD-based assays to monitor disease. In the lung cancer space, we haven't had a lot of clinical trials looking at this prospectively, and this was one of those pilot studies where they looked at circulating free DNA (cfDNA)-based response-adaptive strategy for frontline patients who are PD-L1 positive. So, patients started with pembrolizumab monotherapy, and based on plasma molecular response after 2 cycles, those patients without response received early treatment intensification with a platinum doublet. So the approach essentially was to reduce the chemotherapy exposure in patients who respond to immunotherapy. And only about 17.5% of the patients on the trial received chemotherapy based on lack of molecular response. So, in this trial, what they found was patients with the cfDNA response had a markedly improved PFS of 16.4 months versus 4.8 months. So essentially, like, this is a really nice study to set a foundation on which we have to do larger studies to incorporate molecular markers trying to look at cfDNA response to inform treatment strategy, either escalation or de-escalation strategies. So, I thought it was a very interesting study. Dr. Nate Pennell: Yeah. I mean, we always have this question for patients, “Should they get immunotherapy alone or combined with chemo?” and I think this certainly is intriguing, suggesting that there may be ways you can monitor people and perhaps rescue those that aren't going to respond to single agent. I'd like to see a randomized trial against, you know, this strategy, perhaps against everyone getting, say, chemoimmunotherapy or make sure that you're not potentially harming people by doing this strategy. But I agree, it's time to move beyond just observing that cell-free DNA is prognostic and important and start using it to actually guide treatment. Dr. Vamsi Velcheti: Yeah, and I would just caution though, like, you know, I think we need more data, but, however, it's certainly a very interesting piece of data to kind of help inform future trials. So, there was another abstract that caught my attention, and I think this would be a very interesting abstract in the EGFR space. Abstract 8506, "Patritumab Deruxtecan (HER3-DXd) in Resistant EGFR-Mutant Advanced Non-Small Cell Lung Cancer Patients After Third-Generation EGFR TKI," it's the HERTHENA-Lung02 study. What do you think about the results of this study? Dr. Nate Pennell: Yeah, this was, I would say, very widely anticipated and ultimately a little disappointing, despite being a positive trial. So, these are patients with EGFR-mutant non-small cell lung cancer who have progressed after a third-generation EGFR TKI like osimertinib. This is really an area of major unmet need. We do have drugs like amivantamab in this space, but still definitely an area where essentially patients move from having a highly effective oral therapy to being in the realm of chemotherapy as their best option. So, this HER3 antibody-drug conjugate, patritumab deruxtecan, had some good single-arm data for this. And we're sort of hoping this would become an available option for patients. This trial was designed against platinum-doublet chemotherapy in this setting and with a primary endpoint of progression-free survival. And it actually was positive for improved progression-free survival compared to chemo with a hazard ratio of 0.77. But when you look at the medians, you can see that the median PFS was only 5.8 versus 5.4 months. It was really a modest difference between the two arms. And on the interim analysis, it appeared that there will not be a difference in overall survival between the two arms. In fact, the hazard ratio at the interim analysis was 0.98 for the two arms. So based on this, unfortunately, the company that developed the HER3-DXd has withdrawn their application to the FDA for approval of the drug, anticipating that they probably wouldn't get past approval without that overall survival endpoint. So, unfortunately, probably not, at least for the near future, going to be a new option for these patients. Dr. Vamsi Velcheti: Yeah, I think this is a space that's clearly an unmet need, and this was a big disappointment, I should say. I think all of us were going into the meeting anticipating some change in the standard of care here. Dr. Nate Pennell: Yeah, I agree. It was something that I was telling patients, honestly, that I was expecting this to be coming, and so now, definitely a bit of a disappointment. But it happens and, hopefully, it will still find perhaps a role or other drugs with a similar target. Certainly an active area. Well, let's leave the EGFR-mutant space and move into small cell. There were a couple of very impactful studies. And one of them was Abstract 8006, “Lurbinectedin Plus Atezolizumab as First-Line Maintenance Treatment in Patients With Extensive-Stage Small Cell Lung Cancer, Primary Results from the Phase III IMforte Trial.” So, what was your impression of this? Dr. Vamsi Velcheti: Yeah, I think this is definitely an interesting study, and small cell, I remember those days when we had barely any studies of small cell at ASCO, and now we have a lot of exciting developments in the small cell space. It's really good to see. The IMforte trial is essentially like a maintenance lurbinectedin trial with atezolizumab maintenance. And the study was a positive trial. The primary endpoint was a PFS, and the study showed improvement in both PFS and OS with the addition of lurbinectedin to atezolizumab maintenance. And definitely, it's a positive trial, met its primary endpoint, but I always am a little skeptical of adding maintenance cytotoxic therapies here in this setting. In my practice, and I'd like to hear your opinion, Nate, most patients with small cell after 4 cycles of a platinum doublet, they're kind of really beaten up. Adding more cytotoxic therapy in the maintenance space is going to be tough, I think, for a lot of patients. But also, most importantly, I think this rapidly evolving landscape for patients with small cell lung cancer with multiple new, exciting agents, actually like some FDA-approved like tarlatamab, also like a lot of these emerging therapeutics like I-DXd and other ADCs in this space. You kind of wonder, is it really optimal strategy to bring on like another cytotoxic agent right after induction chemotherapy, or do you kind of delay that? Or maybe have like a different strategy in terms of maintenance. I know that the tarlatamab maintenance trial is probably going to read out at some point too. I think it's a little challenging. The hazard ratio is also 0.73. As I said, it's a positive trial, but it's just incremental benefit of adding lurbi. And also on the trial, we need to also pay attention to the post-progression second-line treatments, number of patients who received tarlatamab or any other investigational agents.  So I think it's a lot of questions still. I'm not quite sure I'd be able to embrace this completely. I think a vast majority of my patients might not be eligible anyway for cytotoxic chemotherapy maintenance right away, but yeah, it's tough. Dr. Nate Pennell: Yeah. I would call this a single and not a home run. It definitely is real. It was a real overall survival benefit. Certainly not surprising that a maintenance therapy would improve progression-free survival. We've known that for a long time in small cell, but first to really show an overall survival benefit. But I completely agree with you. I mean, many people are not going to want to continue further cytotoxics after 4 cycles of platinum-doublet chemo. So I would say, for those that are young and healthy and fly through chemo without a lot of toxicity, I think certainly something worth mentioning. The problem with small cell, of course, is that so many people get sick so quickly while on that observation period after first-line chemo that they don't make it to second-line treatment. And so, giving everyone maintenance therapy essentially ensures everyone gets that second-line treatment. But they also lose that potentially precious few months where they feel good and normal and are able to be off of treatment. So, I would say this is something where we're really going to have to kind of sit and have that shared decision-making visit with patients and decide what's meaningful to them. Dr. Vamsi Velcheti: Yeah, I agree. The next abstract that was a Late-Breaking Abstract, 8000, “Overall Survival of Neoadjuvant Nivolumab Plus Chemotherapy in Patients With Resectable Non-Small Cell Lung Cancer in CheckMate-816.” This was a highly anticipated read-out of the OS data from 816. What did you make of this abstract? Dr. Nate Pennell: Yeah, I thought this was great. Of course, CheckMate-816 changed practice a number of years ago when it first reported out. So, this was the first of the neoadjuvant or perioperative chemoimmunotherapy studies in resectable non-small cell lung cancer. So, just to review, this was a phase 3 study for patients with what we would now consider stage II or stage IIIA resectable non-small cell lung cancer. And they received three cycles of either chemotherapy or chemotherapy plus nivolumab, and that was it. That was the whole treatment. No adjuvant treatment was given afterwards. They went to resection. And patients who received the chemoimmunotherapy had a much higher pathologic complete response rate and a much better event-free survival. And based on this, this regimen was approved and, I think, at least in the United States, widely adopted.  Now, since the first presentation of CheckMate 816, there have been a number of perioperative studies that have included an adjuvant component of immunotherapy – KEYNOTE-671, the AEGEAN study – and these also have shown improved outcomes. The KEYNOTE study with pembrolizumab also with an overall survival benefit. And I think people forgot a little bit about CheckMate-816. So, this was the 5-year overall survival final analysis. And it did show a statistically and, I think, clinically meaningful difference in overall survival with the 3 cycles of neoadjuvant chemo-nivo compared to chemo with a hazard ratio of 0.72. The 5-year overall survival of 65% in the chemo-IO group versus 55% with the chemo alone. So a meaningful improvement. And interestingly, that hazard ratio of 0.72 is very similar to what was seen in the peri-operative pembro study that included the adjuvant component. So, very much still relevant for people who think that perhaps the value of those neoadjuvant treatments might be really where most of the impact comes from this type of approach. They also gave us an update on those with pathologic complete response, showing really astronomically good outcomes. If you have a pathologic complete response, which was more than a quarter of patients, the long-term survival was just phenomenal. I mean, 95% alive at 5 years if they were in that group and suggesting that in those patients at least, the adjuvant treatment may not be all that important.  So, I think this was an exciting update and still leaves very much the open question about the importance of continuing immunotherapy after surgery after the neoadjuvant component. Dr. Vamsi Velcheti: Yeah, I completely agree, Nate. I think the million-dollar question is: “Is there like a population of patients who don't have complete response but like maybe close to complete response?” So, would you like still consider stopping adjuvant IO? I probably would not be comfortable, but I think sometimes, you know, we all have patients who are like very apprehensive of continuing treatments. So, I think that we really need more studies, especially for those patients who don't achieve a complete CR. I think trying to find strategies for like de-escalation based on MRD or other risk factors. But we need more trials in that space to inform not just de-escalation, but there are some patients who don't respond at all to a neoadjuvant IO. So, there may be an opportunity for escalating adjuvant therapies. So, it is an interesting space to watch out for. Dr. Nate Pennell: No, absolutely. Moving to KRAS-mutant space, so our very common situation in patients with non-small cell lung cancer, we had the results of Abstract 8500, “First-Line Adagrasib With Pembrolizumab in Patients With Advanced or Metastatic KRASG12C-Mutated Non-Small Cell Lung Cancer” from the phase 2 portion of the KRYSTAL-7 study. Why was this an interesting and important study? Dr. Vamsi Velcheti: First of all, there were attempts to kind of combine KRASG12C inhibitors in the past with immune checkpoint inhibitors, notably sotorasib with pembrolizumab. Unfortunately, those trials have led to like a lot of toxicity, with increased especially liver toxicity, which was a major issue. This is a phase 2 study of adagrasib in combination with pembrolizumab, and this is a study in the frontline setting in patients with the G12C-mutant metastatic non-small cell lung cancer. And across all the PD-L1 groups, the ORR was 44%, and the median PFS was 11 months, comparable to the previous data that we have seen with adagrasib in this setting. So it's not like a major improvement in clinical efficacy. However, I think the toxicity profile that we were seeing was slightly better than the previous trials in combination with sotorasib, but you still have a fair amount of transaminitis even in the study. At this point, this is not ready for clinical primetime. I don't think we should be using sotorasib or adagrasib in the frontline or even in the second line in combination with checkpoint inhibitors. Combining these drugs with checkpoint inhibitors in the clinical practice might lead to adverse outcomes. So, we need to wait for more data like newer-generation G12C inhibitors which are also being studied in combination, so we'll have to kind of wait for more data to emerge in this space. Dr. Nate Pennell: I agree, this is not immediately practice changing. This is really an attempt to try to combine targeted treatment with immune checkpoint inhibitor. And I agree with you that, you know, it does appear to be perhaps a little bit better tolerated than some of the prior combinations that have tried in this space. The outcomes overall were not that impressive, although in the PD-L1 greater than 50%, it did have a better response rate perhaps than you would expect with either drug alone. And I do think that the company is focusing on that population for a future randomized trial, which certainly would inform this question better. But in the meantime, I agree with you, there's a lot of newer drugs that are coming along that potentially may be more active and better tolerated. And so, I'd say for now, interesting but we'll wait and see. Dr. Vamsi Velcheti: Yeah, so now moving back again to small cell. So, there was a Late-Breaking Abstract, 8008. This is a study of tarlatamab versus chemotherapy as second-line treatment for small cell lung cancer. They presented the primary analysis of the phase III DeLLphi-304 study. What do you think about this? Dr. Nate Pennell: Yeah, I thought this was really exciting. This was, I would say, perhaps the most important lung study that was presented. Tarlatamab is, of course, the anti-DLL3 bispecific T-cell engager compound, which is already FDA approved based on a prior single-arm phase II study, which showed a very nice response rate as a single agent in previously treated small cell lung cancer and relatively manageable side effects, although somewhat unique to solid tumor docs in the use of these bispecific drugs in things like cytokine release syndrome and ICANS, the neurologic toxicities. So, this trial was important because tarlatamab was approved, but there were also other chemotherapy drugs approved in the previously treated space. And so, this was a head-to-head second-line competition comparison between tarlatamab and either topotecan, lurbinectedin, or amrubicin in previously treated small cell patients with a primary endpoint of overall survival. So, a very well-designed trial. And it did show, I think, a very impressive improvement in overall survival with a median overall survival in the tarlatamab group of 13.6 months compared to 8.3 months with chemotherapy, hazard ratio of 0.6. And progression-free survival was also longer at 4.2 months versus 3.2 months, hazard ratio of 0.72. In addition to showing improvements in cancer-related symptoms that were improved in tarlatamab compared to chemotherapy, there was actually also significantly lower rates of serious treatment-related adverse events with tarlatamab compared to chemotherapy. So, you do still see the cytokine release syndrome, which is seen in most people but is manageable because these patients are admitted to the hospital for the first two cycles, as well as a significant number of patients with neurologic side effects, the so-called ICANS, which also can be treated with steroids. And so, I think based upon the very significant improvement in outcomes, I would expect that this should become our kind of standard second-line treatment since it seems to be much better than chemo. However, tarlatamab is definitely a new drug that a lot of places are not used to using, and I think a lot of cancer centers, especially ones that aren't tied to a hospital, may have questions about how to deal with the CRS. So, I'm curious your thoughts on that. Dr. Vamsi Velcheti: Yeah, thank you, Nate. And I completely agree. I think the data looked really promising, and I've already been using tarlatamab in the second-line space. The durability of response and overall, having used tarlatamab quite a bit - like, I participated in some of the early trials and also used it as standard of care - tarlatamab has unique challenges in terms of like need for hospitalization for monitoring for the first few treatments and make sure, you know, we monitor those patients for CRS and ICANS. But once you get past that initial administration and monitoring of CRS, these patients have a much better quality of life, they're off chemotherapy, and I think it's really about the logistics of actually administering tarlatamab and coordination with the hospital and administration in the outpatient setting. It's definitely challenging, but I think it definitely can be done and should be done given what we are seeing in terms of clinical efficacy here. Dr. Nate Pennell: I agree. I think hospital systems now are just going to have to find a way to be able to get this on formulary and use it because it clearly seems to be more effective and generally better tolerated by patients. So, should move forward, I think. Finally, there's an abstract I wanted to ask you about, Abstract 8001, which is the “Neoadjuvant osimertinib with or without chemotherapy versus chemotherapy alone in resectable epidermal growth factor receptor-mutated non-small cell lung cancer: The NeoADAURA Study”. And this is one that I think was also fairly highly anticipated. So, what are your thoughts? Dr. Vamsi Velcheti: You know, I wasn't probably surprised with the results, and I believe we were all expecting a positive trial, and we certainly were handed a positive trial here. It's a phase III trial of osimertinib and chemotherapy or osimertinib in the neoadjuvant space followed by surgery, followed by osimertinib. It's a global phase 3 trial and very well conducted, and patients with stage II to stage IIIB were enrolled in the study. And in the trial, patients who had a neoadjuvant osimertinib with or without chemotherapy showed a significant improvement in major pathologic response rates over chemotherapy alone. And the EFS was also positive for osimertinib and chemotherapy, osimertinib monotherapy as well compared to chemotherapy alone. So overall, the study met its primary endpoint, and I think it sheds light on how we manage our patients with early-stage lung cancer. I think osimertinib, we know that osimertinib is already FDA approved in the adjuvant space, but what we didn't really know is how was osimertinib going to work in the neoadjuvant space. And there are always situations, especially for stage III patients, where we are on the fence about, are these patients already close to being metastatic? They have, like, almost all these patients have micrometastatic disease, even if they have stage III. As we saw in the LAURA data, when you look at the control arm, it was like a very short PFS. Chemoradiation does nothing for those patients, and I think these patients have systemic mets, either gross or micrometastatic disease at onset. So, it's really important to incorporate osimertinib early in the treatment course. And I think, especially for the locally advanced patients, I think it's even more important to kind of incorporate osimertinib in the neoadjuvant space and get effective local control with surgery and treat them with adjuvant. I'm curious to hear your thoughts, Nate. Dr. Nate Pennell: I am a believer and have long been a believer in targeted adjuvant treatments, and, you know, it has always bothered me somewhat that we're using our far and away most effective systemic therapy; we wait until after they go through all their pre-op treatments, they go through surgery, then they go through chemotherapy, and then finally months later, they get their osimertinib, and it still clearly improves survival in the adjuvant setting. Why not just start the osimertinib as soon as you know that the patient has EGFR-mutant non-small cell lung cancer, and then you can move on to surgery and adjuvant treatment afterwards? And I think what was remarkable about this study is that all of these patients almost - 90% in each arm - went to surgery. So, you weren't harming them with the neoadjuvant treatment. And clearly better major pathologic response, nodal downstaging, event-free survival was better. But I don't know that this trial is ever going to show an overall survival difference between neoadjuvant versus just surgery and adjuvant treatment, given how effective the drug is in the adjuvant setting. Nonetheless, I think the data is compelling enough to consider this, certainly for our N2-positive, stage IIIA patients or a IIIB who might be otherwise surgical candidates. I think based on this, I would certainly consider that. Dr. Vamsi Velcheti: Yeah, and especially for EGFR, like even for stage IIIB patients, in the light of the LAURA study, those patients who do not do too well with chemoradiation. So you're kind of delaying effective systemic therapy, as you said, waiting for the chemoradiation to finish. So I think probably time to revisit how we kind of manage these locally advanced EGFR patients. Dr. Nate Pennell: Yep, I agree. Dr. Vamsi Velcheti: Nate, thank you so much for sharing your fantastic insights today on the ASCO Daily News Podcast. It's been an exciting ASCO again. You know, we've seen a lot of positive trials impacting our care of non-small cell lung cancer and small cell lung cancer patients. Dr. Nate Pennell: Thanks for inviting me, Vamsi. Always a pleasure to discuss these with you. Dr. Vamsi Velcheti: And thanks to our listeners for your time today. You will find links to all of the abstracts discussed today in the transcript of the episode. Finally, if you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate, review, 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. More on today's speakers:    Dr. Vamsi Velcheti   @VamsiVelcheti    Dr. Nathan Pennell   @n8pennell   Follow ASCO on social media:     @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn   ASCO on BlueSky   Disclosures:   Dr. Vamsi Velcheti:   Honoraria: ITeos Therapeutics   Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus   Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline   Dr. Nathan Pennell:     Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron    Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi 

hour one: "I want to talk about you" (live excerpt from olympia theatre, paris, france, nov. 18, 1961) john coltrane w/eric dolphy "candy coloured catastrophe" redd kross "stunt queen" redd kross "and I muddled all the ins" position normal "the main attraction" redd kross "19th man to fly an airplane" guided by voices "cancion enojada" redd kross "what`s your safeword?" lum and the insterstellar fornicators "goodtimes propaganda band" redd kross "people like beets" immr "what's in it for you" redd kross hour two: "I'll take your word for it" redd kross "pink" dead bandit "dubbing psycho thriller" dub syndicate "terrible band" redd kross "west coast turnaround" pompous iguana "products throughout the store" (live) stick against stone "stuff" redd kross "back of the cave" redd kross "at play" minibeast "stool confederacy" (excerpt) eugene chadbourne "too good to be true" redd kross "father of africa (tribute to mandela)" brother max "20200609" justin von strasburg "way too happy" redd kross hour thee: "simple magic" redd kross "a service of song" (lyrics by emily dickenson) crane "spirit 30" (11 november 1984 prac at quinn’s house in pacific palisades, ca) treacherous jaywalkers "the witches stand" redd kross "aniara" (act I canto IIIa) relay station + david dellacroce + hatsune miku & friends + oona pearsons symfauxnic partchchestra "butcher of the past" godammit tommy! "lay down and die" redd kross "the shaman's disappearing robe" redd kross "gimmee pop-pop mantra tantra" bomis prendin "the bullet of pain" samuel locke-ward "emanuelle insane" redd kross "lost art of letting go" the twerks "1_0_toques 02" (excerpt) hubbard-liebig "born innocent" redd kross

