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Best podcasts about ctdna

Latest podcast episodes about ctdna

ASCO Daily News
ASCO25 Recap: CHALLENGE, DESTINY-Breast09, and More

ASCO Daily News

Play Episode Listen Later Jun 19, 2025 25:45


Dr. John Sweetenham and Dr. Erika Hamilton highlight key abstracts that were presented at ASCO25, including advances in breast and pancreatic cancers as well as remarkable data from the use of structured exercise programs in cancer care. Transcript Dr. Sweetenham: Hello, and welcome to the ASCO Daily News Podcast. I'm your host, Dr. John Sweetenham. Today, we'll be discussing some of the key advances and novel approaches in cancer care that were presented at the 2025 ASCO Annual Meeting. I'm delighted to be joined again by the chair of the Meeting's Scientific Program, Dr. Erika Hamilton. She is a medical oncologist and director of breast cancer and gynecologic cancer research at the Sarah Cannon Research Institute in Nashville, Tennessee.  Our full disclosures are available in the transcript of this episode. Dr. Hamilton, congratulations on a fantastic meeting. From the practice-changing science to the world-renowned speakers at this year's Meeting, ASCO25 really reflected the amazing progress we're seeing in oncology today and the enormous opportunities that lie ahead of us. And thanks for coming back on to the podcast today to discuss some of these advances. Dr. Hamilton: Thanks, Dr. Sweetenham. I'm happy to join you today. It really was an impactful ASCO Annual Meeting. I probably am biased, but some great research was presented this year, and I heard lots of great conversations happening while we were there. Dr. Sweetenham: Yeah, absolutely. There was a lot of buzz, as well as a lot of media buzz around the meeting this year, and I think that's probably a good place to start. So I'd like to dive into abstract number LBA3510. This was the CHALLENGE trial, which created a lot of buzz at the meeting and subsequently in the media. This is the study that was led by the NCI Canada Clinical Trials Group, which was the first randomized phase 3 trial in patients with stage III and high-risk stage II colon cancer, which demonstrated that a post-treatment structured exercise program is both feasible and effective in improving disease-free survival in this patient group. The study was performed over a long period of time and in many respects is quite remarkable. So, I wonder if you could give us your thoughts about this study and whether you think that this means that our futures are going to be full of structured exercise programs for those patients who may benefit. Dr. Hamilton: It's a fantastic question. I think that this abstract did create a lot of buzz. We were very excited when we read it. It was highlighted in one of the Clinical Science Symposium sessions. But briefly, this was a phase 3 randomized trial. It was conducted at 55 centers, so really a broad experience, and patients that had resected colon cancer who completed adjuvant therapy were allowed to participate. There were essentially 2 groups: a structured exercise program, called ‘the exercise group,' or health education materials alone, so that was called just ‘the health education group.' And this was a 3-year intervention, so very high quality. The primary end point, as you mentioned, was disease-free survival. This actually accrued from 2009 to 2024, so quite a lift, and almost 900 patients underwent randomization to the exercise group or the health education group. And at almost 8 years of follow-up, we saw that the disease-free survival was significantly longer in the exercise group than the health education group. This was essentially 80.3% of patients were disease-free in exercise and 73.9% in the health education group. So a difference of over 6 percentage points, which, you know, at least in the breast cancer world, we make decisions about whether to do chemotherapy or not based on these kind of data. We also looked at overall survival in the exercise group and health education group, and the 8-year overall survival was 90.3% in the exercise group and 83.2% in the health education group. So this was a difference of 7.1%. Still statistically significant. I think this was really a fantastic effort over more than a decade at over 50 institutions with almost 900 patients, really done in a very systematic, high-intervention way that showed a fantastic result. Absolutely generalizable for patients with colon cancer. We have hints in other cancers that this is beneficial, and frankly, for our patients for other comorbidities, such as cardiovascular, etc., I really think that this is an abstract that deserved the press that it received. Dr. Sweetenham: Yeah, absolutely, and it is going to be very interesting, I think, over the next 2 or 3 years to see how much impact this particular study might have on programs across the country and across the world actually, in terms of what they do in this kind of adjuvant setting for structured exercise. Dr. Hamilton: Absolutely.  So let's move on to Abstract 3006. This was an NCI-led effort comparing genomic testing using ctDNA and tissue from patients with less common cancers who were enrolled in but not eligible for a treatment arm of the NCI-MATCH trial. Tell us about your takeaways from this study. Dr. Sweetenham: Yeah, so I thought this was a really interesting study based, as you said, on NCI-MATCH. And many of the listeners will probably remember that the original NCI-MATCH study screened almost 6,000 patients to assess eligibility for those who had an actionable mutation. And it turned out that about 60% of the patients who went on to the study had less common tumors, which were defined as anything other than colon, rectum, breast, non–small cell lung cancer, or prostate cancer. And most of those patients lacked an eligible mutation of interest and so didn't get onto a trial therapy. But with a great deal of foresight, the study group had actually collected plasma samples from these patients so that they would have the opportunity to look at circulating tumor DNA profiles with the potential being that this might be another way for testing for clinically relevant mutations in some of these less common cancer types. So initially, they tested more than 2,000 patients, and to make a somewhat complicated story short, there was a subset of five histologies with a larger representation in terms of sample size. And these were cholangiocarcinoma, small cell lung cancer, esophageal cancer, pancreatic, and salivary gland cancer. And in those particular tumors, when they compared the ctDNA sequencing with the original tumor, there was a concordance there of around 84%, 85%. And in the presentation, the investigators go on to list the specific mutated genes that were identified in each of those tumors. But I think that the other compelling part of this study from my perspective was not just that concordance, which suggests that there's an opportunity there for the use of ctDNA instead of tumor biopsies in some of these situations, but what was also interesting was the fact that there were several clinically relevant mutations which were detected only in the circulating tumor DNA. And a couple of examples of those included IDH1 for cholangiocarcinoma, BRAF and p53 in several histologies, and microsatellite instability was most prevalent in small cell lung cancer in the ctDNA. So I think that what this demonstrates is that liquid biopsy is certainly a viable screening option for patients who are being assessed for matching for targeted therapies in clinical trials. The fact that some of these mutations were only seen in the ctDNA and not in the primary tumor specimen certainly suggests that there's some tumor heterogeneity. But I think that for me, the most compelling part of this study was the fact that many of these mutations were only picked up in the plasma. And so, as the authors concluded, they believe that a comprehensive gene profiling with circulating tumor DNA probably should be included as a primary screening modality in future trials of targeted therapy of this type. Dr. Hamilton: Yeah, I think that that's really interesting and mirrors a lot of data that we've been seeing. At least in breast cancer, you know, we still do a biopsy up front to make sure that our markers, we're still treating the right disease that we think we are. But it really speaks to the utility of using ctDNA for serial monitoring and the emergence of mutations. Dr. Sweetenham: Absolutely. And you mentioned breast cancer, and so I'd like to dwell on that for a moment here because obviously, there was a huge amount of exciting breast cancer data presented at the meeting this year. And in particular, I'd like to ask you about LBA1008, the DESTINY-Breast09 clinical trial, which I think has the potential to establish a new first-line standard of care for metastatic HER2+ breast cancer. And that's an area where we haven't seen a whole lot of innovation for around a decade now. So can you give us some of the highlights of this trial and what your thinking is, having seen the results? Dr. Hamilton: Yeah, absolutely. So this was a trial in the first-line metastatic HER2 setting. So this was looking at trastuzumab deruxtecan. We certainly have had no shortage of reports around this drug, initially approved for later lines. DESTINY-Breast03 brought it into our second-line setting for HER2+ disease and we're now looking at DESTINY-Breast09 in first-line. So this actually was a 3-arm trial where patients were randomized 1:1:1 against standard taxane/trastuzumab/pertuzumab in one arm; trastuzumab deruxtecan with pertuzumab in another arm; and then a third arm, trastuzumab deruxtecan alone. And what we did not see reported was that trastuzumab deruxtecan-alone arm. But we did have reports from the trastuzumab deruxtecan plus pertuzumab versus the chemo/trastuzumab/pertuzumab. And what we saw was a statistically significant improvement in median progression-free survival, 26.9 months up to 40.7, so an improvement of 13.8 months, over a year in PFS. Not to mention that we're now in the 40-month range for PFS in first-line disease. Really, across all subgroups, we really weren't able to pick out a subset of patients that did not benefit. We did see about a 12% ILD rate with trastuzumab deruxtecan. That really is on par with what we've seen in other studies, around 10%-15%. I think that this is going to become a new standard of care in the first-line. I think it did leave some unanswered questions. We saw some data from the PATINA trial this past San Antonio Breast, looking at the addition of endocrine therapy with or without a CDK4/6 inhibitor, palbociclib, for those patients that also have ER+ disease, after taxane has dropped out in the first-line setting. So how we're going to kind of merge all this together is, I suspect that there are going to be patients that we or they just don't have the appetite to continue 3 to 4 years of trastuzumab deruxtecan. And so we're probably going to be looking at a maintenance-type strategy for them, maybe integrating the PATINA data there. But how we really put this into practice in the first-line setting and if or when we think about de-escalating down from trastuzumab deruxtecan to antibody therapy are some lingering questions. Dr. Sweetenham: Okay, so certainly is going to influence practice, but watch this space for a little bit longer, it sounds as though that's what you're saying. Dr. Hamilton: Absolutely.  So let's move on to GI cancer. Abstract 4006 reported preliminary results from the randomized phase 2 study of elraglusib in combination with gemcitabine/nab-paclitaxel versus the chemo gemcitabine/nab-paclitaxel alone in patients with previously untreated metastatic pancreatic cancer. Can you tell us more about this study? Dr. Sweetenham: Yeah, absolutely. As you mentioned, elraglusib is actually a first-in-class inhibitor of GSK3-beta, which has multiple potential actions in pancreatic cancer. But the drug itself may be involved in mediating drug resistance as well as in some tumor immune response modulation. Some of that's not clearly understood, I believe, right now. But certainly, preclinical data suggests that the drug may be effective in preclinical models and may also be effective in combination with chemotherapy and potentially with immune-modulating agents as well. So this particular study, as you said, was an open-label, randomized phase 2 study in which patients with pancreatic cancer were randomized 2:1 in favor of the elraglusib plus GMP—gemcitabine and nab-paclitaxel—versus the chemotherapy alone. And upon completion of the study, which is not right now, median overall survival was the primary end point, but there are a number of other end points which I'll talk about in just a moment. But the sample size was planned to be around 207 patients. The primary analysis included 155 patients in the combination arm versus 78 patients in the gemcitabine/nab-paclitaxel arm. Overall, the 1-year overall survival rate was 44.1% for the patients in the elraglusib-containing arm versus 23.0% in the patients receiving gemcitabine/nab-paclitaxel only. When they look at the median overall survival, it was 9.3 months for the experimental arm versus 7.2 months for chemotherapy alone. So put another way, there's around a 37% reduction in the risk of death with the use of this combination arm. The treatment was overall well-tolerated. There were some issues with grade 1 to 2 transient visual impairment in a large proportion of the patients. The most common treatment-related adverse effects with the elraglusib/GMP combination was transient visual impairment, which affected around 60% of the patients. Most of the more serious treatment-related adverse events included neutropenia, anemia, and fatigue in 50%, 25%, and 16% of the patients, respectively. So the early results from this study show a significant benefit for 1-year overall survival and for median overall survival with, as I mentioned above, a significant reduction in the risk of death. The authors went on to mention that the median overall survival for the control arm in this study is somewhat lower than in other comparable trials, but they think that this may be related to a more advanced disease burden in this particular study. Of interest to me was that right now: there is no apparent difference in progression-free survival between the 2 arms of this study. The authors described this as potentially indicating that this may be related in some way to immune modulation and immune effects on the tumor, which, if I'm completely honest, I don't totally understand. And so, the improvement in overall survival, as far as I can see at the moment, is not matched by an improvement in progression-free survival. So I think we probably need to wait for more time to elapse to see what happens with the study. And so, I think it certainly is an interesting study, and the results are intriguing, but I think it's probably a little early for it to actually shift the treatment paradigm in this disease. Dr. Hamilton: Fantastic. I think we've been waiting for advances in pancreatic cancer for a long time, but this, not unlike others, we learn more and then learn more we don't realize, so. Dr. Sweetenham: Right. Let's shift gears at this point and talk about a couple of other abstracts in kind of a very different space. Let's start out with symptom management for older adults with cancer. We know that undertreated symptoms are common among the older patient population, and Abstract 11002 reported on a randomized trial that demonstrated the effects of remote monitoring for older patients with cancer in terms of kind of symptoms and so on. Can you tell us a little bit about this study and whether you think this approach will potentially improve care for older patients? Dr. Hamilton: Yeah, I really liked this abstract. It was conducted through the Veterans Affairs, and it was based in California, which I'm telling you that because it's going to have a little bit of an implication later on. But essentially, adults that were 75 years or older who were Medicare Advantage beneficiaries were eligible to participate. Forty-three clinics in Southern California and Arizona, and patients were randomized either into a control group of usual clinic care alone, or an intervention group, which was usual care plus a lay health worker-led proactive telephone-based weekly symptom assessment, and this was for 12 months using the validated Edmonton Symptom Assessment System. So, there was a planned enrollment of at least 200 patients in each group. They successfully met that. And this lay health worker reviewed assessments with a physician assistant, who conducted follow-up for symptoms that changed by 2 points from a prior assessment or were rated 4 or greater. So almost a triage system to figure out who needed to be reached out to and to kind of work on symptoms. What I thought was fantastic about this was it was very representative of where it enrolled. There were actually about 50% of patients enrolled here that were Hispanic or Latinos. So some of our underserved populations and really across a wide variety of tumor types. They found that the intervention group had 53% lower odds of emergency room use, 68% lower odds of hospital use than the control group. And when they translated this to actual total cost of care, this was a savings of about $12,000 U.S. per participant and 75% lower odds of a death in an acute care facility. So I thought this was really interesting for a variety of reasons. One, certainly health care utilization and cost, but even more so, I think any of our patients would want to prevent hospitalizations and ER visits. Normally, that's not a fantastic experience having to feel poorly enough that you're in the emergency room or the hospital. And really showing in kind of concrete metrics that we were able to decrease this with this intervention. In terms of sustainability and scalability, I think the question is really the workforce to do this. Obviously, you know, this is going to take dedicated employees to have the ability to reach out to these patients, etc., but I think in value-based care, there's definitely a possibility of having reimbursement and having the funds to institute a program like this. So, definitely thought-provoking, and I hope it leads to more interventions. Dr. Sweetenham: Yeah, we've seen, over several years now, many of these studies which have looked at remote symptom monitoring and so on in this patient population, and many of them do show benefits for that in kinds of end points, not the least in this study being hospitalization and emergency room avoidance. But I think the scalability and personnel issue is a huge one, and I do wonder at some level whether we may see some AI-based platforms coming along that could actually help with this and provide interactions with these patients outside of actual real people, or at least in combination with real people. Dr. Hamilton: Yeah, that's a fantastic point.  So let's talk a little bit about clinical trials. So eligibility assessment for oncology clinical trials, or prescreening, really relies on manual review of unstructured clinical notes. It's time-consuming, it's prone to errors, and Abstract 1508 reported on the final analysis of a randomized trial that looked at the effect of human-AI teams prescreening for clinical trial eligibility versus human-only or AI-only prescreening. So give us more good news about AI. What did the study find? Dr. Sweetenham: Yeah, this is a really, a really interesting study. And of course, any of us who have ever been involved in clinical trials will know that accrual is always a problem. And I think most centers have attempted, and some quite successfully managed to develop prescreening programs so that patients are screened by a health care provider or health care worker prior to being seen in the clinic, and the clinical investigator will then already know whether they're going to be eligible for a trial or not. But as you've already said, it's a slow process. It's typically somewhat inefficient and requires a lot of time on the part of the health care workers to actually do this in a successful way. And so, this was a study from Emory University where they took three models of ways in which they could assess the accuracy of the prescreening of charts for patients who are going to be considered for clinical trials. One of these was essentially the regular way of having two research coordinators physically abstract the charts. The second one was an AI platform which would extract longitudinal EHR data. And then the third one was a combination of the two. So the AI would be augmented by the research coordinator or the other way around. As a gold standard, they had three independent oncology reviewers who went through all of these charts to provide what they regarded as being the benchmark for accuracy. In a way, it's not a surprise to me because I think that a number of other systems which have used this combination of human verification of AI-based tools, it actually ultimately concluded that the combination of the two in terms of chart accuracy was for the most part better than either one individually, either the research coordinator or the AI alone. So I'll give you just a few examples of where specifically that mattered. The human plus AI platform was more accurate in terms of tumor staging, in terms of identifying biomarker testing and biomarker results, as well as biomarker interpretation, and was also superior in terms of listing medications. There are one or two other areas where either the AI alone was somewhat more accurate, but the significant differences were very much in favor of a combination of human + AI screening of these patient charts. So, in full disclosure, this didn't save time, but what the authors reported was that there were definite efficiency gains, and presumably this would actually become even more improved once the research coordinators were somewhat more comfortable and at home with the AI tool. So, I thought it was an interesting way of trying to enhance clinical trial accrual up front by this combination of humans and technology, and I think it's going to be interesting to see if this gets adopted at other centers in the future. Dr. Hamilton: Yeah, I think it's really fascinating, all the different places that we can be using AI, and I love the takeaway that AI and humans together are better than either individually. Dr. Sweetenham: Absolutely.  Thanks once again, Dr. Hamilton, for sharing your insights with us today and for all of the incredible work you did to build a robust program. And also, congratulations on what was, I think, a really remarkable ASCO this year, one of the most exciting for some time, I think. So thank you again for that. Dr. Hamilton: Thanks so much. It was really a pleasure to work on ASCO 2025 this year. Dr. Sweetenham: And thank you to our listeners for joining us today. You'll find links to all the abstracts we discussed today in the transcript of this episode. Be sure to catch up on all of our coverage from the Annual Meeting. You can catch up on my daily reports that were published each day of the Annual Meeting, featuring the key science and innovations presented. And we'll have wrap-up episodes publishing in June, covering the full spectrum of malignancies from ASCO25. If you value the insights you hear on the ASCO Daily News Podcast, please remember 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.   More on today's speakers: Dr. John Sweetenham   Dr. Erika Hamilton @erikahamilton9   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Bluesky  ASCO on Facebook   ASCO on LinkedIn     Disclosures:     Dr. John Sweetenham:     No relationships to disclose    Dr. Erika Hamilton: Consulting or Advisory Role (Inst): Pfizer, Genentech/Roche, Lilly, Daiichi Sankyo, Mersana, AstraZeneca, Novartis, Ellipses Pharma, Olema Pharmaceuticals, Stemline Therapeutics, Tubulis, Verascity Science, Theratechnologies, Accutar Biotechnology, Entos, Fosun Pharma, Gilead Sciences, Jazz Pharmaceuticals, Medical Pharma Services, Hosun Pharma, Zentalis Pharmaceuticals, Jefferies, Tempus Labs, Arvinas, Circle Pharma, Janssen, Johnson and Johnson   Research Funding (Inst): AstraZeneca, Hutchison MediPharma, OncoMed, MedImmune, Stem CentRx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Millenium, TapImmune, Inc., Lilly, Pfizer, Lilly, Pfizer, Tesaro, Boehringer Ingelheim, H3 Biomedicine, Radius Health, Acerta Pharma, Macrogenics, Abbvie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceuticals, EMD Serono, Daiichi Sankyo, ArQule, Syros Pharmaceuticals, Clovis Oncology, CytomX Therapeutics, InventisBio, Deciphera, Sermonix Pharmaceuticals, Zenith Epigentics, Arvinas, Harpoon, Black Diamond, Orinove, Molecular Templates, Seattle Genetics, Compugen, GI Therapeutics, Karyopharm Therapeutics, Dana-Farber Cancer Hospital, Shattuck Labs, PharmaMar, Olema Pharmaceuticals, Immunogen, Plexxikon, Amgen, Akesobio Australia, ADC Therapeutics, AtlasMedx, Aravive, Ellipses Pharma, Incyte, MabSpace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pieris Pharmaceuticals, Pionyr, Repetoire Immune Medicines, Treadwell Therapeutics, Accutar Biotech, Artios, Bliss Biopharmaceutical, Cascadian Therapeutics, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, Relay Therapeutics, Tolmar, Torque, BeiGene, Context Therapeutics, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Cullinan Oncology, Bristol-Myers Squib, Eisai, Fochon Pharmaceuticals, Gilead Sciences, Inspirna, Myriad Genetics, Silverback Therapeutics, Stemline Therapeutics

Oncology Brothers
ASCO 2025 - GI Cancer Highlights: DYNAMIC III, ATOMIC, BREAKWATER, MATTERHORN, DESTINY Gastric04

Oncology Brothers

Play Episode Listen Later Jun 14, 2025 23:58


Welcome to another episode of the Oncology Brothers podcast! In this episode, Drs. Rahul and Rohit Gosain are joined by Dr. Cathy Eng, a renowned GI medical oncologist from the Vanderbilt Ingram Cancer Center, to discuss the most impactful updates from the ASCO 2025 annual meeting, specifically focusing on gastrointestinal (GI) malignancies. Join us as we dive into five pivotal abstracts that are set to change the landscape of GI cancer treatment: 1.⁠ ⁠DYNAMIC III: Discover how ctDNA-guided adjuvant chemotherapy in stage 3 colon cancer did not improve outcomes, highlighting questionable role of escalating approach with ctDNA positivity. 2.⁠ ⁠ATOMIC: Learn about the addition of atezolizumab to FOLFIRI in MSI-H disease stage 3 colon cancer, which improved disease-free survival with a hazard ratio of 0.50. 3.⁠ ⁠BREAKWATER: Explore how the combination of encorafenib, cetuximab, and FOLFOX has established a new standard of care for BRAF V600E mutant metastatic colorectal cancer, doubling overall survival from 15 months to 30.3 months. 4.⁠ ⁠MATTERHORN: Understand the use of durvalumab in the perioperative and postoperative setting with the FLOT regimen for resectable gastric and GE junction adenocarcinoma, showing significant improvements in event-free survival. 5.⁠ ⁠DESTINY Gastric04: Delved into the findings that confirm TDXd as a preferred option in the second line and beyond for HER2 positive metastatic gastric cancer or GE junction adenocarcinoma. YouTube: https://youtu.be/hllyI5S2Dqg Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/ Tune in for an insightful discussion that will keep you updated on the latest advancements in GI oncology! Don't forget to subscribe for more episodes on treatment algorithms, FDA approvals, and conference highlights.

Oncology for the Inquisitive Mind
160. ASCO 2025 - Plenary Part 2

Oncology for the Inquisitive Mind

Play Episode Listen Later Jun 11, 2025 25:44


In our second plenary episode, we're spotlighting two pivotal phase 3 trials: SERENA-6, which explores ctDNA-guided treatment with camizestrant to delay progression in HR-positive, HER2-negative advanced breast cancer with ESR1 mutations, and NIVOPOSTOP, a landmark study showing improved disease-free survival with adjuvant nivolumab in high-risk, resected head and neck squamous cell carcinoma. Join us as we unpack these practice-changing findings with expert insight and a couple of dad jokes along the way.Studies discussed in the episode:SERENA-6NIVOPOSTOPFor more episodes, resources and blog posts, visit www.inquisitiveonc.comPlease find us on Twitter @InquisitiveOnc!If you want us to look at a specific trial or subject, email us at inquisitiveonc@gmail.comArt courtesy of Taryn SilverMusic courtesy of AlisiaBeats: https://pixabay.com/users/alisiabeats-39461785/Disclaimer: This podcast is for educational purposes only. If you are unwell, seek medical advice.Oncology for the Inquisitive Mind is recorded with the support of education grants from our foundation partners Pfizer, Gilead Pharmaceuticals and Merck Pharmaceuticals. Our partners have access to the episode at the same time you do and have no editorial control over the content. Hosted on Acast. See acast.com/privacy for more information.

ReGândim Medicina
#ASCO25: Traseul ideal pentru pacienții Oncologici | Dr. Marius Geantă | #știința360

ReGândim Medicina

Play Episode Listen Later Jun 9, 2025 28:29


În cadrul ediției de pe 3 iunie a emisiunii Știința360 de pe Radio România Cultural, Dr. Marius Geantă, Președintele Centrului pentru Inovație în Medicină, a comentat ultimele noutăți din domeniul sănătății. În fiecare an, milioane de pacienți diagnosticați cu cancer în stadii incipiente trec prin intervenții chirurgicale cu intenție curativă. Însă după operație, rămâne o întrebare esențială: mai există celule canceroase în organism care ar putea cauza recidiva bolii? Tehnologiile actuale, cum ar fi imagistica, nu sunt suficient de sensibile pentru a detecta aceste urme de cancer. În acest context, testarea ADN-ului tumoral circulant (ctDNA) pentru detectarea bolii reziduale minime (MRD) este o soluție inovatoare care poate transforma modul în care sunt monitorizați pacienții după tratament. În cadrul congresului ASCO 2025 a fost prezentat un traseu ideal de îngrijire, creat împreună cu medici, pacienți, cercetători și factori de decizie, menit să integreze testarea ctDNA în practica clinică.Această prezentare reflectă activitatea desfășurată în cadrul proiectului european GUIDE.MRD (GUIding multi-moDal thErapies against Minimal Residual Disease by liquid biopsies), un parteneriat public-privat lansat în 2023 sub inițiativa IHI (Innovative Health Initiative), care reunește 25 de parteneri din întreaga Europă.Scopul proiectului este să răspundă provocării majore din oncologie, identificarea pacienților care, după operație, mai prezintă un risc real de recidivă și ar putea beneficia de tratament suplimentar. Pentru a face acest lucru, consorțiul promovează utilizarea testării ctDNA ca o soluție precisă și personalizată.Mai multe detalii despre subiectele discutate - ▶ Obezitatea și diabetul de tip 2 cresc riscul pentru nouă tipuri de cancere▶ Testarea genetică poate preveni majoritatea reacțiilor adverse ale medicamentelor, mai ales pentru boli cardiovasculare și psihiatrice▶ Traseul ideal pentru pacienții oncologici: o abordare europeană pentru integrarea biopsiei lichide ctDNA în practica medicalăAscultă emisiunea pe Radio România Cultural.

ReGândim Medicina
Diabetul de tip 5, recunoscut pentru prima dată la nivel mondial | Dr. Marius Geantă | #știința360

ReGândim Medicina

Play Episode Listen Later Jun 6, 2025 26:50


În cadrul ediției de pe 27 mai a emisiunii Știința360 de pe Radio România Cultural, Dr. Marius Geantă, Președintele Centrului pentru Inovație în Medicină, a comentat ultimele noutăți din domeniul sănătății. Odată cu creșterea incidenței diabetului zaharat la nivel mondial, comunitatea medicală face pași importanți pentru a înțelege mai bine formele mai puțin cunoscute ale acestei boli complexe. În 2025, Federația Internațională de Diabet (IDF) a recunoscut oficial o formă distinctă de diabet, diabetul asociat malnutriției, acum denumit diabet de tip 5. Această recunoaștere marchează un moment istoric, aducând în prim-plan o afecțiune care a fost mult timp ignorată, în ciuda faptului că afectează milioane de oameni, în special în medii unde accesul la hrană adecvată este limitat.Spre deosebire de diabetul de tip 2, asociat în principal cu obezitatea și supraconsumul alimentar, diabetul de tip 5 este legat de lipsa nutriției esențiale, afectând în special adolescenți și tineri slabi și subnutriți. Timp de decenii, această formă de diabet a rămas neînțeleasă, fiind adesea confundată cu alte tipuri de diabet, ceea ce a dus la tratamente ineficiente și rate alarmante de mortalitate.Recunoașterea diabetului de tip 5 este rezultatul muncii susținute a Dr. Meredith Hawkins, profesoară de medicină și directoare fondatoare a Institutului Global de Diabet de la Albert Einstein College of Medicine. Prin cercetări și colaborări internaționale, ea a reușit să atragă atenția comunității științifice asupra unei probleme majore de sănătate publică.Diabetul asociat malnutriției nu este o descoperire nouă. A fost documentat pentru prima dată în urmă cu mai bine de 70 de ani, iar în 1985, Organizația Mondială a Sănătății (OMS) l-a recunoscut ca o formă separată de diabet. Totuși, din cauza lipsei cercetărilor de urmărire, OMS a retras această clasificare în 1999.Mai multe detalii despre subiectele discutate - ▶ Organizația Mondială a Sănătății adoptă primul acord global pentru prevenirea și gestionarea pandemiilor▶ Diabetul de tip 5, recunoscut pentru prima dată la nivel mondial. Implicații pentru diagnostic și tratament▶ HPV-DeepSeek: un test de biopsie lichidă depistează cu acuratețe cancerele orofaringiene asociate HPV în stadii incipiente▶ Biopsia lichidă bazată pe ctDNA depistează recurențele în cancerul colorectal cu aproape 7 luni înainte de metodele imagisticeAscultă emisiunea pe Radio România Cultural.

ExpertenDialoge
Brustkrebs im Fokus: ctDNA, TRADE und neue Kombinationstherapien

ExpertenDialoge

Play Episode Listen Later Jun 2, 2025 12:21


Michael Patrick Lux und Harald Müller-Huesmann sprechen über aktuelle Studien beim HR-positiven und triple-negativen Mammakarzinom – darunter ctDNA-Monitoring, die TRADE-Studie zur individualisierten Therapiedauer sowie neue Kombinationstherapien bei endokriner Resistenz.

ExpertenDialoge
Von Therapieoptionen zur Nachwuchsförderung: Thoraxonkologie in Chicago

ExpertenDialoge

Play Episode Listen Later Jun 2, 2025 12:08


Cornelia Kropf-Sanchen und Harald Müller-Huesmann diskutieren Studien zum kleinzelligen und nicht-kleinzelligen Lungenkarzinom – darunter Immun-Chemo-Kombinationen, molekulare Rebiopsien bei Resistenzen und ctDNA als Marker für Therapieentscheidungen. Und auch die Nachwuchsförderung wird beleuchtet.

The Uromigos
Episode 422: ACSO 2025 - ctDNA data from NIAGARA

The Uromigos

Play Episode Listen Later Jun 1, 2025 32:40


Matt Galsky discusses the ASCO 2025 data regarding ctDNA from the NIAGARA neoadjuvant chemo +/- durvalumab study.

ASCO Daily News
Day 1: Top Takeaways From ASCO25

ASCO Daily News

Play Episode Listen Later May 30, 2025 10:08


In the first episode of a special daily series during the 2025 ASCO Annual Meeting, Dr. John Sweetenham discusses the results of 2 studies on the treatment of advanced colorectal cancer plus an additional study exploring the association of Medicaid expansion with cancer survival outcomes. Transcript Dr. John Sweetenham: Hello, and welcome to our special coverage of the 2025 ASCO Annual Meeting on the ASCO Daily News Podcast. I'm your host, Dr. John Sweetenham, and I'll be bringing you brief analysis on selected abstracts from each day of the Meeting. My disclosures are available in the transcript of this episode.  Today, I'll be reviewing three abstracts, the first two of which address the treatment of advanced colorectal cancer. Today's first study is Abstract 3501. These data were presented by Dr. Heinz-Josef Lenz from the USC Norris Comprehensive Cancer Center and report on the expanded analysis of the CheckMate-8HW trial. This was a phase 3, international, multicenter trial in patients with MSI-high/MMR-deficient metastatic colorectal cancer, who were randomized between nivolumab (nivo) alone, nivolumab plus ipilumomab (ipi) or investigators' choice of chemotherapy (FOLFOX or FOLFIRI) with or without bevacizumab or cetuximab. The study showed that nivo plus ipi demonstrated superior progression-free survival compared with chemotherapy in the first-line setting and superior progression-free survival compared with nivo alone across all lines of therapy. These results led to the approval of nivo + ipi in the first-line setting in patients with MSI-H/dMMR mCRC in the U.S., the EU, and many other countries.  In today's presentation, Dr. Lenz reported on the expanded analyses of nivo plus ipi versus nivo across all lines of therapy and longer follow-up results for nivo and ipi versus chemo in the first-line setting. With longer follow up (the median is now at 47 months) nivo and ipi continued to show progression-free survival benefit compared with chemotherapy with a median PFS of 54.1 months versus 5.9 months, for a hazard ratio of 0.21.  Additionally, the analysis of the effects on PFS2, defined as the time from randomization to progression after subsequent systemic therapy, start of second subsequent systemic therapy, or death, showed that compared with chemotherapy, first-line nivo and ipi was associated with a 72% reduction in the risk of death or disease progression, despite the fact that 71% of those who progressed following chemotherapy crossed over to receive subsequent immunotherapy. The study also showed that across all lines, nivo and ipi demonstrated superior progression-free survival compared with nivo alone, the median not reached versus 39.3 months, for a hazard ratio of 0.62. No new toxicity signals emerged after further analysis. Most treatment-related adverse events with possible immune etiology were observed within the first six months of therapy. The results for PFS2 are particularly significant. Up to now, there has been some reluctance to use nivo and ipi as first-line therapy, partly because of its toxicity profile and based on the rationale that it would be active after other frontline therapies. The observation in this study that the beneficial effects of nivo and ipi are maintained downstream is compelling. The results suggest that delaying the use of this combination to the second line or later may compromise subsequent PFS and supports the use of nivo and ipi as a standard-of-care frontline option for MSI-H/dMMR metastatic colorectal cancer. Moving on, the next study I'm featuring today is Abstract 3503, presented by Dr. Jeanne Tie from the Peter MacCallum Cancer Centre and the Walter and Eliza Hall Medical Institute of Medical Research from Melbourne, Australia. This study reported the impact of circulating tumor DNA (ctDNA)-guided adjuvant chemotherapy escalation in stage III colon cancer, focused on the primary analysis of the ctDNA-positive cohort from the randomized DYNAMIC-III trial. As background, about 30% of patients with stage III colon cancer will recur following standard-of-care adjuvant therapy with oxaliplatin-based regimens. And current data show that for those patients with high-risk disease, 6 months of chemotherapy is associated with a lower recurrence rate than 3 months. Circulating tumor DNA following initial surgery has been shown to be a strong independent prognostic factor for these patients, but questions remain about how ctDNA can be used for adaptation of treatment. Questions regarding treatment adaptation were addressed in the DYNAMIC-III trials – specifically, does treatment escalation benefit those who are ctDNA positive following surgery, and can therapy be de-escalated for those who are ctDNA negative. The first of these 2 questions – treatment escalation in the positive group – is the subject of this report. One thousand and two patients were randomized in this study, between ctDNA-informed therapy (502) or standard management (500). Of those patients included in the intent to treat cohorts, 129 were ctDNA positive in the ctDNA-informed arm compared with 130 in the standard management arm. Various pre-planned treatment escalation protocols were used, depending on the choice of first-line therapy. With a median follow up of 42.2 months, there was no difference in 3-year relapse free survival between the ctDNA informed group (48%) and the standard management group (52%). There was, however, a highly significant difference in relapse-free survival for patients who cleared ctDNA by the end of treatment compared with those who didn't. The authors concluded that the recurrence risk for this group remains high, at about 50%, after adjuvant therapy and that it increases with higher ctDNA burden, but treatment escalation didn't appear to reduce the recurrence risk. Clearance of ctDNA was associated with a favorable outcome, suggesting that as more effective treatments are developed in the future for this group, ctDNA will likely prove to have major utility. Changing gears now, my final selection for today is Abstract 11006, presented by Dr. Elizabeth Shafer from the American Cancer Society. This study explored the association of Medicaid expansion with 5-year survival after a cancer diagnosis.  Dr. Schafer began her presentation by providing some historical perspective on the impact of the Affordable Care Act on reducing the number of uninsured adults aged less than 65 years in the United States. She then reviewed some recent data on the impact of Medicaid expansion on cancer care, including improved screening rates, improved access to cancer surgery, and an increase in earlier cancer diagnosis. The current study builds on earlier data from the American Cancer Society which showed improved 2-year overall survival for patients with newly diagnosed cancer following Medicaid expansion. The new study reported by Dr. Schafer examined 5-year cause-specific survival in individuals with cancer since Medicaid expansion, analyzed according to cancer type and various demographic and social factors. Using data from more than 813,000 individuals from 26 states that expanded Medicaid compared with more than 610,000 from 12 states that did not, the authors reported that similar improvements in 5-year cause-specific survival were observed in the expansion and the non-expansion states, but when analyzed by other factors, differences in outcome emerged. For example, although similar improvements in survival between expansion and non-expansion states were seen in urban communities, there was a significant improvement of 2.55 percentage points in survival for individuals in rural communities in expansion states compared with those in non-expansion states. Similar trends were observed in high poverty areas, where improvements in survival were superior in expansion versus non-expansion states.  When examined by cancer type, the authors observed greater improvements in 5-year survival for those with pancreatic, lung, and colorectal cancer, possibly due to improvements in screening and early access to treatment.  The authors concluded that those residing in rural and high-poverty areas experienced the most improvement in cause-specific cancer survival following Medicaid expansion. In summary, it's encouraging to see an improving trend in cancer mortality overall, independent of Medicaid expansion, but it's also important to remember that this is yet another study which confirms how implementation of the ACA has improved cancer outcomes and begun to address some of the disparities in cancer care. Join me again tomorrow to hear more top takeaways from ASCO25. And if you value the insights that you hear on the ASCO Daily News Podcast, please remember to rate, review, and subscribe wherever you get your podcasts.   Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.     Find out more about today's speaker:  Dr. John Sweetenham    Follow ASCO on social media:  @ASCO on Twitter  @ASCO on Bluesky  ASCO on Facebook  ASCO on LinkedIn        Disclosures:  Dr. John Sweetenham:  No relationships to disclose 

OncLive® On Air
S13 Ep7: Evolving Molecular Profiling and Liquid Biopsy Practices Guide First-Line CRC Therapy Decisions: With Chandler Park, MD; and Midhun Malla, MD

OncLive® On Air

Play Episode Listen Later May 29, 2025 9:09


Drs Park and Malla began by talking through the clinical utility of ctDNA in patients with stage II and III colon cancer. Dr Malla referenced the DYNAMIC (ACTRN12615000381583) and observational BESPOKE CRC (NCT04264702) trials, noting that ctDNA serves as a prognostic biomarker for recurrence and is increasingly used to guide post-surgical surveillance.

ASCO Daily News
ASCO25 Preview: Key Research Accelerating Cancer Care

ASCO Daily News

Play Episode Listen Later May 22, 2025 20:42


Dr. John Sweetenham and Dr. Erika Hamilton discuss top abstracts that will be presented at the 2025 ASCO Annual Meeting, including research on tech innovations that could shape the future of oncology. Transcript Dr. John Sweetenham: Hello, and welcome to the ASCO Daily News Podcast. I'm your host, Dr. John Sweetenham, and I'm delighted to be joined today by Dr. Erika Hamilton, a medical oncologist and director of breast cancer and gynecologic cancer research at the Sarah Cannon Research Institute in Nashville, Tennessee. Dr. Hamilton is also the chair of the 2025 ASCO Annual Meeting Scientific Program, and she's here to tell us about some of the key abstracts, hot topics, and novel approaches in cancer care that will be featured at this year's Annual Meeting. Our full disclosures are available in the transcript of this episode. Dr. Hamilton, it's great to have you on the podcast today, and thanks so much for being here. Dr. Erika Hamilton: Thanks, Dr. Sweetenham. I'm glad to be here. Dr. John Sweetenham: Dr. Hamilton, the Presidential Theme of the Annual Meeting this year is ‘Driving Knowledge to Action: Building a Better Future,' and that's reflected in many of the sessions that will focus on action-oriented guidance to improve care for our patients. And as always, there'll be great presentations on practice-changing abstracts that will change treatment paradigms and transform care. Can you tell us about some of the hot topics this year and what you're particularly excited about? Dr. Erika Hamilton: You're right. Dr. Robin Zon's theme is ‘Driving Knowledge to Action: Building a Better Future,' and you're going to see that theme really interlaced throughout the ASCO program this year. We had a record number of submissions. Over 5,000 abstracts will be published, and there'll be about 3,000 presentations, either in oral format or poster presentations. We have 200 dynamic sessions. Many of the discussants will be highlighting key takeaways and how we can translate action-oriented guidance to better treat our patients to build a better future. Our state-of-the-art science will include a Plenary Session. This will feature presentations as well as discussion of each of the presentations for clinical late-breaking abstracts. We have Clinical Science Symposia that I'm particularly excited about this year. These will feature key abstracts as well as discussions and a foundational talk around the subject. We're covering novel antibody-drug conjugate targets, turning “cold” tumors “hot” to include CAR T, as well as the future of cancer detection. There'll be rapid oral abstracts, case-based panels, and this will also feature interactive audience polling and case discussions. I also want to highlight the community connection opportunities. There will be 13 Communities of Practice that will be meeting on-site during ASCO, and there's also really a plethora of networking opportunities for trainees and early-career professionals, a Women's Networking Center, a patient advocate space, and I'm happy to report there will also be live music out on the terrace this year at ASCO. Dr. John Sweetenham: Well, that's going to be a really great addition. I have to say, I think this is always a special time of year because excitement starts to mount as the meeting gets closer and closer. And once the abstracts are out there, I certainly personally feel that the excitement builds. Talking of abstracts, let's dive into some of the key abstracts for this year's meeting. I'd like to start out by asking you about Abstract 505. This reports on 15-year outcomes for women with premenopausal hormone receptor-positive early breast cancer in the SOFT and TEXT trials. It assesses the benefits of adjuvant exemestane and ovarian function suppression or tamoxifen and ovarian function suppression. So, could you talk us through this and tell us what you think the key takeaways from this abstract are? Dr. Erika Hamilton: Absolutely. This is essentially the SOFT and TEXT trials. They are trials that we've been following for quite some time, evidenced by the 15-year outcome. And I think it really answers two very important questions for us regarding adjuvant endocrine therapy for patients that are facing hormone receptor-positive disease. The benefit of ovarian function suppression for one, and then second, the benefit of exemestane over tamoxifen, which is our SERM [selective estrogen receptor modulator]. So, in terms of the SOFT trial, when we talk about distance recurrence-free interval, which I really think is probably the most meaningful because secondary cancers, et cetera, are not really what we're getting at here. But in terms of distant recurrence-free interval, certainly with tamoxifen, using tamoxifen plus ovarian function suppression adds a little bit. But where we really get additional benefits are by moving to exemestane, an aromatase inhibitor with the ovarian function suppression. So, for example, in SOFT, for distant recurrence-free interval for patients that have received prior chemotherapy, the distance recurrence-free interval was 73.5% with tamoxifen, bumped up just a tiny bit to 73.8% with ovarian function suppression. But when we used both ovarian function suppression and switched to that aromatase inhibitor, we're now talking about 77.6%. It may seem like these are small numbers, but when we talk about an absolute benefit of 4%, these are the type of decisions that we decide whether to offer chemotherapy based on. So, really just optimizing endocrine therapy really can provide additional benefits for these patients. Just briefly, when we turn to TEXT, similarly, when we look at distance recurrence-free interval for our patients that are at highest risk and receive chemotherapy, tamoxifen and ovarian function suppression, 79%; 81% with exemestane and ovarian function suppression. And when we talk about our patients that did not receive chemotherapy, it increased from 91.6% up to 94.6%—very similar that 3% to 4% number. So, I think that this is just very important information when counseling our patients about the decisions that they're going to make for themselves in the adjuvant setting and how much we want to optimize endocrine therapy. Dr. John Sweetenham: Thanks so much for your insight into that. Dr. Erika Hamilton: Yeah, absolutely. So, let's turn to hematologic malignancies. Abstract 6506 reports exciting results on the new agent ziftomenib in relapsed/refractory NPM1-mutant acute myeloid leukemia. This is a phase 1b clinical activity study and safety results. This was the pivotal KOMET-001 study. And my question is, will this new agent fulfill an unmet need in this NPM1 space? Dr. John Sweetenham: Yeah, great question. And I think the answer is almost certainly ‘yes'. So, just as some brief background, NPM1 mutation is known to be a driver of leukemogenesis in around 30% of patients with AML, and it's a poor prognostic factor. And typically, about 50% of these patients will relapse within a year of their first-line therapy, and only around 10% of them will get a subsequent complete remission with salvage therapy. Menin inhibitors, which disrupt the interaction between menin and KMT2A, are known to be active in NPM1-mutated as well as in KMT2A-rearranged AML. And ziftomenib is a selective oral menin inhibitor, which in this study was evaluated at a dose of 600 mg once a day, as you mentioned, a phase 1b/2 study, which is multicenter and presented by Dr. Eunice Wang from Roswell Park. It's a relatively large study of 112 patients who were treated with this standard dose with relatively short median follow-up at this time. The median age was 69 years, and median prior therapies were two, but with a range of one to seven. And I think very importantly, 60% of these patients had previously been treated with venetoclax, and 23% of them had had a prior transplant. Looking at the results overall for this study, the overall response rate was 35%, which is actually quite impressive. Specifically for those patients in the phase 2 part of the study, around 23% achieved a CR [complete remission] or CRh [complete remission with partial hematologic recovery]. What's very interesting in my mind is that the response rates were comparable in venetoclax-naive and venetoclax-exposed patients. And the drug was very well tolerated, with only 3% of patients having to discontinue because of treatment-related adverse events. And I think the authors appropriately conclude that, first of all, the phase 2 primary endpoint in the study was met, and that ziftomenib achieved deep and durable responses in relapsed and refractory NPM1-mutated AML, regardless of prior venetoclax, with good tolerance of the drug. And so, I think putting all of this together, undoubtedly, these data do support the potential use of this agent as monotherapy and as a new option for those patients who have relapsed or refractory NPM1-mutated acute myeloid leukemia. So, let's move on a little bit more now and change the subject and change gears completely and talk about circulating tumor DNA [ctDNA]. This has been a hot topic over a number of years now, and at this year's meeting, there are quite a few impactful studies on the use of ctDNA. We have time to focus on just one of these, and I wanted to get your thoughts on Abstract 4503. This is from the NIAGARA trial, which looks at ctDNA in patients with muscle-invasive bladder cancer who receive perioperative durvalumab. Could you tell us a little bit about this study? Dr. Erika Hamilton: So, this was the phase 3 NIAGARA trial, and this is literally looking for patients with muscle-invasive bladder cancer that are cisplatin-eligible, and the addition of durvalumab to neoadjuvant chemotherapy. So here, this is a planned exploratory analysis of ctDNA and the association with clinical outcomes from NIAGARA. So, this is really the type of study that helps us determine which of our patients are more likely to have a good outcome and which of our patients are more likely not to. There were 1,000 randomized patients in this study, and 462 comprised the biomarker-evaluable population. There were about half in the control arm and half in the durvalumab arm. And overall, the ctDNA-positive rate at baseline was about 57%, or a little over half, and that had decreased to about 22% after neoadjuvant treatment. ctDNA clearance rates from baseline to pre-radical cystectomy was about 41% among those with durvalumab and 31% among those in control. And the non-pCR rate was 97% among patients with pre-cystectomy ctDNA-positive status. So, this really gives us some information about predicting who is going to have better outcomes here. We did see a disease-free survival benefit with perioperative durvalumab, and this was observed in post-cystectomy ctDNA-positive as well as the ctDNA-negative groups. Shifting gears now to GI cancer, Abstract 3506 is a long-term safety and efficacy study of sotorasib plus panitumumab and FOLFIRI for previously treated KRAS G12C-mutated metastatic colorectal cancer. And this is the CodeBreaK-101 study. What are your thoughts on this study? Dr. John Sweetenham: Yeah, thanks. A very interesting study, and this abstract builds upon the phase 3 CodeBreaK-300 trial, which I think has just been published in the Journal of Clinical Oncology. This showed that the combination of sotorasib and panitumumab improved clinical outcomes in patients with chemorefractory KRAS G12C-mutated metastatic colorectal cancer. The current abstract, as you mentioned, reports the CodeBreaK-101 trial. And this was a phase 1b trial where FOLFIRI therapy was added to sotorasib and panitumumab in previously treated patients with KRAS G12C-mutated metastatic colorectal cancer. The abstract reports the overall and progression-free survival results, as well as some updated safety and response data. So, in this study, patients with this particular mutation who had received at least one prior systemic treatment but were KRAS G12C inhibitor-naive were enrolled into an expansion cohort of the CodeBreaK-101 protocol. And these patients received what apparently now recommended as the standard phase 2 dose of sotorasib of 960 mg daily, plus panitumumab and a standard dose of FOLFIRI. And the primary endpoint of the study was safety, and secondary endpoints included confirmed response, overall response, and progression-free survival, as assessed by the investigator. And by November of last year, 40 patients had been enrolled into this study. Common treatment-related adverse events were cutaneous; some patients developed neutropenia, and stomatitis was fairly widespread. Discontinuation of sotorasib because of adverse events was only seen in 1% of patients, although patients did have to discontinue because of toxicity from some of the other agents in the combination. Looking at the results of this study, the updated objective response rate was 57.5%, and the disease control rate was estimated at 92%, going on 93%, with a median time to response of 1.6 months and a median response duration of 6 months. After a median follow-up of 29.2 months, the median progression-free survival was 8.2 months, and the overall survival 17.9 months. So, the authors have concluded that this combination, including sotorasib, panitumumab, and FOLFIRI, does appear to show quite promising long-term efficacy in pretreated patients with this specific mutation. The ongoing phase 3 study they mentioned, CodeBreaK-301, is aiming to evaluate this combination against the standard of care in the first-line setting for patients with KRAS G12C-mutated colorectal cancer. So, promising results, and we'd be very interested to see how this particular combination performs in the frontline. Dr. Erika Hamilton: Fantastic. Thanks so much for sharing that. Let's shift gears again and really talk about digital technology. I feel that we're all going to have to get much better with this, and really, there are a lot of promises for our patients coming here. There are a lot of abstracts at ASCO that are focusing on innovations in digital technology, including a really interesting psychosocial digital application for caregivers of patients that are undergoing hematopoietic stem cell transplantation. Can you tell us a little bit about this? It's Abstract 11000. Dr. John Sweetenham: Yeah, absolutely. This abstract certainly caught my eye, and I think it's intriguing for a number of reasons, partly because it's app-based, and partly also because it specifically addresses caregiver burden and caregiver needs in the oncology setting, which I think is especially important. And although the context, the clinical context of this study, is hematopoietic stem cell transplantation, I think it has potential applications way beyond that. We all know that caregivers of patients undergoing stem cell transplantation have significant quality-of-life struggles. They are well-documented to have significant psychological and emotional strain before, during, and after stem cell transplantation. And this abstract describes an application called BMT-CARE, which is aimed at improving caregivers' quality of life, caregiver burden, mood symptoms, and coping skills, and so on. So, this was a single-center, randomized trial from MGH [Massachusetts General Hospital] of this app for stem cell transplant caregivers, compared with usual care in those individuals. And the eligible patients, or eligible individuals, were adults caring for patients with heme malignancy undergoing either an autologous or an allogeneic stem cell transplant. Patients were randomly assigned either to use the app or for usual care. And the app itself—and I think it'll be interesting to actually see this at the meeting and visualize it and see how user-friendly and so on it is—but it comprises five modules, which integrate psychoeducation, behavior change, stress management, and they're delivered through a kind of interactive platform of educational games and videos. And then participants were self-reporting at baseline and then 60 days after transplant. So, around 125 patients were enrolled in this study, of around 174 who were initially approached. So, just over 70% uptake from caregivers, which is, I think, relatively high, and evenly distributed between the two randomized arms. And the majority of the participants were spouses. And at 60 days post-stem cell transplant, the intervention participants reported a better quality of life compared with those who received usual care. If you break this down a little bit more, these participants reported lower caregiving burden, lower incidence of depression, fewer PTSD symptoms, and overall better coping skills. So, the authors conclude that this particular app, a digital health intervention, led to pretty substantial improvements in quality of life for these caregivers. So, intriguing. As I said, it'll be particularly interesting to see how this thing looks during the meeting. But if these kind of results can be reproduced, I think this sort of application has potential uses way beyond the stem cell transplant setting. Dr. Erika Hamilton: Yeah, I find that just so fascinating and very needed. I think that the caregiving role is often underestimated in how important that is for the patient and the whole family, and really giving our caregivers more tools in their toolbox certainly is quite helpful. Dr. John Sweetenham: Absolutely. Well, the meeting is getting closer, and as I mentioned earlier, I think anticipation is mounting. And I wanted to say thanks so much to you for chatting with me today about some of the interesting advances in oncology that we're going to see at this year's meeting. There is a great deal more to come. Our listeners can access links to the studies we've discussed today in the transcript of this episode. I'm also looking forward, Dr. Hamilton, to having you back on the podcast after the Annual Meeting to dive into some of the late-breaking abstracts and some of the other key science that's captured the headlines this year. So, thanks once again for joining me today. Dr. Erika Hamilton: Thanks so much for having me. Pleasure. Dr. John Sweetenham: And thank you to our listeners for joining us today. Be sure to catch my “Top Takeaways from ASCO25.” These are short episodes that will drop each day of the meeting at 5:30 p.m. Eastern Time. So, subscribe to the ASCO Daily News Podcast wherever you prefer to listen, and join me for concise analyses of the meeting's key abstracts.   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. John Sweetenham   Dr. Erika Hamilton @erikahamilton9   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Bluesky  ASCO on Facebook   ASCO on LinkedIn     Disclosures:     Dr. John Sweetenham:     No relationships to disclose  Dr. Erika Hamilton: Consulting or Advisory Role (Inst): Pfizer, Genentech/Roche, Lilly, Daiichi Sankyo, Mersana, AstraZeneca, Novartis, Ellipses Pharma, Olema Pharmaceuticals, Stemline Therapeutics, Tubulis, Verascity Science, Theratechnologies, Accutar Biotechnology, Entos, Fosun Pharma, Gilead Sciences, Jazz Pharmaceuticals, Medical Pharma Services, Hosun Pharma, Zentalis Pharmaceuticals, Jefferies, Tempus Labs, Arvinas, Circle Pharma, Janssen, Johnson and Johnson   Research Funding (Inst): AstraZeneca, Hutchison MediPharma, OncoMed, MedImmune, Stem CentRx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Millenium, TapImmune, Inc., Lilly, Pfizer, Lilly, Pfizer, Tesaro, Boehringer Ingelheim, H3 Biomedicine, Radius Health, Acerta Pharma, Macrogenics, Abbvie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceuticals, EMD Serono, Daiichi Sankyo, ArQule, Syros Pharmaceuticals, Clovis Oncology, CytomX Therapeutics, InventisBio, Deciphera, Sermonix Pharmaceuticals, Zenith Epigentics, Arvinas, Harpoon, Black Diamond, Orinove, Molecular Templates, Seattle Genetics, Compugen, GI Therapeutics, Karyopharm Therapeutics, Dana-Farber Cancer Hospital, Shattuck Labs, PharmaMar, Olema Pharmaceuticals, Immunogen, Plexxikon, Amgen, Akesobio Australia, ADC Therapeutics, AtlasMedx, Aravive, Ellipses Pharma, Incyte, MabSpace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pieris Pharmaceuticals, Pionyr, Repetoire Immune Medicines, Treadwell Therapeutics, Accutar Biotech, Artios, Bliss Biopharmaceutical, Cascadian Therapeutics, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, Relay Therapeutics, Tolmar, Torque, BeiGene, Context Therapeutics, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Cullinan Oncology, Bristol-Myers Squib, Eisai, Fochon Pharmaceuticals, Gilead Sciences, Inspirna, Myriad Genetics, Silverback Therapeutics, Stemline Therapeutics

Oncology Times - OT Broadcasts from the iPad Archives
Transforming colorectal cancer management with tumor informed ctDNA testing

Oncology Times - OT Broadcasts from the iPad Archives

Play Episode Listen Later May 22, 2025 14:25


In this episode, Dr. Ruchika Talwar, a urologic oncologist at Vanderbilt University Medical Center, Dr. Adham Jurdi, a medical oncologist and Senior Director of Oncology at Natera, delve into the groundbreaking world of tumor-informed molecular residual disease testing. Discover how circulating tumor DNA (ctDNA) is revolutionizing cancer detection and treatment, providing real-time insights that surpass traditional imaging methods. Learn about the decades-long journey to perfect this technology, its clinical implications, and the exciting advancements on the horizon.

OBR Peer-Spectives
When ESR1 Mutations Arise in Breast Cancer Patients With PIK3CA Mutations: What Next?

OBR Peer-Spectives

Play Episode Listen Later May 6, 2025 10:15


The approach to ESR1 and PIK3CA mutations in patients with hormone receptor–positive metastatic breast cancer continues to evolve. What role does circulating tumor DNA (ctDNA) play in treatment decisions? How should oncologists best approach patients with PIK3CA mutations who subsequently develop ESR1 mutations? VK Gadi, MD, PhD, professor and director of medical oncology and deputy director of the University of Illinois Cancer Center in Chicago, discusses with Robert A. Figlin, MD, the interim director of Cedars-Sinai Cancer in Los Angeles and Steven Spielberg Family Chair in Hematology-Oncology, how recent data are informing care for patients with comutations. “We now have at least one ESR1-targeting drug out there, and more to come,” Dr. Gadi explains. “Elacestrant is the drug I'm of course referencing, and that is used essentially like a single agent and works well for those patients. Even when they have, for example, PIK3CA mutations present.” He and Dr. Figlin consider when to act on ctDNA findings and potential future strategies. Dr. Gadi reported no relevant financial relationships. Dr. Figlin reported various financial relationships.