Drs. Vamsi Velcheti and Nathan Pennell discuss novel approaches and key studies in lung cancer that were showcased at the 2024 ASCO Annual Meeting, including the Plenary abstracts LAURA and ADRIATIC.   TRANSCRIPT Dr. Vamsi Velcheti: Hello, I am Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic medical oncology at the Perlmutter Cancer Center at NYU Langone Health. Today, I'm joined by Dr. Nate Pennell, the co-director of the Cleveland Clinic Lung Cancer Program and the vice chair of clinical research at the Taussig Cancer Center in Cleveland Clinic. Dr. Pennell is also the editor-in-chief of the ASCO Educational Book. Today, we will be discussing practice-changing abstracts and the exciting advances in lung cancer that were featured at the ASCO 2024 Annual Meeting. You'll find our full disclosures in the transcript of the episode. Nate, we're delighted to have you back on the podcast today. Thanks for being here. It was an exciting Annual Meeting with a lot of important updates in lung cancer. Dr. Nate Pennell: Thanks, Vamsi. I'm glad to be back. And yes, it was a huge year for lung. So I'm glad that we got a chance to discuss all of these late-breaking abstracts that we didn't get to talk about during the prelim podcast. Dr. Vamsi Velcheti: Let's dive in. Nate, it was wonderful to see all the exciting data, and one of the abstracts in the Plenary Session caught my attention, LBA3. In this study, the investigators did a comparative large-scale effectiveness trial of early palliative care delivered via telehealth versus in-person among patients with advanced non-small cell lung cancer. And the study is very promising. Could you tell us a little bit more about the study and your take-home messages? Dr. Nate Pennell: Yes, I think this was a very important study. So just to put things in perspective, it's now been more than a decade since Dr. Jennifer Temel and her group at Massachusetts General Hospital did a randomized study that showed that early interventions with palliative medicine consultation in patients with advanced non-small cell lung cancer significantly improves quality of life and in her initial study, perhaps even overall survival. And since then, there have been numerous studies that have basically reproduced this effect, showing that getting palliative medicine involved in people with advanced cancer, multiple different cancer types, really, has benefits.  The difficulty in applying this has been that palliative care-trained specialists are few and far between, and many people simply don't have easy access to palliative medicine-trained physicians and providers. So with that in mind, Dr. Temel and her group designed a randomized study called the REACH PC trial, where 1,250 patients were randomized with advanced non-small cell lung cancer to either in-person palliative medicine visits which is sort of the standard, or one in-person assessment followed by monthly telemedicine video visits with palliative medicine. Primary endpoint was essentially to show that it was equivalent in terms of quality of life and patient satisfaction. And what was exciting about this was that it absolutely was. I mean, pretty much across the board in all the metrics that were measured, the quality-of-life, the patient satisfaction, the anxiety and depression scores, all were equivalent between doing telemedicine visits and in-person visits. And this hopefully will now extend the ability to get this kind of benefit to a much larger group of people who don't have to geographically be located near a palliative medicine program. Dr. Vamsi Velcheti: Yeah, I think it's a great abstract, Nate and I actually was very impressed by the ASCO committee for selecting this for the Plenary. We typically don't see supportive care studies highlighted in such a way at ASCO. This really highlights the need for true interdisciplinary care for our patients. And as you said, this study will clearly address that unmet need in terms of providing access to palliative care for a lot of patients who otherwise wouldn't have access. I'm really glad to see those results. Dr. Nate Pennell: It was. And that really went along with Dr. Schuchter's theme this year of bringing care to patients incorporating supportive care. So I agree with you.  Now, moving to some of the other exciting abstracts in the Plenary Session. So we were talking about how this was a big year for lung cancer. There were actually 3 lung cancer studies in the Plenary Session at the Annual Meeting. And let's move on to the second one, LBA4, the LAURA study. This was the first phase 3 study to assess osimertinib, an EGFR tyrosine kinase inhibitor, in patients with EGFR mutant, unresectable stage III non-small cell lung cancer. What are your takeaways from this study?  Dr. Vamsi Velcheti: This is certainly an exciting study, and all of us in the lung community have been kind of eagerly awaiting the results of the study. As you know, for stage III non-small cell lung cancer patients who are unresectable, the standard of care has been really established by the PACIFIC study with the consolidation durvalumab after definitive concurrent chemoradiation. The problem with that study is it doesn't really answer the question of the role of immunotherapy in patients who are never-smokers, and especially in patients who are EGFR positive tumors, where the role of immunotherapy in a metastatic setting has always been questioned. And in fact, there have been several studies as you know, in patients with EGFR mutation positive metastatic lung cancer where immunotherapy has not been that effective. In fact, in the subgroup analysis in the PACIFIC study, patients with EGFR mutation did not really benefit from adding immunotherapy.  So this is an interesting study where they looked at patients with locally advanced, unresectable stage III patients and they randomized the patients 2:1 to osimertinib versus placebo following concurrent or sequential tumor radiation. The primary endpoint for the study was progression free survival, and a total of 216 patients were enrolled and 143 patients received a study treatment, which is osimertinib, and 73 received placebo. And 80% of the patients on the placebo arm crossed over to getting treatment at the time of progression.  So most of us in the lung cancer community were kind of suspecting this would be a positive trial for PFS. But however, I think the magnitude of the difference was truly remarkable. The median PFS in the osimertinib arm was 39.1 months and placebo was 5.6 months and the hazard ratio of 0.16. So it was a pretty striking difference in terms of DFS benefit with the osimertinib consolidation following chemoradiation. So it was truly a positive study for the primary endpoint and the benefit was seen across all the subgroups and the safety was no unexpected safety signals other than a slight increase in the radiation pneumonitis rates in patients receiving osimertinib and other GI and skin tox were kind of as expected. In my opinion, it's truly practice changing and I think patients with EGFR mutation should not be getting immunotherapy consolidation post chemoradiation. Dr. Nate Pennell: I completely agree with you. I think that this really just continues the understanding of the use of osimertinib in EGFR-mutant lung cancer in earlier stages of disease. We know from the ADAURA trial, presented twice in the Plenary at the ASCO Annual Meeting, that for IB, stage II and resectable IIIA, that you prolong progression free or disease free survival. So this is a very similar, comparable situation, but at an even higher risk population or the unresectable stage III patients. I think that the most discussion about this was the fact that the osimertinib is indefinite and that it is distinct from the adjuvant setting where it's being given for three years and then stopped. But I think all of us had some pause when we saw that after three years, especially in the stage III patients from ADAURA, that there were clearly an increase in recurrences after stopping the drug, suggesting that there are patients who are not cured with a time limited treatment, or at least with 3 years of treatment.  The other thing that is sobering from the study, and was pointed out by the discussant, Dr. Lecia Sequist, is if you look at the two-year disease-free survival in the placebo arm, it was only 13%, meaning almost no one was really cured with chemo radiation alone. And that really suggests that this is not that different from a very early stage IV population where indefinite treatment really is the standard of care. I wonder whether you think that's a reasonable approach. Dr. Vamsi Velcheti: I completely agree with you, Nate, and I don't think we cure a majority of our patients with stage III, and less so in patients who have EGFR-mutant, stage III locally advanced. As you just pointed out, I think very few patients actually make it that far along. And I think there's a very high rate of CNS micrometastatic disease or just systemic micrometastatic disease in this population that an effective systemic therapy of osimertinib can potentially have long term outcomes. But again, we perhaps don't cure a vast majority of them. I think that the next wave of studies should incorporate ctDNA and MRD-based assays to potentially identify those patients who could potentially go off osimertinib at some point. But, again, outside of a trial, I would not be doing that. But I think it's definitely an important question to ask to identify de-escalation strategies with osimertinib. And even immunotherapy for that matter, I think we all know that not all patients really require years and years of immunotherapy. They're still trying to figure out how to use immunotherapy in these post-surgical settings, using the MRD to de-escalate adjuvant therapies. So I think we have to have some sort of strategy here. But outside of a clinical trial, I will not be using those assays here to cite treatments, but certainly an important question to ask.  Moving on to the other exciting late-breaking abstracts, LBA5, the ADRIATIC study. This is another study which was also in the plenary session. This study was designed to address this question of consolidation immunotherapy, post chemo radiation for limited-stage small cell cancer, the treatment arms being durvalumab tremelimumab, and durvalumab observation. So what do you think about the study? This study also received a lot of applause and a lot of attention at the ASCO meeting. Dr. Nate Pennell: It was. It was remarkable to be there and actually watch this study as well as the LAURA study live, because when the disease free survival curves and in the ADRIATIC study, the overall survival curves were shown, the speakers were both interrupted by standing ovation of applause just because there was a recognition that the treatment was changing kind of before our eyes. I thought that was really neat. So in this case, I think this is truly a historic study, not necessarily because it's going to necessarily be an earth shakingly positive study. I mean, it was clearly a positive study, but more simply because of the disease in which it was done, and that is limited-stage small cell lung cancer. We really have not had a change in the way we've treated limited-stage small cell lung cancer, probably 25 years. Maybe the last significant advances in that were the advent of concurrent chemotherapy and radiation and then the use of PCI with a very modest improvement in survival. Both of those, I would say, are still relatively modest advances.  In this case, the addition of immunotherapy, which we know helps patients with small cell lung cancer - it's of course the standard of care in combination chemotherapy for extensive stage small cell lung cancer - in this case, patients who completed concurrent chemo radiation were then randomized to either placebo or durvalumab, as well as the third arm of durvalumab tremelimumab, which is not yet been recorded, and co primary endpoints were overall survival and progression free survival. And extraordinarily, there was an improvement in overall survival seen at the first analysis, with a median overall survival of 55.9 months compared to 33.4 months, hazard ratio of 0.73. So highly clinically and statistically significant, that translates at three years to a difference in overall survival of 56.5%, compared to 47.6%, or almost 10% improvement in survival at three years.  There was also a nearly identical improvement in progression-free survival, also with a hazard ratio of 0.76, suggesting that there's a modest number of patients who benefit. But it seems to be a clear improvement with the curves plateauing out. In my opinion, this is very comparable to what we saw with the PACIFIC study in stage III, unresectable non-small cell lung cancer, which immediately changed practice back when that first was reported. And I expect that this will change practice pretty much immediately for small cell as well. Dr. Vamsi Velcheti: Yeah, I completely agree, Nate. I think it's an exciting advance in patients with limited-stage small cell lung cancer. For sure, it's practice-changing, and I think the results were exciting.  So one thing that really intrigued me was in the extensive-stage setting, the benefit was very mediocre with one-to-two month overall survival benefit in both the PACIFIC and in IMpower trial. Here we are seeing almost two-year of median OS benefit. I was kind of puzzled by that, and I thought it may have to do with patients receiving radiation. And we've seen that with the PACIFIC, and makes you wonder if both the CASPIAN and the IMpower studies actually did not allow consolidation thoracic radiation. Hypothetically, if they had allowed consolidation thoracic radiation, perhaps we would have seen better outcomes. Any thoughts on that? Dr. Nate Pennell: We've been trying to prove that radiation and immunotherapy somehow go together better for a long time. Going back to the first description of the abscopal effect, and I'm not sure if I necessarily believe that to be the case, but in this setting where we truly are trying to cure people rather than merely prolong their survival, maybe this is the situation where it truly is more beneficial. I think what we're seeing is something very similar to what we're seen in PACIFIC, where in the stage IV setting, some people have long term survival with immunotherapy, but it's relatively modest. But perhaps in the curative setting, you're seeing more of an impact. Certainly, looking at these curves, we'll have to see with another couple of years to follow up. But a three-year survival of 56% is pretty extraordinary, and I look forward to seeing if this really maintains over the next couple of years follow up.  Moving beyond the Plenary, there were actually lots of really exciting presentations, even outside the Plenary section. One that I think probably got at least as much attention as the ones that we've already discussed today was actually an update of an old trial that's been presented for several prior years. And I'm curious to get your take on why you thought this was such a remarkable study. And we're talking about the LBA8503, which was the 5-year update from the CROWN study, which looked at previously untreated ALK-positive advanced non-small cell in cancer patients randomly assigned to lorlatinib, the third generation ALK inhibitor, versus crizotinib, the first generation ALK inhibitor. What was so exciting about this study, and why were people talking about it?  Dr. Vamsi Velcheti: Yeah, I agree, Nate. We've seen the data in the past, right? Like on the CROWN data, just first like a quick recap. This is the CROWN study, like the phase 3 study of third generation ALK inhibitor lorlatinib. So global randomized phase 3 study in patients with metastatic disease randomized to lorlatinib versus crizotinib, which is a controller. So the primary endpoint was PFS, and we've seen the results in the past of the CROWN readout quoted, with a positive study and the lorlatinib received FDA approval in the frontline setting. But the current study that was presented at the ASCO annual meeting is a kind of a postdoc analysis of five years. The endpoint for the study with central review stopped at three years, and this is actually a follow up beyond that last readout. Interestingly, in this study, when they looked at the median PFS at five years, the lorlatinib arm did not reach a median PFS even at five years and the hazard ratio is 0.19, which is kind of phenomenal in some ways. At 5 years, the majority of the patients were still on the drug. So that's quite incredible. And the benefit was more profound in patients with brain mets with a hazard ratio of 0.08. And again, speaking to the importance of brain penetrant, small molecule inhibitors, and target therapy, the safety profile, there were no additional safety signals noted in the study. We kind of know about the side effects of lorlatinib already from previous studies readouts. No unusual long-term toxicities.  I should note though, about 40% of patients did have CNS, AEs grade 1, 2 CNS toxicities on the  lorlatinib arm. And the other interesting thing that was also reported in the trial was dose reduction of lorlatinib did not have an impact on the PFS, which is interesting in my opinion. They also did some subgroup analysis, biomarker testing, biomarker populations. Patients who had P53 cooperation did much better with lorlatinib versus crizotinib. So overall, the other thing that they also had shown on the trial was the resistance mechanisms that were seen with lorlatinib were very different than what we are used to seeing with the earlier generation ALK inhibitors. The majority of the patients who develop resistance have bypass mechanisms and alterations in MAP kinase pathway PI3K/MTOR/PTEN pathway, suggesting that lorlatinib is a very potent ALK inhibitor and on target ALK mutations don't happen as frequently as we see with the earlier generation ALK inhibitors.  So I think this really begs the question, should we offer lorlatinib to all our patients with metastatic ALK-positive tumors? I think looking at the long-term data, it's quite tempting to say ‘yes', but I think at the same time we have to take into consideration patient safety tolerability. And again, the competitor arm here is crizotinib. So lorlatinib suddenly seems to be, again, cross trial comparisons, but I think the long-term outcomes here are really phenomenal. But at the same time, I think we've got to kind of think about patient because these patients are on these drugs for years, they have to live with all the toxicities. And I think the patient preferences and safety profile matters in terms of what drug we recommend to patients. Dr. Nate Pennell: I completely agree with you. I think the right answer, is that this has to be an individual discussion with patients. The results are incredibly exciting. I mean, the two-year progression free survival was 70%, and the five-year, three years later is still 60%. Only 10% of people are failing over the subsequent three years. And the line is pretty flat. And as you said, even with brain metastases, the median survival is in reach. It's really extraordinary. Moreover, while we do talk about the significant toxicities of lorlatinib, I thought it was really interesting that only 5% of people were supposedly discontinued the drug because of treatment related AEs, which meant that with dose reduction and management, it seems as though most patients were able to continue on the drug, even though they, as you mentioned, were taking it for several years.  That being said, all of us who've had experience with the second-generation drugs like alectinib and brigatinib, compared to the third-generation drug lorlatinib, can speak to the challenges of some of the unique toxicities that go along with it. I don't think this is going to be a drug for everyone, but I do think it is now worth bringing it up and discussing it with the patients most of the time now. And I do think that there will be many people for whom this is going to be a good choice, which is exciting. Dr. Vamsi Velcheti: Absolutely, completely agree. And I think there are newer ALK inhibitors in clinical development which have cleaner and better safety profiles. So we'll have to kind of wait and see how those pan out.  Moving on to the other exciting abstract, LBA8509, the KRYSTAL-12 study. LBA8509 is a phase 3 study looking at adagrasib versus docetaxel in patients with previously treated advanced metastatic non-small cell cancer with KRASG12C mutation. Nate, there's been a lot of hype around this trial. You've seen the data. Do you think it's practice-changing? How does it differentiate with the other drug that's already FDA approved, sotorasib?  Dr. Nate Pennell: Yeah, this is an interesting one. I think we've all been very excited in recent years about the identification of KRASG12C mutations as targetable mutations. We know that this represents about half of KRAS mutations in patients with non-small cell lung cancer, adenocarcinoma, and there are two FDA-approved drugs. Sotorasib was the first and adagrasib shortly thereafter. We already had seen the CodeBreaK 200 study, which was a phase 3 study of sotorasib versus docetaxel that did modestly prolong progression free survival compared to docetaxel, although did not seem to necessarily translate to an improvement in overall survival. And so now, coming on the heels of that study, the KRYSTAL-12 study compared adagrasib, also the KRASG12C  inhibitor versus docetaxel and those with previously treated non-small cell with KRASG12C. And it did significantly improve progression free survival with a hazard ratio of 0.58. Although when you look at the median numbers, the median PFS was only 5.5 months with the adagrasib arm compared to 3.8 months with docetaxel. So while it is a significant and potentially clinically significant difference, it is still, I would say a modest improvement.   And there were some pretty broad improvements across all the different subgroups, including those with brain metastases. It did improve response rate significantly. So 32% response rate without adagrasib, compared to only 9% with docetaxel. It's about what you would expect with chemotherapy. And very importantly, in this patient population, there was activity in the brain with an intracranial overall response rate among those who had measurable brain metastases of 40%. So certainly important and probably that would distinguish it from drugs like docetaxel, which we don't expect to have a lot of intracranial toxicity. There is certainly a pattern of side effects that go along with that adagrasib, so it does cause especially GI toxicity, like diarrhea, nausea, vomiting, transaminitis. All of these were actually, at least numerically, somewhat higher in the adagrasib arm than in docetaxel, a lot more hematologic toxicity with the docetaxel. But overall, the number of serious adverse events were actually pretty well matched between the two groups. So it wasn't really a home run in terms of favorable toxicity with that adagrasib.  So the question is: “In the absence of any data yet on overall survival, should this change practice?” And I'm not sure it's going to change practice, because I do think that based on the accelerated approval, most physicians are already offering the G12C inhibitors like sotorasib and adagrasib, probably more often than chemotherapy, I think based on perceived improvement in side effects and higher response rates, modestly longer progression-free survival, so I think most people think that represents a modest improvement over chemotherapy. And so I think that will continue. It will be very interesting, however, when the overall survival report is out, if it is not significantly better, what the FDA is going to do when they look at these drugs.  Dr. Vamsi Velcheti: Thanks so much. Very well summarized. And I do agree they look more similar than dissimilar. I think CodeBreaK-200 and the KRYSTAL-12, they kind of are very identical. I should say, though I was a little surprised with the toxicity profile of adagrasib. It seemed, I mean, not significantly, but definitely seemed worse than the earlier readouts that we've seen. The GI tox especially seems much worse on this trial. I'm kind of curious why, but if I recall correctly, I think 5% of the patients had grade 3 diarrhea. A significant proportion of patients had grade 3 nausea and vomiting. And the other complicating thing here is you can't use a lot of the antiemetics because of the QT issues. So that's another problem. But I think it's more comparable to sotorasib, in my opinion.  Dr. Nate Pennell: While this is exciting, I like to think of this as the early days of EGFR, when we were using gefitinib and erlotinib. They were certainly advances, but we now have drugs that are much more effective and long lasting in these patients. And I think that the first-generation inhibitors like sotorasib and adagrasib, while they certainly benefit patients, now is just the beginning. There's a lot of research going on, and we're not going to talk about some of the other abstracts presented, but some of the next generation G12C inhibitors, for example, olomorasib, which did have also in the same session, a presentation in combination with pembrolizumab that had a very impressive response rate with potentially fewer side effects, may end up replacing the first generation drugs when they get a little bit farther along. And then moving on to another one, which I think potentially could change practice. I am curious to hear your take on it, was the LBA8505, which was the PALOMA-3 study. This was interesting in that it compared two different versions of the same drug. So amivantamab, the bispecific, EGFR and MET, which is already approved for EGFR exon 20 non-small cell lung cancer, in this case, in more typical EGFR-mutated non-small cell lung cancer in combination with osimertinib with the intravenous amivantamab, compared to the subcutaneous formulation of amivantamab. Why would this be an important study? Dr. Vamsi Velcheti: I found this study really interesting as well, Nate. And as you know, amivantamab has been FDA approved for patients with exon 20 mutation. And also, we've had, like two positive readouts in patients with classical EGFR mutations. One, the MARIPOSA study in the frontline setting and the MARIPOSA-2, in the second-line post osimertinib setting. For those studies, the intravenous amivantamab was used as a treatment arm, and the intravenous amivantamab had a lot of baggage to go along with it, like the infusion reactions and VTEs and other classic EGFR related toxicity, skin toxicities. So the idea behind developing the subcutaneous formulation of amivantamab was mainly to reduce the burden of infusion, infusion time and most importantly, the infusion related reactions associated with IV formulation.  In a smaller phase 2 study, the PALOMA study, they had looked at various dosing schemas like, subcutaneous formulation, and they found that the infusion related reactions were very, very low with the subcutaneous formulation. So that led to the design of this current study that was presented, the PALOMA-3 study. This was for patients who had classical EGFR mutations like exon 19, L858R. The patients were randomized 1:1 to subcutaneous amivantamab with lazertinib versus IV amivantamab plus lazertinib. The endpoints for the study, it's a non-inferiority study with co primary endpoints of C trough and C2 AUC, Cycle 2 AUC. They were looking at those pharmacological endpoints to kind of demonstrate comparability to the IV formulation. So in this study, they looked at these pharmacokinetic endpoints and they were essentially identical. Both subcutaneous and IV formulations were compatible. And in terms of clinical efficacy as well, the response rate was identical, no significant differences. Duration of response was also identical. The PFS also was comparable to the IV formulation. In fact, numerically, the subcutaneous arm was a little better, though not significant. But it appears like, you know, the overall clinical and pharmacological profile of the subcutaneous amivantamab was comparable. And most interestingly, the AE profile, the skin toxicity was not much different. However, the infusion reactions were substantially lower, 13% with the subcutaneous amivantamab and 66% with IV amivantamab. And also, interestingly, the VTE rates were lower with the subcutaneous version of amivantamab. There was still a substantial proportion of patients, especially those who didn't have prophylactic anticoagulation. 17% of the patients with the subcutaneous amivantamab had VTE versus 26% with IV amivantamab. With prophylaxis, which is lower in both IV and subcutaneous, but still subcutaneous formulation at a lower 7% versus 12% with the IV amivantamab.  So overall, I think this is an interesting study, and also the authors had actually presented some interesting data on administration time. I've never seen this before. Patients reported convenience using a modified score of patient convenience, essentially like patients having to spend a lot of time in the infusion site and convenience of the patient getting the treatment. And it turns out, and no surprise, that subcutaneous amivantamab was found to be more convenient for patients.  So, Nate, I want to ask you your take on this. In a lot of our busy infusion centers, the time it takes for those patients to get the infusion does matter, right? And I think in our clinic where we are kind of fully booked for the infusion, I think having the patients come in and leave in 15, 20 minutes, I think it adds a lot of value to the cancer center operation.  Dr. Nate Pennell: Oh, I completely agree. I think the efficacy results were reassuring. I think the infusion related reaction difference, I think is a huge difference. I mean, I have given a fair amount of amivantamab, and I would say the published IRR rate of 66%, 67% I would say, is maybe even underestimates how many patients get some kind of reaction from that, although it really is a first dose phenomenon. And I think that taking that down to 13% is a tremendous advance. I think fusion share time is not trivial as we get busier and busier. I know our cancer center is also very full and it becomes challenging to schedule people, and being able to do a five-minute treatment versus a five-hour treatment makes a big difference for patients.  It's interesting, there was one slide that was presented from an efficacy standpoint. I'm curious about your take on this. They showed that the overall survival was actually better in the subcu amivantamab arm, hazard ratio of 0.62. Now, this was only an exploratory endpoint. They sort of talk about perhaps some rationale for why this might be the case. But at the very least, I think we can be reassured that it's not less effective to give it and does seem to be more tolerable and so I would expect that this hopefully will be fairly widely adopted. Dr. Vamsi Velcheti: Yeah, I agree. I think this is a welcome change. Like, I think the infusion reactions and the resources it takes to get patients through treatments. I think it's definitely a win-win for patients and also the providers.  And with that, we come to the conclusion of the podcast. Nate, thank you so much for the fantastic insights today. Our listeners will find all the abstracts discussed today in the transcripts of the episode. Thank you so much for joining us today, Dr. Pennell.  Dr. Nate Pennell: Oh, thanks for inviting me. It's always fun to talk about all these exciting advances for our patients. Dr. Vamsi Velcheti: Thanks to our listeners for your time today. You will find links to all the abstracts discussed today in the transcript of the episode. Finally, if you value the insights that you hear from 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. Vamsi Velcheti  @VamsiVelcheti    Dr. Nathan Pennell  @n8pennell    Follow ASCO on social media:      @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:  Dr. Vamsi Velcheti:  Honoraria: ITeos Therapeutics  Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus  Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline  Dr. Nathan Pennell:    Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron   Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi

Original by Leopold Aschenbrenner, this summary is not commissioned or endorsed by him. Short Summary Extrapolating existing trends in compute, spending, algorithmic progress, and energy needs implies AGI (remote jobs being completely automatable) by ~2027. AGI will greatly accelerate AI research itself, leading to vastly superhuman intelligences being created ~1 year after AGI. Superintelligence will confer a decisive strategic advantage militarily by massively accelerating all spheres of science and technology. Electricity use will be a bigger bottleneck on scaling datacentres than investment, but is still doable domestically in the US by using natural gas. AI safety efforts in the US will be mostly irrelevant if other actors steal the model weights of an AGI. US AGI research must employ vastly better cybersecurity, to protect both model weights and algorithmic secrets. Aligning superhuman AI systems is a difficult technical challenge, but probably doable, and we must devote lots of [...] ---Outline:(00:13) Short Summary(02:16) 1. From GPT-4 to AGI: Counting the OOMs(02:24) Past AI progress(05:38) Training data limitations(06:42) Trend extrapolations(07:58) The modal year of AGI is soon(09:30) 2. From AGI to Superintelligence: the Intelligence Explosion(09:37) The basic intelligence explosion case(10:47) Objections and responses(14:07) The power of superintelligence(16:29) III The Challenges(16:32) IIIa. Racing to the Trillion-Dollar Cluster(21:12) IIIb. Lock Down the Labs: Security for AGI(21:20) The power of espionage(22:24) Securing model weights(24:01) Protecting algorithmic insights(24:56) Necessary steps for improved security(26:50) IIIc. Superalignment(29:41) IIId. The Free World Must Prevail(32:41) 4. The Project(35:12) 5. Parting Thoughts(36:17) Responses to Situational AwarenessThe original text contained 1 footnote which was omitted from this narration. --- First published: June 8th, 2024 Source: https://forum.effectivealtruism.org/posts/zmRTWsYZ4ifQKrX26/summary-of-situational-awareness-the-decade-ahead --- Narrated by TYPE III AUDIO. ---Images from the article:Apple Podcasts and Spotify do not show images in the episode description. Try Pocket Casts, or another podcast app.

Original by Leopold Aschenbrenner, this summary is not commissioned or endorsed by him. Short Summary Extrapolating existing trends in compute, spending, algorithmic progress, and energy needs implies AGI (remote jobs being completely automatable) by ~2027. AGI will greatly accelerate AI research itself, leading to vastly superhuman intelligences being created ~1 year after AGI. Superintelligence will confer a decisive strategic advantage militarily by massively accelerating all spheres of science and technology. Electricity use will be a bigger bottleneck on scaling datacentres than investment, but is still doable domestically in the US by using natural gas. AI safety efforts in the US will be mostly irrelevant if other actors steal the model weights of an AGI. US AGI research must employ vastly better cybersecurity, to protect both model weights and algorithmic secrets. Aligning superhuman AI systems is a difficult technical challenge, but probably doable, and we must devote lots of [...] ---Outline:(00:12) Short Summary(02:16) 1. From GPT-4 to AGI: Counting the OOMs(02:23) Past AI progress(05:37) Training data limitations(06:41) Trend extrapolations(07:57) The modal year of AGI is soon(09:29) 2. From AGI to Superintelligence: the Intelligence Explosion(09:36) The basic intelligence explosion case(10:46) Objections and responses(14:06) The power of superintelligence(16:28) III The Challenges(16:31) IIIa. Racing to the Trillion-Dollar Cluster(20:58) IIIb. Lock Down the Labs: Security for AGI(21:05) The power of espionage(22:09) Securing model weights(23:46) Protecting algorithmic insights(24:41) Necessary steps for improved security(26:35) IIIc. Superalignment(29:15) IIId. The Free World Must Prevail(32:15) 4. The Project(34:47) 5. Parting Thoughts(35:51) Responses to Situational AwarenessThe original text contained 1 footnote which was omitted from this narration. --- First published: June 8th, 2024 Source: https://forum.effectivealtruism.org/posts/zmRTWsYZ4ifQKrX26/summary-of-situational-awareness-the-decade-ahead --- Narrated by TYPE III AUDIO.

21 Gennaio 2024 I Messa IIIa B ordinario

21 Gennaio 2024 II Messa IIIa B ordinario

As part of an Around the Practice program, CancerNetwork® spoke with Misako Nagasaka, MD, PhD, about her current treatment strategies for patients with lung cancer as well as relevant updates and potential advancements in the non–small cell lung cancer (NSCLC) space. Nagasaka, a thoracic oncologist and associate clinical professor at the University of California, Irvine, discussed sequencing immunotherapy and chemotherapeutic agents depending on factors including EGFR and ALK mutations as well as a patient's PD-L1 status. She also spoke to the importance of multidisciplinary collaboration at her practice with pulmonologists and surgeons for treating patients in the neoadjuvant and adjuvant settings. Following the FDA approval of pembrolizumab (Keytruda) plus chemotherapyfor patients with resectable NSCLC in October 2023, Nagasaka stated that she was excited to treat those who may benefit from this regimen. The regulatory agency based its approval on data from the phase 3 KEYNOTE-671 trial (NCT03425643), which assessed the regimen among 797 patients with resectable stage II, IIIA, or IIB NSCLC.  The median overall survival was not reached (NR; 95% CI, NR-NR) among patients receiving pembrolizumab compared with 52.4 months in those receiving placebo (95% CI, 45.7-NE; HR, 0.72; 95% CI, 0.56-0.93; P = .0103). Additionally, the median event-free survival was NR (95% CI, 34.1 months to NE) vs 17.0 months (95% CI, 14.3-22.0) in each respective arm (HR, 0.58; 95% CI, 0.46-0.72; P