Oncology Brothers
Perioperative Durvalumab FDA Approval New Standard for Muscle Invasive Bladder Cancer

Oncology Brothers

Play Episode Listen Later May 5, 2025 21:58


Welcome to another episode of the Oncology Brothers podcast! In this episode, we dived into the recent FDA approval of Durvalumab combined with chemotherapy for resectable muscle-invasive bladder cancer, based on the NIAGARA trial. Join us as we chat with Dr. Thomas Powles, a GU medical oncologist and the lead author of the NIAGARA trial. We discussed the study design, the significant improvements in overall survival, and the implications of this new treatment approach. Dr. Powles shared insights on the use of immunotherapy in the perioperative setting, the importance of pathological complete response, and the safety of combining Durvalumab with chemotherapy. Key topics covered in this episode: •⁠  ⁠Overview of the NIAGARA trial and its findings •⁠  ⁠Comparison of Durvalumab and cisplatin-based chemotherapy outcomes •⁠  ⁠The significance of event-free survival and overall survival rates •⁠  ⁠Insights on managing side effects and treatment sequencing •⁠  ⁠The evolving role of ctDNA in determining treatment strategies YouTube: https://youtu.be/s_tXoX5yhV8 Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/ Tune in to learn how these advancements are changing the landscape of bladder cancer treatment and improving patient outcomes. Don't forget to like, subscribe, and check out our other episodes for more insights on oncology and FDA approvals! #OncologyBrothers #BladderCancer #Dervalumab #FDAApproval #NiagaraTrial #Immunotherapy #CancerResearch #OncologyPodcast

JCO Precision Oncology Conversations
Prognostic Artificial Intelligence Scores and Outcomes in Nonmetastatic Prostate Cancer

JCO Precision Oncology Conversations

Play Episode Listen Later Apr 16, 2025 20:49


JCO PO author Dr. Timothy Showalter at Artera and University of Virginia shares insights into his JCO PO article, “Digital Pathology–Based Multimodal Artificial Intelligence Scores and Outcomes in a Randomized Phase III Trial in Men With Nonmetastatic Castration-Resistant Prostate Cancer” . Host Dr. Rafeh Naqash and Dr. Showalter discuss how multimodal AI as a prognostic marker in nonmetastatic castration-resistant prostate cancer may serve as a predictive biomarker with high-risk patients deriving the greatest benefit from treatment with apalutamide. TRANSCRIPT  Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we'll bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, podcast Editor for JCO Precision Oncology and assistant professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today, we are excited to be joined by Dr. Timothy Showalter, Chief Medical Officer at Artera and professor of Radiation Oncology at the University of Virginia and author of the JCO Precision Oncology article entitled, “Digital Pathology Based Multimodal Artificial Intelligence Scores and Outcomes in a Randomized Phase 3 Trial in Men with Non-Metastatic Castration Resistant Prostate Cancer.” At the time of this recording, our guest's disclosures will be linked in the transcript. Dr. Showalter, it's a pleasure to have you here today. Dr. Timothy Showalter: It's a pleasure to be here. Thanks for having me. Dr. Rafeh Naqash: I think this is going to be a very interesting discussion, not just from a biomarker perspective, but also in terms of how technologies have evolved and how we are trying to stratify patients, trying to escalate or deescalate treatments based on biomarkers. And this article is a good example of that. One of the things I do want to highlight as part of this article is that Dr. Felix Feng is the first author for this article. Unfortunately, Dr. Felix Feng passed away in December of 2024. He was a luminary in this field of prostate cancer research. He was also the Chair of the NRG GU Committee as well as Board of Directors for RTOG Foundation and has mentored a lot of individuals from what I have heard. I didn't know Dr. Feng but heard a lot about him from my GU colleagues. It's a huge loss for the community, but it was an interesting surprise for me when I saw his name on this article as I was reviewing it. Could you briefly talk about Dr. Feng for a minute and how you knew him and how he's been an asset to the field? Dr. Timothy Showalter: Yeah. I'm always happy to talk about Felix whenever there's an opportunity. You know, I was fortunate to know Felix Feng for about 20 years as we met during our residency programs through a career development workshop that we both attended and stayed close ever since. And you know, he's someone who made an impact on hundreds of lives of cancer researchers and other radiation oncologists and physicians in addition to the cancer patients he helped, either through direct clinical care or through his innovation. For this project in particular, I first became involved soon after Felix had co-founded Artera, which is, you know the company that developed this. And because Felix was such a prolific researcher, he was actually involved in this and this research project from all different angles, both from the multimodal digital pathology tool to the trial itself and being part of moving the field forward in that way. It's really great to be able to sort of celebrate a great example of Felix's legacy, which is team science, and really moving the field forward in terms of translational projects based on clinical trials. So, it's a great opportunity to highlight some of his work and I'm really happy to talk about it with you. Dr. Rafeh Naqash: Thanks, Tim. Definitely a huge loss for the scientific community. And I did see a while back that there was an international symposium organized, showcasing his work for him to talk about his journey last year where more than 200, 250 people from around the globe actually attended that. That speaks volumes to the kind of impact he's had as an individual and impact he's had on the scientific side of things as well. Dr. Timothy Showalter: Yes. And we just had the second annual Feng Symposium the day before ASCO GU this year with, again, a great turnout and some great science highlighted, as well as a real focus on mentorship and team science and collaboration. Dr. Rafeh Naqash: Thank you so much for telling us all about that. Now going to what you guys published in JCO Precision Oncology, which is this article on using a biomarker approach to stratify non-metastatic prostate cancer using this artificial intelligence based H&E score. Could you tell us the background for what started off this project? And I see there is a clinical trial data set that you guys have used, but there's probably some background to how this score or how this technology came into being. So, could you superficially give us an idea of how that started? Dr. Timothy Showalter: Sure. So, the multimodal AI score was first published in a peer reviewed journal back in 2022 and the test was originally developed through a collaboration with the Radiation Therapy Oncology Group or Energy Oncology Prostate Cancer Research Team. The original publication describes development and validation of a risk stratification tool designed to predict distant metastasis and prostate cancer specific mortality for men with localized prostate cancer. And the first validation was in men who were treated with definitive radiation therapy. There have been subsequent publications in that context and there's a set of algorithms that have been validated in localized prostate cancer and there's a test that's listed on NCCN guidelines based on that technology. The genesis for this paper was really looking at extending that risk stratification tool that was developed in localized prostate cancer to see if it could one, validate in a non-metastatic castrate refractory prostate cancer population for patients enrolled on the SPARTAN trial. And two, whether there was a potential role for the test output in terms of predicting benefit from apalutamide for patients with non-metastatic prostate cancer. For patients who are enrolled on the SPARTAN study, almost 40% of them had H&E stain biopsy slide material available and were eligible to be included in this study. Dr. Rafeh Naqash: Going a step back to how prostate cancer, perhaps on the diagnostic side using the pathology images is different as you guys have Gleason scoring, which to the best of my knowledge is not necessarily something that most other tumor types use. Maybe Ki-67 is somewhat of a comparison in some of the neuroendocrine cancers where high Ki-67 correlates with aggressive biology for prognosis. And similarly high Gleason scores, as we know for some of the trainees, correlates with poor prognosis. So, was the idea behind this based on trying to stratify or sub-stratify Gleason scoring further, where you may not necessarily know what to do with the intermediate high Gleason score individual tumor tissues? Dr. Timothy Showalter: Well, yeah. I mean, Gleason score is a really powerful risk stratification tool. As you know, our clinical risk groupings are really anchored to Gleason scores as an important driver for that. And while that's a powerful tool, I think, you know, some of the original recognition for applying computer vision AI into this context is that there are likely many other features located in the morphology that can be used to build a prognostic model. Going back to the genesis of the discovery project for the multimodal AI model, I think Felix Feng would have described it as doing with digital pathology and computer vision AI what can otherwise be done with gene expression testing. You know, he would have approached it from a genomic perspective. That's what the idea was. So, it's along the line of what you're saying, which is to think about assigning a stronger Gleason score. But I think really more broadly, the motivation was to come up with an advanced complementary risk stratification tool that can be used in conjunction with clinical risk factors to help make better therapy recommendations potentially. So that was the motivation behind it. Dr. Rafeh Naqash: Sure. And one of the, I think, other important teaching points we try to think about, trainees of course, who are listening to this podcast, is trying to differentiate between prognostic and predictive scores. So, highlighting the results that you guys show in relation to the MMAI score, the digital pathology score, and outcomes as far as survival as well as outcomes in general, could you try to help the listeners understand the difference between the prognostic aspect of this test and the predictive aspect of this test? Dr. Timothy Showalter: So let me recap for the listeners what we found in the study and how it kind of fits into the prognostic and the predictive insights. So, one, you know, as I mentioned before, this is ultimately a model that was developed and validated for localized prostate cancer for risk stratification. So, first, the team looked at whether that same tool developed in localized prostate cancer serves as a prognostic tool in non-metastatic castrate-refractory prostate cancer. So, we applied the tool as it was previously developed and identified that about 2/3 of patients on the SPARTAN trial that had specimens available for analysis qualified as high risk and 1/3 of patients as either intermediate or low risk, which we called in the paper ‘non-high risk'. And we're able to show that the multimodal AI score, which ranges from 0 to 1, and risk group, was associated with metastasis free survival time to second progression or PFS 2 and overall survival. And so that shows that it performs as a prognostic tool in this setting. And this paper was the first validation of this tool in non-metastatic castrate-refractory prostate cancer. So, what that means to trainees is basically it helps you understand how aggressive that cancer is or better stratify the risk of progression over time. So that's the prognostic performance. Dr. Rafeh Naqash: Thank you for trying to explain that. It's always useful to get an example and understand the difference between prognostic and predictive. Now again, going back to the technology, which obviously is way more complicated than the four letter word MMAI, I per se haven't necessarily done research in this space, but I've collaborated with some individuals who've done digital pathology assessments, and one of the projects we worked on was TIL estimation and immune checkpoint related adverse events using some correlation and something that one of my collaborators had sent to me when we were working on this project as part of this H&E slide digitalization, you need color deconvolution, you need segmentation cell profiling. Superficially, is that something that was done as part of development of this MMAI score as well? Dr. Timothy Showalter You need a ground truth, right? So, you need to train your model to predict whatever the outcome is. You know, if you're designing an AI algorithm for Ki-67 or something I think you mentioned before, you would need to have a set of Ki-67 scores and train your models to create those scores. In this case, the clinical annotation for how we develop the multimodal AI algorithm is the clinical endpoints. So going back to how this tool was developed, the computer vision AI model is interpreting a set of features on the scan and what it's trying to do is identify high risk features and make a map that would ultimately predict clinical outcomes. So, it's a little bit different than the many digital pathology algorithms where the AI is being trained to predict a particular morphological finding. In this case, the ground truth that the model is trained to predict is the clinical outcome. Dr. Rafeh Naqash: Sure. And from what you explained earlier, obviously, tumors that had a high MMAI score were the ones that were benefiting the most from the ADT plus the applausive. Is this specific for this androgen receptor inhibitor or is it interchangeable with other inhibitors that are currently approved? Dr. Timothy Showalter: That's a great question and we don't know yet. So, as you're alluding to, we did find that the MMAI risk score was predictive for benefit from apalutamide and so it met the statistical definition of having a significant interaction p value so we can call it a predictive performance. And so far, we've only looked in this population for apalutamide. I think you're raising a really interesting point, which is the next question is, is this generalizable to other androgen receptor inhibitors? There will be future research looking at that, but I think it's too early to say. Just for summary, I think I mentioned before, there are about 40% of patients enrolled on the SPARTAN study had specimens available for inclusion in this analysis. So, the SPARTAN study did show in the entire clinical trial set that patients with non-metastatic castrate-refractory prostate cancer benefited from apalutamide. The current study did show that there seems to be a larger magnitude of benefit for those patients who are multimodal AI high risk scores. And I think that's very interesting research and suggests that there's some interaction there. But I certainly would want to emphasize that we have not shown that patients with intermediate or low risk don't benefit from apalutamide. I think we can say that the original study showed that that trial showed a benefit and that we've got this interesting story with multimodal AI as well. Dr. Rafeh Naqash: Sure. And I think from a similar comparison, ctDNA where ctDNA shows prognostic aspects, I treat people with lung cancer especially, and if you're ctDNA positive at a 3 to 4-month period, likely chances of you having a shorter disease-free interval is higher. Same thing I think for colorectal cancers. And now there are studies that are using ctDNA as an integral biomarker to stratify patients positive/negative and then decide on escalation/de-escalation of treatment. So, using a similar approach, is there something that is being done in the context of the H&E based stratification to de-intensify or intensify treatments based on this approach? Dr. Timothy Showalter: You're hitting right on the point in the most promising direction. You know, as we pointed out in the manuscript, one of the most exciting areas as a next step for this is to use a tool like this for stratification for prospective trials. The multimodal AI test is not being used currently in clinical trials of non-metastatic castrate-refractory prostate cancer, which is a disease setting for this paper. There are other trials that are in development or currently accruing where multimodal AI stratification approach is being taken, where you see among the high-risk scores, at least in the postoperative setting for a clinical trial that's open right now, high risk score patients are being randomized to basically a treatment intensification question. And then the multimodal AI low risk patients are being randomized to a de-intensification experimental arm where less androgen deprivation therapy is being given. So, I think it's a really promising area to see, and I think what has been shown is that this tool has been validated really across the disease continuum. And so, I think there are opportunities to do that in multiple clinical scenarios. Dr. Rafeh Naqash: Then moving on to the technological advancements, very fascinating how we've kind of evolved over the last 10 years perhaps, from DNA based biomarkers to RNA expression and now H&E. And when you look at cost savings, if you were to think of H&E as a simpler, easier methodology, perhaps, with the limitations that centers need to digitalize their slides, probably will have more cost savings. But in your experience, as you've tried to navigate this H&E aspect of trying to either develop the model or validate the model, what are some of the logistics that you've experienced can be a challenge? As we evolve in this biomarker space, how can centers try to tackle those challenges early on in terms of digitalizing data, whether it's simple data or slides for that matter? Dr. Timothy Showalter: I think there's two main areas to cover. One, I think that the push towards digitalization is going to be, I think, really driven by increasing availability and access to augmentative technologies like this multimodal AI technology where it's really adding some sort of a clinical insight beyond what is going to be generated through routine human diagnostic pathology. I think that when you can get these sorts of algorithms for patient care and have them so readily accessible with a fast turnaround time, I think that's really going to drive the field forward. Right now, in the United States, the latest data I've seen is that less than 10% of pathology labs have gone digital. So, we're still at an early stage in that. I hope that this test and similar ones are part of that push to go more digital. The other, I think, more interesting challenge that's a technical challenge but isn't about necessarily how you collect the data, but it certainly creates data volume challenges, is how do you deal with image robustness and sort of translating these tools into routine real-world settings. And as you can imagine, there's a lot of variation for staining protocols, intensity scanner variations, all these things that can affect the reliability of your test. And at least for this research group that I'm a part of that has developed this multimodal AI tool can tell you that the development is sophisticated, but very data and energy intensive in terms of how to deal with making a tool that can be consistent across a whole range of image parameters. And so that presents its own challenges for dealing with a large amount of compute time and AI cycles to make robust algorithms like that. And practically speaking, I think moving into other diseases and making this widely available, the size of data required and the amount of cloud compute time will be a real challenge. Dr. Rafeh Naqash: Thank you for summarizing. I can say that definitely, you know, this is maybe a small step in prostate cancer biomarker research, but perhaps a big step in the overall landscape of biomarker research in general. So definitely very interesting. Now, moving on to the next part of the discussion is more about you as a researcher, as an individual, your career path, if you can summarize that for us. And more interestingly, this intersection between being part of industry as well as academia for perhaps some of the listeners, trainees who might be thinking about what path they want to choose. Dr. Timothy Showalter: Sure. So, as you may know, I'm a professor at the University of Virginia and I climbed the academic ladder and had a full research grant program and thought I'd be in academia forever. And my story is that along the way, I kind of by accident ended up founding a medical device company that was called Advaray and that was related to NCI SBIR funding. And I found myself as a company founder and ultimately in that process, I started to learn about the opportunity to make an impact by being an innovator within the industry space. And that was really the starting point for me. About four years ago, soon after Felix Feng co-founded Artera, he called me and told me that he needed me to join the company. For those who were lucky to know Felix well, at that very moment, it was inevitable that I was going to join Artera and be a part of this. He was just so persuasive. So, I will say, you know, from my experience of being sort of in between the academic and industry area, it's been a really great opportunity for me to enter a space where there's another way of making an impact within cancer care. I've gotten to work with top notch collaborators, work on great science, and be part of a team that's growing a company that can make technology like this available. Dr. Rafeh Naqash: Thank you so much, Tim, for sharing some of those thoughts and insights. We really appreciate you discussing this very interesting work with us and also appreciate you submitting this to JCO Precision Oncology and hopefully we'll see more of this as this space evolves and maybe perhaps bigger more better validation studies in the context of this test. Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

OncLive® On Air
S12 Ep37: Bladder-Sparing Strategies and ctDNA-Guided Strategies Take Center Stage in MIBC: With Chandler Park, MD; and Vadim Koshkin, MD

OncLive® On Air

Play Episode Listen Later Apr 14, 2025 5:28


In this week's episode of MedNews Week's Oncology Unplugged, host Chandler Park, MD, a medical oncologist at Norton Cancer Institute in Louisville, Kentucky, concluded a 3-part series with Vadim Koshkin, MD, an associate professor of medicine in the Division of Hematology and Oncology in the Department of Medicine at the University of California, San Francisco (UCSF) School of Medicine, as well as a genitourinary medical oncologist at the UCSF Helen Diller Comprehensive Cancer Center. In part 3 of this 3-part episode series, Drs Park and Koshkin explored the clinical implications of practice-changing data from the phase 3 NIAGARA trial (NCT03732677) of perioperative durvalumab plus neoadjuvant chemotherapy in patients with resectable bladder cancer and discussed how the evolving perioperative treatment paradigm may affect future treatment sequencing decisions for this population. Additional topics included ongoing research efforts focused on bladder-sparing strategies, the utility of circulating tumor DNA and advanced imaging to guide treatment intensity, and the role of biomarker-driven approaches to personalize therapy for patients with muscle-invasive disease.

Oncology Brothers
How to Manage & Treat Pancreatic Cancer

Oncology Brothers

Play Episode Listen Later Apr 7, 2025 24:06


Join us in this insightful episode of the Oncology Brothers podcast as we dive deep into the current treatment landscape of pancreatic cancer. Drs. Rohit and Rahul Gosain are joined by Dr. Emil Lou, a medical and neuro-oncologist from the University of Minnesota, to discuss the challenges and advancements in managing this complex disease. In this episode, we covered: •⁠  ⁠The importance of a multidisciplinary approach in treating early-stage pancreatic cancer. •⁠  ⁠The role of neoadjuvant and adjuvant therapies, including the latest insights on chemotherapy regimens like FOLFIRINOX, nal-IRI and gemcitabine. •⁠  ⁠The significance of germline and next-generation sequencing (NGS) testing in personalizing treatment plans. •⁠  ⁠The current state of clinical trials and emerging therapies, including PARP inhibitors for BRCA mutations and the implications of ctDNA testing. •⁠  ⁠Prognostic discussions around metastatic pancreatic cancer and the importance of managing side effects to improve patient quality of life. Key takeaways include the necessity of balancing treatment efficacy with adverse events, the critical role of genetic testing, and the need for vigilance regarding venous thromboembolism (VTE) in pancreatic cancer patients. Don't miss this comprehensive discussion that aims to shed light on the ongoing efforts to improve outcomes for patients battling pancreatic cancer.   YouTube: https://youtu.be/HCKQxmOqRTI   Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/ Subscribe to our channel for more discussions on oncology and stay updated on the latest in cancer treatment!

Answers from the Lab
Liquid Biopsy Enables Precision Cancer Care: Bill Morice, M.D., Ph.D.

Answers from the Lab

Play Episode Listen Later Apr 3, 2025 11:09


In this episode of “Answers From the Lab,” William Morice II, M.D., Ph.D., CEO and president of Mayo Clinic Laboratories, invited Min-Han Tan, M.B.B.S., FRCP, Ph.D., founding CEO and medical director of Lucence, to discuss liquid biopsy cancer testing. Mayo Clinic Laboratories and Lucence recently announced a collaboration to expand access to this cutting-edge cancer test that is designed to detect clinically relevant biomarkers in ctDNA and ctRNA.During their conversation, Dr. Morice and Dr. Tan explore:Inspiration for developing the liquid biopsy.Features that differentiate LiquidHALLMARK® from existing cancer tests.Patients who will benefit from the test and how an oncologist might use the results.The future potential of liquid biopsy advancements.

ASCO Daily News
Personalizing Lung Cancer Management With ctDNA: Where We Are and Where We Are Headed

ASCO Daily News

Play Episode Listen Later Apr 3, 2025 19:09


Dr. Vamsi Velcheti and Dr. Charu Aggarwal discuss the evolution of ctDNA as a critical tool in precision oncology and its implications for lung cancer management, including its potential role in the early-stage setting. TRANSCRIPT Dr. Vamsi Velcheti: Hello. I am Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I am a professor of medicine and director of thoracic medical oncology at the Perlmutter Cancer Center at NYU Langone Health.  The management of small cell lung cancer has rapidly evolved over the past few decades, and today, molecular testing and biomarker testing for lung cancer are absolutely critical in terms of designing treatment options for our patients with metastatic non-small cell lung cancer. Today, I'm delighted to be joined by Dr. Charu Aggarwal for a discussion on ctDNA (circulating tumor DNA) and the role of ctDNA in lung cancer management. Dr. Aggarwal is the Leslye Heisler Professor of Lung Cancer Excellence and section chief of thoracic and head and neck oncology at University of Pennsylvania Abramson Cancer Center.  You'll find our full disclosures in the transcript of that episode.  Dr. Agrawal, it's great to have you on the podcast today. Thank you for being here. Dr. Charu Aggarwal: Thank you for having me. Dr. Vamsi Velcheti: Let's start off with setting the stage for ctDNA technology. These technologies have rapidly evolved from experimental conceptual stage to essential clinical tools for day-to-day clinical practice. Could you briefly discuss how recent advancements in ctDNA technologies are shaping our approach to precision medicine, especially in lung cancer? Dr. Charu Aggarwal: Absolutely. And you know, I think we need to just level set a little bit. What exactly is circulating tumor DNA? This is a way to assess exactly that. Every tumor sheds little pieces of tumor-derived DNA into the bloodstream, and this occurs in a variety of solid tumors. But now we have the technology to be able to derive this DNA that's actually being shed from the tumor into the bloodstream, these minute fragments of DNA, take them out, amplify them and sequence them with a variety of different mechanisms. They can be DNA sequencing alone, they can be DNA and RNA sequencing, they can be whole transcriptome sequencing. The technology, as you rightly pointed out, Dr. Velcheti, has significantly improved from just being able to look at circulating tumor DNA to now being able to amplify it, sequence it, and use it to offer personalized therapy. I think lung cancer is definitely the poster child for such an approach as we have a lot of data that has shown clinical utility and validity of being able to use circulating tumor DNA next-generation gene sequencing to guide therapy. Dr. Vamsi Velcheti: There have been so many technological leaps. It's really impressive how far we've come to advance these sequencing platforms. Recent advances with AI and machine learning are also playing important roles in interpreting ctDNA data. How are these computational advances really enhancing clinical decision-making in day-to-day clinical practice? Dr. Charu Aggarwal: I think while we have firmly established the role of ctDNA in the management of patients with metastatic lung cancer, some of the approaches that you talked about are still experimental. So let me backtrack a little bit and set the stage for how we use ctDNA in clinical practice right now. I think most patients, when they come in with a new diagnosis of stage IV lung cancer, we want to test for biomarkers. And this should actually be the established standard. Now included in the NCCN guidelines and actually also international guidelines, is to consider using blood-based testing or plasma-based testing to look for biomarkers, not just tissue-based testing which had been our historical standard, but to use these plasma guided approaches to identify the seven to nine biomarkers that may be truly implicated in either first- or second-line therapy that are called as your immediately actionable mutations.  What you're talking about is AI computational methods. I think there's a lot of excitement about how we can use genomic signatures that are derived from either tissue or ctDNA-based biomarker testing, combine it with radiomic features, combine it with histologic features, look at H & E patterns, use AI algorithmic learning to be able to actually predict recurrence scores, or can we actually come up with predictive signatures that may be extremely helpful?  So, I think some of the techniques and technologies that you're talking about are incoming. They are provocative. I think they're very exciting, but very early. Dr. Vamsi Velcheti: I think it's really amazing how many advances we have with these platforms. You know, the challenge really is the significant gap in terms of uptake of molecular testing. Even today, in 2025, there are significant gaps in terms of all metastatic lung cancer patients being tested for all biomarkers.  So, why do you think there's such a challenge in testing patients with lung cancer? In most academic practices, we try to achieve 100% testing for all our patients, but we know from recent studies that that's not the case across the country. What do you think the gaps are? Dr. Charu Aggarwal: Biomarker testing is so essential, like you pointed out, for us to be able to guide the right therapy for our patients. And we see this in our practice every day as you and I see patients with lung cancer, that a large proportion of our patients either don't get tested or they start therapy before their test results come back. So, I think this is a real problem.  However, to add some optimism to this problem, I do think that we are making a move in the right direction. So, four or five years ago, there was a lot of data being presented at national meetings, including ones from the American Society of Clinical Oncology, where we saw that, nationally, the rates of biomarker testing were probably in the rate of 40 to 50%. However, now with the availability of both tissue and plasma, I do think that the rates of biomarker testing are increasing. And if you were to survey a sample or even perform retrospective data research, I believe that the number is closer to 70% of all patients with metastatic non-small cell lung cancer.  And you know, you asked why is it not 100%? I think there are many reasons. I think the number one reason is tissue availability. Many times, the biopsies are small, or the tumor is very necrotic. So, either the tissue quantity itself is small, or the tissue quantity is insufficient to perform gene sequencing. And that's exactly where plasma comes in. When you don't have tissue availability, we have shown, as have others, that you can use plasma effectively to increase the proportion of patients who are not only tested but also receive the right therapy. I think there are also other barriers, including inertia. You know, I think this is both patient and physician inertia, where patients want to get started quickly, they don't want to wait. Physicians are very busy and sometimes want to be able to deliver treatment as soon as possible. We have seen there are some institutional barriers. Not every institution has in-house gene sequencing testing. So how do you really operationalize, send out these tests in a fast, efficient manner so that you get results back? Is it a pathologist who sends out the test? Is it the medical oncologist? Is it the pulmonologist or the interventionalist? I think there is this need to develop reflex testing mechanisms which some institutions do really well and some don't. And then finally, there are financial implications as well. How do we do this in a most cost-efficient fashion?  So there are many barriers, but I'm happy to say that we are making a move in the right direction as we are understanding that it's important to do it, it's easy to do it maybe with a value add of plasma, and finally, as you said, you know, as these technologies become more available, they're actually getting more cost-effective. Dr. Vamsi Velcheti: Dr. Aggarwal, you've been at the cutting edge of these advanced platforms and testing. So, what do you do in UPenn? How do you handle all these barriers and what is your workflow for patients in University of Pennsylvania? Dr. Charu Aggarwal: One of the things that I mentioned to you was there may be institutional barriers when it comes to gene sequencing. So, we actually, several years ago now, instituted a very robust reflex testing paradigm where almost all of our patients, regardless of stage, with a non-squamous non-small cell lung cancer diagnosis, would automatically be reflexively sent to our molecular pathology lab where they would get gene sequencing both for the DNA as well as with an RNA fusion-based platform. And the reason we did this was because we wanted to expedite and reduce the turnaround time. We also wanted to ensure that we were not just doing DNA testing, which I think is really important for our listeners here. There are many fusions as well as certain skipping mutations like MET exon 14 that may be missed on DNA testing alone. So, it's really incredibly important to run both DNA and RNA samples.  So, we do this routinely, and based on our research and others, what we also do routinely is that we send concurrent tissue and liquid biopsies or plasma MGS testing upon initial diagnosis. For example, if a patient comes in with a diagnosis of stage IV non-small cell lung cancer, their tissue might already be at my molecular pathology lab based on the reflex mechanism that I just described to you. But upon their initial meeting with me, we will send off plasma. And I will tell you this, that Penn is not just one institution, right? We have a large network of sites. And as part of my research, one of the things that we wanted to do was implement wide scale means to improve biomarker testing. And we have done this with the use of technology like you mentioned, Dr. Velcheti: How can we actually use AI? How can we leverage our electronic medical record to identify these patients? So, we have a nudge-based mechanism which actually facilitates the pending of orders for biomarker testing for patients with new diagnosis of metastatic non-small cell lung cancer. And we are looking at our rates of biomarker testing but also rates of completion of biomarker testing before first-line therapy started. So many of our participating sites are clusters for our randomized control trial to increase molecular testing. And I'm really excited about the fact that we're able to implement it not just at our main satellite, downtown Penn Hospital, but also across our community. Dr. Vamsi Velcheti: I think that's great. Thank you so much for those insights, Dr. Aggarwal. I think it's so important because having the best technology is just not enough. I think implementation science is actually a real thing. And I think we need to all learn from each other, advance these things.  So, I want to ask you about the new emerging paradigm in terms of using ctDNA. Of course, in the metastatic setting, we've been using ctDNA for molecular profiling for a while now. But the recent data around monitoring early-stage disease, especially post-operative monitoring, is an exciting area. There are a lot of opportunities there. Could you please talk us through the emerging data in lung cancer and how do we incorporate ctDNA-based monitoring MRD or should we even do that right now? Is the data ripe enough for us to kind of deploy this in a clinical setting? Dr. Charu Aggarwal: I think using ctDNA in the early-stage setting is our next frontier in lung cancer. I think naturally we have been able to successfully deploy this in the stage 4 setting. It made a meaningful difference in the lives of our patients, and we are a little bit behind the A ball in terms of how MRD is used in lung cancer. Because, you know, colorectal cancer has already done large-randomized trials based on ctDNA and MRD. It's routinely used in hematological malignancy. So, it makes sense that we should start to use it.  However, when I say this, I say this with excitement, but also a little bit of gentle caution saying that we actually don't quite have the prospective randomized data just yet on how to deploy. Yes, intuitively we would say that if you detect ctDNA and MRD, that patient is at higher risk. So, we identify that, but we actually don't know what to do with the second part of that information once you identify a patient with high risk. Are there other techniques that we can then come in with or other drugs that we can come in with to modify that risk? And that's the thing that I think we don't have right now. The other thing that we don't have right now is the timing of the assay, when to use it. Is it to be tested in the pre-op setting? Is the post-op test the best timing, or is it monitoring and dynamics of ctDNA that are most important? And the third thing I will say in terms of precautionary cause is that we don't know which test just yet. There are actually a few commercially available tests out in the market right now. We know about them and I'm sure our community colleagues know about them. Some of them even have Medicare approval. However, many of these tests are currently tissue informed. We don't have tissue uninformed tests. And what does that mean? Tissue uninformed means that you actually take a piece of tumor tissue, you sequence that tumor and based on the gene profile of that tumor, you actually design a panel that can then be used to track the mutations in the blood-based pack. This requires, as the name implies, a tumor. So can this be used in the pre-op setting is a large question. Because coming back to the idea of tissue availability, you and I both know that when we get FNAS and we use it for PDL-1 testing and we use it for gene sequencing, there often isn't enough tissue left for us to then either do whole genome sequencing or even whole transcriptome sequencing, which may be required to build some of these assays.  I think the future lies in this idea of tumor uninformed assays because if we could go to a blood only or a plasma only approach using novel signatures like proteomics or methylation, I think that's where the future is. But we're still a little bit early in the discovery stages of those, as well as to come are the validation stages so that we can be confident that these blood-only assays may actually give us an answer.  So, with those three cautionary notes, I would say that optimism is still very high. I think ctDNA MRD is the right place to think about. We need to do this for our patients to better identify high-risk patients and to think about means to escalate treatment for them. Dr. Vamsi Velcheti: Yeah, I completely agree, and I think with all the changes and evolution of treatments in the management of early-stage lung cancer now with neoadjuvant and adjuvant, there's really a need for an escalation and de-escalation of therapies post-operatively. And I think it's a huge opportunity. I think we all could learn from our colorectal colleagues. I think they've done a really good job at actually doing prospective trials in this setting. I think we're kind of a little behind here.  Dr. Charu Aggarwal: I think in the metastatic setting there are ongoing trials to look at this exact question. How do you choose an appropriate first-line therapy, a monitor ctDNA at the six-week trial? It's being evaluated in a trial called the “Shedders” trial, where if patients are still ctDNA positive at six weeks, then you can escalate treatment because they haven't “cleared” their ctDNA. There has been a lot of research that has shown that lack of ctDNA clearance in the metastatic setting may be a poor prognostic factor. We and others have shown that if you do clear your ctDNA or if you have a reduction in ctDNA load overall, that that is directly related to both an improved progression-free survival and overall survival. This has been shown with both tissue informed and uninformed assays. So I think it's very clear that yes, you can track it. I think the question is: Can you apply that data to the early-stage setting? And that's an open research question. A lot of groups are looking at that and I think it's completely reasonable, especially to determine duration of therapy, to determine optimal timing, optimal timing of scans even. And I think these are just such interesting questions that will be answered in the future. Dr. Vamsi Velcheti: And also like a kind of early detection of resistance patterns that might inform early initiation of combination strategies. And I think it's a lot of opportunities I think yet to be explored. A lot of exciting things to come and I'm sure we'll kind of see more and more data in the next few years.  Dr. Aggarwal, thank you so much for sharing your fantastic insights today on the ASCO Daily News Podcast. It's been a pleasure to have you on the podcast today. Hope to see you at ASCO. Dr. Charu Aggarwal: Thank you so much. This was great and I remain so excited by all of the possibilities to improve outcomes for our patients. Dr. Vamsi Velcheti: Thank you to all the listeners for your time today. If you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you so much. 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. Vamsidhar Velcheti  @VamsiVelcheti  @vamsivelcheti.bsky.social Dr. Charu Aggarwal @CharuAggarwalMD   Follow ASCO on social media:  @ASCO on X (formerly Twitter)  ASCO on Bluesky ASCO on Facebook  ASCO on LinkedIn    Disclosures: Dr. Vamsidhar Velcheti:  Honoraria: Glavanize Therapeutics Consulting or Advisory Role: Bristol-Myers Squibb, Merck, AstraZeneca/MedImmune, GSK, Amgen, Taiho Oncology, Novocure, Takeda, Janssen Oncology, Picture Health, Regeneron 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. Charu Aggarwal: Consulting or Advisory Role: AstraZeneca, Daiichi Sankyo/AstraZeneca, Regeneron/Sanofi, Pfizer, Boehringer Ingelheim, Takeda, Arcus Biosciences, Gilead Sciences, Novocure, Abbvie Speakers' Bureau: AstraZeneca (an immediate family member) Research Funding (Inst): Merck Sharp & Dohme, AstraZeneca/MedImmune, Daiichi Sankyo/AstraZeneca, Lilly@Loxo, Candel Therapeutics  