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 this podcast, Cancer.Net Associate Editor for Lung Cancer, Dr. Charu Aggarwal, and Cancer.Net Specialty Editor for Thymoma, Dr. Ryan Gentzler, discuss what people with early-stage non-small cell lung cancer should know about their treatment options before and after surgery, called neoadjuvant therapy and adjuvant therapy, respectively. 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. Dr. Gentzler is a thoracic medical oncologist and Associate Professor of Medicine in the Division of Hematology/Oncology at the University of Virginia (UVA) Comprehensive Cancer Center. View disclosures for Dr. Aggarwal and Dr. Gentzler at Cancer.Net.  To begin, Dr. Gentzler will discuss what people with early-stage non-small cell lung cancer should know about neoadjuvant treatment options before lung surgery. Welcome, Dr. Gentzler. Dr. Gentzler: Hi, this is Ryan Gentzler from the University of Virginia. We're here to discuss the role of neoadjuvant chemotherapy and immunotherapy for the treatment of locally advanced non-small cell lung cancer. So first, I thought I'd address some of the data and definition of what is neoadjuvant treatment. So when we think about treating lung cancer that is not metastatic, that is earlier stage disease, there typically involves multimodality treatment. Sometimes these lesions or tumors can be very small and can be stage I and treated with surgery alone or perhaps radiation alone and no further treatment is needed. But the vast majority of lung cancers that are considered early stage are in fact either larger tumors, involve lymph nodes, and typically fall into the category of stage II or III lung cancers. And these are cancers that often require multiple treatments beyond the local surgery approach alone. When we think about how we deliver that treatment, it can either be given before surgery or after a surgery. If we give treatment before a surgery, we call that neoadjuvant. If it is given after the surgery, we call that adjuvant. And most of the data that we have today in lung cancer uses one or the other of these approaches, and we don't typically give treatments both before and after, at least in terms of the chemotherapy part of that treatment. Historically, most of the data exists in the adjuvant treatment of lung cancer going back several decades that showed that the benefit of chemotherapy after a surgery, particularly for those with stage II and stage III lung cancer, derived a clear benefit of survival by giving chemotherapy after surgery. More recently, with the advent of immune therapy, which we have used in patients with stage IV lung cancer as well as those with stage III lung cancer who cannot undergo surgery, those immunotherapy drugs have been shown to improve overall survival and improve clinical outcomes for a wide range of patients with more advanced disease. And so in the last 4 or 5 years, we have really looked at new trials that have added immunotherapy in what we call perioperative space, either before surgery or after surgery for those that have surgically resectable disease. I'm going to focus on the neoadjuvant approaches that we have seen today, and this largely all started with data from Patrick Forde out of Johns Hopkins and Jamie Chaft from Memorial Sloan Kettering looking at single agent treatment with nivolumab immunotherapy. This was no chemotherapy given for 3 treatments prior to or three cycles prior to surgery. And that trial demonstrated a high degree of patients with tumor reduction and more importantly, we saw that the pathologic response, meaning how much tumor was left under the microscope at the time of surgery, was higher than what anyone anticipated with just immunotherapy alone. That launched a whole series of larger randomized prospective trials evaluating largely the combination of chemotherapy and immune therapy prior to surgery. Now, before we get into some of the results of these trials, I really wanted to emphasize some of the theoretical advantages to neoadjuvant approach. Now, the first potential advantage of giving neoadjuvant treatment is that we know when you start with immunotherapy and chemotherapy regimens and that's the first type of treatment, everyone is guaranteed to get that treatment. And we know that the completion rate prior to surgery is higher than it is after surgery. These patients can get all of the prescribed treatment and will be more likely to get it than if they get it after surgery. So this is one advantage. The other is potentially starting these medications which go throughout the body and treat the cancer, wherever it may be, earlier. We know that one of the risks of all cancers, but lung cancer in particular, is that even with good surgery and removing all of that cancer, there is a chance that there are cancer cells left behind, which leads to risk of recurrence in the years to come after surgery. Naturally, if we start the treatment that can eliminate those cancer cells, wherever they may be, and do that first, perhaps we catch this earlier with fewer cells that have escaped and have a more likely chance of success of eliminating the cancer and resulting in a cure. The third, I think, is one that we still have yet to learn more about, but if we give immunotherapy in particular, these are medications that activate the immune system, particularly the type of immune system cell called a T cell. If that T cell is able to recognize tumor cells, it is more likely to be able to continue to attack those tumor cells. And if we give that treatment prior to removal of the tumor, perhaps that activates the immune system in a more robust way that it can go after these cancer cells and eliminate those that are left behind after the surgery. If you give the immunotherapy after a surgery and the bulk of the tumor, most of the cancer cells have been removed, it may be harder to find those antigens or foreign proteins that are expressed in cancer cells. So the immune system may not be as robustly able to go after cancer if you give it solely after a surgery. Another potential advantage of neoadjuvant approaches is that it really helps us learn as oncologists how well a cancer is responding to a treatment. If we give these treatments for 4 cycles after a surgery, we don't know whether it's eliminating those residual cancer cells or whether it is totally ineffective. If we give it before a surgery and we see that there is tumor reduction or that there is a complete elimination of the cancer, we know that that treatment was an effective treatment at attacking the cancer cells and eliminating them. We know that the cancer was sensitive to that treatment. We can then better prognosticate how well the patients are going to do after surgery. We know based on the latest data that if you achieve what we call a pathologic complete response with chemotherapy and immunotherapy prior to surgery, meaning there are no cancer cells left when we look at that surgical specimen under the microscope, we know that those patients have a much better likelihood of surviving for longer periods of time than those who have active cancer at the time of surgery after prior treatment. And so neoadjuvant approaches allow us in a 2-month time frame to get a great sense of how well our treatments are working and able to prognosticate outcomes based on how well those cancer cells have been eliminated at the time of surgery. One large phase 3 trial called the CheckMate 816 trial was a randomized phase 3 trial and that enrolled patients with stage IB through IIIA non-small cell lung cancer using the old staging system of the 7th edition. These would all now be categorized as stage II and stage III non-small cell lung cancer patients. And it randomized these patients to 3 cycles of chemotherapy plus nivolumab, which is an immunotherapy drug, and compared that to patients treated with chemotherapy alone for 3 cycles. After these 3 cycles of chemotherapy, which is about a 9-week time frame, patients had surgical resection of their tumors. And then after surgery, patients received no further treatment, although treating physicians were allowed to give additional treatments like chemotherapy or radiation if they thought it would be beneficial for these patients, although it was not mandated by the study. One of the first results we saw from this study was that there was a much higher rate of pathologic complete response of 24% of patients achieving a path CR [pathologic complete response] with the nivolumab plus chemotherapy combination compared to only 2.2% with chemotherapy alone. This was highly statistically significant and demonstrated a clear benefit for those receiving the immunotherapy. The other main endpoint of this study was event-free survival, meaning that the time that the patients were alive and without any significant event like cancer progression or death after the enrollment of the trial. And in this analysis, the median event-free survival was significantly longer in those who have received the immunotherapy plus chemotherapy combination prior to surgery. One of the potential concerns about neoadjuvant treatment is that it may render patients unfit for surgery who otherwise could have had their cancer removed. When we look at the outcomes from this CheckMate 816 trial, it actually did not appear to be the case to a large degree. In fact, those that got the nivolumab plus chemotherapy combination were more likely to proceed on with surgery, and the majority did; 83% received the planned surgery. There were patients who were unable to receive surgery due to adverse events of their treatment, but that was only 1% of patients enrolled in the trial. Other reasons for canceling the surgery included disease progression, meaning the cancer got worse to the point where they could not undergo surgery, or other reasons, such as the patient declined surgery, or it was found to be unresectable at the time the surgeon wanted to remove the cancer, or poor lung function.   One of the insights we got from the surgical data from this trial were that those who received the combination of chemotherapy and immunotherapy had slightly higher rates of smaller surgeries like a lobectomy compared to a pneumonectomy for those who had received [chemotherapy alone.] There were also fewer numbers of patients who required a conversion from a minimally invasive surgical procedure to an open surgical procedure if they were getting the immunotherapy combination. A higher number of patients also were able to have complete resection of their tumor if they received the immunotherapy/chemotherapy combination. The length of hospitalization was slightly lower, and the rates of pain were slightly lower in those who received the combination as well. These comparisons were not statistically significantly different, but numerically, there seems to be at least a trend toward benefit in surgical outcomes in this neoadjuvant chemotherapy/immunotherapy approach. And I think this makes sense. We know that this combination is more able to eliminate a cancer and make it a pathologic complete response when we look at it under the microscope, and therefore, if there is shrinking the tumor to a higher degree, naturally, it seems there would be more likely of completely removing the tumor, using a smaller incision to remove that tumor, shortening the length of stay in the hospital and recovery time and pain control. All makes sense if we know that the treatment itself is able to reduce that size of the tumor. There are many other phase 3 trials ongoing studying the impact of immunotherapy plus chemotherapy in the neoadjuvant setting. The AEGEAN trial has recently reported data at the AACR meeting this year in 2023 with similar results that we saw with the CheckMate 816 trial. There are 3 other phase 3 trials that are ongoing, one of which we will see later this summer called the KEYNOTE-671 trial evaluating pembrolizumab plus chemotherapy in the neoadjuvant setting and then 2 other trials evaluating nivolumab, the CheckMate 77T trial, or atezolizumab in the IMpower030 trial. Each of these more recent trials typically have used 4 cycles of chemotherapy plus immunotherapy prior to surgery and also continued the immunotherapy after surgery for a period of time, most commonly approximately 1 year. From the data we have seen so far, it remains uncertain whether additional immunotherapy beyond the 3 or 4 cycles given in the neoadjuvant setting provides any additional benefit. We still do not understand what to do with patients who did not achieve a pathologic response whether further treatment would be of any additional benefit. We do not know if there will be further benefit even in those that achieved a pathologic complete response whether a slightly longer duration of immunotherapy would further improve outcomes in that group. We suspect with longer-term follow-up over the years of all of these phase 3 trials that some of these questions will be answered. So what are some key questions that patients should ask when considering a neoadjuvant chemotherapy/immunotherapy approach? I think the first question that's key is what is my tumor stage? We know that the trials that enrolled patients with a neoadjuvant approach enrolled patients using our current staging system would be a stage II or stage III lung cancer. And this is where it gets really tricky is, what subdivision of stage III is it? We tend to think of stage IIIA's as being one that it would be surgically resectable, with a smaller number of stage IIIBs, and then stage IIIC, one that we would not typically recommend surgery for. I think the next question within the tumor stage is, is this based on imaging or based on the biopsies? And we know that biopsies are really the best way to stage locally advanced cancers, particularly getting samples of lymph nodes in the mediastinum. Sometimes what looks like a stage I or stage II on imaging is, in fact, a stage III based on biopsies that are done at the time of surgery. It's ideal to know that information prior to making the decision about surgery so that that surgery is not futile.   On the opposite side, sometimes there is imaging suggestive of lymph nodes that are enlarged in the mediastinum, and it's presumed that this is a more advanced stage III and is not surgically resectable. However, if you go and biopsy those lymph nodes, sometimes they are benign. Sometimes they are inflammation related to infection or cancer but do not actually contain cancer cells. And so we typically advise that getting biopsies of lymph nodes in the mediastinum, at least any that are particularly suspicious, is highly recommended for these locally advanced cancers. I think the next question that's key to ask is, what are my tumor biomarkers? And there are multiple biomarkers that we look at in non-small cell lung cancer that help us decide what is the best treatment. What is the best approach? What is the best medicine to treat the cancer? We know that one of these biomarkers that is a key is a mutation. So multiple different mutations can occur in lung cancers, particularly those that are adenocarcinoma subtypes. And these mutations may be less likely to benefit from immunotherapy and we may want to take a different approach with surgery, chemotherapy, and potentially targeted therapies that specifically target that mutation that exists in the tumor. The other key biomarker here is PD-L1. We know that tumors with a higher level of PD-L1 are more likely to respond and benefit from immunotherapy. As of right now, that PD-L1 status plays a more important role in the adjuvant setting. All of the chemotherapy plus immunotherapy combinations in the neoadjuvant setting seem to benefit the group as a whole regardless of that PD-L1 status. But still, an important biomarker that we should have prior to making all final decisions on treatment. I think another question that should be asked any time you have an earlier stage cancer is, is my tumor surgically resectable? And there can be many reasons why cancers are not resectable, perhaps due to the anatomy of where the tumor is located, if it invades into the mediastinum, for example, or is near large blood vessels, or perhaps because there are too many lymph nodes and this is a more advanced stage. And so I think the main reasons for not being surgically resectable would be the tumor is too large, if the stage is too high, or is it more of a function of fitness for surgery and that can be because of other underlying lung disease. Perhaps removing part or all of a lung would not be safe due to impaired lung function to begin with. And I think it's important to understand that sometimes stage III lung cancers are resectable and sometimes they are not, and understanding the reason why they are not, I think, is important. And then I think lastly and ultimately when we're talking about a neoadjuvant approach, you want to ask your treating oncologist, "Would it be better to give my treatment before surgery or after surgery?" And really discuss the pros and cons with the physician and have them incorporate all of the factors that go into these treatment decisions. How well you'll tolerate chemotherapy, other medical conditions that may play a role in the likeliness of getting through those treatments safely, perhaps underlying diseases that may increase the risk of immune-related side effects with immunotherapy. You really want to factor in all of these things and discuss the pros and cons of a systemic treatment first versus surgery first before making final decisions on how to treat locally advanced lung cancer. All right. Thank you. ASCO: Thank you, Dr. Gentzler. Next, Dr. Aggarwal will discuss what people with early-stage non-small cell lung cancer should know about their adjuvant treatment options for after lung surgery.   Dr. Aggarwal: This is Dr. Charu Aggarwal. I'm the Leslye Heisler Associate Professor for Lung Cancer Excellence at University of Pennsylvania's Abramson Cancer Center. And today I will talk to you about the use of adjuvant immunotherapy in the setting of early-stage non-small cell lung cancer. We'll start by discussing what adjuvant therapy is, what types of options we have for adjuvant therapy, what kind of testing is important, and what options there may be in terms of adjuvant immunotherapy. So let's get started. Early-stage lung cancer comprises of stages between stage I to stage III. These stages vary by the size of the tumor as well as the level of lymph node involvement. In the setting of very early-stage lung cancer, such as stage I and stage II, as well as some select stage III lung cancers, we recommend surgical resection. And in these patients, the use of additional treatment is recommended based upon the pathological determination of the tumor size as well as the lymph node status. If usually lymph nodes are involved, we recommend adjuvant chemotherapy, and also, many experts will deliver adjuvant chemotherapy for tumors that may be larger than 4 centimeters even in the absence of lymph node involvement. The data for adjuvant chemotherapy comes from several large clinical trials that were conducted about a couple of decades ago now that demonstrated not only an improvement in preventing recurrence of the cancer but also a modest improvement in overall survival, really laying the ground for improvement and therefore becoming the gold standard. Four cycles of chemotherapy are usually administered about 6 to 12 weeks following surgical resection, and this is really the basis of our treatment in the early-stage setting. In today's time and age, we now have several other options. We have treatment options that include molecular therapy, which is biomarker driven, as well as the use of immunotherapy. So it's actually very important for us in the adjuvant setting--or in the post-surgical setting--to test for mutations such as EGFR. It's also important for us to test PD-L1 status. So let's dive into why each of these may be important. Patients with EGFR mutations, especially those with sensitizing mutations in EGFR exon 19 or 21, now have the opportunity to receive a targeted therapy in the form of osimertinib, which is an oral drug, very targeted and specific for the EGFR mutation that has been studied in a clinical trial setting in patients with early-stage non-small cell lung cancer. In patients with stage IB to IIIA non-small cell lung cancer with EGFR mutation, use of osimertinib was associated with a significant improvement in our ability to delay the recurrence of cancer. Based on this significant improvement, FDA approved therapy with osimertinib, and it is currently available and ready to use. We usually recommend it for 3 years, so daily therapy for 3 years, and patients are monitored with routine CAT scans and lab work. For patients who don't have an EGFR mutation, we do recommend broad panel testing. Of course, this is not the standard, but I think it's important for us to identify patients who may not benefit from immunotherapy. Patients that have an ALK mutation, for example, or ROS1 translocation, may not have the best chances of responding to adjuvant immunotherapy, and therefore, I think testing should be performed to make sure that we are having a shared decision-making conversation with our patients about the use of the correct adjuvant options. In terms of adjuvant immunotherapy, we now have 2 approved agents. One of them is atezolizumab, and the other one that was just recently approved is pembrolizumab. Atezolizumab was approved on the basis of a large clinical trial called the IMpower010 study, which randomized 1,280 patients with stage IB to IIIA non-small cell lung cancer to either 1 year of atezolizumab or best supportive care. Of note, all of these patients had to have had adjuvant chemotherapy that included a cisplatin platinum chemotherapy. In the first analysis, we found that the disease-free survival or the probability of the patients remaining cancer-free was significantly improved in those patients that had a tumor expression of PD-L1 greater than or equal to 1% and received atezolizumab compared to patients who did not receive atezolizumab. On the basis of this positive primary endpoint, the U.S. FDA approved the use of adjuvant atezolizumab for patients with stage II to IIIA resected non-small cell lung cancer after surgical resection and adjuvant chemotherapy. Recently, we heard that this does lead to small but significant improvement in overall survival. There is a trend towards improvement in overall survival. However, the data are quite immature at this point, and we do need longer follow-up to be able to follow this trend. The greatest magnitude of overall survival benefit was found in patients who had the PD-L1 greater than or equal to 50%. So it's important to know what the PD-L1 level of a patient may be when I'm thinking about adjuvant immunotherapy because adjuvant immunotherapy is most likely to benefit those that don't have an actionable mutation, such as EGFR, and those that have the highest PD-L1 staining, at least in the IMpower trial. Secondly, the PEARLS clinical trial is a clinical trial that evaluated the use of pembrolizumab, which is another immunotherapy agent, again, in the adjuvant setting. For this clinical trial as well, there was a small but significant improvement in disease-free survival, again preventing the probability of recurrence in all patients that received pembrolizumab compared to the best supportive care. And basically, this led to also an approval by the FDA for the use of pembrolizumab. Again, now we have 2 options. Both of these are administered for 1 year. What should patients know about therapy? These drugs are usually administered once every 3 weeks. They are given intravenously. Sometimes, we can change the treatment schedule to be either once every 4 weeks in the case of atezolizumab or every 6 weeks in the case of pembrolizumab. These may be associated with some side effects. Immunotherapy side effects that are most common are fatigue, chills, myalgias, or basically a feeling of pains in the body or joints. But also, some serious life-threatening reactions can occur such as activation of the immune system to such an extent that the immune system may start to attack the body's organs. So this may lead to swelling or inflammation in the organs that may manifest itself as colitis if the gut gets inflamed, or pneumonitis if the lungs were to get inflamed, or pancreatitis if the pancreas were to get inflamed. Any organ in the body can really get inflamed. We've certainly seen cases of thyroiditis. We've seen cases of polyarthritis. We've seen cases where the brain may also get inflamed or the pituitary may get inflamed. So there are definitely some life-threatening reactions or side effects that can occur with the use of immunotherapy that should be closely monitored. The benefit of having used immunotherapy in the metastatic setting is that now we have a lot of experience managing these side effects. And if recognized early, these side effects can be managed appropriately with the use of steroids as well as holding therapy. Many of the times, we can even reinstitute immunotherapy without significant harm to the patients. However, I think immunotherapy benefits as well as side effects should be discussed in detail with the provider, especially in the adjuvant setting. Patients may ask if neoadjuvant immunotherapy along with chemotherapy is a better approach compared to adjuvant immunotherapy. At this time, we don't have a clinical trial that is comparing neoadjuvant chemoimmunotherapy followed by surgery to an approach that is surgery followed by adjuvant immunotherapy. In general, I would say that if the decision by a multidisciplinary team has been made to proceed with surgery, careful discussion should be had about adjuvant chemotherapy as well as the use of adjuvant immunotherapy, and molecular testing should be performed. All patients with early-stage disease should have a multidisciplinary tumor board discussion, which includes engagement with surgeons, radiation oncologists, pulmonologists, pathologists, and medical oncologists so that they can ensure that many experts have had the chance to weigh into their case as well as come to the right conclusion on whether or not to use new adjuvant chemoimmunotherapy or just to proceed with surgical resection. ASCO: Thank you, Dr. Aggarwal. You can learn more about neoadjuvant and adjuvant treatment options for early-stage non-small cell lung cancer at www.cancer.net/lung. 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 continue to read the Catechism concerning the Sacrament of Holy Orders. In particular we study the distinctions of Major and Minor Orders and why the Church used to designate seven different "orders" encompassed within this sacrament. It is within the scope of the church's power to order itself and make a division of labor with respect to the sacrament of the Eucharist- and we see that all of the orders are at the service of the priest. Additionally, we read two excerpts from the Summa Theologica concerning the division and multiplicity of orders. (ST. IIIa. Supplement Q. 37 a. 1 and a. 2)

Bienvenidos a este podcast donde se abordarán los temas de mayor interés en el ámbito oncológico para Latinoamérica. A lo largo de este proyecto los Dres. Diego Ballén y Mauricio Lema, oncólogos clínicos colombianos, entrevistarán a un invitado especial para abordar con base en evidencia científica y a su experiencia a aquellas interrogantes que llegan a surgir diariamente en la práctica clínica. Durante este episodio el Dr. Andrés Felipe Cardona, oncólogo clínico, Director de Investigación y Educación Científica de la Fundación CTIC en Bogotá, Colombia, discutirá en conjunto con nuestros coordinadores sobre la inmunoterapia neoadyuvante en cáncer de pulmón. Los datos que se abordaron están basados en 5 estudios que inscribieron a pacientes con cáncer de pulmón de células no pequeñas. El primero que se comentó fue el CheckMate 816, un estudio fase III, aleatorizado, de nivolumab + quimioterapia doble con platino frente a la quimioterapia en pacientes con enfermedad temprana que no presentaban mutaciones de EGFR y ALK. El segundo estudio fue el NADIM II, un fase II, que examinó la respuesta patológica completa con nivolumab + quimioterapia (paclitaxel y carboplatino) neoadyuvante o solo quimioterapia en pacientes con enfermedad localmente avanzada y resecable, sin mutaciones de EGFR y ALK; si los pacientes alcanzaban resección completa se les brindaba nivolumab por 6 meses. El siguiente estudio que se discutió fue el AEGEAN, un estudio fase III, aleatorizado, de durvalumab neo/adyuvante + quimioterapia basada en platinos en comparación con la quimioterapia para el tratamiento de pacientes con enfermedad resecable en estadios II y III. El cuarto estudio que explicaron fue el KEYNOTE-671, un fase III, aleatorizado, de quimioterapia doble con platino +/- pembrolizumab como terapia neo/adyuvante para pacientes con enfermedad resecable en estadio II, IIIA y IIIB. El último estudio que se trató fue el NEOTORCH, un fase III, aleatorizado, de toripalimab + quimioterapia doble con platino en comparación con quimioterapia para pacientes en etapas II – III, resecable. Con base en los resultados presentados de cada estudio, los expertos respondieron a las siguientes interrogantes: ¿Actualmente la quimioterapia + inmunoterapia neoadyuvante es un estándar de tratamiento en cáncer de pulmón? ¿Qué implica que un paciente alcance respuesta patológica completa o mayor? ¿Sería importante recibir en el reporte de patología estos resultados de forma regular? ¿Qué opinión hay del grupo EGFR mutado que se agregó en el estudio KEYNOTE-671? En el caso de pacientes resecables, sin mutaciones de EGFR y ALK conocidas y con expresión alta de PD-L1 ¿sería apropiado un tratamiento neoadyuvante con quimioterapia + inmunoterapia o un tratamiento convencional seguido de inmunoterapia adyuvante? ¿Qué es el efecto de muerte inmunogénica de la quimioterapia? ¿qué diferencias existen entre los citotóxicos disponibles? ¿Cómo se valora el flare nodal inmunológico? ¿Vale la pena reestadificar el mediastino después del tratamiento neoadyuvante con quimioterapia + inmunoterapia? Considerando que no hubo una participación Latinoamericana sustancial en ninguno de estos estudios, excepto por el AEGEAN, ¿existe alguna razón para considerar que la respuesta a la quimiterapia + inmunoterapia neoadyuvante en población latina funcione diferente? Fecha de grabación: 4 de septiembre de 2023. El podcast “ACHO: actualidad del cáncer en Colombia” es una iniciativa de ACHO.        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.