Besties with Breasties Podcast
S5E17: Pros/Cons & Emotional Implications of CT DNA Testing for Cancer Patients

Besties with Breasties Podcast

Play Episode Listen Later Mar 25, 2025 34:42


In this episode, Sarah Hall and Beth Wilmes continue the discussion of topics around reducing recurrence/disease progression by introduce the topic of CTDNA testing, also known as liquid biopsy. They explain how this test measures small fragments of cancer DNA in the blood and its potential benefits and limitations. The conversation includes insights from Dr. Cynthia Ax, an integrative breast surgical oncologist, who shares her perspectives on why doctors and patients opt for CTDNA testing, the emotional impacts of receiving test results, and the importance of a holistic approach to cancer care. The episode also touches on issues like the challenge of making lifestyle changes post-diagnosis, the collaborative potential between medical practitioners, and the critical role of mental health in the healing process. Dr. Cythia Aks: https://www.linkedin.com/in/cynthia-aks-865bb423/ Guest Profile: https://www.bestieswithbreastiespodcast.com/guests/cynthia-aks/ 00:00 Welcome to Besties with Breasty 00:58 Introduction to CT DNA Testing 02:38 Guest Introduction: Dr. Cynthia Ax 02:56 Sponsor Message: Faith Through Fire Survivorship Bootcamp 04:11 In-Depth Discussion with Dr. Ax 10:04 Challenges in Patient Lifestyle Changes 14:43 The Role of Primary Care in Survivorship 20:36 Boobs in the News: Peeled Bananas Mystery 21:11 The Mysterious Banana Plates 21:54 Community Reactions and Theories 23:31 Personal Anecdotes and Banana Dislike 25:06 Cancer Cells and Immune System 25:56 Empowering Patients with Knowledge 27:35 The Importance of Mental Health 32:05 Final Thoughts and Sponsor Message

Oncology Brothers
How to Treat Renal Cell Carcinoma (RCC) using a Treatment Algorithm with Dr. Katy Beckermann

Oncology Brothers

Play Episode Listen Later Mar 17, 2025 19:56


Join us for an insightful episode of the Oncology Brothers podcast as we dive deep into the world of renal cell carcinoma (RCC) with Dr. Katy Beckermann, the Medical GU Director of Cancer Research at Tennessee Oncology. In this episode, hosts Drs. Rahul & Rohit Gosain, practicing medical oncologists, discuss the latest advancements in RCC treatment, including: •⁠  ⁠The role of Pembrolizumab in the adjuvant setting based on the Keynote 564 study and its implications for early-stage disease. •⁠  ⁠Current treatment paradigms for metastatic RCC, including dual checkpoint inhibitors, TKI with immunotherapy, and single-agent options. •⁠  ⁠The importance of patient characteristics and IMDC risk categorization in treatment decisions. •⁠  ⁠Insights into sequencing therapies, including the use of Belzutifan for refractory disease and the management of side effects. •⁠  ⁠The role of ctDNA, PD-L1 testing, and NGS in RCC. Whether you're a community oncologist or simply interested in the latest in cancer care, this episode is packed with valuable information to help you stay informed and provide the best care for your patients. YouTube: https://youtu.be/Bbv9N7-YKIM Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/ Don't forget to like, subscribe, and leave a review to let us know how we're doing and how we can continue to support you in the community!  

Two Onc Docs
Localized Colon Cancer 2025 UPDATE

Two Onc Docs

Play Episode Listen Later Mar 3, 2025 21:07


Today's episode is focusing on what you need to know regarding early stage colorectal cancer (CRC) as of 2025. The last time we covered this topic was in 2023 and things continue to change. We will go over all the important details on the diagnosis, presentation, diagnostic work-up, role of ctDNA, staging, treatment, and surveillance of localized CRC. 

ASCO Daily News
Practice-Informing Research Across GU Oncology: Highlights From GU25

ASCO Daily News

Play Episode Listen Later Feb 27, 2025 28:18


Dr. Neeraj Agarwal and Dr. Peter Hoskin discuss key abstracts in GU cancers from the 2025 ASCO Genitourinary Cancers Symposium, including novel therapies in prostate, bladder, and kidney cancer and the impact of combination therapies on patient outcomes. TRANSCSRIPT Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program and professor of medicine at the Huntsman Cancer Institute at the University of Utah, and editor-in-chief of ASCO Daily News. Today, we'll be discussing practice-informing abstracts and other key advances in GU oncology featured at the 2025 ASCO Genitourinary Cancers Symposium. Joining me for this discussion is Dr. Peter Hoskin, the chair of this year's ASCO GU Symposium. Dr. Hoskin is a professor in clinical oncology in the University of Manchester and honorary consultant in clinical oncology at the Christie Hospital, Manchester, and University College Hospital London, in the United Kingdom. Our full disclosures are available in the transcript of this episode. Peter, thank you for joining us today. Dr. Peter Hoskin: Thank you so much, Neeraj. I am very pleased to be here. Dr. Neeraj Agarwal: The GU meeting highlighted remarkable advancements across the spectrum of GU malignancies. What stood out to you as the most exciting developments at the ASCO GU Symposium?  Dr. Peter Hoskin: The theme of this year's meeting was "Driving Innovation, Improving Patient Care," and this reflected ASCO GU's incredible milestone in GU cancer research over the years. We were thrilled to welcome almost 6,000 attendees on this occasion from over 70 countries, and most of them were attending in person and not online, although this was a hybrid meeting. Furthermore, we had more than 1,000 abstract submissions. You can imagine then that it fostered fantastic networking opportunities and facilitated valuable knowledge and idea exchanges among experts, trainees, and mentees. So, to start I'd like to come back to you for a second because the first day started with a focus on prostate cancer and some of the key clinical trials. And congratulations to you, Neeraj, on sharing the data from the TALAPRO-2 trial, which we were eagerly awaiting. I'd love to get your thoughts on the data that you presented. Could you tell us more about that trial, Abstract LBA18?  Dr. Neeraj Agarwal: Yes, Peter, I agree with you. It was such an exciting conference overall and thank you for your leadership of this conference. So, let's talk about the TALAPRO-2 trial. First of all, I would like to remind our audience that the combination of talazoparib plus enzalutamide was approved by the U.S. FDA in June 2023 in patients with metastatic castration-resistant prostate cancer harboring HRR gene alterations, after this combination improved the primary endpoint of radiographic progression-free survival compared to enzalutamide alone in the randomized, double-blind, placebo-controlled, multi-cohort phase 3 TALAPRO-2 trial. In the abstract I presented at ASCO GU 2025, we reported the final overall survival data, which was a key alpha-protected secondary endpoint in cohort 1, which enrolled an all-comer population of patients with mCRPC. So, at a median follow-up of around 53 months, in the intention-to-treat population, the combination of talazoparib plus enzalutamide significantly reduced the risk of death by 20% compared to enzalutamide alone, with a median OS of 45.8 months in the experimental arm versus 37 months in the control arm, which was an active control arm of enzalutamide. This improvement was consistent in patients with HRR alterations with a hazard ratio of 0.54 and in those with non-deficient or unknown HRR status, with a hazard ratio of 0.87. In a post hoc analysis, the hazard ratio for OS was 0.78 favoring the combination in those patients who did not have any HRR gene alteration in their tumors by both tissue and ctDNA testing. Consistent with the primary analysis, the updated rPFS data also favored the experimental arm with a median rPFS of 33.1 compared to 19.5 months in the control arm, and a hazard ratio of 0.667. No new safety signals were identified with extended follow-up. Thus, TALAPRO-2 is the first PARP inhibitor plus ARPI study to show a statistically significant and a clinically meaningful improvement in OS compared to standard-of-care enzalutamide as first-line treatment in patients with mCRPC unselected for HRR gene alterations. Dr. Peter Hoskin: Thank you, Neeraj. That's a great summary of the data presented and very important data indeed. There was another abstract also featured in the same session, Abstract 20, titled “Which patients with metastatic hormone-sensitive prostate cancer benefit more from androgen receptor pathway inhibitors? STOPCAP meta-analyses of individual participant data.” Neeraj, could you tell us more about this abstract? Dr. Neeraj Agarwal: Absolutely, I would be delighted to. So, in this meta-analysis, Dr. David Fischer and colleagues pooled individual participant data from different randomized phase 3 trials in the mHSPC setting to assess the potential ARPI effect modifiers and determine who benefits more from an ARPI plus ADT doublet. The primary outcome was OS for main effects and PFS for subgroup analyses. Prostate cancer specific survival was a sensitivity outcome. The investigators pooled data from 11 ARPI trials and more than 11,000 patients. Overall, there was a clear benefit of adding an ARPI on both OS and PFS, with hazard ratios of 0.66 and 0.51, respectively, representing a 13% and 21% absolute improvement at 5 years, respectively, with no clear difference by the class of agent. When stratifying the patients by age group, the effects of adding an ARPI on OS and PFS were slightly smaller in patients older than 75, than in those younger than 65, or aged between 65 and 75 years. Notably, in the trials assessing the use of abiraterone, we saw very little OS effects in the group of patients older than 75, however there was some benefit maintained in prostate-cancer specific survival, suggesting that other causes of death may be having an impact. The effects of the other ARPIs, or ‘lutamides' as I would call them, were similar across all three age subgroups on both OS and PFS. Therefore, the majority of patients with mHSPC benefit from the addition of ARPIs, and the benefits/risks of abiraterone and other ‘amides' must be considered in older patients.  Dr. Peter Hoskin: Thanks, Neeraj. Another great summary relevant to our day-to-day practice. Of course, there's ongoing collection of individual patient data from other key trials, which will allow robust comparison of ARPI doublet with triplet therapy (including docetaxel), guiding more personalized treatment.   Dr. Neeraj Agarwal: I agree with you, Peter, we need more data to help guide personalized treatment for patients with mHSPC and potentially guide de-escalation versus escalation strategies. Now, moving on to a different setting in prostate cancer, would you like to mention Abstract 17 titled, “Overall survival and quality of life with Lu-PSMA-617 plus enzalutamide versus enzalutamide alone in poor-risk, metastatic, castration-resistant prostate cancer in ENZA-p (ANZUP 1901),” presented by Dr. Louise Emmett? Dr. Peter Hoskin: Of course I will. So, ENZA-p was a multicenter, open-label, randomized, phase 2 trial conducted in Australia. It randomized 163 patients into adaptive doses (2 or 4 cycles) of Lu-PSMA-617 plus enzalutamide versus enzalutamide alone as first-line treatment in PSMA-PET-CT-positive, poor-risk, mCRPC. The interim analysis of ENZA-p with median follow-up 20 months showed improved PSA-progression-free survival with the addition of Lu-PSMA-617 to enzalutamide. Here, the investigators reported the secondary outcomes, overall survival, and health-related quality of life (HRQOL). After a median follow up of 34 months, overall survival was longer in the combination arm compared to the enzalutamide arm, with a median OS of 34 months compared to 26 months; with an HR of 0.55. Moreover, the combination improved both deterioration-free survival and health-related quality of life indicators for pain, fatigue, physical function, and overall health and quality of life compared to the control arm. Consistent with the primary analysis, the rPFS also favored the experimental arm with a median rPFS of 17 months compared to 14 months with a HR of 0.61. So, the addition of LuPSMA improved overall survival, and HRQOL in patients with high-risk mCRPC. Dr. Neeraj Agarwal: Thank you, Peter. Great summary, and promising results with Lu-177 and ARPI combination in first line treatment for mCRPC among patients who had two or more high risk features associated with early enzalutamide failure. Before we move on to bladder cancer, would you like to tell us about Abstract 15 titled, “World-wide oligometastatic prostate cancer (omPC) meta-analysis leveraging individual patient data (IPD) from randomized trials (WOLVERINE): An analysis from the X-MET collaboration,” presented by Dr. Chad Tang?  Dr. Peter Hoskin: Sure. So, with metastatic-directed therapy (MDT), we have a number of phase 2 studies making up the database, and the X-MET collaboration aimed to consolidate all randomized data on oligometastatic solid tumors. This abstract presented pooled individual patient data from all the published trials involving patients with oligometastatic prostate cancer who received MDT alongside standard of care (SOC) against SOC alone. The analysis included data from five trials, encompassing 472 patients with oligometastatic prostate cancer, and followed for a median of 41 months. Patients were randomly assigned in a 1:1 ratio to receive either MDT plus SOC or SOC alone. The addition of MDT significantly improved PFS. The median PFS was 32 months with MDT compared to 14.9 months with SOC alone, with an HR of 0.45. Subgroup analyses further confirmed the consistent benefits of MDT across different patient groups. Regardless of factors like castration status, receipt of prior primary treatment, stage, or number of metastases, MDT consistently improved PFS. In patients with mHSPC, MDT significantly delayed the time to castration resistance by nine months, extending it to a median of 72 months compared to 63 months in the SOC group with an HR of 0.58. In terms of OS, the addition of MDT improved the 48-month survival rate by 12%, with OS rates of 87% in the MDT+SOC group compared to 75% in the SOC alone group. Dr. Neeraj Agarwal: Thank you, Peter. These data demonstrate that adding MDT to systemic therapy significantly improves PFS, rPFS, and castration resistance-free survival, reinforcing its potential role in the treatment of oligometastatic prostate cancer. So, let's switch gears to bladder cancer and start with Abstract 658 reporting the OS analysis of the CheckMate-274 trial. Would you like to tell us about this abstract?  Dr. Peter Hoskin: Yes, sure, Neeraj. This was presented by Dr. Matt Milowsky, and it was additional efficacy outcomes, including overall survival, from the CheckMate-274 trial which evaluated adjuvant nivolumab versus placebo in patients with high-risk muscle-invasive bladder cancer after radical surgery. The phase 3 trial previously demonstrated a significant improvement in disease-free survival with nivolumab. With a median follow-up of 36.1 months, disease-free survival was longer with nivolumab compared to placebo across all patients with muscle-invasive bladder cancer, reducing the risk of disease recurrence or death by 37%. Among patients who had received prior neoadjuvant cisplatin-based chemotherapy, nivolumab reduced this risk by 42%, whilst in those who had not received chemotherapy, the risk was reduced by 31%. Overall survival also favored nivolumab over placebo, reducing the risk of death by 30% in all patients with muscle-invasive bladder cancer and by 52% in those with tumors expressing PD-L1 at 1% or higher. Among patients who had received prior neoadjuvant chemotherapy, nivolumab reduced the risk of death by 26%, whilst in those who had not received chemotherapy, the risk was reduced by 33%. Alongside this, the safety profile remained consistent with previous findings. Dr. Neeraj Agarwal: Thank you, Peter, for such a nice overview of this abstract. These results reinforce adjuvant nivolumab as a standard of care for high-risk muscle-invasive bladder cancer, offering the potential for a curative outcome for our patients. Dr. Peter Hoskin: I agree with you Neeraj. Perhaps you would like to mention Abstract 659 titled, “Additional efficacy and safety outcomes and an exploratory analysis of the impact of pathological complete response (pCR) on long-term outcomes from NIAGARA.” Dr. Neeraj Agarwal: Of course. Dr. Galsky presented additional outcomes from the phase 3 NIAGARA study, which evaluated perioperative durvalumab combined with neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer. The study previously demonstrated a significant improvement in event-free survival and overall survival with durvalumab compared to chemotherapy alone, with a manageable safety profile and no negative impact on the ability to undergo radical cystectomy. Among the 1,063 randomized patients, those who received durvalumab had a 33% reduction in the risk of developing distant metastases or death and a 31% reduction in the risk of dying from bladder cancer compared to those who received chemotherapy alone. More patients who received durvalumab achieved a pathological complete response at the time of surgery with 37% compared to 28% in the chemotherapy-alone group. Patients who achieved a pathological complete response had better event-free survival and overall survival compared to those who did not. In both groups, durvalumab provided additional survival benefits, reducing the risk of disease progression or death by 42% and the risk of death by 28% in patients with a pathological complete response, while in those patients without a pathological complete response, the risk of disease progression or death was reduced by 23% and the risk of death by 16% when durvalumab was added to the chemotherapy. Immune-mediated adverse events occurred in 21% of patients in the durvalumab group compared to 3% in the chemotherapy-alone group, with grade 3 or higher events occurring in 3% compared to 0.2%. The most common immune-related adverse events included hypothyroidism in 10% of patients treated with durvalumab compared to 1% in the chemotherapy-alone group, and hyperthyroidism in 3% versus 0.8%. At the time of the data cutoff, these adverse events had resolved in 41% of affected patients in the durvalumab group and 44% in the chemotherapy-alone group. Dr. Peter Hoskin: Thank you, Neeraj, for the great summary. These findings further support the role of perioperative durvalumab as a potential standard of care for patients with muscle-invasive bladder cancer. Dr. Neeraj Agarwal: I concur with your thoughts, Peter. Before wrapping up the bladder cancer section, would you like to mention Abstract 664 reporting updated results from the EV-302 trial, which evaluated enfortumab vedotin in combination with pembrolizumab compared to chemotherapy as first-line treatment for patients with previously untreated locally advanced or metastatic urothelial carcinoma? Dr. Peter Hoskin: Yes, of course. Dr. Tom Powles presented updated findings from the EV-302 study, and in this abstract presented 12 months of additional follow-up for EV-302 (>2 y of median follow-up) and an exploratory analysis of patients with confirmed complete response (cCR). The study had a median follow-up of 29.1 months and previously demonstrated significant improvements in progression-free survival and overall survival with enfortumab vedotin and pembrolizumab. This is now the standard of care in global treatment guidelines. Among the 886 randomized patients, enfortumab vedotin and pembrolizumab reduced the risk of disease progression or death by 52% and the risk of death by 49% compared to chemotherapy. The survival benefit was consistent regardless of cisplatin eligibility or the presence of liver metastases. The confirmed objective response rate was higher with enfortumab vedotin and pembrolizumab at 67.5% compared to 44.2% with chemotherapy. The median duration of response was 23.3 months with enfortumab vedotin and pembrolizumab compared to 7.0 months with chemotherapy. A complete response was achieved in 30.4% of patients in the enfortumab vedotin and pembrolizumab group compared to 14.5% in the chemotherapy group, with the median duration of complete response not yet reached in the enfortumab vedotin and pembrolizumab group compared to 15.2 months in the chemotherapy group. Severe treatment-related adverse events occurred in 57.3% of patients treated with enfortumab vedotin and pembrolizumab compared to 69.5% in the chemotherapy group, while in patients who achieved a complete response, severe adverse events occurred in 61.7% of those treated with enfortumab vedotin and pembrolizumab compared to 71.9% with chemotherapy. Treatment-related deaths were reported in 1.1% of patients treated with enfortumab vedotin and pembrolizumab compared to 0.9% with chemotherapy, with no treatment-related deaths occurring in those who achieved a complete response. These findings clearly confirm the durable efficacy of enfortumab vedotin and pembrolizumab, reinforcing its role as the standard of care for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma, and no new safety concerns have been identified. Dr. Neeraj Agarwal: Thank you for this great summary. Moving on to kidney cancer, let's talk about Abstract 439 titled, “Nivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): Final follow-up results from the CheckMate-9ER trial.” Dr. Peter Hoskin: Sure. Dr. Motzer presented the final results from the phase 3 CheckMate-9ER trial, which compared the combination of cabozantinib and nivolumab against sunitinib in previously untreated advanced renal cell carcinoma. The data after more than five years follow-up show that the combination therapy provided sustained superior efficacy compared to sunitinib. In terms of overall survival, we see an 11-month improvement in median OS, 46.5 months for the cabo-nivo versus 35.5 months for sunitinib and a 42% reduction in the risk of disease progression or death, with median progression-free survival nearly doubling – that's 16.4 months in the combination group and 8.3 months with sunitinib. Importantly, the safety profile was consistent with the known safety profiles of the individual medicines, with no new safety concerns identified. Dr. Neeraj Agarwal: Great summary, Peter. These data further support the efficacy of cabo-nivo combination therapy in advanced renal cell carcinoma, which is showing a 11-month difference in overall survival. Dr. Peter Hoskin: Neeraj, before wrapping up this podcast, would you like to tell us about Abstract 618? This is titled “Prospective COTRIMS (Cologne trial of retroperitoneal lymphadenectomy in metastatic seminoma) trial: Final results.” Dr. Neeraj Agarwal: Sure, Peter. I would be delighted to. Dr Heidenrich from the University of Cologne in Germany presented the COTRIMS data evaluating retroperitoneal LN dissection in patients with clinical stage 2A/B seminomas. Seminomas are classified as 2A or B when the disease spreads to the retroperitoneal lymph nodes of up to 2 cm (CS IIA) or of more than 2 cm to up to 5 cm (CS 2B) in maximum diameter, respectively. They account for 10-15% of seminomas and they are usually treated with radiation and chemotherapy. However, radiation and chemo can be associated with long-term toxicities such as cardiovascular toxicities, diabetes, solid cancers, leukemia, particularly for younger patients. From this standpoint, Dr Heidenrich and colleagues evaluated unilateral, modified template, nerve-sparing retroperitoneal lymph node dissection as a less toxic alternative compared to chemo and radiation. They included 34 patients with negative AFP, beta-HCG, and clinical stage 2A/B seminomas. At a median follow-up of 43.2 months, the trial demonstrated great outcomes: a 99.3% treatment-free survival rate and 100% overall survival, with only four relapses. Antegrade ejaculation was preserved in 88% of patients, and severe complications such as grade 3 and 4 were observed in 12% of patients. Pathological analysis revealed metastatic seminoma in 85% of cases, with miR371 being true positive in 23 out of 24 cases and true negative in 100% of cases. It appears to be a valid biomarker for predicting the presence of lymph node metastases. These findings highlight retroperitoneal lymph node dissection is feasible; it has low morbidity, and excellent oncologic outcomes, avoiding overtreatment in 80% of patients and sparing unnecessary chemotherapy or radiotherapy in 10-15% of cases. Dr. Peter Hoskin: Great summary and important data on retroperitoneal lymphadenectomy in metastatic seminoma. These findings will help shape clinical practice. Any final remarks before we conclude today's podcast? Dr. Neeraj Agarwal: Before wrapping up this podcast, I would like to say that we have reviewed several abstracts addressing prostate, bladder, kidney cancers, and seminoma, which are impacting our medical practices now and in the near future. Peter, thank you for sharing your insights with us today. These updates are undoubtedly exciting for the entire GU oncology community, and we greatly appreciate your valuable contribution to the discussion and your leadership of the conference. Many thanks. Dr. Peter Hoskin: Thank you, Neeraj. Thank you for the opportunity to share this information more widely. I'm aware that whilst we have nearly 6,000 delegates, there are many other tens of thousands of colleagues around the world who need to have access to this information. And it was a great privilege to chair this ASCO GU25. So, thank you once again, Neeraj, for this opportunity to share more of this information that we discussed over those few days. Dr. Neeraj Agarwal: Thank you, Peter. And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  Find out more about today's speakers:   Dr. Neeraj Agarwal    @neerajaiims    Dr. Peter Hoskin Follow ASCO on social media:      @ASCO on Twitter      ASCO on Bluesky  ASCO on Facebook      ASCO on LinkedIn      Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas Dr. Peter Hoskin: Research Funding (Institution): Varian Medical Systems, Astellas Pharma, Bayer, Roche, Pfizer, Elekta, Bristol Myers  

JCO Precision Oncology Conversations
Adagrasib Following Sotorasib-Related Hepatotoxicity