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. The theme of the 2023 ASCO Annual Meeting was “Partnering With Patients: The Cornerstone of Cancer Care and Research.” From June 2 to 6 in Chicago, Illinois, and online, cancer researchers and clinicians from around the world gathered to discuss the latest cancer research and how to ensure that all people receive the cancer care they need. In the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field presented at the meeting and explain what it means for people with cancer. In today's episode, our guests will discuss new research advances in treating non-small cell lung cancer, small cell lung cancer, and mesothelioma.  Dr. Charu 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 2023 Cancer.Net Associate Editor for Lung Cancer. Dr. Melina Marmarelis is an assistant professor at the University of Pennsylvania, the Medical Director of the Penn Medicine Mesothelioma Program, and the co-director of the Molecular Tumor Board at the University of Pennsylvania. She is also the 2023 Cancer.Net Specialty Editor for Mesothelioma. Dr. Kristin Higgins is a radiation oncologist, Professor and Vice Chair in Clinical Research in the Department of Radiation Oncology at Emory University School of Medicine and medical director of radiation oncology of The Emory Clinic at Winship Cancer Institute's Clifton campus location. She is also a 2023 Cancer.Net Advisory Panelist for Lung Cancer. You can view disclosures for Dr. Aggarwal, Dr. Marmarelis, and Dr. Higgins at Cancer.Net. Dr. Aggarwal: Hello and welcome to this Cancer.Net Research Round Up podcast. Today, we will be talking about the latest research from the Annual Meeting of the American Society of Clinical Oncology from June 2023, and I'm joined today by 2 experts in the field of lung cancer. Before I introduce them, I'd like to introduce myself. I'm Dr. Charu Aggarwal. I'm an associate professor for lung cancer excellence at the University of Pennsylvania's Abramson Cancer Center. I'd now like to introduce Dr. Melina Marmarelis. Dr. Marmarelis: Hi, so happy to be here. I'm Melina Marmarelis. I'm an assistant professor at the University of Pennsylvania and the medical director of the Penn mesothelioma program. Dr. Aggarwal: And Dr. Kristin Higgins. Dr. Higgins: Hi, everyone. I'm Kristin Higgins. I am a thoracic radiation oncologist at Winship Cancer Institute of Emory University. I'm a professor and vice chair for clinical research for radiation oncology. Dr. Aggarwal: Fantastic. So today, we'll talk about relevant research as it applies to practical implications in the clinic for practitioners, but most importantly, patients with lung cancer. I'd like to start off by discussing 2 key studies, and I would love for perspectives from our faculty here. The first study I want to highlight is the ADAURA trial. This is a trial that has already sort of changed practice in most recent years when the study was presented at the Annual Meeting of the American Society of Clinical Oncology in 2020, but we have new updates on this study as of 2023. So, in brief, this was a study that looked at the value of administering an oral pill called osimertinib that is a tyrosine kinase inhibitor against the EGFR, or the epidermal growth factor receptor, in patients with non-small cell lung cancer. We know that non-small cell lung cancer is quite a heterogeneous disease with some subsets of patients having mutations that may render them increasingly sensitive to the effects of these tyrosine kinase inhibitors. In fact, these pills have been used in the metastatic setting for several years based on an improvement in overall survival. What the ADAURA study tried to do was ask the question if this pill would add an incremental advantage after receiving curative-intent surgical resection in those with early-stage lung cancer. So this study enrolled patients with stage IB to IIIA non-small cell lung cancer after surgical resection and focused only on those patients that had sensitizing EGFR mutations with EGFR exon 19 deletion or L858R mutations. Patients could receive chemotherapy after having the surgery and then were basically randomized into 2 groups, one of whom received osimertinib at a dose of 80 milligrams once daily for a total of 3 years. Patients were followed up for recurrence. We already know from the earlier results that patients who received osimertinib had a better chance of delaying the recurrence of disease. However, what we found at the Annual Meeting this year is that the administration of this osimertinib also improved overall survival, which is really what we all look for in the oncology world. If you're administering a therapy, especially for a long duration, we want to be able to see a survival benefit, and that's what we saw. In fact, in patients who received osimertinib, there was a 49% less likelihood of dying from lung cancer compared to those who did not receive osimertinib. This, I think, is practice-affirming. It may not be practice-changing because some of the practitioners started using osimertinib after its FDA approval in December of 2020, but I think it just confirms our practice as it delivers an overall survival advantage in these patients. One thing that's increasingly important is to identify patients who have this mutation, so now we have efforts underway locally as well as nationally to perform molecular genotyping on all patients with lung cancer so that we can adequately and appropriately treat those with early-stage lung cancer following curative resection or following surgery. Melina and Kristin, what are your thoughts? Dr. Marmarelis: Well, I think these results are really important because it did, as you say, affirm kind of what we're already doing, but I think the most convincing part of this for me is the prevention of spread of disease to the brain. This is not comparing osimertinib after surgery versus osimertinib ever, which I think is a difficult part about interpreting this trial. But I think the fact that it prevented disease from going to the brain is really meaningful to everyone, to patients, to the physicians that are caring for them, so I think that's a really important endpoint. Dr. Higgins: I agree with Melina. I think this is really exciting for our patients. It's exciting to have more treatment options for early-stage lung cancer. I think patients that are diagnosed with early-stage lung cancer are highly motivated to do everything they can to improve their likelihood of being cured. So I tend to have a lot of conversations about side effects and toxicities with patients that have questions and are sort of wondering how it will affect their quality of life, and of course, that is an important piece of it because patients that do have curable lung cancer are probably starting off with a better overall quality of life, but I think generally speaking, our patients have tolerated it well. I'm also kind of excited from a radiation oncology point of view. We treat patients with stereotactic body radiation therapy [SBRT] that are medically inoperable. And we have another trial with a cohort looking at osimertinib for those patients that have EGFR mutations, too, and that's ongoing, again, applying the same concept of trying to really use these SBRTs that work really well in the advanced setting, moving them into earlier stages of disease to help us care for more patients. So overall, I think it's really exciting, and I think it's a huge win for the clinical research community. Dr. Aggarwal: Well, that's wonderful. And I think this certainly advances the field as this is the first targeted therapy approved for patients with early-stage non-small cell lung cancer. I should add that AstraZeneca, the company that makes this drug, has provided institutional research funding to my institution, and I also serve as an advisor to them, but I was not involved personally in the research of this clinical trial. I'd like to move on but stay within the field of early-stage lung cancer and talk about another study called the KEYNOTE-671 study, and this is important because it really applies the idea of using immunotherapy before and after surgical resection in patients with early-stage lung cancer. Just to give a little bit of background to our listeners, we now have 3 approvals for the use of immunotherapy in patients with early-stage lung cancer. Two of those are in the adjuvant setting, meaning that if a patient undergoes surgical resection or surgery for early-stage lung cancer, they can receive either atezolizumab or pembrolizumab following that surgery, and that has been shown to improve outcomes in terms of reducing the chances of recurrence. We also have another approval, which is the third approval in early-stage lung cancer, where 3 cycles of chemotherapy and immunotherapy are administered prior to surgery, also called as the neoadjuvant chemo-immunotherapy approach. This drug that has been approved in combination with chemotherapy is nivolumab, and this approval came from a clinical trial called CheckMate 816 that showed both that patients who received this neoadjuvant chemo-immunotherapy approach had a higher proportion of patients who had complete response or pathologic complete response in their tumors at the time of surgery and also showed that the chances of the disease coming back after surgical resection was much lower amongst those that had received this intervention. The current study, the KEYNOTE-671 study, builds upon this concept and adds both a before-surgery intervention as well as an after-surgery intervention. So what this study did was it enrolled patients with early-stage, stage II to IIIB non-small cell lung cancer, and patients in the intervention arm received 4 cycles of chemotherapy in combination with pembrolizumab, underwent surgery, and then received immunotherapy with pembrolizumab for up to 13 cycles. Patients in the control arm received only chemotherapy prior to surgery and then placebo for up to 13 cycles after. This was a large study with about 786 patients randomized, and what we found was that those patients that received the intervention had a much higher likelihood of remaining disease-free or event-free following surgical resection as well as in the early analysis, an improvement in overall survival with about a 27% reduction in the risk of death. So I do think that this is the first study that shows us that use of both neoadjuvant as well as adjuvant. So sort of this perioperative approach of using immunotherapy before and after surgical resection can actually lead to improved outcomes. This is ultimately what we want for our patients, improvement in overall survival, improvement in cure rates, etc. The study has been silent on the use of radiation therapy, although it has gone into details in terms of the kinds of surgery that was done. Kristin, what are your views about this? Dr. Higgins: I think postoperative radiation after resection for non-small cell lung cancer has sort of started to fall out of favor because of the Lung ART trial that was published in Europe, a randomized phase III trial that showed no differences in disease-free survival or overall survival. And that's not to say that there aren't more study questions on ways to give it safer and ways to incorporate radiation in with the chemo-IO approach, and there are some novel ways to do that, and we're going to see some data presented at the World Lung Cancer Conference looking at some of those novel approaches. But standardly, when patients receive neoadjuvant chemo-immunotherapy followed by surgery, we typically would not offer radiation. There are instances, though, when patients have positive margins, for example, and in that situation, it's sort of a discussion on a case-by-case basis. But ideally, we're hoping that most of these patients that go to surgery are able to get a complete resection, and that's really the key component of the decision-making for deciding if patients are eligible for this approach. Dr. Aggarwal: I agree. Melina, any additional thoughts on this trial? Dr. Marmarelis: I think it's an exciting trial for the reasons that you mentioned. I think it does bring up a number of questions about whether both neoadjuvant and adjuvant immunotherapy are needed. I tend to like the idea of having immunotherapy present when the tumor is present before surgery, so I like kind of having that on board, but I think we still don't know which is more important. Dr. Aggarwal: So it certainly raises many more questions, which hopefully will be answered in the future. KEYNOTE-671 trial was conducted by Merck that produces the drug Keytruda, or pembrolizumab. We have received institutional research funding for other trials. I was not personally involved in this clinical trial. I do serve as an advisor for Merck. I think we'll bring you more research from the ASCO Annual Meeting. And I'll turn it over to Dr. Marmarelis to discuss some more exciting research. Dr. Marmarelis: Thanks, Charu. So perhaps it's not surprising that one of the exciting things I picked from ASCO has to do with mesothelioma. And I just want to put into context a little bit about why this trial was important. This is IND227. It was a cooperative group trial done across Canada, France, and Italy, and this was chemotherapy plus or minus pembrolizumab in patients with pleural mesothelioma that did not undergo surgery. So this was their first treatment, and they were not undergoing surgery. And the reason this trial was important is that in the last few years, we had results from CheckMate 743, which was looking at IPI/NIVO, so a combination of immunotherapies versus chemotherapy. And there was an improvement in survival for those that received double immunotherapy, and that improvement was most pronounced in the non-epithelioid population, which is actually a smaller subset of pleural mesotheliomas. And so as we've seen in the lung when we look at immunotherapy versus chemo, it raises the question of whether combination immunotherapy plus chemotherapy would actually be better for all and, in particular, for all histologies in pleural mesothelioma. So this was looking at that concept. It took the standard chemotherapy, carboplatin-pemetrexed or cisplatin-pemetrexed, and then combined it with one immunotherapy, so slightly less than the combo immunotherapy seen in CheckMate 743, and that was pembrolizumab. And what they saw was that there was a small overall survival improvement in the group that got pembrolizumab. Again, that was most pronounced in patients in the non-epithelioid group, so those with sarcomatoid or biphasic histology. And this is really a prelude to several other trials that are coming out in mesothelioma, namely the DREAM3R trial, which is looking at chemotherapy plus or minus durvalumab. That control arm also includes IPI/NIVO, so that will be really important to be able to compare those, and then also the BEAT-meso trial, which is looking at chemotherapy-immunotherapy but also with an anti-VEGF agent, bevacizumab. So I think this was an important trial. It's a little bit of proof of concept, but there's still a lot that we're looking forward to. It's not quite practice-changing in the clinic, although I think it's certainly an option that people are using, but I'm looking for more data going forward. Dr. Aggarwal: It's incredible to see how far we've come in mesothelioma within the last decade. We are introducing immunotherapy. We're introducing novel agents in the first-line setting. Dr. Marmarelis: The other trial that I was interested in was KEYNOTE-789, which is looking also at patients with EGFR mutations and those that had the original osimertinib as their first-line treatment or another tyrosine kinase inhibitor and then had disease progression on that TKI. And this is an area of huge need. We have patients that do really well on targeted therapies, and then they have disease progression, and we're looking for additional targeted options, but we're also looking for effective chemotherapy options. And one of the questions that has risen from this is whether there's a role for immunotherapy. We know that immunotherapy alone in patients with EGFR mutations is not very effective when you look at a broad population, but in combination with chemotherapy, it's possible that it can add some benefit. So this trial looked at those that had EGFR mutations, had disease progression after a targeted therapy, and then it randomized them to chemotherapy plus or minus pembrolizumab, so chemotherapy plus or minus immunotherapy, and interestingly, it had no difference in the progression-free survival or the overall survival. So the 2 arms were really similar in terms of outcomes. There was also no difference in the overall response rates of the amount that the drug actually shrinks the tumor. So it really doesn't look like immunotherapy is adding much to chemotherapy for these patients. I think we still need to look a little bit closer because there are probably some patients with EGFR mutations that could benefit from immunotherapy, but we're really not very good at identifying those. One of the questions that comes up in this space is whether to add anti-VEGF treatment in addition to chemotherapy and immunotherapy. So there are some upcoming trials looking at that. Dr. Aggarwal: I think this was a trial that was actually very important and again, practice-affirming that this idea of continuing chemotherapy without adding immunotherapy, patients are not losing much. In fact, they're not gaining anything by adding immunotherapy as shown in this clinical trial. I think continuing immunotherapy, so continuing osimertinib, may be important in this setting also because we know that osimertinib can cross the blood-brain barrier. It can provide that CNS [central nervous system] protection. Dr. Marmarelis: Yeah, I think that's a great point that the comparison here is not chemotherapy plus osimertinib. It's chemotherapy alone. So I agree that the control arm is not quite what some of us do. I agree. I do the same as you do. I also just want to mention that the KEYNOTE trial and the previous trial about mesothelioma used pembrolizumab, which is made by Merck. We have received institutional funding, and I've served as an advisor as well as received honorarium from Merck.   Dr. Aggarwal: Melina, those were 2 very important studies and certainly, I think, answer some very relevant questions in clinic in the management of patients with EGFR-mutant lung cancer, for example. And then I think we look forward to more practice-changing data in mesothelioma. Kristin, I would love to hear research from ASCO from you. What caught your interest? Dr. Higgins: So I have a special interest in small cell lung cancer. And I think there was one important small cell lung cancer trial that I wanted to review with everyone. It was SWOG S1929. And SWOG is the Southwest Oncology Group, and it's a cooperative group that conducts clinical trials in cancer funded by the National Cancer Institute. And this is a randomized phase II trial of atezolizumab and chemotherapy followed by randomization to continuing the maintenance of atezolizumab with a PARP inhibitor. Now, we know from prior data that PARP inhibition is attractive for small cell lung cancer because PARP is expressed frequently in small cell lung cancer, and there is a biomarker called Schlafen-11 that preclinical data and prior data has shown can predict response to PARP inhibition. And this trial was sort of a proof-of-concept trial, a small, randomized phase II trial testing whether or not that Schlafen-11 biomarker could be used to direct therapy. Now, in this trial, there were 309 patients that were registered. They then had to have their tumor samples sent for central testing for the Schlafen-11 expression. One thing that I think is important to bring up is that in small cell lung cancer, there's this belief that it's really hard to get tissue samples from small cell lung cancer and it's a difficult thing logistically because it's just a lot harder to access these tumors. But interestingly, in this trial, 80% of patients had tumors that were evaluable for the biomarker, and the median time to the test result was only 7 days. So patients were able to get their tumor tested, get it sent out, get results in a rapid manner, and then be randomized based on these results. The primary endpoint for this trial was progression-free survival, and the primary endpoint was met. Progression-free survival was 4.2 months versus 2.8 months. Now, I think many people will say the magnitude of benefit here is not very much, but it's small cell lung cancer, and we don't have a lot of positive trials in this space, and we also don't have many trials that have used a biomarker to direct therapy. So I think for those reasons, it's really exciting to see these results. It was also conducted within a cooperative group with multiple different sites across the United States, and the fact of the matter is that we can do trials like this in small cell lung cancer patients, and I think it will sort of serve as a precedent for future trial design. Now, the overall survival for the trial is still premature. It didn't look that much different with the PARP inhibitor, but that doesn't mean that, again, things could change with more follow-up. And I really like the approach of this trial design, and I'm excited to see biomarker-driven trials in small cell lung cancer. Charu and Melina, what do you guys think about this study? And what do you think about our small cell lung cancer patients and our ability to conduct future trials like this? Dr. Aggarwal: I think this is certainly an advance. As you pointed out, Kristin, it shows us that we can conduct trials in the space. I think it offers a lens into the potential of personalized therapy in small cell lung cancer, which has eluded us for a very long time. The standard of small cell lung cancer has not changed significantly for a very long time, so I think this is very exciting and can't wait to see more things come in the future. Dr. Marmarelis: Yeah, I agree. I think we've always been asking for additional biomarkers, especially in such a difficult disease like small cell. And so this is really exciting to see potential biomarkers and that it was feasible to actually pose that question and study it. So that part's really exciting. Dr. Higgins: Great. And I should also say I was not involved in the study, and I'm not associated with any of the pharmaceutical companies that were involved in the study for S1929. And the final study that we wanted to talk about was the phase III LUNAR study, and this is sort of a different type of trial in the setting of advanced non-small cell lung cancer. It was studying tumor treatment fields with standard of care in metastatic non-small cell lung cancer after progression with platinum-based therapies. And first, I just want to step back and explain what tumor treating fields are. Tumor treating fields are applied to a patient with a transducer that's placed on the skin, and what it does is it applies an electrical field, and that disrupts mitosis when the cancer cells are trying to divide. And the mechanism of cell death is a little bit unclear. There are sort of many mechanisms that are postulated, one of which is immunogenic cell death, but we don't really know, I think, what's happening. But there have been studies that show improved results with tumor treating fields and other diseases. For example, particularly in glioblastoma multiforme, tumor treating fields are used in combination with surgery, radiation, and temozolomide (Temodar). So it's something that's being used in other disease sites, and this is some of the early data that we've seen in metastatic non-small cell lung cancer. And so in this trial, 276 patients were randomized to tumor treating fields plus standard of care or standard of care alone. Now, I should mention that this trial began enrolling patients in 2016, and so the standard of care was very different. After platinum-based therapies, the standard was considered docetaxel. Of course, platinum-based therapy alone for frontline treatment of advanced non-small cell lung cancer is also not the standard of care anymore. And so I think with that in the background, it does make interpretation of these results somewhat difficult, and that's probably the major caveat to this study. But nonetheless, patients were randomized, 276 patients. The primary endpoint of the study was overall survival. They were looking at progression-free survival and overall response rates as secondary endpoints as well as overall survival in patients that received immunotherapy versus just chemotherapy alone. And the trial was positive. Overall survival was improved. The median overall survival was 13.2 months for patients that received tumor treating fields with standard of care versus 9.9 months for standard of care alone. If you look at 3-year survival, it was 18% versus 7%. I think this is a new type of therapy for our patients with non-small cell lung cancer. It is somewhat of a difficult thing to wear the transducer, and you have to wear it for many, many hours. So that is one thing that I think can be difficult for patients that are using this treatment, but nonetheless, it is something new for advanced non-small cell lung cancer. I do know that the technology of tumor treating fields is being studied in other settings for non-small cell lung cancer, for stage III non-small cell lung cancer, for example, and also in the frontline setting. I think this trial kind of speaks to the fact that the landscape of advanced non-small cell lung cancer is changing so rapidly, and when we're studying something novel, we have to make sure that we make these trials feasible for enrollment so that we can get them completed rapidly, and we can get a readout and it doesn't become obsolete based on this shift in the standard of care. So I think it just really kind of drives home that we need to make sure that we're taking that into account with trial design. It's not standard of care changing right now, but it'll be interesting to see how the data evolves over time. Melina, I'm interested to hear your point of view because I know that these can be used in mesothelioma, maybe not that frequently. What is your experience with tumor treating fields, if any? Dr. Marmarelis: Tumor treating fields are approved as a device in pleural mesothelioma in the first-line setting in combination with chemotherapy. They have been used off-label in other settings, but that's the device approval. The trial that looked at tumor treating fields in mesothelioma was a single-arm trial, so there was no control arm, and it was really actually just looking at the safety of the device. So I have not used it personally in mesothelioma, although I know of patients and I know of real-world studies looking at its use, and I think it's potentially an interesting modality of treatment, especially in combination with immunotherapy, given that it really doesn't have a lot of additive toxicity. But I think the question is really, which patients are benefiting from it, and which patients are able to actually wear the vest in the case of mesothelioma? Dr. Higgins: Yeah. Any thoughts, Charu? Dr. Aggarwal: I agree, and I think this is going to be largely driven by patient experience. I think this is going to be quite onerous to wear this, carry the suitcase, so I would be very interested in patient reported outcomes as well as patient experiences and stories, which will really drive our use here. Dr. Higgins: Yeah, that's a great point. I should say that this trial was sponsored by Novocure. My institution does have other Novocure studies underway, and we receive research funding, but I was not involved in the study, and I did not personally receive any research funding. Dr. Aggarwal: Thank you, Kristin. This has been a wonderful review of practice-changing and some promising research that came out of the ASCO Annual Meeting. I hope our listeners enjoyed it, and we'll be sure to update you with the next annual research conference. Thank you, everyone. ASCO: Thank you, Dr. Aggarwal, Dr. Marmarelis, and Dr. Higgins. 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.

Dr. Michael Atkins and Dr. Vernon Sondak highlight the latest updates to the systemic therapy for melanoma recommendations in this newest guideline. The discussion covers neoadjuvant and adjuvant therapy for resected cutaneous melanoma, options for unresectable and/or metastatic cutaneous melanoma, and therapies for noncutaneous melanoma. They review the importance of this guideline and the most pressing outstanding questions to help inform better treatment strategies for patients with melanoma. Read the full guideline update, "Systemic Therapy for Melanoma: ASCO Guideline Update" at www.asco.org/melanoma-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/melanoma-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO. 23.01136 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Michael Atkins from Georgetown Lombardi Comprehensive Cancer Center, and Dr. Vernon Sondak from H. Lee Moffitt Cancer Center and Research Institute, authors on “Systemic Therapy for Melanoma: ASCO Guideline Update.”   Thank you for being here today, Dr. Atkins and Dr. Sondak. Dr. Vernon Sondak: Happy to be here. Dr. Michael Atkins: Yeah, it's a pleasure. Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Sondak and Dr. Atkins, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content here, Dr. Sondak, what prompted this full update to the Systemic Therapy for Melanoma Guideline, which was initially published in 2018? Dr. Vernon Sondak: Well, the last 10 years or so have seen enormous advances in the management of metastatic melanoma and localized melanoma with systemic therapy, and the last few years haven't slowed up at all. So since 2018, we've seen new approvals, we've seen key pivotal trials that have shown some amazing results that we'll talk about, and all of these things together weighed into the decision to update the systemic therapy guidelines. Brittany Harvey: Great. Thank you for that background on what prompted the update. So then, this guideline provides updated recommendations across four clinical questions. I'd like to review the key updated recommendations for our listeners. So first, Dr. Sondak, what has changed in the updated recommendations regarding neoadjuvant therapy for adults with resectable cutaneous melanoma? Dr. Vernon Sondak: Neoadjuvant therapy is one of the most rapidly evolving and exciting parts of the management of melanoma with systemic therapy. The updated guidelines now include neoadjuvant pembrolizumab as a new recommendation for patients with resectable stage IIIB to IV cutaneous melanoma. This is based on the SWOG S1801 clinical trial, which was a very simple and yet incredibly influential clinical trial. It took patients with resectable metastatic melanoma, either metastatic to the lymph nodes or beyond, as long as it could be removed surgically, and randomized all of the patients to either get surgery, followed by a year of adjuvant pembrolizumab, which is very standard, or the same exact surgery and the same total amount of pembrolizumab, but with three of the doses given before surgery. So that simplicity, that ability to just compare the effect of neoadjuvant or preoperative pembrolizumab to entirely postoperative adjuvant pembrolizumab, made this trial a really pure assessment of the value of neoadjuvant pembrolizumab.  Impressively, this study showed a significant improvement in event-free survival for patients who got those three doses of pembrolizumab upfront. What's event-free survival? That includes relapse-free survival, but also the kinds of events that you can see happening with neoadjuvant therapy, such as progression of the disease prior to surgery that makes the patient unresectable. And the bottom line is that there was really the same number of issues with neoadjuvant pembrolizumab as with surgery, followed by adjuvant therapy, but there were many fewer recurrences among the patients who got neoadjuvant pembrolizumab. So that's why this was put into the guidelines. Brittany Harvey: Excellent. I appreciate you reviewing the evidence behind those recommendations and what's new for neoadjuvant therapy. So then, Dr. Atkins, moving into adjuvant therapy, for patients with resected cutaneous melanoma, what is new in the recommendations regarding adjuvant systemic therapy options? Dr. Michael Atkins: Sure. In the prior version, adjuvant therapy was recommended for patients with stage IIIB, IIIC, and for some patients with stage IV resected to NED. And those were based on studies with adjuvant pembrolizumab, adjuvant ipilimumab, and adjuvant nivolumab compared to ipilimumab. But what's happened since then is some really important adjuvant studies have been carried out in patients with stage IIB, IIC, and IIIA disease who are at slightly lower risk of recurrence, but still have substantial risk of recurrence, and make up a large percentage of the patients who eventually develop stage IV disease. And in these studies, one with pembrolizumab compared to placebo, there was about a 40% to 50% reduction in relapse-free survival observed, leading to the FDA approval of pembrolizumab in that setting. And then recently we saw the results of a similar study involving nivolumab that showed maybe even a slightly better reduction in the risk of relapse in that same patient population. Ultimately, this will lead to FDA approval as well. And we felt it was important to put in the guidelines the results of these studies so that people can have informed discussions with their patients about whether they want to receive this therapy going forward. It's important to point out that we don't have good data yet on overall survival. We just have data on relapse-free survival. So we don't, for sure, know that treating patients early, rather than waiting until a subset of them relapse and treating those late leads to an improved overall survival. That's an important discussion to have with patients to provide them with this option. In addition, we saw the results of the IMMUNED trial, which looked at nivo-ipi or nivo monotherapy versus placebo or observation in patients with stage IV disease that had been completely resected. And we saw dramatic improvement for the nivo-ipi combination compared to nivo or observation in those patients with stage IV NED. And we felt that, therefore, this was also an important patient population where we should offer guidance Brittany Harvey: Absolutely. That shared patient-clinician decision-making is paramount. And then you've both reviewed the options for resected cutaneous melanoma. But Dr. Atkins, what is new regarding systemic therapy options for patients with unresectable and/or metastatic cutaneous melanoma? Dr. Michael Atkins: Yes. For patients with unresectable metastatic cutaneous melanoma, there was a new drug combination that was approved combining nivolumab with relatlimab, which is an anti-lag-3 antibody that showed benefit compared to nivolumab monotherapy across almost all subgroups. In particular, the benefit was similar regardless of BRAF mutation status, regardless of elevated LDH, and regardless of patient stage. That led to FDA approval, and this is now an available treatment option, which is associated with less toxicity and similar efficacy to the standard of care nivo-ipi. In addition, although nivolumab-ipilimumab had been approved and was in our last recommendation for patients with BRAF-mutated melanoma, we didn't really know whether they should receive BRAF/MEK inhibitors, which were also approved, versus nivolumab-ipilimumab as their initial therapy. And so in the past few years, we saw the results of the DREAMseq trial, which randomized patients with BRAF-mutant melanoma to either nivolumab-ipilimumab, followed by BRAF-MEK inhibitor progression, versus the converse sequence. And we saw that at two years, the starting with a nivolumab-ipilimumab had a 20% improvement in two-year overall survival. This prompted the NCCN to change their guidelines to list nivolumab-ipilimumab or other immunotherapies as a preferred frontline therapy. And we thought that this data was important enough and somewhat validated by a randomized phase II trial, the SECOMBIT, which had a lot smaller numbers to encourage us to change the guidelines. Other minor things that we did were to take T-VEC and no longer recommend that as an option for patients with BRAF-wild type disease who had progressed on anti-PD-1 therapy and that ipilimumab and ipilimumab-containing regimens were no longer recommended for patients with BRAF-mutated disease after progression on other immunotherapy. We felt that those patients probably are best served to get BRAF/MEK inhibitors. Brittany Harvey: It's good to have clarity on some of those sequencing options for patients and also on which treatments are working better for patients in these subpopulations. So then, Dr. Sondak, the last set of recommendations. What has changed regarding options available for patients with noncutaneous melanoma?  Dr. Vernon Sondak: There's no question that our patients with noncutaneous melanomas, such as uveal melanoma or mucosal melanoma, have many fewer options and haven't benefited as much from the revolution in treatment that we've seen with our cutaneous melanoma patients, but there have been definite improvements and progress. The full update incorporates new recommendations for uveal melanoma that were published in 2022 as a rapid recommendation update, specifically a new drug called tebentafusp, which is restricted to HLA-A*02:01-positive patients. It's HLA-type restricted, but it is active in patients with metastatic uveal melanoma. And so the new guideline is that previously untreated patients with metastatic uveal melanoma who are HLA-A*02:01-positive should be offered tebentafusp as a treatment option. So that means all our patients with metastatic uveal melanoma should get HLA typed, so they know if they're a person who is eligible for this treatment and it should be considered early on in the treatment paradigm. Brittany Harvey: Well, thank you both for reviewing the updates to these evidence-based recommendations. There's a lot that's new in this field.  So then, Dr. Atkins, what is the importance of this guideline? And in your view, how will it impact clinicians, and also how will these guideline recommendations affect patients? Dr. Michael Atkins: Sure. Well, we have new treatments such as relatlimab and tebentafusp that are available and should be offered to appropriate patients, and new data on how to optimally apply previously approved treatments such as nivolumab-ipilimumab in patients with BRAF-mutated or resected stage IV melanoma, pembrolizumab use in the neoadjuvant setting, and nivo and pembro in earlier stage disease. And with this new information out there and included in the guidelines, hopefully, this will allow practitioners to give the best possible treatments to their patients, and patients to receive treatments which will improve their outcomes. Brittany Harvey: Absolutely. It's great to have new data to better inform treatment options for patients with melanoma.   So then, finally, Dr. Sondak, what are some of the most pressing outstanding questions regarding systemic therapy for patients with melanoma that may need to be addressed in a future guideline update? Dr. Vernon Sondak: Every advance brings up new questions. In neoadjuvant therapy, we have single-agent pembrolizumab with strong data from the randomized trial I spoke about. We anticipate more data about combination immunotherapy, specifically low-dose ipilimumab and nivolumab in the setting of neoadjuvant therapy. There are some trials going on with that. The best neoadjuvant treatment, the best sequence, how long should we treat, and even should we change the surgery based on the results of neoadjuvant therapy, not just the surgery, but the postoperative adjuvant therapy? Those are all questions that are key in the neoadjuvant side.  In the adjuvant therapy side, we have much more clarity now about BRAF versus immunotherapy in unresectable disease, but we still don't know always what's the best adjuvant therapy for our BRAF-mutated patients. That's an area we hope will eventually get more clarity, but I think it's going to take a while for that.   And finally, we'll learn more about the optimum sequencing of patients with metastatic disease, but especially for the patients who've already failed adjuvant or neoadjuvant therapy. So much of the data that Dr. Atkins and I talked about in metastatic disease, whether cutaneous or noncutaneous, involved previously untreated patients. But so many of our metastatic disease patients today have come to us already with some form of treatment in the adjuvant or neoadjuvant setting. We still have a lot of work to do to define the best treatment strategies for those patients.  Brittany Harvey: Definitely. Well, we'll look forward to learning more as new data comes out and as some of that research comes to fruition. So I want to thank you so much for your work to update this guideline and thank you for your time today, Dr. Sondak and Dr. Atkins. Dr. Vernon Sondak: Thank you. Dr. Michael Atkins: You're very welcome. Thanks a lot. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/melanoma-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 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.    

In this episode we continue our discussion of the integral parts of the sacrament of penance discussing confession. We discuss the necessity of confession and how it is beneficial to the individual and society. Additionally we read some articles concerning this same matter from the Summa Theologica. (ST. IIIa. Supplement selections from Q. 6-Q.7)

In this episode we read the Catechism's treatment concerning why Penance is a sacrament and we also begin to discuss its matter and form. Additionally we read from the Summa Theologica concerning these subjects and especially why the acts of the penitent may be considered the matter of Penance. (ST. IIIa. Q. 84 a.1 and a.2)

In this episode we commence our study of the sacrament of penance. The Catechism first explains the various meanings of the word penance, and then explains that penance is, first of all, a virtue. IN addition we read an article from the Summa Theologica in which St Thomas Aquinas justifies the saying of St Jerome that "penance is a second plank." (ST. IIIa. Q. 84, a. 6)

In this episode we read the Catechism concerning the reception of the Eucharist. Although canon law has changed the requirements concerning fast and abstinence before receiving the Eucharist it is instructive to read the stricter laws that were in place in the sixteenth century as they reflect the sort of disposition that Catholics should have in receiving the Eucharist. We also take a look at three articles from the Summa Theologica concerning the reception of this sacrament. (ST. IIIa. Q. 80 a. 1, a. 2, a. 10)

In this episode we read about the manifold effects of the sacrament of the Eucharist. Many of the effects of the sacrament may be adduced by a comaprison with the effects that physical food has on the living body. We also read about the effects of the Eucharist from the Summa Theologica. (ST. IIIa. Q.79)

Continuing last week's sermon, we learn more about the blessings available in the name of Jesus. The devil comes to steal, kill, and destroy... and it's time we use Jesus' name to demand what is ours. Some might hesitate and think they can't demand anything from God... Can we?

In this episode we discuss the manner in which the whole Christ (i.e. the body, blood soul and Divinity) is contained in both species, although differently. We discuss the meaning of the term "concomitance" and how the substance of Christ is contained in every part of the Eucharistic species. Additionally we read portions of the first three articles from question 76 "Of the way in which Christ is contained in this sacrament." (ST. IIIa. Q. 76 a. 1-3)

In this episode we read the Catechism concerning the words used in the consecration of the bread and the wine effecting the transubstantiation. These words are the form of the sacrament. In addition we read the replies in several articles of the Summa Theologica where St Thomas talks about the form of the Eucharist. (IIIa. Q. 78. a. 1, a. 3, and a. 4)

El Dr. Jorge A. Alatorre, oncólogo médico adscrito al Centro Médico ABC en la Ciudad de México, México, charlará en este segundo episodio de “Cáncer de pulmón en contexto” sobre el estudio NADIM II y el uso de la neoadyuvancia en pacientes con etapa III. Como invitado se encuentra el Dr. Mariano Provencio, oncólogo médico, Jefe del Servicio de Oncología Médica en el Hospital Puerta de Hierro, Madrid, España. El estudio NADIM II es un fase II, abierto, aleatorizado, de dos brazos, que evaluó el uso neoadyuvante de la quimioterapia (QT) + inmunoterapia vs. la QT sola en pacientes con cáncer de pulmón de células no pequeñas (CPCNP) localmente avanzado (etapa IIIA y IIIB) y potencialmente resecable. Recibieron 3 ciclos de nivolumab (360 mg) + QT y después de 3 ciclos, los pacientes se operaron y recibieron 6 ciclos de tratamiento adyuvante con nivolumab. Este estudio se centró en la búsqueda de la respuesta patológica completa y respuesta patológica mayor en este grupo de pacientes.  Los expertos, con base en evidencia científica y en su experiencia, contestan a las siguientes interrogantes: 1. ¿Por qué se enfocaron en los pacientes en etapas III en este estudio de NADIM II? 2. ¿Qué características deben tener los pacientes para un mayor beneficio con este esquema? 3. ¿Por qué hicieron evaluación del mediastino al inicio y al término del tratamiento con QT + inmuno? 4. El esquema de tratamiento utilizado en el estudio ¿beneficia a algún grupo en específico de pacientes? 5. ¿Cuál considera que es el futuro de los tratamientos neoadyuvantes y adyuvantes en esta neoplasia? Fecha de grabación: 6 de mayo de 2023. 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 this episode we commence our study of the Eucharist. The Catechism explains why it is a sacrament and when it was instituted. It also sets forth the various names for this sacrament and why it is only one sacrament although contained under the species of bread and wine. As a supplement to our study we read several articles from Question 73 in the thrid part of the Summa Theologica. (IIIa. Q. 73. a.1-5)

In this episode we consider the words of the form of Confirmation and mention the changes that have been made in this form after the Second Vatican Council. As St. Thomas Aquinas argues in article 8 of question 60 (Tertia Pars) a change in the words of the form does not render a sacraent invalid so long as the change does not destroy the essential sense of the words. Additionally we read the Catechism concerning the ordinary minister of the sacrament as well as why a sponsor is needed and again- who does the church desire to be confirmed? (ST. IIIa. Q. 72 a. 4 and a. 11)

The liberals prepare to imprison a Marine for protecting subway riders from a violent criminal, Trump breaks CNN, and a man wins a Pulitzer Prize after admitting that porn trans-ed him.Ep.1245- - - Click here to join the member exclusive portion of my show: https://utm.io/ueSEl- - - DailyWire+:Become a DailyWire+ member to gain access to movies, shows, documentaries, and more: https://bit.ly/3jJQBQ7 Pre-order your Jeremy's Chocolate here: https://bit.ly/3EQeVagShop all Jeremy's Razors products here: https://bit.ly/3xuFD43 Get your Michael Knowles merch here: https://bit.ly/3X6tlKY  - - - Today's SponsorsBulletproof Everyone - FREE IIIA backpack with IIIA clothing purchase. Promo code KNOWLES at http://www.BULLETPROOFEVERYONE.COM PureTalk - Switch to PureTalk and get a FREE 5G Samsung Galaxy phone! https://www.puretalk.com/landing/KNOWLES- - -Socials:Follow on Twitter: https://bit.ly/3RwKpq6 Follow on Instagram: https://bit.ly/3BqZLXA Follow on Facebook: https://bit.ly/3eEmwyg Subscribe on YouTube: https://bit.ly/3L273Ek  Learn more about your ad choices. Visit podcastchoices.com/adchoices

The liberals prepare to imprison a Marine for protecting subway riders from a violent criminal, Trump breaks CNN, and a man wins a Pulitzer Prize after admitting that porn trans-ed him. Ep.1245 - - -  Click here to join the member exclusive portion of my show: https://utm.io/ueSEl - - -  DailyWire+: Become a DailyWire+ member to gain access to movies, shows, documentaries, and more: https://bit.ly/3jJQBQ7  Pre-order your Jeremy's Chocolate here: https://bit.ly/3EQeVag Shop all Jeremy's Razors products here: https://bit.ly/3xuFD43  Get your Michael Knowles merch here: https://bit.ly/3X6tlKY   - - -  Today's Sponsors Bulletproof Everyone - FREE IIIA backpack with IIIA clothing purchase. Promo code KNOWLES at http://www.BULLETPROOFEVERYONE.COM  PureTalk - Switch to PureTalk and get a FREE 5G Samsung Galaxy phone! https://www.puretalk.com/landing/KNOWLES - - - Socials: Follow on Twitter: https://bit.ly/3RwKpq6  Follow on Instagram: https://bit.ly/3BqZLXA  Follow on Facebook: https://bit.ly/3eEmwyg  Subscribe on YouTube: https://bit.ly/3L273Ek  Learn more about your ad choices. Visit podcastchoices.com/adchoices

In this episode we discuss the dispositions necessary for the recipient of Baptism (intention, Faith, and repentance). We also read several articles in support of the Catechisms teaching from the Summa Theologica. (ST. IIIa, Q. 68. a.4-a.9)

In this, the 48th episode of the world's most popular podcast, Anthony, Paul, Theo, and Mike shift their attention to one of the oldest camera makers in the world and one that had produced some of the most innovative, interesting, and high quality cameras ever made...except no one wanted to talk about them! Okay, that's not exactly accurate as three people did show up.  Returning callers Raymond Nason, Mark Faulkner, and Brian Howard answered the call and came to chat with us about their favorite Konica cameras. Kicking off the discussion was Mike who gave a short history of Japan's oldest camera maker with early models such as the Cherry Hand Camera and the Rokuoh-Sha Pearlette.  We quickly moved onto the sexy Pearl folding cameras and the early Konica 35mm rangefinders.  Ray brought with the very rare Konica F, the company's first attempt at a 35mm SLR, and then we bounced around between the Koni-Omega Rapid models, the Auto-Reflex series, we spent some time chatting about the Konica Eye half-frame camera, and eventually some of the company's more memorable point and shoots. In addition to 96 minutes worth of Konica love, Theo, Mike, and Brian learned all about the American craze for elaborate senior photos, Mike explained the difference between automatic parallax and automatic field correction, Paul shares with us his least favorite 1990s premium camera, Mike complained (again) about the Konica AiBorg, his least favorite camera ever made, we explore a huge range of strange cameras designed by F.A. Porsche, and Ray gives an update on the 4th and final Yarovsky camera auction, which we discussed previously in Episode 44. As always, the topics we discuss on the Camerosity Podcast are influenced by you!  We would love to hear from more listeners, especially those who are new to shooting film or collecting cameras.  Please don't feel like you have to be an expert on a specific type of camera, or have the level of knowledge on par with other people on the show.  We LOVE people who are new to shooting and are interested in having an episode dedicated to people new to the hobby, so please don't consider your knowledge level to be a prerequisite for joining! The guys and I rarely know where each episode is going to go until it happens, so if you'd like to join us on a future episode, be sure to look out for our show announcements on our Camerosity Podcast Facebook page, and right here on mikeeckman.com.  We usually record every other Monday and announcements, along with the Zoom link are typically shared 2-3 days in advance. For our next episode, we've decided to go half...half-frame that is.  If you ever thought that 24mm x 36mm images are too large, and found that 18mm x 24mm was the ideal size for your negatives, Episode 49 is the one for you!  Join us as we will no doubt cover many wonderful half-frame shooters like the Olympus Pen F, Canon Dial 35, the Yashica Samurai, and the Konica Auto-Reflex....wait, we talked about that already!  Be sure to look out for our next show announcement.  Episode 49 will be recorded on Monday, May 15th.  We hope to see you there! This Week's Episode Paul is Headed to Another Auction and Isn't Going to Buy Anything...SUUUURRREEE!!!! A Short Early History of Konica / Rokuoh-Sha Pearlette / Contessa-Nettel Picolette / Zeiss-Ikon Cocarette Konica Got Into 35mm With a Bunch of Scale Focus and Rangefinder Models / Konica I Konishiroku Snappy is a 17.5 mm "Hit Style" Camera / Konica Konilette Shoots Non-Perforated 35mm Film Anthony Tells A Story About Karl Havens Dropping His Konishiroku Pearl II / Theo Loves the Pearl II Mark Shares his 1938 Semi Pearl, the Predecessor to the Pearl / Semi is Japanese for 4.5x6 Konishiroku Pearl IV (SEXY ALERT!) Konica II and Konica III / Variants of the Konica III, the IIIA, and IIIM / Konica's First Half-Frame 35mm Camera Konica's First SLR was the Konica F from 1960 / Wards am551 (Konica Auto S2) / Konica FS Auto Parallax and Auto Field Correction in a Rangefinder Koni-Omega Rapid Cameras / The Konica F Has a Moving Film Pressure Plate The Koni-Omegas Were Horrible for Frame Spacing / The Koni-Omega TLRs Were Even Stranger What the Heck is Senior Photography? / Studios That Specialize in Nothing But Senior Photography Anthony's Favorite Konica is the Auto-Reflex / Shooting Full and Half Frame On the Same Roll is Super Cool / Dedicated Half Frame Lenses for the Auto-Reflex The Konica Eye is a Nice Half-Frame Camera with an Interesting Logo Konica Autoreflex T-Series Have TTL Metering and Shutter Priority AE / Autoreflex T3 Was the Last Good Body Konica's First SLR Lens Mount was the F-Mount, the Konica AR-mount came out in 1966 / Konica FT-1 Wasn't Very Good Konica C35 AF Was the First Point and Shoot with AF / Paul Had One of the First Konica Hexar AF Cameras in the US When Konica and Minolta Merged, Who Bought Who? / The Merger Was the Only Reason Both Companies Survived Mike's Number One Least Favorite Camera He's Ever Shot is the Konica AiBorg Samsung ECX-1 / Rollei QZ35W and T /  Olympus O-Product / Minolta Prod 20s / Olympus Écru Paul's Least Favorite Premium 90s Camera Was the Nikon 35Ti Konica Hexanon Lenses Are Great / Konica 40mm f/1.8 Lens / Mike Loves 40mm Lenses Konica's Colored Point and Shoots / Konica Tomato and Pop Series / Konica Recorder Konica Even Made APS Cameras / Konica Revio CL with Selfie Mirror Konica Genba Kantoku Rugged Cameras / Fuji HD Job Site Cameras Ray Bought Cameras from the 4th Yarovsky Auction We Talked About in Episode 44 / More of the Same Links If you would like to offer feedback or contact us with questions or ideas for future episodes, please contact us in the Comments Section below, our Camerosity Facebook Group or Instagram page, or email us at camerosity.podcast@gmail.com. The Official Camerosity Facebook Group - https://www.facebook.com/groups/camerositypodcast Camerosity Instagram - https://www.instagram.com/camerosity_podcast/ Camerosity Twitter - https://twitter.com/CamerosityPod Theo's Review of the Pearl II - https://photothinking.com/2022-02-23-konica-pearl-ii-the-queen-of-gems/ Mark Faulkner - https://thegashaus.com/ Mike Eckman - https://mikeeckman.com/ Theo Panagopoulos - https://www.photothinking.com/ Paul Rybolt - https://www.ebay.com/usr/paulkris and https://www.etsy.com/shop/Camerasandpictures Anthony Rue - https://www.instagram.com/kino_pravda/ and https://www.facebook.com/VoltaGNV/