JCO Precision Oncology Conversations

Play Episode Listen Later Feb 19, 2025 22:00


JCO PO author Dr. Hatim Husain at University of California San Diego, shares insights into his JCO PO article, “Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRASG12C-Mutated Non–Small Cell Lung Cancer: A Case Series and Literature Review”, one of the top downloaded articles of 2024. Host Dr. Rafeh Naqash and Dr. Husain discuss how to utilize real-world and clinical trial data to discern the safety of adagrasib (another KRASG12C inhibitor), following sotorasib discontinuation due to hepatotoxicity. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Stephenson Cancer Center.  Today, I'm very excited to be joined by Dr. Hatim Hussain, Professor of Medicine at the University of California, San Diego, and author of the JCO Precision Oncology article, “Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRAS-G12C-Mutated Non-Small Cell Lung Cancer: A Case Series and Literature Review.” This was one of the top downloaded articles of 2024. And the other interesting thing is we generally don't do podcasts for case reports or case series, so this is one of the very few that we have selected for the podcast.  And at the time of the recording, our guest disclosures will be linked in the transcript.  Dr. Hussain, welcome to our podcast and thank you for joining us today. Dr. Hatim Husain: Thank you Dr. Naqash. Such a pleasure to be here and to speak with you all. Dr. Rafeh Naqash: And for the sake of this podcast, we'll refer to each other using our first names. So again, as I mentioned earlier that this is one of the very few case reports that we have selected for podcasts in JCOPO and the intention was very deliberate because it caters to something that is emerging where we are trying to treat more KRAS mutant patients with different KRAS inhibitors. And you tried to address one very unique aspect of it in this article which pertains to toxicity, especially hepatotoxicity. So for the sake of our listeners who tend to be community oncologists, trainees, academic faculty, can you tell us what are KRAS inhibitors? What is KRAS-G12C? And how do some of these approved KRAS inhibitors try to inhibit KRAS-G12C? Dr. Hatim Husain: Sure. For a long time actually we've not had a selective way to inhibit mutant KRAS. And over the last several years actually now, we've seen some dramatic advances here, particularly with the FDA approval of some of the selective inhibitors against the G12C variant. So KRAS-G12C is an isoform of KRAS that is most common in lung cancer and in fact actually is a transversion mutation in the KRAS gene that is a product of the carcinogen of tobacco. And in fact, the incidence of KRAS-G12C in lung cancer, it's quite astounding where as many KRAS-G12C patients there are, there can be, as you know, more than EGFR patients in certain populations and cohorts. The medicines sotorasib and adagrasib were rationally designed to be selective KRAS-G12C inhibitors. And the way that they do this is that they lock the KRAS protein in the OFF state. KRAS is a protein that oscillates between an ON and an OFF state and by virtue of locking the protein in an OFF state, it has shown inhibition of downstream signaling and mitigation of tumor growth and, in fact, tumor cell death. Dr. Rafeh Naqash: I absolutely love the way you describe the ON and OFF state, the oscillation where the ON is bound to the GTP and the OFF is bound to the GDP. The two KRAS inhibitors as currently FDA approved, as you mentioned, are RAS OFF inhibitors and they're emerging KRAS inhibitors that are RAS ON. So now, as we have known from previous data related to immunotherapy and EGFR TKIs such as osimirtinib where toxicity tends to be a compounded effect when you have osimertinib given within a certain timeline of previous checkpoint therapy, we've seen that in the clinic as the data for these KRAS inhibitors is emerging, you talk about some very interesting aspects and data about what has been published so far with regards to prior use of immunotherapy or chemo immunotherapy and the subsequent use of KRAS inhibitors. Could you elaborate upon that? Dr. Hatim Husain: Sure. So for this population of patients, the first line approved strategy is a strategy that most cases will incorporate immune therapy and chemotherapy. Immune therapy can have some important responses for patients with KRAS-G12C. This may be due to the fact that KRAS-G12C patients may have a higher incidence of prior smoking, perhaps higher mutation burdens in some patients, and perhaps immunogenicity is defined in that context. So the standard of care in the first line currently includes immune therapy or immune therapy and chemotherapy. Where the current FDA approvals for selective G12C inhibitors are are after the first line of therapy. There are a number of trials exploring these medicines in the first line to see if they may be incorporated into a future treatment paradigm. Dr. Rafeh Naqash: Thank you for that explanation. Now, going to what you published in this manuscript, can you help us understand the context of why you looked at this? Even though the data just comprises a case series of a handful of patients, but the observations are very interesting and these are real world scenarios where we often tend to be in situations where an individual has had toxicity on a certain drug and may have some response to that drug, but at the same time, the toxicity is challenging. And then you try to debate whether another drug in the same class might be beneficial without those toxicities. So you've tried to address that to some extent using this data set. So can you elaborate upon the question, the methodology, what you tried to look at, and important observations that you have? Dr. Hatim Husain: Yes, our paper was actually inspired by one of my patients. My patient was a patient who had received chemotherapy and immune therapy and actually in the past, even, you know, additional lines of immune therapies, it was really coming to the edge of where standard treatments would exist. It was right at the same time that these selective inhibitors had been approved and the patient had received sotorasib. And what was remarkable was, when given sotorasib, patient had a very high peak and spike in the transaminases. And we would do different trials of strategies around dose, around interruptions. And it was becoming quite difficult, actually, for the patient to proceed with additional therapy. It was around similar times, actually, and I do want to make a note that the patient was progressing, driven in large fact by the fact that we've had to interrupt the medicine. So we feel and believe that the patient had had inadequate dosing because of the level of toxicity that the patient was having with transaminase increase. So it was around the same time that adagrasib was first commercially available that we were at that point, and we did a trial of adagrasib post-sotorasib, largely driven by necessity, without having additional options to provide this patient in our environment. What was remarkable was when the patient received the adagrasib, there were no spikes in transaminases similar to what we had seen before. And that really led us thinking and to say, “Is this adverse event of transaminase increase or hepatotoxicity, is this a class effect with KRAS-G12C inhibitors, or is it more nuanced than that? Are there different, perhaps, mechanisms by which the medicines may work that may more or less differentially contribute to this adverse event?” And so that inspired us to kind of do a larger analysis, kind of really reach out to a larger network of physicians to gather insights and to gather responses in patients who had had a serial approach of sotorasib and then adagrasib.  What we found in this process was, in fact, actually there were many more cases of patients who resembled my patient, where the sequence of sotorasib going to adagrasib may have demonstrated differential contribution of hepatotoxicity in that context. And that really motivated us to put the publication together to due diligence, and in the publication spend a lot of time to kind of outline each patient case in detail around metrics surrounding time from last immune therapy, the number of days on sotorasib, the best response to sotorasib, the interval between sotorasib and adagrasib, the duration of adagrasib and then the grade of hepatotoxicity seen in each of the contexts, and particularly kind of the adagrasib and patient disease status as well. We were quite inspired by the effort to try to, if we do not have randomized data in comparison of one medicine to another, which we do not at this juncture, we do not have a randomized analysis to really diligently and rigorously compare the rates of AEs across each medicine, and even in sequence, we do not have that with immune therapy. But what we felt was trying to get more analysis of this sequential approach of, if patients had received a medicine, had to be taken off because of toxicity and then actually tried on a new medicine, what were those rates? We felt like that was at least some information to try to get at this question. Dr. Rafeh Naqash: And you bring forward a very important point, which is, a lot of times in the real world setting we don't have cross trial comparisons that can be fully applicable, or we don't have trials that compare two drugs of the same class with respect to the AE profile or efficacy. And observations like the one that you described that led to this study are extremely critical in trying to help answer these questions.  From a data standpoint, and you allude to it to some extent in your manuscript, the trials that are trying to address combination of KRAS-G12C with immunotherapy, especially sotorasib or adagrasib, can you elaborate on that data, what has been published so far and summarize it for our listeners? Dr. Hatim Husain: So there is data from clinical trials looking at patients actually who have received concomitant immune therapy and sotorasib. What was seen in this, in a real world analysis, was that some patients actually who had received sotorasib within a close proximity of immune therapy, as well as a larger study actually which showed in combination there were higher rates of hepatotoxicity in that context. In fact, there were rates of grade 3 hepatotoxicity. And I think built upon that data there's a recognition in the field that we have to be very diligent in terms of even the clinical trial designs in how to understand the pairing between immune therapy and selective G12C inhibitors. There are many trials that are ongoing, one of the studies that is ongoing is known as the KRYSTAL-7 study, which is evaluating adagrasib in combination with pembrolizumab in the first line. And we await more information on that strategy as well. In the context of sotorasib, because of some of the trials that have shown higher rates of hepatotoxicity, there are some additional trials now looking at sotorasib in combination with chemotherapy, and those also have some information that have been reported as well. Dr. Rafeh Naqash: From a drug development standpoint, as you mentioned, there's always a tendency to combine something with something else. And in my practice, and I'm sure in your practice too, when we do early phase trials, many trials are still focused on choosing the maximum tolerated dose, which may be something that we need to gradually move away from as we try to implement these combinations of multiple antibodies plus some of these target agents from maybe the biological optimal dose rather than the maximal tolerant dose is a better way to look at the drugs, the pharmacokinetic profile, and then see what is likely the safest combination with the most appropriate target engagement. Do you have any thoughts on that or insights on that from a drug development perspective? Dr. Hatim Husain: It's a wonderful question and I think it is a very insightful question and understanding of where we are in space right now. And I agree with you that historically, cancer drug development was really hinged upon medicines that perhaps required higher doses to see a benefit or to inch out kind of marginal increases upon where we were at. Now, in combination with medicines that have non-overlapping mechanisms of action, the concept is: Can there actually be more synergy across an approach using combinatorial strategies rather than just additive effects? And I think that in some cases this is being studied with immune therapy, in some cases actually even in the context of other novel mechanisms for cancer therapy. I think that in my practice, I will really try to see how a patient at an approved dose will respond. But definitely I'm open to the concept that there may be a dose that doesn't have to be the maximally tolerated dose, but rather the dose that responses can be seen and perhaps actually at a lower dose than what drives many toxicities. Dr. Rafeh Naqash: I often describe this to my patients as individual patient dose optimization outside of a clinical trial, where I'm sure you've probably done this, where in older adults maybe a lower dose of osimertinib is tolerated better, or a lower dose of sotorasib or adagrasib for that matter, tolerated better with perhaps a similar level of efficacy, since we don't have comparisons between doses and efficacy so far.  So I think in the bigger picture, as we discussed in a nutshell, what I would really like the listeners to understand is as we try to move towards this field of precision medicine targeting more and more of the undruggable genes, there's bound to be a certain level of toxicity patterns that we'll start observing. So I think these real world scenarios which may not be addressed using clinical trials because it is in the real world setting where you cycle one treatment after another after another, which may or may not be allowed in most trials and the real world setting can inform, in certain cases, subsequent trial designs. So I think the most important message, at least that I took from your manuscript, was that these real world observations can make a huge difference and inform practice, even though the data sets may be small. Of course, you want to validate some of these findings in a bigger, broader setting, but proof of concept is there. And I think next time I see an individual in my clinic where I see better toxicity, I'll definitely try to talk to them about subsequent treatment with another KRAS inhibitor, maybe adagrasib or something else, if and when appropriate.  Do you have any closing thoughts on some of these things that we discussed? Dr. Hatim Husain: I just want to leave the audience actually with this concept that sometimes we group targeted therapy side effects as being class effects unanimously. And I do think actually that each inhibitor may have different off target effects on where medicine may act. We don't truly understand the mechanism of hepatotoxicity in the context of selective KRAS-G12C inhibitors. One of the hypotheses may be due to off target cysteine reactivity in the numerous off target binding sites that certain medicines may have over others. And just even qualitatively which off target binding sites there may be, and how that may lead to either immunogenic responses and other organs or such. So I do think that we do need more research to understand the mechanism. But I think where we are at right now in this space is not assuming that all medicines are going to have the exact same toxicity. I think especially when patients may not have other options, this is something to consider as well. Dr. Rafeh Naqash: Thank you so much. Now, outside of the scientific insights, Hatim, I know you a little bit from before. And knowing the kind of work that you've done in precision medicine, I'm really interested to know about where you started, how you started, how things have been, and what kind of advice you have for junior faculty fellows who are interested in this field of precision medicine that is becoming more and more exciting as we progress in the oncology space. Dr. Hatim Husain: Thank you, Rafeh. I will say, actually as a medical student, I was actually very interested in oncology, partly because it was then and still remains one disease or a constellation of diseases that just has such a high psychological burden on patients. And through the experiences I've had, I really can understand and relate with that concept. I did my medical school at Northwestern, residency at the University of Southern California, and then my oncology fellowship at Johns Hopkins University.  And now I've been on faculty at University of California, San Diego, for about 12 years now. It's been a great experience paralleled with the fact that during these last 12 years, I've really seen how the developments in precision oncology, both targeted therapy as well as immune therapy, have really blossomed and unfolded. A large area of my research in my career has kind of focused on cancer genome and integration of novel technologies to really see how they may have clinical application. When I was in my fellowship and as a young faculty, the liquid biopsy was actually coming into development. And this was hinged upon information that had come forward in the prenatal space where some patients actually who were undergoing prenatal testing during pregnancy were found to have complex karyotypes and genomic alterations and then retrospectively found to have cancer.  And doing my fellowship at Johns Hopkins, some of the pioneers in liquid biopsy were my mentors and really kind of instilled in me that passion for really thinking through how cancer genomics can be integrated through time. And some of the research that I have been doing has been looking at clonal evolution of cancer, how cancer is changing over time, and how we can think through the right surveillance strategies to really understand how that change is occurring. The dynamics of ctDNA in retrospective cohorts have been studied and shown that, you know, there can be associations between progression-free survival and other clinical endpoints. The current paper that we are speaking about parallels that in a certain way where, rather than say, looking at clonal evolution and say, the efficacy answer of sotorasib first and then adagrasib and how frequently can adagrasib salvage patients, this looks at it from a different angle around toxicity. And I think that is a key point because, at my core, I really do enjoy the clinical aspect of complex decision making on behalf of patients weighing efficacy and toxicity that they may have as they try to get the best quality of life through this journey. Dr. Rafeh Naqash: Thank you again, Hatim, for all those insights, both from the scientific perspective as well as personal perspective. We appreciate that you chose JCOPO as the destination for your work.  And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Dr. Hatem Husain Disclosures Consulting or Advisory Role: AstraZeneca, Foundation Medicine, Janssen, NeoGenomics Laboratories, Mirati Speakers' Bureau: AstraZeneca, Janssen Institution Research Funding: Pfizer, Bristol-Myers Squibb, Regeneron, Lilly Travel, Accommodations, Expenses: AstraZeneca, Janssen, Foundation Medicine  

ASCO Daily News
Therapeutic Advances Across GI Cancers: Highlights From GI25

ASCO Daily News

Play Episode Listen Later Feb 6, 2025 21:13


Dr. Shaalan Beg and Dr. David Wang discuss key abstracts in GI cancers from the 2025 ASCO Gastrointestinal Cancers Symposium, including major advances in CRC, neoadjuvant approaches in esophageal cancer, and innovative studies on ctDNA. TRANSCRIPT Dr. Shaalan Beg: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg. I'm a medical oncologist and an adjunct associate professor at UT Southwestern Medical Center in Dallas. Today, we're bringing you some key highlights from the 2025 ASCO Gastrointestinal Cancers Symposium, and I'm delighted to be joined by the chair of GI25, Dr. David Wang. Dr. Wang is a GI medical oncologist at the University of Michigan. Our full disclosures are available in the transcript of this episode.  Dr. Wang, thanks for coming on the podcast today. Dr. David Wang: Well, thank you. It's a pleasure to be here. Dr. Shaalan Beg: GI25 featured major therapeutic advances across the spectrum of GI malignancies, and it was exciting to hear about innovations and novel approaches that are shaping the future of our field. Before we start talking about specific abstracts, could you share some of your key highlights from the meeting? Dr. David Wang: Sure. Our theme this year was “Breaking Boundaries to Enhance Patient Centered Care.” Past years' themes have focused more on precision oncology, but we wanted to broaden our focus on patients and to be more holistic, which kind of led us into some of the Intersection [sessions] that we had. Each day started with a different Intersection. The first one was “Emerging Therapies in GI Cancers”, where invited speakers talked about bispecific antibody drug conjugates, theranostics, CAR T and other cell-based therapies. The second day was on “Personalized Risk Assessment for GI Cancers,” and this included looking at polygenic risk scores for colorectal cancer, microRNAs and liquid biopsies such as exosomes and pancreatic cancer and non-endoscopic screening modalities in esophageal cancer. And on our final day, we wanted to talk about “Integrative Oncology and Integrative Medicine,” looking at evidence-based uses of acupuncture and supplements in patients who are receiving treatment for cancer, mindfulness-based practices and exercise. And of course, we had a fantastic keynote talk by Dr. Pamela Kunz from the Yale School of Medicine titled, “Disrupting Gastrointestinal Oncology: Shattering Barriers with Inclusive Science.” She highlighted the intersection of science, patient care, and health and gender equity. And I would encourage your podcast listeners to access the lecture in ASCO's Meeting Library if they haven't yet had a chance to hear Dr. Kunz's wonderful lecture.  We were really happy this year because the attendance hit a new record. We had over 5,000 people attend either in person or virtually from their home or office, and we had almost 1,000 abstracts submitted to the meeting, so these were either record or near record numbers. We offered a lot of different networking opportunities throughout the meeting, and attending found these to be incredibly rewarding and important and this will continue to be an area of emphasis in future meetings. Dr. Shaalan Beg: Let's take a deeper dive into the exciting studies presented at GI25. The late breaking abstract LBA143 was CheckMate-8HW. This was the first results of NIVO + IPI versus NIVO monotherapy for MSI-high metastatic colorectal cancer. What are your thoughts about this study? Dr. David Wang: Yeah, so we know that colorectal cancer patients with MSI-high tumors don't necessarily respond well to chemotherapy. And we were fortunate because last year CheckMate-8HW actually looked at two different arms – so this was NIVO + IPI compared to standard of care chemotherapy and showed its very significant improvement in median progression-free survival. And that was actually published in the New England Journal of Medicine back in November of 2024. This year's presentation actually focused now on NIVO + IPI versus NIVO monotherapy. And as you know IPI+NIVO can be quite toxic. So this was an important analysis to be done. So we know that NIVO is definitely more easily tolerated. So what was interesting was that the 2-year and 3-year progression-free survival not surprisingly favored IPI+NIVO and this was statistically significant. And the overall response rate was also better with IPI+NIVO versus NIVO alone. I know we're always concerned about toxicities and there were higher grade 3 and 4 toxicity incidences in the combination arm versus the monotherapy arm, but overall, only about 28 additional events in several hundred patients treated. So I think that's well-tolerated. Our discussant Dr. Wells Messersmith actually said that, with this new data, he would consider doing combination immunotherapy in any patient that presented in the front line with MSI-high or deficient mismatch repair colorectal cancer that was metastatic. Dr. Shaalan Beg: One of the focuses for directing first-line therapy for colorectal cancer has been right and left sided colon cancer because we know these are two different cancers with their own unique molecular subtypes. We heard on Abstract 17, the DEEPER trial, the final analysis of modified FOLFOXIRI plus cetuximab versus bevacizumab for RAS wild-type and left sided metastatic colorectal cancer. How do you summarize the findings of this study and what should our readers be aware of? Dr. David Wang: Interestingly, this was a phase 2 study and the emphasis of the abstract was actually a subgroup analysis of those patients with RAS wild-type and BRAF wild-type as well as left sided cancers. So, I think the entire study enrolled 359 patients, but the analysis that was discussed at the meeting really focused on 178 patients that fit that characteristic. Very similar to what we've seen in prior studies, left-sided tumors have better response to cetuximab versus bevacizumab. And if you flip it so that you now are looking at right sided tumors, targeting EGFR is actually detrimental. The depth of response was better with cetuximab in these left sided RAS and BRAF mutant tumors. And so the lead author actually suggested that this could be a new first-line standard of care. And the question is, is there a benefit of doing this triple agent regimen with modified FOLFIRINOX? We know there's a lot more toxicity with that. Not clear that there's a benefit for that over FOLFOX, maybe in younger patients that could tolerate it. When our discussant, again Dr. Wells Messersmith, spoke about this, he said that, in his practice he would, again, favor cetuximab over bevacizumab in combination with chemo, these left-sided RAS and BRAF wild-type tumors, but that he would actually prefer a doublet versus a triplet chemo regimen, and that is consistent with the current NCCN guidelines. Dr. Shaalan Beg: Another area where colorectal cancer has been a wonderful model to study new technology has been in the area of circulating tumor DNA (ctDNA). And the BESPOKE CRC trial is looking to see if ctDNA can inform adjuvant treatment decisions for stage II and III colorectal cancer. And in Abstract 15, we heard final results of the BESPOKE CRC sub-cohort. What were the findings there? Dr. David Wang: BESPOKE CRC is another one of these important ctDNA studies. It was an observational study, not a randomized trial, but it did provide a lot of different insights to us. We know that there were over 1,700 patients enrolled, and so it was reported that this is the largest ctDNA study in colorectal cancer performed in the United States. And they were able to analyze over 1,100 patients.  Some of the key findings were that postoperative adjuvant therapy management decisions actually changed in 1 out of 6 patients, so that's pretty significant. In terms of surveillance, we know that patients who have ctDNA positivity, this is prognostic of recurrence. In terms of patients who have positive ctDNA post-surgery, it looked like, at least in this observational study, the majority of patients who received any benefit were those who had positive ctDNA. So adjuvant therapy, even in stage II and stage III patients seemed to only benefit those patients who have positive ctDNA. I think that does raise the question, and this also was brought up in the discussion, which is “Can we de-escalate adjuvant therapy in terms of patients who are ctDNA-negative post-op?” And Dr. Richard Kim from Moffitt felt that we are not yet there. Obviously, we need randomized control trials where we are taking ctDNA results and then randomizing patients to receive adjuvant or non-adjuvant to really know the difference.  Other questions that come up with use of ctDNA include: What do you do with these patients who turn positive? This study for BESPOKE actually followed patients out to two years after surgery. So what you do with a positive ctDNA result wasn't really clear. It seems to suggest that once you turn positive, patients go on to more intensive surveillance. You know, again as an observation, patients who did turn positive were able to go to metastasis-directed therapy much more quickly. And again, this was supposedly to improve their curative intent therapy. And I think the other question that has been brought up all the time is, is this really cost effective? Patients want to know, and we want to give patients that information, but I think we're still stuck with what to do with a positive ctDNA level in a patient that's on surveillance because no randomized control studies have actually suggested that we need to start systemic therapy right away. Dr. Shaalan Beg: Yeah. And I guess in terms of practice informing or practice changing, these results may not give us a clear answer. But because a lot of patients are asking for these tests, it does give us some real world experiences on what to expect in terms of conversion of these positive into negative and the outcome so we can have a shared decision making with our patients in the clinic and then come up with a determination on whether ctDNA for molecular residual disease is something which would be worthwhile for the care of our patient. But more to come, I guess, in coming years to answer different problems around this challenge. Dr. David Wang: Yes, I agree. Dr. Shaalan Beg: The BREAKWATER trial looked at the use of encorafenib, cetuximab and chemotherapy for BRAF V600E-mutant metastatic colorectal cancer. We've covered this combination for a second- third-line treatment in metastatic colorectal cancer previously. Abstract 16 from GI25 was evaluating the use of this regimen in the first-line space. Everyone was looking forward to these results, and what did the investigators present? Dr. David Wang: I think this is, as you mentioned, a nice follow up to later lines of therapy where Dr. Kopetz from MD Anderson pioneered use of encorafenib, cetuximab and binimetinib in the BEACON trial. Everybody was kind of curious what would happen now if you use encorafenib plus cetuximab plus chemotherapy in the first-line setting. And so this is an interim analysis that was pre-planned in the phase 3 open label BREAKWATER trial. And even though there were three arms, and so the three arms were encorafenib plus cetuximab, encorafenib plus cetuximab plus FOLFOX, or standard of care chemo, only two arms were presented in the abstract. So basically looking at encorafenib plus cetuximab and FOLFOX-6 versus standard of care therapy, and the overall response rate was statistically significant with a 60.9% overall response rate encorafenib plus cetuximab plus chemo arm versus standard of care chemo was only 40%. The interim overall survival also was different. It was 92% versus 87% at 6 months and 79% versus 66% at 12 months, again favoring the chemotherapy plus encorafenib plus cetuximab. In terms of the statistics, the p was 0.0004. However, the pre-plan analysis required the p-value to be 1x10 to the -8. And so even though this looks really good, it hasn't quite met its pre-specified significance level. The good thing is that this is only interim analysis and the study is ongoing with future analysis planned.  So the real question is: Does it matter when we actually use this regimen? We know that the regimen's approved in the second third-line setting. What about in the first line? And there was some preclinical data that the discussant reviewed that shows that patients actually benefit if this is done in the first-line setting. For example, there was some preclinical data showing that even FOLFIRI, for example, can upregulate RAS, which would make tumors more resistant to this combination. This was thought to be practice-changing in a patient that has B600E showing up treatment naive that we should probably consider this regimen. And actually this did receive accelerated FDA approval about a month ago. Dr. Shaalan Beg: Yeah, and for what it's worth, I put up a Twitter poll asking my Twitter followers on how the BREAKWATER trial results will change their approach for newly diagnosed BRAF mutated colorectal cancer. We got 112 responses; 72% said that they will incorporate encorafenib, cetuximab, FOLFOX for their frontline BRAF mutated patients. But 23% said that they would like to wait for overall survival results. Dr. David Wang: Wow, that's interesting. They really want that 1x10 to the -8. Dr. Shaalan Beg: I guess so. All right. Let's change gears and talk about esophageal cancer. LBA329 was the SCIENCE study which presented preliminary results from a randomized phase 3 trial comparing sintilimab and chemoradiotherapy plus sintilimab versus chemoradiotherapy for neoadjuvant resectable locally advanced squamous esophageal cancer. Where are we in this space? Dr. David Wang: Okay. So, yeah, this was an interesting trial. Again, just to set the context, esophageal squamous cell carcinoma is more prevalent in Asia. And the study sites as well as the patients were mostly from Asia. So this was again a phase 3 trial with interim results. They only rolled 146 out of the planned 420 for this interim analysis. And yeah, they're using immune checkpoint inhibitor that we don't use in the United States, sintilimab, combined with their two standards of neoadjuvant therapy, either chemotherapy, which is more common in Asia, or or chemoradiation, which is more common in the US and Western Europe, versus chemoradiation. And so they actually had two primary endpoints, but only were reporting one. So their two primary endpoints were pathCR and the other one was event-free survival. The event-free survival, again, was not reported at the meeting.  What they found was that in terms of pathCR rate, if you take the two arms that are really informative about that, chemoradiation plus sintilimab versus chemoradiation alone, the pathCR rate was 60% versus 47%. We know that chemo alone doesn't induce as much of a pathCR rate, and that was 13%. So it was found that the delta in terms of pathCR between the chemoradiation arms, one with sintilimab and one without, was significant. And this actually confirms data again from Asia, like for the ESCORT-NEO trial where it used another immune checkpoint inhibitor pembrolizumab in addition to neoadjuvant chemo.  So as our discussant for this abstract said, yes, we know that radiation combined with chemotherapy improves pathCR rates, but we have recent data from the ESOPEC trial, we don't know that that necessarily will translate to overall survival. So again, waiting for additional enrollments and longer term follow up before incorporating this into clinical care here. Dr. Shaalan Beg: So David, how do the results of the SCIENCE trial compare with our practice in the United States and ongoing studies asking questions for neoadjuvant therapy for esophageal carcinoma in the United States? Dr. David Wang: I think obviously immune checkpoint inhibitor in the new adjuvant setting is important. Jennifer Eads at UPenn is running that EA2174 which is looking at chemoradiation plus or minus nivolumab, and then in non-pathCR responders randomized to adjuvant nivolumab per CheckMate 577 or nivolumab with intensification adding ipilimumab. We know that the ESOPEC trial just came out, and was published actually during the meeting, and that really focuses on adenocarcinomas. So adenocarcinomas of the GE junction, distal esophagus, now, we would probably treat very similarly to gastric using perioperative FLOT. However, the standard in the US for esophageal squamous cell carcinoma remains neoadjuvant chemoradiation. We know that squamous cell carcinomas are more exquisitely sensitive to radiotherapy. And then obviously in those patients who don't achieve a pathologic complete response, the expectation would be that they would go on to receive nivolumab per CheckMate 577. Again, the thought is that these tumors are more sensitive to immunotherapy given their higher incidences of mutational changes. And so again, this kind of goes along with the positive results seen in the SCIENCE trial that we just discussed with sintilimab but also EFFECT-neo with pembrolizumab. Obviously, we await the results of Jennifer's trial. Dr. Shaalan Beg: And the last abstract I was hoping we could get your perspective on was Abstract 652, which is a Phase 3 study of everolimus plus lanreotide versus everolimus monotherapy for unresectable or recurrent gastroenteropancreatic neuroendocrine tumors, the STARTER-NET trial. What were the results of this study? Dr. David Wang: So, I just want to give a shout out because we did have a session at this year's GI ASCO that looked at more rare tumors. So appendiceal tumors, neuroendocrine tumors, those kinds of things. So again, I would encourage your listeners to listen to that session if they have interest in that. Another type of rare tumor was adenosquamous tumors.  But in terms of the STARTER-NET trial, this was again an interim analysis of his phase 3trial and it was looking at combining everolimus plus lanreotide versus everolimus. So we know that in pancreatic-gastric neuroendocrine tumors, if you have low Ki-67, a well differentiated tumor, that the standard of care really is a somatostatin analog, and sometimes if they're more aggressive, we kind of consider molecular targeted therapy with everolimus. This was asking the question of whether we should do the combination on the frontline. And what was interesting is in this study, the patients were actually more of a poor prognostic set. So they had Ki-67 up to 20% or these were patients that actually had multiple liver lesions. And what they found was a median for progression free survival was improved with a combination out to 29.7 months versus 11.5 months with the somatostatin analog alone, and that the overall response rate was 23% versus 8.3%, again, favoring the combination. If you looked at subgroup analysis, it was actually those patients who had Ki-67 greater than 10%, so the more aggressive tumors, or those with diffuse liver lesions that had the most benefit. So I think that would be the patient population I would consider this new combination with using would be those patients again with poorer prognosis neuroendocrine tumor phenotype. Dr. Shaalan Beg: Thank you very much, Dr. Wang, for sharing your insights with us today and your great work to build a robust GI Cancers Symposium this year. Dr. David Wang: Well, thank you. I mean that really is a cooperative effort. We appreciate all the members of the GI25 Program Committee as well as the ASCO staff that just made it an outstanding meeting. Dr. Shaalan Beg: And thank you to all our listeners for your time today. You'll find links to the abstracts discussed today on the transcript of this episode.  Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:  Dr. Shaalan Beg @ShaalanBeg  Dr. David Wang Follow ASCO on social media:   @ASCO on Twitter  @ASCO on BlueSky ASCO on Facebook   ASCO on LinkedIn   Disclosures:  Dr. Shaalan Beg:  Employment: Science 37  Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine  Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals  Dr. David Wang: Honoraria:  Novartis Consulting or Advisory Role: Novartis, Cardinal Health, Bristol-Myers Squibb, BeiGene, Eisai  

Research To Practice | Oncology Videos
5-Minute Journal Club Issue 3 with Dr Seth Wander: Reviewing the Role of Oral SERDs in the Management of ER-Positive Metastatic Breast Cancer

Research To Practice | Oncology Videos

Play Episode Listen Later Jan 31, 2025 11:58


Featuring an interview with Dr Seth Wander, including the following topics: The clinical utility of ESR1 mutations in HR-positive, HER2-negative advanced breast cancer Grinshpun A et al. The clinical utility of ESR1 mutations in hormone receptor-positive, HER2-negative advanced breast cancer. Hematol Oncol Clin North Am 2023;37(1):169-81. Abstract (0:00) Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and in combination with targeted therapy for ER-positive, HER2-negative advanced breast cancer Jhaveri KL et al. Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and in combination with targeted therapy in estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Phase Ia/Ib EMBER study. J Clin Oncol 2024;[Online ahead of print]. Abstract (6:01) EORTC-2129-BCG: Elacestrant for ER-positive/HER2-negative breast cancer patients with ctDNA relapse Ignatiadis M et al. EORTC-2129-BCG: Elacestrant for treating ER+/HER2- breast cancer patients with ctDNA relapse (TREAT ctDNA). ESMO 2024;Abstract 338TiP. (8:20) CME information and select publications  

JCO Precision Oncology Conversations
ctDNA as a Prognostic Biomarker in EGC

JCO Precision Oncology Conversations

Play Episode Listen Later Jan 29, 2025 5:51


In this JCO PO Article Insights episode, Harold Nathan Tan summarizes findings from the JCO PO article, “Circulating Tumor DNA as a Prognostic Biomarker for Recurrence in Patients With Locoregional Esophagogastric Cancers With a Pathologic Complete Response.” TRANSCRIPT Harold Nathan Tan: Welcome to JCO Precision Oncology Article Insights where we explore cutting-edge discoveries in the world of cancer treatment and research. I'm Harold Nathan Tan, your host for today's episode. Let's dive into a fascinating study published in JCO Precision Oncology entitled, “Circulating Tumor DNA as a Prognostic Biomarker for Recurrence in Patients With Locoregional Esophagogastric Cancers With a Pathologic Complete Response.” This study led by Dr. Eric Michael Lander and colleagues examines a critical question: Can circulating tumor DNA help predict recurrence in patients with esophagogastric cancer who have achieved a favorable pathologic response after treatment? Esophagogastric cancer ranks as the seventh leading cause of cancer-related deaths worldwide. Despite aggressive treatment including neoadjuvant therapy followed by surgery, recurrence remains a grim reality for many patients. Interestingly, even those who achieve a pathologic complete response face a recurrence risk of up to 25%. This highlights a need for better tools to identify high-risk patients post-treatment. Circulating tumor DNA, or ctDNA for short, is emerging as a powerful biomarker in oncology. This minimally invasive blood-based test detects fragments of tumor DNA in the bloodstream, potentially signaling molecular residual disease before any radiographic evidence of recurrence appears. In this study, researchers focused on patients with locoregional esophagogastric cancer who had undergone neoadjuvant therapy followed by surgery, achieving either a complete or near complete pathologic response. Blood samples were collected postoperatively within a 16-week molecular residual disease window and during routine surveillance. The aim is to determine whether ctDNA positivity correlates with recurrence-free survival. The study analyzed 309 plasma samples from 42 patients across 11 institutions. Detectable ctDNA within the 16-week postoperative window was associated with a significantly higher recurrence risk. Among those with detectable ctDNA, 67% experienced recurrence compared to only 15% for those with undetectable ctDNA. This corresponds to a hazard ratio of 6.2, an alarming figure that underscores the potential for ctDNA as a prognostic tool. But the story doesn't end there. Postoperative surveillance ctDNA testing more than 16 weeks after surgery also proved to be a powerful prognostic indicator. Every patient with detectable ctDNA during surveillance eventually experienced recurrence, while only 7.4% of those with undetectable ctDNA relapse. These findings suggest that ctDNA testing could provide a critical lead time, enabling earlier interventions and personalized treatment strategies. Now let's talk about the clinical implications. Currently, patients who achieve a pathologic complete response often aren't considered for adjuvant therapies as the absence of visible disease is taken as a sign of remission. However, this study challenges that assumption. By integrating ctDNA testing into routine post-treatment surveillance, clinicians could identify high-risk patients who might benefit from additional therapy even when traditional imaging shows no signs of recurrence. This brings us to the bigger picture. Esophagogastric cancer treatment is evolving rapidly, with trials like CheckMate 577 and ESOPEC offering new insights into perioperative strategies. However, this study highlights a critical gap, the need for personalized, biomarker-driven approaches in the adjuvant setting. ctDNA could fill that gap, offering a non-invasive, dynamic way to monitor patients and guide clinical decisions. Of course, no study is without its limitations. The authors acknowledge the relatively small sample size and the retrospective nature of their analysis. They also note the variability in ctDNA testing and imaging schedules across institutions. However, the robust association between ctDNA positivity and recurrence-free survival makes a compelling case for further research in larger prospective cohorts. Looking ahead, what's the next step? The authors call for prospective validation of ctDNA as a prognostic tool, emphasizing its potential to refine risk stratification and optimize treatment strategies. Imagine a future where a simple blood test could dictate not only the need for additional therapies, but also the timing and type of intervention. As we wrap up, let's reflect on the broader impact of the study. By integrating ctDNA into routine cancer care, we could move closer to a world where treatments are not just effective, but also precisely tailored to each patient's unique biology and disease dynamics. Thank you for tuning into JCO Precision Oncology Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. Until then, stay informed and stay inspired.   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.  