In this episode we continue our study of Baptism focusing on sponsors (Godparents) - why they are necessary, who is eligible to be a sponsor and the duites that sponsors have to their Godchildren. We also take a brief look at St Thomas' discussion of these topics (ST. IIIa. Q. 67 a.7-8)

In this episode we discuss the distinction between when Baptism was instituted as a sacrament and when it was made obligatory to receive. We also discuss the various gradations among the ministers of Baptism and to whom it primarily belongs to baptize. (ST. IIIa. Q. 66 a. 2 and Q. 67 a. 2)

CME credits: 0.25 Valid until: 17-04-2024 Claim your CME credit at https://reachmd.com/programs/cme/keeping-pace-in-lung-cancer-personalizing-treatment-in-nsclc-early-stage-disease-stage-i-iiia/15138/ The optimal management of non-small cell lung cancer (NSCLC) has fundamentally changed. Targeted agents, mono and combination immunotherapy, and immunochemotherapy options continue to emerge. You also need to factor in new and investigational neoadjuvant and adjuvant regimens. So how do you determine which patients will benefit most within this new landscape of options? Join Drs. Mark Socinski and Patrick Forde as they address these questions and provide a measure of order in the chaos.=

In this episode we conclude our reading of the Catechism's treatment of the 'Sacraments in General'. The sacraments have two effects "Sanctiying Grace" and a "Character." As an aid to our understanding of these effects we also turn to several articles in the third part of the Summa Theologica concerning these two effects of the sacraments. (ST. IIIa, Q.62 a. 1, Q63. a.1 -3)

In this episode we begin reading the Catechism in its treatment on the sacraments in particular. Beginning with Baptism, after disucssing the importance of instruction concerning Baptism, the Catechism then sets forth its definition. We also read the first article from Question 66 from the Summa Theologica "Whether Baptism is the mere washing?" (ST. IIIa. Q. 63 a.1)

In this episode we discuss the necessity of the sacraments relative to one another. Are all the sacraments equally necessary for salvation? Additionally, we discuss the distinction between the principle author of the sacraments as opposed to the instrumental agency of his ministers. Finally we discuss the question whether wicked ministers are able to validly confer the sacraments. To aid us in this discussion we continue to supplement our reading of the Catechism with selections from the Summa Theologica, Tertia Pars Q64 and Q65. (ST. IIIa. Q64. a.1. a.2. a.5 and Q65. a.4)

In this episode we discuss the number of the sacraments. The Catechism of the Council of Trent sets forth the doctrine of seven sacraments following St Thomas Aquinas in his Summa where he draws and analogy to the seven things that are necessary for the life of man in his corporal nature. In addition we read from the third part of the Summa where St Thomas asks "Whether there should be seven sacraments?" (ST. IIIa. Q. 65. a1)

In this episode, we commence our study of Article VII of the Apostles Creed, "From Thence He Shall Come to Judge the Living and the Dead." We discuss the two judgements, the "particular" and the "general," and the reasons for them. Additionally we take a brief look at the fifth article of Question 59 of the Summa Theologica regarding the general judgement. (ST. IIIA. Q.59. a.5)

In this episode we wrap up our reading concerning the sixth article of the Apostles Creed concerning the Ascension of Christ. We see that Christ's ascension is that to which His incarnation is finally ordered. The Ascension is the consummate fulfillment of the sacred scripture when Our Lord says He that is humbled shall be exalted. The ascension also serves to increase our Faith, Hope and Charity. In finishing our discussion we also read from the Summa Theologica of Saint Thomas Aquinas when he asks Whether Christ's ascension is the cause of our salvation. (IIIa. Q. 57. A.6)

Stephanie is a retired hair stylist, writer, and advocate for AdvancedBreastCancer.net. Stephanie was diagnosed stage IIIa at 25, and then stage IV at 31. In this episode Stephanie reads their essay “My Life and Being Wrong” from Wildfire Magazine's 2022 “Legacy Stories” issue. Stephanie's unusual cancer story is about a very unexpected pregnancy. Stephanie and April will discuss the importance of using your story for advocacy, reasons for being private with your cancer story, and being an example to our children when it comes to cancer. They will also talk about Stephanie's future plans to write a book with helpful tips on how to get started. More about Stephanie: https://www.instagram.com/_the_radiatedlizard/Purchase a print or digital copy of the “Legacy Stories” issue of Wildfire Magazine: https://www.wildfirecommunity.org/shop/mbc22More breast cancer stories from LBGTQIA2S+ community members: “Slowing Down to Write One Moment with Dawn Amodeo” https://player.captivate.fm/episode/a082c76d-bd6e-4345-adc5-2b3ac29af98fGet the free Wildfire email newsletter: https://www.wildfirecommunity.orgLearn about Wildfire writing workshops: https://www.wildfirecommunity.org/workshopsShop Wildfire merch & more: https://www.wildfirecommunity.org/shopSend your voice recording testimonial to editor@wildfirecommunity.org*Free* The Burn Writing Companion: Guided Prompt Journal (Vol. 1): https://www.wildfirecommunity.org/the-burnBuy the Wildfire book “Igniting the Fire Within: Stories of Healing, Hope & Humor, Inside Today's Young Breast Cancer Community”: https://www.amazon.com/dp/B0BJVJ629F?ref_=pe_3052080_397514860Other resources mentioned in this episode:Bright Spot Network https://www.brightspotnetwork.org/Mighty and Bright https://mightyandbright.com/Camp Kesem https://www.kesem.org/AdvancedBreastCancer.net https://advancedbreastcancer.net/

In this episode we conclude our study of Article V of the Apostles Creed "He Descended into Hell, The third day He rose again from the dead." The Catechism sets forth four reasons why the resurrection is necessary: as manifesting God's justice, increases our faith, increases our hope, and to complete the work of our salvation. We also discuss how Christ's resurrection effects the resurrection of our bodies and our souls. (ST. IIIa. Q. 57. a.1 and a.2)

In this episode we focus on the second part of Article V of the Apostles Creed "Third Day He Rose Again From The Dead." The Catechism instructs us about why it was appropriate that Christ rose on the third day - not sooner or later. It also tells us what perfect resurrection entails. Additionally, reading some brief sections from the "Tertia Pars" of the Summa Theologica we discuss five reasons why the resurrection was necessary. (ST. IIIa. Q. 53, a.1 a.2 a.3)

In this episode we conclude our reading and discussion of Article Four in the Catechism "He suffered died and was buried." We focus spefically on the words of the Catechism as they concern themselves with the bitterness of the passion of Christ. Christ's suffering exceeded the suffering of any man. We see that the Catechism follows the inspiration of St Thomas Aquinas in this treatment of the passion of Christ in Part III of the Summa Theologica- particularly in questions 46-48. In this episode we read the replies of both articles 5 and 6 in Question 46. (i.e. S.T. IIIa, Q. 46. a. 5, a. 6)

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.03.510585v1?rss=1 Authors: Douek, A. M., Salavaty, A., Kreuder, F., Stamatis, S.-A., Steele, J. R., Hanchapola, I., Shah, A. D., Schittenhelm, R. B., Ramialison, M., Currie, P. D., Kaslin, J. Abstract: Mucopolysaccharidoses are lysosomal storage diseases that collectively represent a major cause of lethal, treatment-refractory childhood dementias 1-7. Clinically-useful interventions are hampered due to an incomplete understanding of their neuropathological origins. Using the zebrafish sgsh model of mucopolysaccharidosis IIIA 8 (MPS IIIA, Sanfilippo syndrome A), we conducted several 'omics-based analyses, and developed and benchmarked a novel bioinformatic feature classification and ranking model for high-throughput datasets - ExIR - to prioritise important features in the progression of neurological manifestations of the disease. We find that the massive endolysosomal burden resulting from increased lysosomal storage of heparan sulfate and other secondarily accumulating substrates, such as sphingolipids, induces abnormal microtubule organisation and vesicle trafficking in neurons. This results in a gradual impairment of synaptic vesicle localisation at the presynaptic terminal and consequently impaired neuronal activity. Importantly, the endolysosomal phenotype in MPS IIIA zebrafish well-precedes the onset of neural pathology, though the larval MPS IIIA brain was found to be more susceptible to perturbation than wild type siblings. Collectively, these analyses demonstrate the presence of a progressive 'functional neurodegenerative' phenotype underpinning neurological disease in MPS IIIA. Our findings provide direct mechanistic evidence linking the well-described lysosomal storage basis for MPS IIIA to its disproportionately severe neural clinical involvement, enabling development and refinement of future therapeutic interventions for this currently untreatable disorder. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Em 2020 o estudo ADAURA avaliou o osimertinibe como tratamento adjuvante, após a cirurgia, para pacientes com câncer de pulmão não pequenas células EGFR mutados. Esse grande e importante Estudo mostrou, em sua primeira análise, que o osimertinib adjuvante obteve um benefício significativo de sobrevida livre de doença (SLD) quando comparado com o placebo em pacientes com câncer de pulmão EGFRm completamente ressecado, ± quimioterapia adjuvante (QT). O estudo incluiu pacientes estágio II-IIIA com Hazard Ratio (HR) pra SLD de 0,17 (p

Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we round out our discussion of early stage lung cancer treatment!* When deciding if a patient can get surgery upfront or not, remember the three “Fellow on Call” criteria for early stage lung cancer: - Mass invading other structures or mediastinum- Central lymph nodes (single digit)- Tumor >7 cm* If surgery is NOT an option at this time, where do we go from here?- Treat with upfront concurrent definitive chemoradiation- Treat with “induction” chemotherapy or induction concurrent chemoradiation**If surgery is/may be possible***What are the goals of “induction” treatments? - Eradicate microscopic disease- Improved local control, possibly shrinkage- Adding radiation may allow you to downstage tumor or lymph nodes to have a possible improvement in surgical outcomes* What sorts of discussions are being had a thoracic tumor board in patients with newly diagnosed early stage NSCLC? - Is the patient a surgical candidate?- If the patient is not a surgical candidate, then what are the options:--Definitive concurrent chemoradiation (usually) followed by immunotherapy---Pearl 1: Always choose this if surgeon thinks the patient is unresectable in general even with an induction approach---Pearl 2: Always choose this if 2 out of 3 criteria we discussed above are met---Pearl 3: Always choose this if N3 disease- “Induction” regimen with either chemotherapy alone or concurrent chemoradiation followed by surgery * What's the idea behind “induction” chemo or chemoradiation? - There is a chance that patients with these high risk features may already have micrometastatic disease, so treatment upfront can help address that- There is a chance that after surgery, patient may suffer deconditioning, which may preclude the use of chemo +/- radiation (up to 90% of patients are often eligible for chemoradiation before surgery; this drops to ~60% after surgery)- Local disease control to achieve the best possible surgical outcome (R0 resection) and also prevent any microscopic residual disease from then having the opportunity to spread systemically, especially in areas where the mass may be adjacent to many blood vessels or lymph nodes* What to treat with in the neoadjuvant setting?- Platinum containing regimens (“platinum doublets”):-- Carboplatin + paclitaxel-- Cisplatin + etoposide-- Cisplatin + gemcitable-- Cistplain + pemetrexed- Can combine this with radiation* How does the data about chemotherapy+IO in the neoadjuvant setting fit in here (CHECKMATE 816)?- In patients with Stage IIB to IIIA (8th edition) WITHOUT EGFR or ALK mutation, treatment with NEOADJUVANT chemotherapy q3w x3 cycles (most got cisplatin based therapy) + nivolumab 360mg q3w x3 cycles resulted in improved event free survival (31.6 months vs. 20.8 months) AND pathological complete response was 24.0% vs. 2.2%- Current NCCN guidelines state that if nivolumab is used in neoadjuvant setting, it should not be used in adjuvant setting- There is still uncertainty about how this fits into treatment compared to “traditional” neoadjuvant approaches with chemo+/-radiation*So after neoadjuvant treatment, does everyone go to surgery?- Always re-assess the status of the disease; if there is progression of disease, then will go to definitive chemoradiation- Discuss with surgeons to confirm if the patient is still a surgery candidate* If patient undergoes surgery, then what?- If patient got neoadjuvant therapy and an R0, then they are done with treatment- If R0 resection was not able to achieved, then either radiation “boost” to the area (if they previously got radiation), a course of radiation (if they just got induction chemo) or re-resection- We discuss the adjuvant setting in more detail in Episode 026 (https://www.thefellowoncall.com/tfocpodcast/episode-001disclaimer-wfhgf-ml3b6-9m66a-8rrc4-k8w87-x7xdd-wrzye-4xg8x-t73gt-cxc5s-nmg8f-cfyd6-hgs35-5pcwx-tf6dh-trggt-xzkt7-923gg-rpjzx-6s36p-hk27n-bbpgx-jymml-9lfam-76m4s)** If surgery is not possible*** If patient cannot go through to surgery Definitive chemoradiation:- Same chemotherapy agents as above, but treatment course is longer.- For instance, for NSCLC, total 60Gy in 2Gy divided fractions (5 days/week, 6 weeks of treatment) with chemotherapy* Additional therapy after chemoradiation (PACIFIC Trial) - Found that “consolidation” durvalumab 44% PFS 18 months vs 20% 5year survival benefit 40% vs. ~30% without treatmentReferences:https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450 - NCCN Lung Cancer guidelines https://www.nejm.org/doi/full/10.1056/nejmoa1709937 - PACIFIC Trial (NEJM 2017)https://www.nejm.org/doi/10.1056/NEJMoa2202170 - CHECKMATE 816 (NEJM 2022) Please visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google Podcast

La Dra. Carolina Blanco Vázquez, oncóloga médica adscrita al Centro Médico ABC, en la Ciudad de México, México, nos habla sobre lo más destacado en el día 3 del Congreso Anual de la Sociedad Europea de Oncología Médica 2022, resaltando los siguientes estudios: Cáncer de pulmón: ADAURA: Estudio global, aleatorizado 1:1, doble ciego, controlado con placebo para el tratamiento adyuvante con osimertinib en 682 pacientes con cáncer de pulmón de células no pequeñas en estadio IB, II y IIIA, con mutación de EGFR, resección completa del tumor y quimioterapia adyuvante, esta última si así lo decidía el médico o paciente. El objetivo primario fue la supervivencia libre de enfermedad (SLE) en pacientes en estadio II-IIIA y los objetivos secundarios fueron la SLE en pacientes en estadio IB-IIIA, supervivencia global y seguridad POSEIDON: Estudio fase III, aleatorizado, abierto, multicéntrico y global de durvalumab más quimioterapia (QT) o durvalumab más tremelimumab y QT vs. QT sola, para el tratamiento de primera línea de 1,013 pacientes con cáncer de pulmón de células no pequeñas metastásico (se excluyeron a aquellos con ciertas mutaciones en EGFR y ALK). Los objetivos primarios fueron la supervivencia libre de progresión (SLP) y la supervivencia global (SG) para el brazo de durvalumab más QT. Los objetivos secundarios incluyeron SLP y SG en el triplete experimental. Fecha de grabación: 11 de septiembre de 2022. 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.