Oncology for the Inquisitive Mind
142. San Antonio Breast Cancer Symposium 2024 - Part 1

Oncology for the Inquisitive Mind

Play Episode Listen Later Jan 26, 2025 28:06


Welcome back to Oncology for the Inquisitive Mind, where we head back to late 2024 and cover some pivotal trials and ideas from the San Antonio Breast Cancer Conference 2024.This episode broadly covers hormone receptor-positive breast cancer and looks at another CDK comparison (real-world data). While the idea is not new, the potential implications from well-gathered "phase 4" data is a curious discussion point. Other topics include the ESR1 mutation and Imlunestrant, Patritumab Deruxtecan in hormone receptor-positive disease and the role of CTDNA in tumour burden and recurrence in early breast cancerStudies discussed in the episode:SOLTI-VALENTINEEMBER 3ctDNA in EBCCDK ComparisonFor more episodes, resources and blog posts, visit www.inquisitiveonc.comPlease find us on Twitter @InquisitiveOnc!If you want us to look at a specific trial or subject, email us at inquisitiveonc@gmail.comArt courtesy of Taryn SilverMusic courtesy of AlisiaBeats: https://pixabay.com/users/alisiabeats-39461785/Disclaimer: This podcast is for educational purposes only. If you are unwell, seek medical advice.Oncology for the Inquisitive Mind is recorded with the support of education grants from our foundation partners Pfizer, Gilead Pharmaceuticals and Merck Pharmaceuticals. Our partners have no editorial rights or early previews, and they have access to the episode at the same time you do. Hosted on Acast. See acast.com/privacy for more information.

JCO Precision Oncology Conversations
Proteomics Predictor for Immunotherapy Benefit

JCO Precision Oncology Conversations

Play Episode Listen Later Jan 15, 2025 21:21


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

ASCO Guidelines Podcast Series
Germline and Somatic Genomic Testing for Metastatic Prostate Cancer Guideline

ASCO Guidelines Podcast Series

Play Episode Listen Later Jan 9, 2025 16:25


Dr. Evan Yu presents the new evidence-based guideline on genetic testing for metastatic prostate cancer. He discusses who should receive germline and somatic testing with next-generation sequencing technologies, what samples are preferred for testing, and the therapeutic & prognosistc impacts of genetic testing. Dr. Yu emphasizes the need for awareness and refers to areas of active investigation and future research to improve personalized therapies for patients with metastatic prostate cancer.  Read the full guideline, “Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline” at www.asco.org/genitourinary-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02608 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. Evan Yu from the University of Washington and Fred Hutchinson Cancer Center, lead author on “Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline”. Thank you for being here today, Dr. Yu. Dr. Evan Yu: Thanks for having me on. 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 entire guideline, including Dr. Yu, who has 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, Dr. Yu, to start us off on the content of this guideline, could you first provide an overview of both the purpose and scope of this guideline? Dr. Evan Yu: Yeah, absolutely. So I think the one key thing to recognize is that prostate cancer is the highest incidence of all cancers in males. Additionally, it's the second highest cause of mortality in males, and that's about 35,000 deaths in 2024. So with that being said and done, it's a disease where we need to do better. And part of that is recognizing that we now have many targeted therapies, precision medicine type of therapies, but unlike a lot of other cancers out there, prostate cancer patients are not always getting sequencing, next generation DNA sequencing, let's say, to identify both inherited and also spontaneously develop what we call somatic mutations in their tumor. And I suspect that's partially because other cancers like breast cancer, we're so used to- in the first line, you present the patient, you throw out their estrogen receptor status, progesterone receptor status, HER2, ER/PR HER2; in lung cancer it's EGFR, ALK, ROS1, etc. In things like prostate cancer, things like BRCA2 have major important patient treatment implications and potentially family counseling and downstream cascade testing implications. But it hasn't made their way into that first-line presentation yet. And for that reason, there are some studies out there that show that testing in the community may be as low as 15% of patients with metastatic prostate cancer. We want to bring awareness to that and hopefully increase testing down the road so that we can better help our patients with metastatic prostate cancer. Brittany Harvey: Absolutely. It's important to get these targeted therapies to the patients who can benefit most. Using that context, I'd like to next review the key recommendations of this guideline across the six clinical questions that the panel addressed. So, starting with: Who should receive germline testing with next generation sequencing technologies? Dr. Evan Yu: Yeah. We think that it's common enough that everyone with metastatic prostate cancer should receive germline genetic testing. And the reason for that is there have been studies that have looked at this and have shown that 12% of men with metastatic prostate cancer have some sort of inherited germline mutation in a gene, mostly DNA repair genes. But 12% have something that is inherited and that loved ones, first degree relatives, siblings, offspring might have also inherited. Now, most of these are in the DNA repair genes, but that being said and done, there's not only treatment implications for the patient, where there are newer drugs that that patient could get treated with, but other loved ones that might have inherited these gene mutations, that these things can cause other cancers as well - not just prostate cancer, but breast cancer, endometrial cancer, ovarian cancer, pancreatic cancer. So, it's very important to test, with as high of an incidence as 12%, to test, and if you identify it in a patient, it's our job to talk to the patient about it and talk to them about the pros and cons of family counseling and talking to their loved ones and potentially having their loved ones get tested. Because if they test positive, then their doctors may want to know and may screen them very, very aggressively and differently for a whole host of other cancers. And the whole idea is you find the cancer very early and cure the patients before the cancer really takes hold and has the ability to spread so we can save a lot of lives down the road. Brittany Harvey: Absolutely. This germline testing is important not just for the patient, but has wider implications for their families as well, as you mentioned. So then, beyond those recommendations for germline testing, which patients should receive somatic testing with next-generation sequencing technologies? Dr. Evan Yu: So let's talk a little bit about somatic testing. So germline again, as we know, is inherited. The patient inherited it in every single cell in their body, then it becomes very easy, many of these are cancer predispositions for them to lose the other allele and then to have biallelic loss and then develop the cancer. Now, somatic just means it spontaneously occurred. Certainly, it's not going to occur in every cell in the body, but you can get one hit, lose one allele and then lose the other allele. And if that gene is truly carcinogenic and leading to that cancer, then that can have implications potentially for treatment as well. So we recommend that all patients with metastatic prostate cancer also undergo somatic next-generation sequencing testing. We recognize that at this point in time it's only those with metastatic castration-resistant prostate cancer or hormone-resistant prostate cancer, which is a later disease state where there are drugs that may target those mutations, for instance, like PARP inhibitors, but that early identification for a patient population that's fit and that can benefit from these therapies makes sense so that you know it's in place already and you have your treatments outlined and mapped out for the future. So we recommend it for everybody - somatic testing also for everyone with metastatic prostate cancer. Brittany Harvey: Understood. And then when patients are receiving that somatic testing, what is recommended for somatic testing? Primary tumor archival tissue? Fresh metastatic biopsy tissue? Or circulating tumor DNA testing? Dr. Evan Yu: We recommend that in the initial setting when you're first diagnosed, that archival tissue samples are fine and preferred. But circulating tumor DNA is good when there's no accessible archival tissue, or if the archival tissue, let's say, is very old and it's been sitting around for a long time, or you can't get it anymore because it's many years back when maybe a patient had a prostate needle biopsy. So if it's not accessible, then we recommend ctDNA. We believe that is preferred and also that ctDNA is recommended in a situation where you can't easily biopsy a metastatic site. Sometimes it's just not in a safe area to go after. Sometimes it's just a small lesion. So in general, we recommend tissue when available, and when we think that the tissue sample will yield clean results, if not, then we recommend doing ctDNA at that point in time. Brittany Harvey: So you have described who should get germline and somatic genomic testing. But what are the therapeutic impacts of this germline or somatic testing for single gene genetic variants? Dr. Evan Yu: We pulled this panel together and we met like every single month for like 12 months straight, and part of it was to review the literature. And as part of this literature review, we were able to pull a whole bunch of different trials. I think there was like 1713 papers we identified in the literature search. Eventually, we narrowed it down because with ASCO, we want to present the data with the highest level evidence, level 1 evidence, randomized controlled prospective data. And after reviewing 1713 papers, we narrowed it down to 14 papers. With those 14 papers, if you look at it, there are a lot of things that we think may have implications for treatment or prognosis, but we didn't feel was the highest level of evidence that we could support. So the things that have the highest level of evidence that we can support are certain DNA repair gene alterations, especially BRCA2, and treatment with PARP inhibitors because there are many PARP inhibitor prospective trials that show progression-free survival benefit and even overall survival benefit. And so that's the type of study that achieved the level of evidence that we could include. So I would say BRCA1 and BRCA2 highest level of evidence and PARP inhibitor use also is included in that. Brittany Harvey: Understood. I appreciate you reviewing those therapeutic options. So then, the last clinical question, which you just touched on briefly, but what are the prognostic impacts of germline and/or somatic testing? Dr. Evan Yu: Whenever you do testing, especially if you use panel testing, you find a lot of information. There's a lot of different mutations and some of which are VUSs (variants of unknown significance) where we don't quite know what it means yet, but we can track that, especially if it's germline. But with somatic, we find lots of things that have implications, but maybe just not treatment implications. A perfect example is p53. p53 is one of the most common tumor suppressor gene mutations on all cancers, but in prostate cancer they can occur and they can usually occur late, although there can even be germline inherited p53 alterations. There's no treatment that targets p53 right now, but we know that if you have a p53 mutation that those patients may have more aggressive disease and that prognostic information is important to give to the patient. And I think it's important for future clinical trial design and direction. So we do not recommend making treatment recommendations or changes based on these prognostic only biomarkers at this point in time. But we do recommend that, based on this, we can design intensification trials for those patients who have these poor risk biomarkers and de-intensification trials for patients who may have a good risk biomarker. So for instance, SPOP is a gene where we think these patients may have better outcomes, they might respond better to certain hormonal therapies like abiraterone. I say might because the level of evidence isn't quite there. But what I would say is that these prognostic only biomarkers, we just don't think they cut the mustard yet to be able to make treatment decisions. But we do think that they can drive counseling for the patient and potential selection and trial design for the future to say, “Okay. This is a patient population that has a more aggressive cancer. We need to be more aggressive in treating these patients.” “This patient population might have a less aggressive cancer. Maybe we can de-intensify and say side effects and quality of life may be better for the patients.” Brittany Harvey: Definitely. It's important for thinking through how to personalize care for these patients. So then you've talked about this a little bit in talking through the recommendations, but could you expand on what is the importance of this guideline and how it will impact both clinicians and patients with metastatic prostate cancer? Dr. Evan Yu: Yeah, I think the number one thing is awareness. I think the data's out there and people that are in my field, they know this. But by evidence of the fact that it's not first-line presentation lingo that everyone's talking about things like BRCA status, it means it hasn't necessarily disseminated all the way through. So it's increasing awareness of the fact that both germline and somatic alterations can occur and that these may have impacts on the patient for their treatment and their prognosis, and basically to increase testing for the future. I really think that in the future, there'll be other reasons that we may want to serially even retest and we may find that there may be mutations that develop as mechanisms of resistance that might guide therapy down the road. So we need to get people to start doing this for everyone with metastatic prostate cancer, because someday we might be doing it not just once, but over and over again. Brittany Harvey. Absolutely. We hope this guideline reaches a wide audience and that these recommendations can be put into practice. Finally, you've talked about how not all the data in the field has yet risen to the level of evidence that made it into the guidelines. So what are the outstanding questions in future research areas for both germline and somatic genomic testing for metastatic prostate cancer? Dr. Evan Yu: It was in our discussion, but it clearly- it's not common enough for there to be randomized prospective trials that would reach that level of evidence to make it in this guideline recommendation. But we all know that for any solid tumor, you can get mismatched repair deficiency, microsatellite instability leading to hypermutation or high tumor mutational burden. And that happens in maybe 3 to 5% of patients with metastatic prostate cancer as well. There is evidence and data that these patients can potentially benefit from immunotherapies like pembrolizumab. But again, it's just not common enough for there to be those randomized prospective controlled trials out there. But we mention it because we know it's FDA-approved across all the tumor types, so we felt like we have to mention it because that's something that has treatment implications for the patient. But also, I alluded to this earlier, I think an area of active investigation is the tried and true number one driver of prostate cancer, which is androgen receptor. Testosterone binds to androgen receptors, stimulates it. That's how androgen deprivation therapy works. That's how abiraterone and the amides like enzalutamide, apalutamide, darolutamide, that's how they all work. But even beyond that, we're starting to identify that maybe 15%, 20% of patients with metastatic castration resistant prostate cancer have androgen receptor mutations. And there are newer classes of therapies like androgen receptor degraders like CYP11A1 antagonist that lead to complete adrenal annihilation of other steroid hormones that might promiscuously stimulate these androgen receptor mutants. These things develop as mechanisms of resistance, and in the future, we might want to serially test- and that's an active area of investigation in the future, to say you've been treated, let's say, with androgen deprivation therapy and abiraterone for years. There are certain mutations that might develop as a resistance mechanism. We might need to serially test somebody because you didn't have that mutation earlier on, but later in the disease course you might. And then there might be a new drug X out there that we would want to use. Again, we need the data, we need the randomized prospective controlled trials, but they're happening out there. And somewhere down the road we may rewrite this guideline and have a lot more recommendations to add to it. Brittany Harvey: Yes, we'll look forward to more research in this field to better provide targeted therapies for patients with metastatic prostate cancer across the treatment paradigm. And we'll look forward to report outs from those trials that you mentioned. So I want to thank you so much for your work to develop this guideline and thank you for your time today, Dr. Yu. Dr. Evan Yu: Thank you so much. It's wonderful to be here today. 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/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is 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.  

OncLive® On Air
S11 Ep46: The Evolving Role of ctDNA in Guiding Adjuvant Chemotherapy Decisions in CRC: Insights from Stacey A. Cohen, MD

OncLive® On Air

Play Episode Listen Later Dec 24, 2024 17:51


In our exclusive interview, Dr Cohen provided insights into the evolving role of circulating tumor DNA (ctDNA) in clinical decision-making for patients with colorectal cancer (CRC), particularly through findings from the CIRCULATE-Japan GALAXY trial (UMIN000039205). She highlighted how ctDNA has emerged as a strong prognostic factor for recurrence risk in CRC and explored its potential to guide therapy escalation or de-escalation. She also discussed the heterogeneity in the patient population included in the CIRCULATE-Japan GALAXY study and how ctDNA negativity correlates with improved disease-free and overall survival. Additionally, Dr Cohen outlined what data are still needed to integrate ctDNA testing into routine clinical practice and how sustained vs transient ctDNA clearance may influence treatment and surveillance strategies moving forward.

JCO Precision Oncology Conversations
Transcriptome and ctDNA Associates with Pembrolizumab Benefit

JCO Precision Oncology Conversations

Play Episode Listen Later Dec 18, 2024 23:19


JCO PO authors Dr. Philippe Bedard (Staff Medical Oncologist at Princess Margaret Cancer Centre and Professor of Medicine at University of Toronto) and Dr. Alberto Hernando Calvo (Medical Oncologist at Vall d´Hebron University Hospital) share insights into their JCO PO article, “Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in Advanced Solid Tumors Treated With Pembrolizumab,” one of the top downloaded articles of 2024. Host Dr. Rafeh Naqash and Drs. Bedard and Hernando Calvo discuss how combined transcriptome and ctDNA longitudinal analysis associates with pembrolizumab outcomes. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, podcast editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.  Today we are excited to be joined by Dr. Philippe Bedard, Staff Medical Oncologist at the Princess Margaret Cancer Center and Professor of Medicine at the University of Toronto, as well as by Dr. Alberto Hernando-Calvo, Medical Oncologist at the Vall d'Hebron University Hospital, both authors of the JCO Precision Oncology article titled, “Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in Advanced Solid Tumors Treated With Pembrolizumab.”  Thank you for joining us today. Phil and Alberto. Dr. Alberto Hernando-Calvo: Thank you. Dr. Philippe Bedard: Great to be with you. Thanks for having us.  Dr. Rafeh Naqash: One of the reasons we do this podcast, as some of the listeners who listen to this podcast regularly may know, is to bring in novel approaches and try to understand how the field is moving towards a space where we are understanding biomarkers better. So your manuscript that was published in JCO Precision Oncology fulfills many of those criteria. And interestingly enough, I was at a conference at the Society for Immunotherapy of Cancer last month earlier in November and a lot of excitement at SITC was revolving around novel transcriptomic biomarkers, proteomic biomarkers or imaging based biomarkers. So could you tell us a little bit about why you started looking at biomarkers? This is an extremely competitive field. Why did you think that looking at the transcriptome is somewhat different from or more interesting from tumor mutational burden PDL-1 than other biomarkers that we currently use? And that question is for you Alberto to start off.  Dr. Alberto Hernando-Calvo: So I think gene expression profiles may have a predictive performance as compared to already existing biomarkers and this was one of the points that we describe in our manuscript. The gene expression signature that we developed back in 2019 at Vall d'Hebron Institute of Oncology was initially developed based on over 45 different tumor types and tested in over 1000 patients treated with antiPD-1 and anti PDL-1. And back then and in this manuscript, we proved that for instance the gene expression signature VIGex that we developed has a potential complementary role to other predictive biomarkers. In this case, we observe this predictive power with ctDNA dynamics and we then see a correlation with other existing biomarkers such as tumor mutational burden. So I don't think we need to use one or the other, but rather they may have additive predictive power. So we need to better individualize predictive biomarkers based on tumor types and select the best combination possible to improve the performance.  Dr. Rafeh Naqash: I completely agree that one size does not fit all, especially in the landscape of immunotherapy. From your perspective, when you developed the original signature, how did you choose what genes to look at? I looked at the manuscript, on the methodology side, some of the signatures are pro-inflammatory STING interferon gamma based, so how did you try to identify that these are the 7 to 10 or whatever number of signatures on the transcriptome side? And then why did you try to combine it with ctDNA based changes?  Dr. Alberto Hernando-Calvo: Back in our initial manuscript, published in Med from Cell Press, we developed the VIGex gene expression signature, as I mentioned, with taking into consideration over 1000 tumor samples from FFPE that we can consider real world samples because they are from real patients coming from the clinic notes as part of real investigational protocol doing or performing biopsies on patients. We did observe after doing a VIGex research and doing different tests, we eventually collected these 12 different genes. Because there is a combination of both genes involved in the interferon gamma pathway, we have genes associated with Tregs as well as T cell memory cells. So it's not only looking at genes that are associated with T cell activation or CD8+ T cell infiltration, but also looking at genes that may be overactivated, overexpressed, an immunosuppressive tumor microenvironment. So it was both selecting genes, the minimum number of genes to do it more scalable and having the minimum dataset of genes and including in the signature genes that are already at targets for immune sequent inhibitors or are being tested in immunotherapy combinations.  Dr. Rafeh Naqash: Thank you. And Phil, for the sake of our listeners, could you elaborate upon this aspect of using ctDNA? So this was tumor-informed ctDNA from what I understood in the manuscript. You guys basically try to use it to understand changes in the ctDNA with treatment and then try to combine it with the transcriptome signature. How did the idea come up initially and how did you plan on combining this with an RNA-based signature? Because I have seen manuscripts and other data where people are either using one or the other, but not necessarily both together. So how did you guys come up with that idea? Dr. Philippe Bedard: Well, we thought that this was a great opportunity to look at the combination of the transcriptome as well as the ctDNA dynamics because we had run an investigator-initiated phase 2 clinical trial called INSPIRE at our institution at Princess Margaret from 2016 to 2018, where patients across five different tumor groups received single agent pembrolizumab. And we really did a deep dive on these patients where there were tumor biopsies before and while on treatment. We did exome sequencing, we did RNA sequencing to capture the transcriptome. And in a prior analysis, we had partnered with Natera to look at their Signatera assay, which is a bespoke ctDNA assay, to look at ctDNA dynamics using this test and the association with response outcomes as well as survival outcomes. So we thought that this was a really unique data set to try and address the question of whether or not there was complementarity in terms of looking at the transcriptome and transcriptome signatures of IO benefit together with the ctDNA dynamics. Dr. Rafeh Naqash: From a patient treatment standpoint, it sounded like you mostly tried to include individuals who were treated with pembrolizumab. Did this not include individuals who were treated with chemoimmunotherapy or chemotherapy with pembrolizumab? Just pembrolizumab alone? And if that's the case, some of the tumor types there included, from what I remember, ovarian cancer and some other unusual cancers that don't necessarily have approvals for single agent pembrolizumab, but perhaps in the TMB-high setting. So can you elaborate on the patient selection there for the study?  Dr. Philippe Bedard: Yeah, that's a great question. So at the time that the study was designed in 2015, this was really the early days of immune checkpoint inhibitor therapy, so we didn't have the approvals that we have now in specific tumor types for immunotherapy and chemotherapy combinations. So when the study was designed as an investigator initiated clinical trial, the idea was really to capture patients across different tumor types - so head and neck squamous cell carcinoma, malignant melanoma, ovarian cancer, triple negative breast cancer, and a kind of mixed histology solid tumor cohort, where we knew that there were some patients who were going to be immunotherapy responsive, where there was already approvals or evidence of single agent activity, and others where the responses were more anecdotal, to try and understand in a phase 2 clinical trial with kind of a deep dive, which patients benefited from treatment and which didn't. Dr. Rafeh Naqash: Interesting approach. Going to the results, Alberto, could you help us understand some of the important findings from these data? Because there's different sections of how you tried to look at the response rates, the survival, looking at the immune deconvolution, if you could explain that. Dr. Alberto Hernando-Calvo: So the first thing that we tried was to further confirm the external validation of this immune gene expression signature, VIGex in the INSPIRE asset. So what we observed at VIGex-Hot, the category defined by VIGex-Hot tumor microenvironment, was associated with better progression free survival. After including that in a multivariable analysis adjusted by other biomarkers such as TMB, PDL-1 or tumor type, this was also confirmed for overall survival. So then the next step was to really try to hypothesize if the addition of ctDNA dynamics, taking into consideration the ctDNA quantification at baseline as compared to cycle three, if those dynamics could further improve the predictive performance of VIGex categories taken in the baseline samples. What we did observe was that, for instance, VIGex-Hot tumors in baseline tumor samples that were having a ctDNA decrease, as I mentioned before on cycle three assessment as compared to baseline, were having both better progression free survival and better prognosis overall. Another important finding was the evaluation of response rate across tumor types considering both biomarkers. I would say the most important finding is that when we were considering a cold tumor microenvironment in baseline samples before pembrolizumab initiation plus an increase in ctDNA values, what we observed is that those patients were having a 0% response rate. So this may help as a future strategy either for intensification of immunotherapy regimens in a more individualized way or for an early stop to immunotherapy and try to avoid financial toxicities as well as toxicities for our patients. Dr. Rafeh Naqash: From the data that you showed, it seems that there was a strong correlation, as you sort of mentioned, between individuals that had ctDNA clearance and baseline immune pro-inflammatory signatures. So do you really need the transcriptome signature or could the ctDNA just serve as an easy quick surrogate? Because from a cost standpoint, doing whole transcriptome sequencing or more RNA sequencing or tissue standpoint, where tissue is often limited, can become a big issue. So do you think that validation of this may perhaps more revolve around using ctDNA as an easier metric or surrogate? Or am I overestimating the utility of ctDNA? Dr. Philippe Bedard: I think it's a really good question. In our data set which was relatively small, there were 10 patients who had ctDNA clearance, meaning ctDNA that was positive at baseline was not detected. And so 9 out of those 10 patients, as you alluded to, were VIGex-Hot. So the question is a good one, could you do the same with just ctDNA clearance alone, particularly in identifying these patients who really do well, who have long term disease control on immunotherapy? I think it's a tough question to answer because the field is also changing in terms of sensitivity of detection of ctDNA tests. So we know now that there are newer generations of tests which can detect even at logs down in terms of allele variants in the circulation. So I think we need more data to address the question. I think it is important as to what is the best test, what is the endpoint that we should be using from a drug development point of view in terms of really trying to push and understand which treatment regimens are the most effective and have early readouts in terms of activity. Because we all recognize in the clinic that radiographic response doesn't tell the whole story, especially early radiographic assessments using RECIST or other criteria that we apply in clinical trials. Dr. Rafeh Naqash: From a clinical trial standpoint, we often talk about validation of these studies. You may have heard of other tests where, for example, the NCI iMatch, which is incorporating transcriptome sequencing based approach to stratify patients as an integral biomarker for treatment stratification. Is that something that you guys are thinking of using, this approach where individuals who are signature highly inflamed perhaps get lesser therapies or there's a de-intensification of some sort similar to what people are trying to do with ctDNA-based approaches? Dr. Philippe Bedard: I think that's a great question. I think it makes a lot of sense. And certainly, with the new wave antibody drug conjugates in terms of identifying patients who have expression of targets for antibody drug conjugates, that's very attractive as an approach because we don't necessarily have IHC markers for all of the different targets of antibody drug conjugates. We don't necessarily have IHC markers to completely understand different contributions to the tumor microenvironment and whether or not tumors are inflamed. But it's also a challenging approach too because RNA-seq currently is not a routine clinical test. Sometimes there are issues, particularly in patients who have stored specimens that are formalin-fixed and paraffin-embedded in terms of the quality of the RNA for RNA sequencing. And it's not always feasible to get pre-treatment biopsies and turn them around in an approach. So I think it is an attractive approach for clinical trials, but it's a hypothesis that needs to be tested. It's not something that is ready for clinical prime time today in 2024. Dr. Rafeh Naqash: One of the other interesting observations that I came across in your manuscript was that tumor mutational burden, interestingly, did not correlate with signature high tumors. What is the explanation for that? Because generally you would expect a TMB high to perhaps also have an immune gene high signature. Could it have something to do with the tumor types because there was a heterogeneous mixture of tumor type? Or I'm not sure. What else could you possibly think of that you didn't see those correlations or just sample size limitations? Dr. Alberto Hernando-Calvo: Yes. So our findings are consistent with prior data suggesting for instance T cell inflamed gene expression profile was also not correlated with tumor mutational burden and both biomarkers in a prior publication. So to have additive predictive performance for identifying patients most likely to benefit from anti PD-1 regimen, so we somehow were expecting this observation, the fact that both biomarkers are not very correlated. Dr. Rafeh Naqash: So given the proof of concept findings from your study, Phil, what is the next interesting step that you guys are thinking of to expand this? Would you think that a nivolumab-ipilimumab treated cohort would have similar findings? Or is this a treatment specific single agent immunotherapy specific correlation that you found versus something else that you may find in a nivo-ipi cohort or a doublet immune checkpoint cohort?  Dr. Philippe Bedard: The findings are really hypothesis generating. They require additional validation. And you're quite right, there may be nuances in terms of specific tumor types, combinations with other immunotherapy or combinations with chemotherapy or other agents. So I think it would be great if there are other data sets that are collecting this type of information that have ctDNA dynamics and also have transcriptome and potentially exome or genome analysis to look at these types of questions because the field is moving quickly and we really need more data sets in order to understand some of the nuances and greater numbers to validate the signals that we see. Dr. Rafeh Naqash: And one thing, as you said, the field is definitely moving very quickly. I was meeting with a company an hour back and they have an imaging-based approach using fresh tissue to look at pharmacodynamic biomarkers. And I used to work in the NCI with a group that was very interested and they developed an immuno-oncology pharmacodynamic panel that has been used and published in a few clinical trials where they did phosphorylation status. So the final theme that comes out of most of these research based studies that are being done is that one size does not fit all. But the question that comes to my mind is how many things do you necessarily need to combine to get to a predictive biomarker that is useful, that is patient centric, and that perhaps is able to identify the right therapy for the right patient. What is your take on that, Phil?  Dr. Philippe Bedard: Yeah, that's a great question too. The challenge is it depends on the context in terms of what degree of positive predictive value do you need as well as the negative predictive value to drive clinical decisions. So I think in certain situations where you don't have other approved treatment options and with a therapy that is potentially low toxicity and low financial toxicity, then I think the bar is very high in terms of being able to really confidently identify that patients aren't going to benefit. I think the nuance and the challenge becomes when you move into earlier lines of therapy, or when you talk about combinations of agents, or trying to understand within the context of other available options, particularly with treatments that have significant side effect profiles as well as financial risks, then it becomes a much more nuanced question and you really need comparative studies to understand how it fits versus the existing treatment paradigm. So I'm not really answering your question with a specific number because I think it's hard to give you a number. Some of that we also need input from patients in terms of what kind of level of validation do you need and what kind of level of discrimination do you need in order to drive decisions that are meaningful for them. Dr. Rafeh Naqash: Definitely early days, as you pointed out. More and more work in this field will hopefully lead us in the direction that we all want to go in.  Now, going to a different aspect of this podcast, which is trying to understand the trajectories for both of you, Phil and Alberto. And as you mentioned, this project seemed to have started in 2015. So I'm guessing there's a history there between Princess Margaret and Vall d'Hebron. Could you highlight that a little bit? And then perhaps, Alberto, after that you could tell us a little bit about your career when you worked at Princess Margaret as a fellow and then now back at Vall d'Hebron. Phil, you as well. Dr. Philippe Bedard: So absolutely. We have a long history of collaborating with Vall d'Hebron in Barcelona. It's really a great cancer institution with a lot of like minded individuals. We have a formal partnership and we have a lot of informal links in terms of scientists and clinicians who we work with and who we collaborate with on early phase clinical trials, as well as through different investigator networks and other translational projects. So this was really how this collaboration came about and we were fortunate to have Alberto, who came to work with us for two years and brought this great idea of looking at this signature they had developed at Vall d'Hebron in their phase one group and applying it to a data set that we had through the INSPIRE clinical trial.  Dr. Rafeh Naqash: Sounds like a very successful academia-academic collaboration, which is very nice to see. So, Alberto, could you tell us a little bit about your career trajectory and how you ended up at Princess Margaret and then back at Vall d'Hebron and what you do currently? Dr. Alberto Hernando-Calvo: Yes. So I did my oncology residency at Vall d'Hebron in Barcelona, Spain. Then I decided to further specialize in early drug development as well as head and neck cancer oncology. So I decided to pursue a clinical research fellowship under the supervision of Phil Bedard, among others. And so we decided to further validate the signature that we had developed both in the cancer genomic lab at Vall d'Hebron Institute of Oncology and the phase one unit at Vall d'Hebron, and apply the signature that have been originally tested in patients receiving anti PD-1 or anti PDL-1 combinations in early phase clinical trials. In the phase 2 clinical trial of INSPIRE, where we also had ctDNA dynamics and allowed us to test both biomarkers and see that additive predictive power when we were using both. That was one of my research topics under the mentorship of Dr. Bedard and my fellowship at Princess Margaret. And this was one of the manuscripts describing all the findings of this collaboration between Vall d'Hebron and Princess Margaret Cancer Center. Dr. Rafeh Naqash: And then, Phil, if you could highlight some of the things that you've done over the course of your career and perhaps some advice for early career junior investigators and trainees.  Dr. Philippe Bedard: I finished my oncology, medical oncology training at the University of Toronto in 2008. And then I did a breast cancer fellowship in Brussels at Breast International Group. At the time, I was really intrigued because it was really kind of the early days of microarray and RNA signatures in terms of expressing signatures were being used as part of a clinical trial that BIG was running called the MINDACT Study. And so when I finished my fellowship, I came back to Princess Margaret, started on staff. I've been here now for 15 years. I was fortunate to work with the phase 1 group and kind of my career has sort of morphed in terms of early drug development as well as genomics. I've been involved with the American Association for Cancer Research project GENIE, where I'm the current chair. This is really an international data sharing project with panel based sequencing, which both Princess Margaret and Vall d'Hebron have contributed to. And I've been fortunate to work with a number of really talented early career investigators like Alberto, who spend time with us in our drug development program and launched transitional research projects that leverage some existing data sets at their own institutions and also bring together with different research groups at our institution to lead to publications like this one. Dr. Rafeh Naqash: Thank you so much. This was very exciting. Phil and Albert, thanks for joining us today and thank you for allowing us to discuss your interesting manuscript and hopefully we'll see more of this biomarker work from you guys in the near future, perhaps published in JCO Precision Oncology.   And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.     The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Oncology Overdrive
“Back to the Future”: Developments in Immunotherapy with David Gandara, MD

Oncology Overdrive

Play Episode Listen Later Dec 12, 2024 39:30


In this episode, host Shikha Jain, MD, speaks with David Gandara, MD, about how ctDNA and CAR-T cell therapies are transforming precision medicine, the importance of patient reported outcomes and more. •    Welcome to another exciting episode of Oncology Overdrive 0:14 •    About Gandara 0:19 •    The interview 1:02 •    Can you tell me a little more about what you are working on now? 1:25 •    How did you get engaged with the community in Hawaii?  6:30 •    What do you think is going to happen with ctDNA moving forward? 8:29 •    Can you utilize ctDNA and minimal residual disease information to determine how long patients need to be on adjuvant therapy?  11:42 •    How did you get into the ctDNA space?  15:06 •    How do you see AI transforming health care beyond providing patients with more information and taking more ownership of their health?  18:28 •    Can you tell us more about how a second opinion clinic works? How did this type of clinic develop and become part of what you do?  23:17 •    What are some of your predictions as to what will happen in oncology care over the next ten to twenty years?  29:00 •    If someone could only listen to the last few minutes of this episode, what would you want listeners to take away? 37:30 •    How to contact Gandara 38:47 •    Thanks for listening 39:10 David Gandara, MD, is a clinician-scientist and lung cancer specialist internationally recognized for his expertise in thoracic cancers, cancer drug development and biomarker development. We'd love to hear from you! Send your comments/questions to Dr. Jain at oncologyoverdrive@healio.com. Follow Healio on X and LinkedIn: @HemOncToday and https://www.linkedin.com/company/hemonctoday/. Follow Dr. Jain on X: @ShikhaJainMD. Dr. Gandara can be reached via email drgandara@ucdavis.edu.  Disclosures: Jain reports no relevant financial disclosures. Gandara reports institutional research grants from Astex, Amgen and Genentech; institutional consulting for AstraZenica, Exact Sciences, Genentech, Guardant Health, IO Biotech and Oncohost; consulting for Adagene, Henlius USA, Foundation Medicine and Sanofi; serves on the advisory board of Abbvie, Janssen, Merck, Mirati, Regeneron and Revolution Medicine. 

Ophthalmology Journal
cfDNA in Ocular Histiocytosis

Ophthalmology Journal

Play Episode Listen Later Nov 7, 2024 28:09


Dr. Rajesh Rao speaks with Dr. Jasmine H. Francis on whether sequencing of plasma-derived ctDNA can noninvasively diagnose ocular-involving histiocytosis. From her Ophthalmology Science article, “Plasma-Derived Cell-Free DNA for the Diagnosis of Ocular-Involving Histiocytosis.” Plasma-Derived Cell-Free DNA for the Diagnosis of Ocular-Involving Histiocytosis. Francis, Jasmine H. et al. Ophthalmology Science, Volume 4, Issue 5.

JCO Precision Oncology Conversations
Transcriptomic Profiling of Non-Localized Prostate Cancer

JCO Precision Oncology Conversations

Play Episode Listen Later Oct 16, 2024 27:07


JCO PO author Dr. Amar U. Kishan, Professor, Executive Vice Chair, and Chief of Genitourinary Oncology Service in the Department of Radiation Oncology at the University of California, Los Angeles, shares insights into his JCO PO article, “Transcriptomic Profiling of Primary Prostate Cancers and Nonlocalized Disease on Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography: A Multicenter Retrospective Study.”  Host Dr. Rafeh Naqash and Dr. Kishan discuss the relationship between Decipher genomic classifier scores and prostate-specific membrane antigen (PSMA) PET/CT-based metastatic spread. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO articles. I'm your host, Dr. Rafeh Naqash, Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today we are joined by Dr. Amar Kishan, Executive Vice Chair of the Department of Radiation Oncology at the David Geffen School of Medicine at UCLA and UCLA Jonsson Comprehensive Cancer Center, and also the corresponding and senior author of the JCO Precision Oncology article entitled, “Transcriptomic Profiling of Primary Prostate Cancers and Non Localized Disease on Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography/Computed Tomography: A Multicenter Retrospective Study.” Dr. Kishan, welcome to our podcast and thank you for joining us today. Dr. Amar Kishan: Thank you so much for that kind introduction and the invitation to be here today. Dr. Rafeh Naqash: Well, it seems to me that there's a theme that people in the GU space, investigators in the GU space, are very interested in trying to understand risk predictors for prostate cancer. We had somebody, I believe from Huntsman Cancer Center a few months back on a previous podcast, where they were trying to do risk prediction modeling as well. Could you tell us why that's something that the GU community is very interested in? What's the background? Is it because there's no risk prediction approaches currently? And would this somehow influence management in the near future? Dr. Amar Kishan: Yeah, that's a great question. So, I think this goes back to the point that we're in the era of precision medicine now, and many cancers have these molecular stratification scores and all that. Prostate cancer has lagged a little bit behind in that regard, despite the fact that it's such a common cancer that affects so many people across the country and across the world. So, we do have risk stratification schemes for prostate cancer. These are based off clinical and pathologic variables, like the level of PSA, the size of the tumor on digital rectal examination, now, we're incorporating MRI imaging as well, and then what the cancer looks like under the microscope, the Gleason score. And now there have been revisions to the Gleason score, but it's really kind of the architecture, what the biopsy looks like. And this was kind of developed many, many years ago by Donald Gleason, a pathologist at the VA. What we're not necessarily taking into account routinely is kind of the biology of the cancer per se. You know, what are the molecular drivers? How could that influence ultimate outcome? And that's very important because we have these risk groups, low risk, very low risk, favorable intermediate risk, unfavorable intermediate risk, high risk, very high risk. But within each of those groups, based on the clinical kind of pathological characteristics, there's a huge heterogeneity in outpatients too, and our treatments are effective, but they can be morbid. Putting someone on hormone therapy for an extended period of time has a lot of side effects. Dose escalating radiotherapy or doing surgery and then radiation afterwards, these are big things that have a big impact on the patient, and I think we really need better risk stratification tools to understand who needs intensification and who we can de-escalate treatment for. Dr. Rafeh Naqash: I think those are absolutely valid points, perhaps not just for prostate cancer, more so for all cancers that we currently treat, especially in the current day and age, where we have a tendency to add more and more therapies, combination therapies for patients, and as you mentioned, risk stratification to help identify high risk versus low risk, where you can de intensify treatment, is of high value from a patient standpoint as well as from a financial toxicity standpoint. So then, going to this next part of the approach that you used, and from what I understand in this paper, you had the radiological aspect, which is the PSMA PET, which we'll talk about. Then you had the genomic aspect, where you did some genomic risk-based stratification. Then you had the transcriptomic score based on the Decipher score. So, could you go into some of the details, first, for the PSMA PET, when is it used? What is the utilization? What is it based on, the science behind the PSMA PET? And then we can talk about some of the other genomic transcriptomic predictors that you use in this study. Dr. Amar Kishan: Sure. Absolutely. So, a PSMA PET is an advanced molecular imaging tool. PSMA stands for prostate specific membrane antigen. It's a membrane protein that is expressed on the surface of prostate cancer cells. It is expressed elsewhere in the body as well. The utilization of this for imaging has been a revolution in the staging of prostate cancer, both upfront and in the recurrent setting. We basically had fairly recent approval for PSMA PET being used more routinely in upfront staging and recurrent staging in 2022. Essentially, what this is it gives us an ability to detect whether prostate cancer has spread at a time of diagnosis or try to localize the recurrence. Now, no imaging test is perfect, of course, and a PET has a resolution of about 3 mm. There are questions about the sensitivity of the PET. You get it on a patient with high-risk disease, the PET is negative; you do surgery, there are positive lymph nodes. That can happen, but it's far superior to the tools that we have had before. For instance, beforehand, all we would have is a contrast enhanced CT, bone scan, and MRI. And the sensitivity of those is far below that of a PSMA PET. And that has actually been shown in a randomized trial called the ProPSMA trial out of Australia, where they compared conventional upfront imaging versus PSMA upfront imaging with a crossover design, and there was better detection of disease with the PSMA PET. So that's been a revolution in how we stage prostate cancer. But I'm sure many of your listeners and others are aware of the concerns. When you get a new test and you're detecting disease that's extra prostatic, for instance, are you seeing truly significant new disease that we do need to change our management for, or are we just seeing stuff that wasn't there before that actually wouldn't impact anything? And what I mean by that is, let's say you're seeing things that would never have made a difference to the patient, but now you're saying they have metastatic disease. You're changing their entire treatment paradigm, all kinds of things like that. There's implications to this that hasn't been fully fleshed out. But very recently, like we're talking in July of 2024, essentially, there was a Lancet Oncology paper that looked at the long-term prognosis of patients who had extra prostatic disease on PSMA PET, judged by something called a PROMISE score, kind of gives a quantification on the volume of disease, the brightness of disease, and they correlated that with long term outcomes. And that was really the first time that we have long term follow up data that this extra prostatic disease on PSMA PET actually is prognostically important. So, we're getting there. I mean, now that it's approved and, in some sense, the cat is out of the bag, patients are coming in asking for a PSMA PET, etc. I'm sure everyone has experienced that, but I think we now do have good evidence that it actually is prognostically important as well. Dr. Rafeh Naqash: Thank you for that explanation. And again, to put this into context for things that I've seen and that might also help the listeners in other tumors, so, for example, melanoma surveillance tends to be or while on treatment, patients tend to have more PET scans than what you see, maybe in individuals with lung cancer, where you get a baseline PET and then you have follow up CT scan based imaging is that something that you guys have shifted from in the prostate cancer space with the approval for PSMA PET, where follow up imaging, whether patient is on treatment or surveillance imaging, is PSMA PET based? Dr. Amar Kishan: Yeah, that's a good question. I think there's actually less robust data to support it as a means of treatment response. But in terms of evaluating a recurrence, then, yes, that has become kind of a standard tool. It's very complicated because all of the metrics that we have for, say, a treatment failing are based on conventionally detected metastases or something that shows up on a CT or bone scan. So, again, that question arises if someone is on systemic therapy and then you see something on a PSMA PET, are you going to abandon the therapy that you're on? It technically would be earlier than you would otherwise have done that, or what are you going to do? So, that hasn't been fully fleshed out, but it is used in that circumstance. So, I'd say less for treatment monitoring and more for evaluation of suspected recurrence. Dr. Rafeh Naqash: Understood. And I'm guessing, as a futuristic approach, somebody out there may perhaps do a trial using PSMA PET based imaging to decide whether treatment change needs to be made or does not need to be made. Dr. Amar Kishan: Yeah. It is being incorporated into trials as we speak, I think. Dr. Rafeh Naqash: Now, going to the second part of this paper is the Decipher score. Could you explain what the score is, what its components are, how it's calculated? Is it DNA, is it RNA, is it both combined? Is it tissue based; is it blood based? Dr. Amar Kishan: Yeah. So, the Decipher is also an approved test now, was approved in 2018. What it is, essentially, and how it's derived is based on the idea originally that patients might have a recurrence after surgery for prostate cancer. And it's just a PSA recurrence. It's this way. It's literally what we call a biochemical recurrence. That patient might not have any problems, whereas other patients with a recurrence might go on to develop metastatic disease. And we didn't have a good way of determining which patient is which. Get back to that prognostic problem that we have. So, some investigators, they looked at men that had radical prostatectomy from 1987 to 2001 at the Mayo Clinic that had archived tissue. They looked at FFPE, or basically paraffin embedded tissue. They extracted the RNA and then did a microarray analysis and looked at transcriptomic signatures and wanted to see, could this discern the patients who had mets, who had clinically significant recurrences from those that didn't? And out of that exercise came the Decipher Genomic Classifier, which basically is based on 22 genes. These are involved with cell proliferation, etc., but it's an RNA-based, tissue-based assay. So, if you wanted to order a Decipher on somebody, you would need to use a biopsy or prostatectomy specimen to do so. Essentially, that the samples, they would take the highest grade, highest Gleason grade specimen, send it to their lab. Their main lab is in California. The company is called Veracyte. And then they will do this RNA express analysis with a microarray and then return a score. The score is 0 to 1. Basically, 0 is the lowest, one is the highest, and it is a way of prognosticating the risk of metastasis. Originally, when you get a Decipher report, it actually will tell you the 5 and 10-year risks of distant metastasis, and we'll quantify that. Dr. Rafeh Naqash: And you said this is approved or has been approved in 2018. So, is this insurance reimbursable at this point? Dr. Amar Kishan: Most insurances do, not all, and the criteria for getting it can vary, so we can talk about it, but it was initially developed in this post-op setting. On the basis of a significant amount of validation studies, it has been moved to being used in the upfront setting as well. So, if you look at some of the ongoing NRG trials, for instance, they are stratifying patients based off the upfront Decipher score. And this is based off of validation studies that have been conducted looking at past RTOG trials and other trials. That said, sometimes it is not approved by commercial insurances in the upfront setting, because that wasn't where it was initially validated and derived. But honestly, here in 2024, that's very uncommon. It's much more common that it's approved. Dr. Rafeh Naqash: Understood. And in your practice, or the medical oncologist practice at your institution or other institutions, is this something that is commonly used for some sort of treatment decision making that you've seen? Dr. Amar Kishan: Yeah. So, as a radiation oncologist, I do think it's a useful test, because my approach is, if we're talking about adding hormone therapy, for instance, which is oftentimes dominating the conversation, we know that it offers a relative benefit to a lot of patients. We've published on this; others have published on it. Let's say it reduces the chance of metastasis by about 40%. 10-year risk of metastasis has a ratio of 0.6. So, 40% reduction. But if your risk of metastasis is 2%, that benefit is not that much in absolute terms. And we don't historically have a great way of saying, what is your absolute risk of metastasis? And I think Decipher is one tool that does tell us that - it literally gives it on the report. Now, is that a holy grail? Is it 100% accurate? Nothing is 100% accurate. But it does give us some quantification. Then I can go back to the patient and say, yes, you will get a benefit from adding hormone therapy, but you're talking about going from 2% to 1%, and so they can decide if that's worth it to them. Conversely, it could be a situation where they really don't want hormone therapy, but it comes back that their risk of metastasis is 20%, and then there's actually a big absolute benefit. So that's how I use it as a radiation oncologist, and we would use it upfront. Now surgeons, and if I was consulting on a post operative patient, maybe it plays more of a role. And do we need to do post operative radiotherapy on this patient, or do we need to add hormone therapy in the postoperative situation? From the medical oncology perspective, there are emerging data that may be useful in the choice of systemic therapy for metastatic disease, but that is a little bit earlier in the investigational stage, I would say. So, when I'm working with medical oncologists, it's often still in this localized setting, and typically, do we add hormone therapy or not, and that type of thing. Dr. Rafeh Naqash: Understood. And from a reporting standpoint, so the Decipher score, I'm guessing it's some sort of a report that comes back to the ordering physician and you basically see the score, it gives you a potential recurrence free survival percentage or a metastasis percentage of what is your risk for having metastasis in the next five years - is that how they generally do it? Because I've personally never seen one, so I'm just curious. Dr. Amar Kishan: Yeah, essentially, it comes back with a score, a numerical score, again, from 0 to 1, and it will basically give you the five-year risk of distant metastasis. The ten-year risk of distant metastasis. You can request an extended report that provides additional, not as well supported signatures that are out there, like ADT response signature, etc. But those maybe may have been published, but are not clinically validated as much, but the actual Decipher report, which goes to patients too, just has this kind of 5,10-year risk of distant metastasis. They have some estimations on prostate cancer specific mortality as well. Dr. Rafeh Naqash: Sure. Now, the third part of this project, and correct me if I'm wrong, the grid database of the 265 genomic signature score. From what I understood, this is a different component than the Decipher score. Is that a fair statement? Dr. Amar Kishan: Yeah. No, that's exactly correct. And that was an exploratory part of this analysis, to be honest. Basically, I think our main focus in the paper was those advances that we've talked about PSMA and Decipher, those happened concurrently. People started developing PSMA PET, people started developing Decipher. And so, what we wanted to understand was, if you have a patient that has extra prosthetic disease on PSMA PET, are those biologically more aggressive cancers, is their Decipher score going to be higher? What can we learn about the biology of this? And we were the first, to my knowledge, where we actually had a large data set of patients that actually received PSMA PETs and Decipher. And that's kind of the gist of the paper. We have patients in the upfront setting, patients in the post radical prostatectomy setting, and we're essentially showing that there is this correlation. In the upfront setting, the odds of extra prosthetic disease are higher for higher Decipher scores, which is kind of maybe validating that this biology is capturing something that's akin to this ability to spread. And in the post-op setting, because we have time to failure, technically, we can calculate a hazard ratio rather than odds ratio. So, we have a hazard ratio that's significantly associated with an increased risk of spread for patients with higher Decipher. The grid portion, which is the genomic resource information database, was more of an exploratory part where I mentioned the Decipher score is based off this microarray, they're looking at 1.4 million transcripts. Only 22 are part of the Decipher, but you can request the rest of the signature data as well. And so, we wanted to look at other pathways, other signatures that have been published, like looking at DNA repair, neuroendocrine pathway, just to see if we could see any correlations there that's not necessarily as clinically actionable. These are more exploratory. But again, we were trying to just look at whether patients who had non localized disease on their PSMA PET, whether their primary had more aggressive biology. We did see that. So that's kind of loosely speaking things like PTEN loss, androgen receptor, DNA repair, metabolism, neuroendocrine signaling, which are thought to be portenders of aggressive disease. Those pathways were upregulated at the RNA level in patients who had non-localized disease. And that's kind of the take home from that. But I wouldn't say any of that is clinically actionable at this point. It's more kind of defining biology. Dr. Rafeh Naqash: Some of the interesting correlations that you make here, at least in the figures that we see, you're looking at different local occurrences, nodal metastases, M1A and M1B disease. And one thing that I'm a little curious about is the Decipher score seems to be lower in pelvic nodal metastasis, that is, PSMA PET positive versus local recurrence, which has a slightly higher Decipher score. Is that just because of a sample size difference, or is there a biologically different explanation for that? Dr. Amar Kishan: Yeah, that's a good point. I would assume that's probably because of a sample size in this case, and it's a little bit complicated. It wasn't statistically different. And it was 0.76 on average for patients with local recurrence and 0.7 for patients with a pelvic nodal metastasis. Well, what I think is interesting is we can maybe think that in this post-op setting the time to failure could have been long in some of these cases. So, it is conceivable that an isolated nodal recurrence 10 years after the surgery, for instance, is not as aggressive a cancer as a local recurrence in a short time after the surgery. And that's not taken into account when you're just looking at median scores like we are in this fox and whiskers plot. But overall, I think what it's suggesting is that there are patients who have more indolent disease. That's actually pretty widespread there. There are pretty indolent cases that have these nodal metastases. So just because you have a nodal metastasis doesn't mean it's an incredibly aggressive cancer, biologically. Dr. Rafeh Naqash: Now, the exploratory component, as you mentioned, is the grid part where you do look at TP53, which is a cell cycle gene, and higher TP53 associated with worse recurrences, from what I understand. Do you see that just from a cell cycle standpoint? Because from what I, again, see in the paper, there's a couple of other cell cycle related signatures that you're using. Is that just a surrogate for potential Gleason score? Have you guys done any correlations where higher Gleason score is associated with maybe higher cell cycle checkpoint, pathway related alterations and replication stress and DNA damage and perhaps more aggressive cancers? Dr. Amar Kishan: Yeah, that's a great question. We haven't done that in this paper, but it has been published before that there is this correlation loosely between grade and some of these parameters - so repair, metabolism, androgen receptor signaling. However, it's a very great point that you bring up, which is that it's pretty heterogeneous and that's why we need something like this as opposed to Gleason score. So, you can have Gleason 10 cancer. I mean, that would be pretty uncommon. But within the Gleason 9, at least, which we have published on and looked at, there's a heterogeneity. There are some that are biologically not that aggressive. And the converse Gleason 7, you can have some that are actually biologically aggressive. That's why it may be useful to move away from just the pathological architecture and get a little bit more into some of these pathways. Dr. Rafeh Naqash: What's the next step here? I know this perhaps isn't ready for primetime. How would you try to emphasize the message in a way that makes it interesting and clinically applicable for your colleagues in the GU community? Dr. Amar Kishan: Yeah. I think for me, what I would try to emphasize here and what I think is the main takeaway is this is kind of a validation that having extra prostatic disease on PSMA PET is likely suggestive of a more aggressive disease biology. And I think what this stresses to me is the importance of getting a PSMA PET, particularly in patients with high-risk prostate cancer. This isn't always happening. And I think if we see things on a PSMA PET, we really need to consider systemic therapy intensification. And what do I mean by that as a practical point? You have a high-risk prostate cancer patient. You get a PSMA PET, you see an isolated pelvic lymph node. If we believe the results of the study, that's a more aggressive biology likely. Whether we have the Decipher or whether we have genomic signatures, which we may or may not have, maybe that patient should get treated with something like an androgen receptor signaling inhibitor in addition to ADT, more akin to a clinically node positive case. So, intensify the systemic therapy, more aggressive disease. That's how I would incorporate it practically into my practice, that really what we're seeing on the PSMA PET is real. It's a reflection of biology that's aggressive. It's not just some Will Rogers effect where you're upstaging stuff needlessly. I think this is telling us some true biology. So that's kind of what my takeaway would be. I think future areas of investigation would be, honestly, to try to have a better idea of what's going on in these metastases. So, if you could design a study potentially, where your biopsy some of these and actually do sequencing and understand a little bit more of that. And so, we're looking into stuff like that. But my takeaway for like the everyday clinician would be to try to get a PSMA PET, if you can, and to intensify therapy on the basis of that, or at least consider it, discuss it in a multidisciplinary setting. Dr. Rafeh Naqash: And I'm guessing somebody out there, perhaps even you, are thinking or planning on doing a ctDNA MRD based correlation here, since that's up and coming in this space. Dr. Amar Kishan: That is up and coming, I think one of the challenges in prostate cancer is the amount of ctDNA can be low. But yes, you're right, that's certainly things that a lot of us are looking at, too. Dr. Rafeh Naqash: Excellent. Well, thank you for the science discussion, Dr. Kishan, could you tell us a little bit about yourself, your career trajectory, where you started, what you're doing, and perhaps some advice for early career junior investigators, trainees, things that might have worked for you, that could also work for them as they are progressing in their careers. Dr. Amar Kishan: Sure. So, yeah, I'm a radiation oncologist at UCLA. I run the prostate cancer radiation program. Clinically. I'm also heavily involved in our research enterprise, so I kind of oversee the clinical and translational research aspect. That's what I do currently. So, I did my residency in radiation oncology at UCLA. Just on a personal note, my wife is from LA, her parents live in LA. We really wanted to stay in LA, so I was fortunate to be able to join the faculty here. I always liked GU oncology, so that was kind of a natural thing for me to kind of go into this position here and try to build the GU program. I've been very fortunate to have great collaborators. My message to students and trainees is to try to reach outside your department for mentorship as well. It's important to have people inside your department who can mentor you. But as a radiation oncologist, I work so closely with urology, so closely with medical oncology that I'm very fortunate to have individuals in those departments who have a vested interest in me and my success as well. I like working with them. It's important to be a team player. If they need help, you help them. If you need help, you ask for help from them. So, I think that's the single biggest thing that I would say to any trainee is don't be intimidated. Please reach outside of your department. Lots of people are willing to help and provide mentorship, and it's helpful to have that perspective. We are in a very multidisciplinary environment and era of practicing medicine. Dr. Rafeh Naqash: Well, thank you again for those personal insights and especially for submitting your work to JCO PO. And we hope to see more of this work perhaps in the subsequent sessions for JCO PO, and maybe we'll bring you back again. And at that point, the Decipher and the PSMA PET scan will have more data, more implementation in the clinically relevant real-world setting. Dr. Amar Kishan: Thank you very much. And if I could just give one quick shout out. The first author of this work, which I presented, was Dr. John Nikitas, who is a trainee that works with me here at UCLA a PGY5 resident. So, I do want to give credit to him as well. Dr. Rafeh Naqash: And John, if you're listening to this hopefully, it's always great to get a shout out from your mentor. Thank you both again for putting in the work and effort to submit this manuscript. Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Disclosures  Dr. Kishan Honoraria Company: Varian Medical Systems, Boston Scientific,  Janssen Oncology  Consulting or Advisory Role Company: Janssen, Boston Scientific, Lantheus  Research Funding Company: Janssen , Point Biopharma

BackTable Urology
Ep. 193 Bladder Cancer Innovations: ESMO 2024 Highlights with Dr. Andrea Apolo

BackTable Urology

Play Episode Listen Later Oct 8, 2024 52:14


Catch up on the latest breakthroughs in bladder cancer management. In this episode of the BackTable Urology Podcast, Dr. Bogdana Schmidt (University of Utah) speaks with Dr. Andrea Apolo, a medical oncologist at the National Cancer Institute, about recent advancements in bladder cancer treatment presented at the 2024 European Society of Medical Oncology (ESMO) Congress. --- SYNPOSIS They review pivotal trials like the NIAGARA and AMBASSADOR studies, the TAR-200 drug delivery system, the use of bladder-sparing treatment, and the role of ctDNA as a biomarker. Further, they detail the effectiveness of systemic therapies such as gemcitabine and pembrolizumab, the implications of perioperative immunotherapy, and the future role of antibody-drug conjugates. The conversation highlights the trend towards less invasive approaches while improving survival rates from bladder cancer. --- TIMESTAMPS 00:00 - Introduction 03:49 - NIAGARA Trial 09:10 - Challenges in Bladder Cancer Treatment 18:56 - AMBASSADOR Trial 25:30 - Adjuvant Immunotherapy 29:30 - Exploring Biomarkers and ctDNA 36:34 - Surgery and Less Invasive Therapies 46:31 - Future Directions in Bladder Cancer Treatment --- RESOURCES ESMO https://www.esmo.org/

The Syneos Health Podcast
Circulating Tumor DNA: Transforming Oncology Clinical Trials

The Syneos Health Podcast

Play Episode Listen Later Oct 2, 2024 20:01


Use of circulating tumor DNA (ctDNA) – small fragments of DNA that are released into the bloodstream by cancer cells – as a diagnostic tool represents a significant shift toward more precise, personalized cancer care, enhancing both trial efficiency and patient experience. Unlike traditional tissue biopsies, which sample a single tumor site, ctDNA offers a real-time, comprehensive view of the genetic mutations present in the tumor throughout the body. By offering faster, more detailed insights than traditional imaging, ctDNA can identify tumor mutations earlier and help clinicians adjust treatments sooner.In this episode of the Syneos Health Podcast, Chief Scientific Officer Nick Kenny is joined by oncology experts Dr. Patrick Kelly and Dr. Wael Harb to discuss how circulating tumor DNA (ctDNA) is transforming cancer treatment and clinical trial design, and its potential to drive more patient-centric, adaptive clinical trials. Find all of our oncology-related insights on our Insights Hub here.The views expressed in this podcast belong solely to the speakers and do not represent those of their organization. If you want access to more future-focused, actionable insights to help biopharmaceutical companies better execute and succeed in a constantly evolving environment, visit the Syneos Health Insights Hub. The perspectives you'll find there are driven by dynamic research and crafted by subject matter experts focused on real answers to help guide decision-making and investment. You can find it all at insightshub.health. Like what you're hearing? Be sure to rate and review us! We want to hear from you! If there's a topic you'd like us to cover on a future episode, contact us at podcast@syneoshealth.com.