Dr. Diwakar Davar and Dr. Jason Luke, both of the University of Pittsburgh's Hillman Cancer Center, highlight key advances in early phase therapeutics and immunotherapy that were featured at the 2022 ASCO Annual Meeting and also address toxicities, including immune checkpoint inhibitor-associated myocarditis. TRANSCRIPT Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. My name is Dr. Diwakar Davar, and I'm an assistant professor of Medical Oncology, specializing in melanoma and phase 1 therapeutics at the University of Pittsburgh's Hillman Cancer Center. I am the guest host of today's podcast. My guest today is Dr. Jason Luke, a colleague and the director of the Cancer Immunotherapeutics Center at the UPMC Hillman Cancer Center here.  Today, we'll be discussing advances in early-phase therapeutics and immunotherapy that were featured at the 2022 ASCO Annual Meeting.   You'll find our full disclosures in the show notes, and the disclosures of all guests on the podcast are available on our transcripts at asco.org/podcasts.  Jason, thank you for coming on the podcast today.  Dr. Jason Luke: Thanks so much for the invitation. It was a great ASCO, and I hope everyone had a good time.  Dr. Diwakar Davar: So, onto our abstracts. So, the first one that we'll be discussing, and Jason as you know we've done this before. We'll be rapidly transitioning between phase 1 therapeutics, melanoma, and advanced phase 2 and 3 trials, but you know this is something you do very well. So Abstract 2504, it's a phase 1 trial of TIM-3 inhibitor cobomilab immunotherapy and in combination with PD-1 inhibitors nivolumab and dostarlimab. The AMBER Trial that was presented recently, and in full disclosure, both you and I actually are on this abstract. So, what do you think of this abstract? What do you think of the data that is discussed, and how do we contextualize this in relation to what needs to be done in this space?  Dr. Jason Luke: So, I think this is an exciting abstract because it brings forward what may be the next high-priority immune checkpoint to try to target in clinical oncology. To level-set, I think everybody listening will know about PD-1 and CTLA-4 as immune checkpoints. In the last year, we've had LAG-3 come forward as now a standard of care element of armamentarium in melanoma, and we look forward to further studies of LAG-3 and other tumor types as we think it should be a good partner where PD-1 is otherwise approved.  So here now, we hear about TIM-3, which is another negative regulatory checkpoint on a number of different immune subsets. And in this abstract, the antibody targeting TIM-3 was cobolimab. So, TIM-3 is a very interesting molecule. It has, what you might call, pleiotropic effects in the immune system. So, while in the context of this abstract, it was being targeted as another immune checkpoint on T cells, it's important to point out that TIM-3 has other regulatory roles in other immune subsets such as myeloid cells and very particularly dendritic cells, and that's important because it might bring in another element of the innate immune system to try to drive anti-tumor responses. So, it's an exciting target because it might be able to expand the groups of patients who could benefit from immune checkpoint blockade.  So, in this abstract, we see initially the phase 1 data of combining cobolimab, anti-TIM-3 with anti-PD-1 of a couple of different flavors. And what you could take from this abstract is that in the phase 1 setting, the drug was well-tolerated and combined well, and had pharmacokinetic properties that would be consistent with what we'd expect for this kind of a monoclonal antibody. I think we have to marry this abstract, which is really the phase 1 data about safety in pharmacokinetic (PK) to another abstract presented in the melanoma session, which showed an expansion cohort of patients who got cobolimab plus nivolumab or dostarlimab.  And there we did see a 50% response rate, albeit that there was heterogeneity of patients being treatment naïve versus treatment-experienced. So, what I would say to this on a high level is that I think these data are preliminarily exciting, suggesting that further investigation into TIM-3 may be valuable in terms of expanding the population of patients initially in melanoma, but there will data coming soon in lung cancer and in other tumor types with another novel checkpoint. And I think if we think ahead into the future, the question is probably going to end up being, which combinations of checkpoints for which patients. That's pretty exciting to think about. We've seen a lot of data of PD-1 plus other molecules, and I think some future biomarker stratification really will be necessary to know which patient would benefit the most from which of these combos, but for the time being, this is exciting data to see where the field is going to go over the next couple of years.  Dr. Diwakar Davar: Great. And I guess, to your point, one important thing to highlight from the abstract is your point about the role of the different compartments. There was actually a very interesting dose-response relationship with the highest dose of the drug not necessarily being the most effective dose, suggesting that yes, as you escalate, you may have different effects in different compartments, and maybe therefore a broad selection of doses might be required to ensure that you have optimal engagement of the optimal target.  So, the next abstract is Abstract 3007. This is the tumor-agnostic efficacy and safety of erdafitinib. So, we now know that FGFR pathway aberrations are found from 77% of all malignancies, FGFR targets are now U.S. Food and Drug Administration (FDA) approved in cholangiocarcinoma with pemigatinib, infigratinib, and as well with erdafitinib metastatic urothelial cancer. We know that these agents are not necessarily effective tests in 1 tumor type because these alterations have risen in multiple tumor types. So, the RAGNAR trial, looking at this across multiple tumor types, what do you make of the interim analysis result presented by Dr. Loriot?  Dr. Jason Luke: So, I'd say that this is probably the future of targeted therapy. And so, I think that where we have activity in 1 disease, it's very likely we would have activity in others. So, the author has described this as the largest basket trial of a molecularly defined subset that's been pursued to date. There are upwards of more than 200 patients in the study. I think it's really important, as we think about the data, to realize, though, that all FGFR alterations are not exactly the same thing. And so, in this study, they gave erdafitinib to patients with solid tumors of any FGFR altered status. And so that's FGFR1, 2, 3, 4 mutations or gene fusions. And that's a lot of heterogeneity in there actually.  And in this study, there were two-thirds fusions and one-third mutations, mostly in FGFR2 and 3. That will become relevant as we start to think about the results. On a high level, I have to say that it is impressive in pan-cancer fashion, just selecting by FGFR alteration, there's about a 30% response rate observed. I think that no matter what, that's going to be valuable considering these were patients with refractory tumors with 3 lines of prior therapy on median. I think what we need to know more is the breakdown of which specific molecular alteration and FGFR in which tumor types drove most of the benefit.  So, for example, in bladder cancer where erdafitinib is already approved, that's almost entirely an FGFR3 fusion setting. So we know the drug is effective there. And so I think there will be a further breakdown of the data. As it matures more, you really start to tease out, is it really the case that any FGFR alteration can be treated or there are some that really ought to be the high priorities that we really ought to be going after. I think it would be remiss not to also note, however, that while there's excitement about this sort of pan-cancer approach, the current generation of FGFR inhibitors are not exactly the easiest drugs to take.  And so, the in-class, hypophosphatemia and stomatitis really does lead to dose reductions in a lot of the patients. And I think that that's probably really important to emphasize is that despite the pan-tumor activity, there's still a lot of potential in this field to refine further because it's almost certainly the case that if we had less off-target toxicity, so to say, we could improve the efficacy beyond that 30% that we saw here.  All the same, I think this is exciting for the concept of a pan-cancer tumor agnostic sort of approach, and we'll really look forward to more data to come from this study over the next, hopefully, few months.  Dr. Diwakar Davar: And I guess 1 corollary to that is that we now need to start looking for FGFR alterations in multiple tumor types. So, tests, tests, tests. All right, Abstract 3004, phase 1a/1b dose escalation and expansion study of the MDM2-p53 antagonist BI 907828 in patients with multiple solid tumors including advanced, metastatic, liposarcoma. So, we've recently had data of the previously undruggable KRAS, and now we've got previously undruggable p53, for which we now have targets. So, Jason, what do you make of the p53 targeting approach, in this case, using MDM2 and this particular drug from Boehringer Ingelheim?  Dr. Jason Luke: So, I think that this is an exciting abstract exactly for the reason that you mentioned, which is that p53 has been, and unfortunately, to some degree, still remains, one of those holy grails but undruggable targets in oncology. So MDM2, for those who are listening but might not be aware, is a negative regulator of p53. So, the concept here then is if you drug it, you might release p53 to reactivate activity in that pathway, and then p53 being the guardian of the genome, so to say, potentially leading to apoptosis of cancer cells.  And so, this drug binds MDM2 and MDM2 can be amplified as a resistance mechanism in p53 and several tumor types. And so here, they showed data for the early part of a clinical trial investigating the small molecule, BI 907828, but then they focus specifically in liposarcoma, which is a disease known to be an MDM2 amplified. And so, the results were pretty interesting. The toxicity of this kind of an approach, just to note, is really in class. It leads to some gastrointestinal (GI) toxicities as well as hematologic problems, and this goes again for most regulators of the cell cycle will have these effects, whether they're CDK inhibitors or MDM2 or p53 modulators.  But I think what was very interesting, this is a disease liposarcoma where chemotherapy, functionally speaking, has no role. We, unfortunately, give it to some patients sometimes, but it has almost no activity, and they observe that in poorly differentiated liposarcomas, the response rate was about 12%, but the stable disease was quite durable. And so, I think that really is potentially a big deal because this is an orphan disease. It really lacks any other treatment. But as you zoom out from that, if you start to think about targeting amplified MDM2 in other settings, I think the activity that we see here is intriguing, and potentially suggests that we may be coming to a future where we'll have multiple, sort of, orthogonal approaches after reactivating p53. There were actually other abstracts at ASCO Annual Meeting of other molecules that were less mature also along this line.  So, I think, very exciting to take away from this, one, a potential treatment for liposarcoma for all of those patients that anybody listening actually sees, but secondarily this concept of targeting p53, which I think we'll see a lot more of over the next couple of years.  Dr. Diwakar Davar: Excellent. Moving on to the Abstract 3002, this is a phase 1, two-part multicenter, first-in-human study of DS-6000a of an antibody-drug conjugate comprising the anti-CDH6 IgG1 monoclonal antibody that is attached to a topoisomerase I inhibitor payload via a cleavable linker. And so basically, a way in which you can give topoisomerase: (1) TOP1 inhibitor, (2) CDH6-expressing cells. This was studied in advanced renal cell carcinoma (RCC) and advanced ovarian cancer in this abstract presented by Dr. Hamilton. Jason, what do you think of the results and what do you think of this approach in general, this antibody-drug conjugate (ADC) approach using novel targets as well as novel payloads?  Dr. Jason Luke: I think this is one of those that you can't help but be pretty excited about, and I think in the context of the data shown at the plenary session in breast cancer for antibody-drug conjugates (LBA3), I think this is really where the field is going to start to go. So, you mentioned that this is an antibody-drug conjugate that targets cadherin 6 or CDH6, which people will remember from biochemistry class and medical school, or something is a cell-cell adhesion molecule, really a basement membrane protein. So, the concept of targeting it really is just to go after a latch mechanism to get the molecule into the tumor where you want. And CDH expression is very high in renal cell carcinoma, upwards of 80% of samples, also high in ovarian cancer, which is why they chose those 2 tumors to go after.  So, the ADCC, and you described its structure just a little bit, but it's essentially the same backbone as trastuzumab deruxtecan, which we saw this outstanding activity for HER2 and breast cancer on the plenary, with these 8 chemotherapies moieties attached to it, but here now, targeting it instead to HER2, with this molecule now to CDH6. And I think, again, you can't help but be impressed. There were treatment responses on almost every dose level of the dose escalation in this study. There's in fact only 1 patient whose tumor was not, at least, stable disease or a PR, and I think that that just goes to show the power of truly bringing the chemotherapy in a targeted manner into the tumor microenvironment. Responses were heterogeneous. They were not super deep responses per se, but the stable disease was quite durable in the study, and the patients were going out more than 7 months. And again, realizing this is at the lower dose levels as we're increasing the dose and move this in their earlier lives of therapy is likely to be even more effective.  They did show a waterfall plot of the reduction in CA 125 for the patients with ovarian cancer that really looked quite impressive. And given that that's our clinical biomarker that we commonly follow, it may actually even more indicative of the benefit we would see as opposed to resist.  Now, again, there is some toxicity. It is a chemotherapy moiety that's conjugated to the ADCs. So, the most common toxicities were nausea, vomiting, and low platelet counts, but these are kind of toxicities that we're quite accustomed to with chemotherapy. Just to summarize, I think there's a lot of promise for this kind of antibody-drug conjugate targeting, and I think it can only be impressive that they had this amount of activity in the dose escalation of the study. [I] very much look forward to the expansion cohorts in renal and ovarian, which we'll presumably expect to see later this year, early in the next year.  Dr. Diwakar Davar: And as you alluded to, this really was parallel that ASCO, by the standing ovation given to Dr. Modi when she presented the DESTINY04 data of trastuzumab deruxtecan in HER2-low breast cancer, basically now redefining breast cancer from 4 camps, now we have to think of not just HER2 amplified or HER2-high, but also HER2-low. So yes, really have to now rethink how we classify these diseases (LBA3).  So Abstract 2509, the efficacy of anti-PD-1/PD-L1 immunotherapy in non–small cell lung cancer dependent based on CD8 and PD-L1 status. So really Dr. Galon taking us into what he has now described as the immunoscore—really a way of characterizing tumors. A way of thinking about tumors that you've also championed, Jason, in terms of this T cell-inflamed and uninflamed hypothesis. So, tell us a little bit about how these jives with your work and how you would think about lung cancer patients responding and not responding to immune checkpoint inhibitors (ICI) therapy in this context?  Dr. Jason Luke: Yeah. I think the focus quickly here on the immunoscore, so the people are aware of that, I think is really important for diving into these specific results. You have to realize our fundamental underlying predicate for immune checkpoint blockade inhibitor response is that patients have mounted an adaptive immune response. So, CD8 T-cells have gone into the tumor where they elaborate chemokines and cytokines like interferon gamma, which upregulates the expression of PD-L1 in the tumor but also in the surrounding immune cells.  So, you realize that even though antibodies are targeting PD-1, it's really that we're targeting that tumor microenvironment. So, the more robustly we can measure that, and we understand it, the more likely we are to know whether or not the patient is going to benefit. So, this is where the immunoscore comes in. The immunoscore is actually a fairly simple test. It's one slide, immunohistochemistry slide where they can stain jointly for CD8 and PD-L1 on the same slide. And that allows them to do a number of different things beyond just testing the total level of PD-L1. They can test the CD8 density, the PD-L1 expression, but then also the interaction between CD8 T-cells, their distance from each other, from PD-L1 expressing cells, and so on and so forth.  And so really [this] can give us a much more robust analysis of what all is going on in the tumor microenvironment again, off of a single slide. So here then, in this abstract, for patients with non–small cell lung cancer receiving anti-PD-1, they then compared the utility of only PD-L1 testing versus doing the immunoscore. And so, it was actually quite a large set. They had about 250 patients in their analytical set and then split about 150 or 180 or something into the training and validation sets, and they compared the immunoscore against 2 different standard PD-L1 antibodies, the 22C3 as well as the SP263. And what they saw was a high concordance for expression between PD-L1 and the immunoscore.  That's good, because, again, they're measuring PD-L1 in both of those. And so that was a good, sort of, level set. The immunoscore, however, allows them to look to 7 different parameters, again, beyond just PD-L1, as I mentioned. So, CD8 density, interaction, distance, and this kind of thing. Then in these test and training cohorts, they were able to actually split out patients who are PD-L1 positive into further groups, those that were immunoscore low and that were high. And in so doing, they were actually able to sort of dramatically predict the likely progression-free survival on PD-1 checkpoint blockade in those different non–small cell lung cancer groups.  So why is this important? Selection of patients by PD-1 has been very useful in the field of non–small cell lung cancer, but it's hardly a panacea. You're not at all assured your patient is going to do well just because they're PD-L1. And here comes a second assay that can be done in a standard of care setting. So, the immunoscore is a test. You could just order it, and that really does give you much more predictive power about who's likely to do well and who isn't. And I think this test and more broadly multi-spectral imaging is really going to become a core component to how we risk stratify and predict outcomes to checkpoint blockade and lung cancer, but broadly in other tumor types over the next couple of years.  Dr. Diwakar Davar: Okay. Now, moving on from a biomarker for PD-L1 and PD-1 to a setting in which PD-1 was just recently U.S. Food and Drug Administration (FDA)-approved, so I'll give a brief background to the trial that you've actually developed and led. And so, this is KEYNOTE-716, the abstract in question is LBA9500 (late-breaking abstract) 9500, but this is the distant metastasis-free survival (DMFS) data readout. The DMFS, distant metastasis-free survival with pembrolizumab versus placebo in the adjuvant setting for patients with stage IIB or IIC, that is high-risk node-negative melanoma and the data from the phase 3 KEYNOTE-716 study.  So, this data, at least the recurrence-free survival (RFS) data was actually earlier published, you had presented it earlier last year and also more recently this year, but it was published recently in Lancet. And we know that 716 is a study in which, for the first time ever, we have an immune checkpoint inhibitor PD-1 that was studied against placebo with the high-risk node-negative setting in stage IIB and C melanoma, demonstrated a significant RFS benefit in the setting against placebo. And now we have the DMFS readout.  Maybe you could tell us a little bit about both the RFS and the DMFS data, and why this is such an important advance for these patients.  Dr. Jason Luke: Thanks. And I agree this really is a sea change in how we thought about stratification of patients with melanoma, but I think this broadly has implications for other tumor types as well. So, in melanoma, we've historically thought of its involvement of the lymph nodes—stage III as being the high-risk disease, but we also, if you look at the outcomes from the AJCC, we see the patients with stage IIB and IIC, so deep primary lesions, actually have similar bad outcomes as those patients with stage IIIA and IIIB. And so anti-PD1 and adjuvant therapy and melanoma were originally proved for stage III, but having understood that about 5 years ago actually, started to think, well, why not also treat the patients with stage II if they're at similar risk.  And we pursued KEYNOTE-716 as you mentioned, and it read out last year as a positive trial for recurrence-free survival. And the abstract here then was to look at the impact on distant metastasis-free survival. So, while the regulatory consideration for approval, and it is approved and it's available for patients now, was based on relapse, what we really want to be preventing is the development of metastatic disease because presumably that would correlate with the eventual death of the patient from cancer.  So, in the abstract here, we see the first update for DMFS, which also was positive on its first analysis, the hazard ratio at 0.64. And so, again, very similar to the RFS benefit, showing about a 35-36% reduction in distant metastasis-free survival. And this is a theme that we've seen across adjuvant studies in melanoma, all the adjuvant studies in fact, is that the RFS improvement, the relapse-free survival hazard ratio mirrors very closely the distant metastasis-free survival ratio. We saw that again here. I think it just emphasizes that anti-PD-1 immunotherapy is highly effective in melanoma no matter what stage it's in, but rather related to the risk of death for melanoma.  And so this really has a practice changing in the field of melanoma oncology. Patients need to be referred to medical oncology early for discussion around risk stratification and consideration of adjuvant therapy—I think even at the same time that they're having resection of their primary lesion, and it even calls into  question of whether or not we should even fully be doing procedures like sentinel lymph node biopsies any longer, considering we can make the decision to give adjuvant therapy now based on the primary—albeit that's a controversial area of discussion.  And I would just love for this to start to penetrate into other disease settings. We've seen more recently, approval for neoadjuvant therapy in lung cancer and we see in kidney cancer, bladder cancer. We see adjuvant therapy in—I think we're going to see immunotherapy starting to become an important part of the armamentarium in these hard-to-treat cancers, even at the time that perioperatively before or after surgery.  So definitely a major change in the way we're thinking about stratifying patients and emphasizes that you need to get those patients with melanoma in to have that discussion around adjuvant therapy probably at the time of the primary lesion resection.  Dr. Diwakar Davar: And finally, Abstract 2507, single-cell profiling of human heart and blood in patients with checkpoint inhibitor-associated myocarditis. So, this is data from the NGH Group, Dr. Villani and colleagues are presented by Dr. Blum. We know that myocarditis is an uncommon but very serious immune related adverse event (irAE), and here in this particular dataset, this group which has done a lot of underlying work to really uncover the role of certain key phenotypes, cellular phenotypes, in the development of myocarditis it's presenting the data in the context of ICI-related myocarditis. So, what do you think of this data, what do you think of the use of checkpoint inhibitors are now, as you've said, migrated linear in the lifecycle of the patient, what do we need to be thinking about and how does this improve our understanding of both the use of the drug and what we need to be worried about?  Dr. Jason Luke: I think the toxicities of immunotherapy, while, less frequent than, say, chemotherapy, can actually be more disastrous. In the rare patients, we have extreme immune-related adverse events, there is an incidence of actually life-threatening and fatal events. And so, myocarditis, associated with checkpoint blockade, is one of those things that could be seen, and here at ASCO Annual Meeting, we saw a couple of abstracts summarizing the experience from the National Cancer Institute following myocarditis events, and then this abstract in a translational level trying to better understand what is actually going on in terms of the immune response in those myocarditis cases.  And so, I thought this was actually a very interesting abstract. There was only a small number of patients. They had 13 samples from patients who had had endomyocardial biopsies in the context of immune-related myocarditis, and you might say, well, only 13 samples, but fortunately, this is quite a rare event, less than 1% of patients who get immune checkpoint inhibitors. And what they saw was relatively unsurprising, which is that in patients who were having myocarditis, they saw an increase in T cells and in K-cells, as well as activated CD8 and CD4 T-cells.  I think what was very interesting was when they started to dig into what were the phenotypes of the cells and what were the pathways that were turned on. Again, it was not especially surprising to see that they saw increased levels of interferon signaling and immune-receptor signaling as well as motility and adhesion, but this really, I think emphasizes that there are potentially interventions beyond just the general immune-suppression approaches that we give. They could be more nuanced but perhaps more efficacious because sadly, patients do pass away when they develop this. And in their cohort of 13 patients, 3 of those patients died. And specifically, in looking in those 3 patients, they actually saw that all 3 patients had a shared T cell cluster. And they can't exactly say what it is exactly yet, but I think it's very interesting to see that because it suggests that there's probably something about the T cell response in those patients that disproportionately triggered a fatal event.  And if we can understand that better, we then may be able to really tailor our interventions in a way that is more useful. Because, frankly, the way these patients usually present is they show up in the emergency room (ER), and they're seen by an ER doctor who thinks they're having acute coronary. They ship them off to the catheterization (cath) lab. They open him up, and then they get in there, and there's nothing going on. There's no plaque. And so now, all of a sudden, everyone is quite confused. And so, if we had better ways to search for that ahead of time to be aware of it, we might have better interventions because usually what happens right at that moment is everybody gets very confused and starts calling the oncologist, and we start slapping on steroids and other immunomodulatory agents, but sometimes it's late.  So, I think this is a great abstract. It's really starting to preliminary give us an idea of what is the actual biology that underpins these terrible events, and we can hope that we can build off that over time hopefully to eventually come up with better predictors and then obviously better interventions to try to avoid these outcomes in a small but real number of patients.  Dr. Diwakar Davar: Excellent. One other point is you and I are both involved in drug development, and as we start thinking of side effects. Side effects are really on the flip side of responses in drug development. So really 1 point to make of this is that when people start developing side effects rather than, as you say, putting your hands up in the air and waving them around, 1 of the things that we should be doing in drug development is possibly biopsying these patients because we could get new PD insights into how these drugs work, why they work, and particularly which sub-populations themselves they work on, particularly in the early-drug development setting when you oftentimes don't have that many responses.  With that, thank you, Jason, for sharing your insights with us today.  Dr. Jason Luke: Thank you.  Dr. Diwakar Davar: 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. So, thank you for your attention, and we will sign out.      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  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.     

A team effort as Demi Beneru, Michel Tchan and Kate Billmore explain how they successfully supported a mother with GSD IIIa during her pregnancy. Glycogen storage disease type IIIa in pregnant women: A guide to management Demi Beneru, Michel C. Tchan, Kate Billmore, Roshini Nayyar https://doi.org/10.1002/jmd2.12282

Review mini lecture --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

Listen to a soundcast of the October 15, 2021 FDA approval of Tecentriq (atezolizumab) for adjuvant treatment following resection and platinum-based chemotherapy in patients with stage II to IIIA non-small cell lung cancer.