JCO Precision Oncology Conversations
MCED Test Preferentially Detects High-Grade Prostate Cancers

JCO Precision Oncology Conversations

Play Episode Listen Later Sep 25, 2024 7:49


In this JCO Precision Oncology Article Insights episode, Mitchell Elliot summarizes an editorial: “A Targeted Methylation–Based Multicancer Early Detection Blood Test Preferentially Detects High-Grade Prostate Cancer While Minimizing Overdiagnosis of Indolent Disease” by Dr. Brandon A. Mahal, et al. published on August 29, 2024.  TRANSCRIPT Mitchell Elliott: Hello and welcome to JCO Precision Oncology Article Insights. My name is Mitchell Elliott, a JCO Editorial Fellow. Today, I'll be discussing the article, “A Targeted Methylation–Based Multicancer Early Detection Blood Test Preferentially Detects High-Grade Prostate Cancer While Minimizing Overdiagnosis of Indolent Disease,” by Mahal et al. Cancer overdiagnosis, particularly of low-risk conditions that are unlikely to cause harm, is a common issue in screening tests. In prostate cancer screening, overdiagnosis affects 23% to 42% of cases, often due to the prevalence of low-grade cancers and the low specificity of the prostate specific antigen or PSA tests. Data from previous studies have highlighted that men with low grade prostate cancer often die with prostate cancer and not of prostate cancer. Over diagnosis can lead to unnecessary treatments, increased patient anxiety, side effects, and excessive healthcare costs. Multicancer early detection, or MCED tests offer a new approach by detecting multiple cancer types from a single blood sample with low false positive rates, typically less than 2%, and they also have the ability to predict the cancer type from this one test. The GRAIL Galleri test, based on methylation patterns of circulating tumor DNA, showed high accuracy detecting over 50 cancer types, including prostate cancer, in the circulating cell free genome atlas or CCGA in PATHFINDER studies. This type of MCED test paradigm is being developed for use alongside traditional screening methods in adults over the age of 50. This study evaluated this particular MCED test ability to detect both indolent and aggressive prostate cancer, aiming to assess its potential to contribute to over diagnosis. This cohort was part of the circulating cell free genome atlas or CCGA study, a multicenter case control study with three phases to validate this particular MCED test. The CCGA enrolled 15,254 participants, of which 8,584 had cancer and 6,670 did not. Enrollment was carried out in 142 North American sites between 2016 and 2019. Eligibility for cancer cases required a confirmed diagnosis or high suspicion with planned biopsy or surgery within six weeks of enrollment. This study evaluated 420 recently diagnosed men with prostate cancer from substudy 3, the independent clinical validation arm. The PATHFINDER study was a prospective cohort study of 6,662 adults over the age of 50 enrolled from seven US health networks between December 2019 and December 2020. Participants underwent testing with the GRAIL Galleri test, with results shared with physicians and participants. The test indicated the presence or absence of a cancer signal and predicted the cancer signal of origin if detected. This study's prostate cancer cohort included 18 men diagnosed through MCED testing or PSA screening, excluding two with recurrent disease. PSA testing was not collected in this particular study. Detectability by the Gleason group, clinical stage, association of detection status with tumor methylation fraction, and overall survival were assessed in these studies. The results are broken down by each substudy evaluated. Substudy three of the CCGA enrolled a clinically relevant patient population. The median age of the men enrolled were 65. Ethnic diversity was not represented, however, in this cohort, with only 15% of participants reporting as non-white, non-Hispanic. It is important to note that only 8.4% of patients included in the study self-identified as black non-Hispanic, a particular group of participants with a higher incidence in more aggressive prostate cancer. The overall MCED test sensitivity for prostate cancer detection was low in 11.2% or 47 out of 420 patients included in this cohort. The cancer signal of origin prediction accuracy was 91.5% with 43 of 47 patients having prostate cancer predicted. The test did not detect any low-grade tumors. It detected 3 of 157 favorable or intermediate grade tumors as well as 4 of 78 unfavorable intermediate grade tumors, and finally 36 of 113 high grade tumors, typically, Gleason score 4 and 5. Detection increase was staged with only 3.2% or 3 of 95 of stage one disease detected with the MCED test, while 14.9% or 7 of 47 with stage 3 and 81.5% 22 out of 27 patients with stage four disease. Compared with expected overall survival estimated from the United States SEER database, non-detected cancer cases had roughly three times better overall survival with a hazard ratio of 0.263 with a 95% interval of 0.1 to 0.5 with a p value of less than 0.05, and detected case that had similar survival, the hazard ratio of 0.672 with a 95% interval crossing one and a p value of 0.2 when adjusted for age, Gleason grade, and clinical stage. This suggests that patients identified to be ctDNA positive at diagnosis have an overall worse outcome than those who are ctDNA negative, a consistent phenomenon with previous studies using the same or different tumor informed and diagnostic ctDNA assays. Next, the authors evaluated the outcomes in the PATHFINDER cohort of 18 participants. The characteristics of patients enrolled were similar to the previous cohort. Only one case was detected, which was between Gleason group 3 and 5, and had either stage 3 or stage 4 disease not defined in the manuscript. Because only a single case of prostate cancer was identified in PATHFINDER via this test, cancer signal of origin, predicted accuracy, tumor methylation fraction, and survival outcomes were not calculated. In summary, this test preferentially detected high grade and advanced stage prostate cancers, identifying 93% of Gleason grade 3 to 5 and 67% of stages 3 and 4 cases, while notably did not detect Gleason grade 1, having only 1.9% of Gleason grade 2 detected and 4.2% of stage 1 and stage 2 cancers overall. Importantly, around one third of the detected cases in substudy three of the CCGA, involved non metastatic disease, including stage 1 to stage 3 were Gleason grade 3 to 5, which are potentially curable. Prostate cancers that were not detected via this test had better survival rates after adjusting for age, grade and stage in the SEER database. This suggested that MCED testing is unlikely to contribute to the overdiagnosis of indolent prostate cancers. Additionally, a positive cancer signal with a predicted prostate origin strongly indicates the presence of aggressive disease, warranting immediate diagnostic investigation. One limitation of the study is the lack of representative inclusion of patients from diverse ethnic backgrounds. Overdiagnosis of prostate cancer due to PSA levels disproportionately affects black men, and the generalizability of these findings in the study is limited by the fact that over 85% of the study cohort was self-reported as white non-Hispanic. Further data is required to understand the biology of cancer in this community and limit the bias of molecular screening tests so they are effective regardless of ethnicity.   Thank you for listening to JCO Precision Oncology Article Insights. This was a summary on “A Targeted Methylation–Based Multicancer Early Detection Blood Test Preferentially Detects High-Grade Prostate Cancer While Minimizing Overdiagnosis of Indolent Disease.” Please follow and subscribe on your favorite streaming platforms. For more podcasts from ASCO, visit www.asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

OncLive® On Air
S11 Ep4: Park and Kasi Expand on Perioperative Immunotherapy Updates in CRC

OncLive® On Air

Play Episode Listen Later Aug 21, 2024 10:46


Drs Park and Kasi delve into the shift toward neoadjuvant immunotherapy and the use of ctDNA as a prognostic tool in colorectal cancer.

Oncology Brothers
How to treat Cutaneous Melanoma (Skin Cancer) - Dr. Allison Betof Warner

Oncology Brothers

Play Episode Listen Later Aug 8, 2024 26:08


In this episode of the Oncology Brothers podcast, Dr. Allison Betof Warner from Stanford University joins hosts Drs. Rahul and Rohit Gosain discuss the current standard of care and recent advances in cutaneous melanoma treatment. Key Points Covered: •⁠  ⁠Early Stage Melanoma: Discussion on the standard of care for different stages, including the role of neoadjuvant immunotherapy. •⁠  ⁠Adjuvant Therapy: Controversies and considerations for stage 2 and beyond, including the use of ctDNA as a predictive tool. •⁠  ⁠Neoadjuvant Therapy: Insights into recent trials and the evolving landscape of neoadjuvant treatment for melanoma. •⁠  ⁠Metastatic Stage: Exploration of treatment options, including immunotherapy combinations and BRAF MEK inhibitors. •⁠  ⁠TILS Therapy: Overview of the recent approval of Tumor Infiltrating Lymphocytes (TILS) therapy for melanoma patients. Stay informed on the latest in melanoma treatment by listening to this insightful discussion with Dr. Warner. Don't miss out on valuable insights that can impact patient care and treatment decisions. Subscribe now to the Oncology Brothers podcast for more updates on oncology practices and advancements.   Website: http://www.oncbrothers.com/ Twitter: https://twitter.com/oncbrothers Contact us at info@oncbrothers.com

ASCO Daily News
How to Enhance Early-Stage Breast Cancer Survivorship

ASCO Daily News

Play Episode Listen Later Jul 25, 2024 18:28


Drs. Hope Rugo, Diana Lam, Sheri Shen, and Mitchell Elliot discuss key strategies and emerging technology in early-stage breast cancer survivorship, including mitigating risk through lifestyle modification, surveillance for distant recurrence, and optimization of breast imaging. TRANSCRIPT  Dr. Hope Rugo: Hello, I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco's Comprehensive Cancer Center. I'm also an associate editor of the ASCO Educational Book.   There are currently about 4 million breast cancer survivors in the United States, according to the American Cancer Society, and this number is expected to rise as more women are being diagnosed at early stages of this disease, thanks to advances in early detection and the delivery of more effective adjuvant and neoadjuvant treatment leading to successful outcomes.  In today's episode, we'll be discussing current and emerging clinical strategies for the survivorship period, focusing on a multidisciplinary approach. Joining me for this discussion are Drs. Mitchell Elliott, Sherry Shen, and Diana Lam, who co-authored, along with others, a recently published article in the 2024 ASCO Educational Book titled, “Enhancing Early-Stage Breast Cancer Survivorship: Evidence-Based Strategies, Surveillance Testing, and Imaging Guidelines.”  They also addressed this topic in an Education Session presented at the recent ASCO Annual Meeting. Dr. Elliott is a drug development fellow and clinician scientist trainee at the Princess Margaret Cancer Center in Toronto, Canada. Dr. Sherry Shen is a breast oncologist and assistant attending at the Memorial Sloan Kettering Cancer Center in New York. Dr. Diana Lam is a breast radiologist and associate professor at the University of Washington Fred Hutchinson Cancer Center in Seattle.  Our full disclosures are available in the transcript of this episode.  It's great to have you all on the podcast today. Thank you for being here. Dr. Mitchell Elliott: Thank you so much.  Dr. Sherry Shen: Thank you.  Dr. Hope Rugo: Let's go into the meat of the article now and try to provide some interesting answers to questions that I think come up for clinicians all the time in practice. Your article points out that addressing the challenges in early-stage breast cancer survivorship requires a comprehensive, patient-centered approach, focusing on mitigating risk through lifestyle modification, surveillance for distant recurrence, and optimization of breast imaging.   Dr. Shen, surveillance can facilitate the early detection of recurrence, but ultimately the goal is to prevent recurrence. Lifestyle modifications are a key component of survivorship care, and there are many interventions in this context. Could you summarize the best approaches for mitigating risk of breast cancer recurrence through lifestyle modification and how we might accomplish that in clinical practice? Dr. Sherry Shen: Absolutely. This is a question that we get asked a lot by our breast cancer patients who are so interested in what changes they can make within their lifestyle to improve their breast cancer outcomes. I always tell them that there are three main things, three main lifestyle factors that can improve their breast cancer outcomes.  Firstly, enough physical activity. So the threshold for physical activity seems to be around 150 minutes of a moderately vigorous level per week. So moderately vigorous means something that gets the heart rate up, like walking quickly on rolling hills, for example. Or patients can do a vigorous level of physical activity for at least 75 minutes per week. Vigorous meaning playing a sport, swimming, for example, running, something that really gets the heart rate up.   The second really important lifestyle modification is limiting alcohol use. Keeping alcohol to less than 4 to 7 drinks per week is particularly important for breast cancer outcomes, especially in women who are postmenopausal and have hormone receptor positive diseases. That's where the strongest connection is seen. Lastly, maintaining a healthy weight. We know that women who gain more than 5% to 10% of their diagnosis body weight have a higher risk of breast cancer recurrence and worse breast cancer outcomes. That, of course, is easier said than done, and it's primarily through dietary modifications.  I always tell women that in terms of specific things in the diet, it's really hard to study at a population level because diets vary so much between patients. But what is really important is consuming a plant-forward whole foods diet that prioritizes nutrients and the quality of the diet. A little bit more specifically, it's important to limit the amount of red and processed meats in the diet, really limit the amount of sugar sweetened beverages, ideally to cut that out of the diet entirely, and to consume an appropriate amount of dietary fiber in the range of 20 to 30 grams per day. Those are more specific things that have been associated with breast cancer outcomes.  Dr. Hope Rugo: This is such helpful, practical information for clinicians and for patients. Thank you.  But let's move on to another area, surveillance testing for distant recurrence, an area of great interest, in fact highlighted in a special session at ASCO 2024. In clinic, we've seen that many cancer survivors expressed surprise at the less intensive approach to surveillance testing for recurrence, with the whole idea that if you detected it earlier, the outcome would be better. But it does raise an important question. What is the optimal strategy for monitoring for recurrence? And importantly, can early detection through surveillance testing impact outcome?   Dr. Elliot, your research has focused on ctDNA surveillance and the evolving role of minimal residual disease, or MRD. Can you comment on the current surveillance guidelines for distant recurrence, and then, how we really define true MRD?  Dr. Mitchell Elliott: Those are excellent questions, and I think leaving that Education Session at ASCO left us with even more questions than answers with the current role of MRD in this setting. I think a lot of this comes from wanting to help patients and trying to identify the patients at highest risk of cancer recurrence, with the goal of intervening with effective targeted therapy to prevent metastatic relapse.  Current international guidelines in the United States done by ASCO and the NCCN, as well as ESMO guidelines in Europe and even our local Canadian guidelines, do not suggest that patients undergo routine screening in asymptomatic individuals, whether it be blood work or routine radiographic imaging, as there were some studies that were done in the late 1990s and early 2000s that didn't actually show benefit and actually maybe favored a little bit of harm in these situations. So these recommendations are based on these initial studies. However, we know that in the last 10, 15 years, even 20 years, that breast cancer and the landscape of breast cancer has changed significantly with the introduction of our typical standard classification of breast cancer, the emergence of HER2 positive breast cancer, and thus triple negative breast cancer, which was not actually routine standard testing at the time of these studies, and also the most effective therapies we have to date, including immunotherapy, HER2 targeted therapy and the advent of antibody drug conjugates. We're at prime time right now to potentially revisit this question, but the question is, do we have the right technology to do so? And this is where the circulating tumor DNA has really emerged as a potential option, given its minimally invasive opportunity with a standard blood test to actually identify tumor specific DNA that is highly predictive of distant metastatic recurrence or patient recurrence in general.   The evolving role – we still have a lot of questions in this setting. There have been a lot of retrospective analyses of cohort studies and clinical trials that have shown that modern fit for purpose MRD based tests actually have a high positive predictive value at identifying patients with imminent risk of breast cancer recurrence. The most important thing in this setting is that there are different fit for purpose tests. The initial ctDNA assays were actually genotyping based assays, which look for the presence of mutations in the blood. But we know that the sensitivity of these assays is quite challenging at the level of ctDNA required to actually diagnose patients with very small amounts of residual disease. So the fit for purpose MRD assays are now emerging on the market. And we have several that are in clinical development, several that are in research development, but the high specificity in the setting is very important, which we're seeing some evolving and emerging technologies in this setting. We really don't have the data about if these interventions, so if we were to effectively deploy these MRD based ctDNA assays prospectively in patients, if they will actually improve patient outcomes, and how do we correct and address lead time bias, which might potentially affect study results?  Also, the important thing to think about in this setting is if we are able to find something, we also should have an effective therapy to actually intervene for patients, because the outcome in these trials will actually be dependent not only on identifying early breast cancer occurrence, but also delivering the best targeted intervention for that individual patient, which currently we don't understand fully.   Another really interesting thing is there was a trial, the ZEST trial, as many of our listeners may know, that was randomizing patients with patients with ctDNA detected in the adjuvant setting were randomized through either intervention or standard follow up. And going forward, is it actually an opportunity, or is it possible to actually randomize patients knowing that they have a near 100% likelihood of breast cancer recurrence to observation? So these are several ongoing questions that we have to address as we move forward to deploying this technology in the clinical space.  Dr. Hope Rugo: Really fascinating, and thanks for sharing that. I think really broad and helpful information on these ctDNA [assays] and also our surveillance guidelines, which I think really suggests that you only do surveillance for cause, other than looking for local recurrence and new cancers with breast imaging. So it is really an interesting time where we're seeing evolving technologies and evolving understanding of how we can best do this kind of testing when there are so many different assays out there. I think it's going to take a little while. And also understanding, as you pointed out, trying to target treatments when patients have emerging ctDNA to mutations. And we just have no idea yet if we're going to ultimately change outcomes. This is really helpful, and I think we'll give people a good understanding of where to think about this right now, what to look for in the future.  Now, of course, it's a nice segue into the idea of breast imaging for early breast cancer survivors because that's where we do have data. Dr. Lam, let's talk about how we optimize breast imaging in early-stage breast cancer survivors, because there's such a wide variation in breast cancer imaging survival protocols between different centers and different countries. And of course, here our group is representing two countries and really a broad geographic area. So some of the variations are when to do imaging in terms of frequency, when to start imaging and what kind of examination to do, screening versus diagnostic, MRI versus mammogram. And of course, there are some emerging imaging techniques as well. Could you tell us a little bit about the variation in imaging surveillance protocols in survivors, and the challenges and what you recommend?  Dr. Diana Lam: First off, I want to say that surveillance mammography saves lives and annual intervals are uniformly recommended among both national and international guidelines. However, we know that in practice there are variations in imaging surveillance protocols, with approximately 40% of sites performing imaging at more frequent or six-month intervals for at least one to two years. In addition, there's variation in what type of mammogram someone gets in terms of the indication. They might be getting initial diagnostic mammograms for a short period of time or screening mammograms. However, overall, there is limited evidence in improved outcomes in women getting a diagnostic versus a screening exam for asymptomatic surveillance. In addition, there is limited evidence in increased frequency of surveillance, for example, every six months versus one year.  The real difference between a screen and a diagnostic mammogram, if someone is asymptomatic in the surveillance population, primarily has to do with workflow. For screening examinations, the imaging is generally viewed after a patient leaves the facility, and it might actually take days, maybe even weeks, for the results to be delivered to the patient. In addition, if more imaging is needed, the patient will need to return back to the facility, which does diagnostic imaging work for us to work up this finding. And this practice approach causes diagnostic delays in care. It also disproportionately affects Black and Hispanic women. For diagnostic mammography surveillance, there's generally real time interpretation with immediate results. However, there are both access and scheduling limitations, as not all facilities actually perform these types of examinations. There may also be out of pocket costs which are increased due to the diagnostic indication of this exam.  So  what we found, which is an approach that can aid in minimizing patient costs and decreasing these health disparities, is to provide immediate interpretations of these screening mammography surveillance exams, or so-called online screens where diagnostic workup and potential biopsy can be performed on the same day. Dr. Hope Rugo: This is all very interesting, but what do we tell our patients? How do we, as oncologists, decide on how frequently to get mammograms? Should we be getting diagnostic or screening? And do we sequence MRI with mammograms for everybody or just for certain patients? And then some patients will say, “Well, my doctor does an ultrasound to mammogram.” We don't do that for screening. When do you recommend that? Dr. Diana Lam: We do know that compared to people without a personal history of breast cancer, surveillance mammography is actually less sensitive. It's only about 70% versus 87% or so percent sensitive with over four times more interval cancers or cancers diagnosed after a negative surveillance mammogram compared to the general screening population without a personal history of breast cancer. In addition, about 35% of invasive second breast cancers are actually interval cancers or those not detected by surveillance mammography. However, there is currently no guideline consensus on supplemental breast imaging or additional imaging beyond surveillance mammography. Contrast-enhanced breast MRI is most often recommended, particularly for patients who are already at high risk for breast cancer, such as those with genetic mutations, or patients who have had primary breast cancer diagnosed at a younger age to less than 50 years old, or those patients who have dense breast tissue on mammography.  There is a question about whole breast ultrasound and this is generally not specified or recommended unless the patient is unable to undergo breast MRI. This is primarily due to the number of false positive examinations or findings that are seen that do not amount to breast cancer. We do have the opportunity here to tailor surveillance imaging by selecting people who are at high risk for interval second breast cancers in order to decrease harms and improve patient outcomes. We know that there are a number of factors such as primary breast cancer subtype which affects second breast cancer risk. We know that women who have ER negative and/or hormonal negative breast cancers have significantly higher recurrence rates within the five years of treatment with no significant difference after that 5 years. We also know that there are certain factors such as imaging factors where patients are more likely to develop an interval second cancer with mammography surveillance only. And these are factors such as if their primary breast cancer was hormone negative, if they had an interval presentation to start, or if they had breast conservation without radiation therapy. So, in terms of the future of local breast imaging surveillance, this can be improved with upfront risk prediction and stratification based on the patient, primary breast cancer and treatment factors, as well as looking at imaging test performance to optimally guide the modality and frequency of surveillance imaging.  Dr. Hope Rugo: Really interesting.   Well, thank you all three of you for sharing your valuable insights. This has been so interesting and a great addition to the ASCO Daily News Podcast. I would encourage everyone to actually read the article as well because there's some really great tables and interesting information there that of course we don't have time to cover, but thank you, all three of you.  Dr. Diana Lam: Thank you. Dr. Mitchell Elliott: Thank you for having us. Dr. Hope Rugo: And thank you to our listeners for joining us today. You'll find a link to the article that you can read and look at and cut out the tables discussed today in the transcript of this episode. I encourage all of our listeners also to check out the 2024 ASCO Educational Book where there is an incredible wealth of useful information. Finally, if you value the insights that you've heard today and here on ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thanks again.   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 opinion 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. Hope Rugo   @hoperugo   @MitchElliott18 Dr. Sherry Shen @SherryShenMD    Follow ASCO on social media:       @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn        Disclosures:      Dr. Hope Rugo:    Honoraria: Mylan/Viatris, Chugai Pharma Consulting or Advisory Role: Napo Pharmaceuticals, Puma Biotechnology, Sanofi Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Merck, Daiichi Sankyo, AstraZeneca, Gilead Sciences, Hoffmann-LaRoche AG/Genentech, Inc., Stemline Therapeutics, Ambryx   Dr. Diana Lam: No relationships to disclose   Dr. Sherry Shen: Honoraria: MJH Life Sciences Research Funding (Inst.): Merck, Sermonix Pharmaceuticals   Dr. Mitchell Elliott:  No relationships to disclose

Healthcare Unfiltered
ASCO Updates in GU Oncology With Drs. Rana McKay and Petros Grivas

Healthcare Unfiltered

Play Episode Listen Later Jul 23, 2024 57:43


Chadi is joined by Drs. Rana McKay and Petros Grivas to discuss the latest genitourinary oncology research updates from the 2024 ASCO Annual Meeting, covering topics such as the prognostic ability of KIM-1 in kidney cancer, patient-reported outcomes from enfortumab vedotin/pembrolizumab treatment, and the final overall survival update from the JAVELIN Renal 101 trial. The conversation also delves into studies on IO/TKI biomarkers, adaptive trials with ctDNA, and the latest findings from trials like KEYNOTE-426, CLEAR, PSMAfore, and SURE-01. Check out Chadi's website for all Healthcare Unfiltered episodes and other content. www.chadinabhan.com/ Watch all Healthcare Unfiltered episodes on YouTube. www.youtube.com/channel/UCjiJPTpIJdIiukcq0UaMFsA

ASCO Daily News
An Era of Promise for Cancer Vaccines

ASCO Daily News

Play Episode Listen Later Jul 11, 2024 19:21


Dr. Pedro Barata and Dr. Lillian Siu discuss recent advances in cancer vaccines and biomarkers, including the potential of the neoantigen and immune modulatory vaccines and the challenges surrounding cancer vaccine development. TRANSCRIPT Dr. Pedro Barata: Hello, I'm Dr. Pedro Barata, your guest host for the ASCO Daily News Podcast today. I'm a GU medical oncologist at the University Hospitals Seidman Cancer Center in Cleveland, Ohio, and an associate professor of medicine at Case Western Reserve University School of Medicine. I'm also an associate editor of the ASCO Educational Book. And today we'll be discussing a timely article that was recently published in the Educational Book titled, “State-Of-The-Art Advancements on Cancer Vaccines and Biomarkers.”   I'm delighted to welcome one of the article's co-authors and a world-renowned oncologist, Dr. Lillian Siu. She is a senior medical oncologist and director of the Phase 1 Program at the Princess Margaret Cancer Center and a professor of medicine at the University of Toronto.  Welcome, Dr. Siu. Dr. Lillian Siu: Thank you, Dr. Barata; it's great to be here. Dr. Pedro Barata: Wonderful. Dr. Siu will discuss new tools for cancer vaccine development, strategies for combating the immunosuppressive and tumor microenvironment. She will also address cancer vaccine guidelines and patient recruitment strategies to optimize patient selection and access to cancer vaccine trials. I should say that Dr. Siu and her co-authors also addressed this topic during an Education Session at the ASCO 2024 Annual Meeting.  Finally, our full disclosures are available in the transcript of this episode.  So again, Dr. Siu, great to be speaking with you today. I'm looking forward to our discussion.  Dr. Lillian Siu: Thank you, Dr. Barata. And before I begin, I want to acknowledge Dr. Jeffrey Weber and Dr. Inge Marie Svane, who both presented during the ASCO session you mentioned. They gave excellent presentations related to the topic of neoantigen vaccines and immune-modulatory vaccines, which we will talk about later. Dr. Pedro Barata: Wonderful. So let's get started. Cancer vaccines are among the most promising frontiers for breakthrough innovations and new strategies in the fight against cancer. The successes in vaccine development during the COVID-19 pandemic, I think, inspired further research in this area. Why do you think it's important that we harness these recent successes and technological advances to really accelerate progress in vaccine development? Dr. Lillian Siu: Absolutely. I think all of us who have lived through COVID really appreciated how important the COVID vaccine development was to all of us. It saved millions of lives. And I think we witnessed a paradigm change in drug development that none of us thought was possible, that we're able to actually bring a concept to a drug from bench to bedside within an extremely short time. That timeline is not something we would ever imagine to have happened, and it did. And I think it gives us hope that perhaps this is not just limited to the COVID vaccine; it's also extrapolatable to other therapeutics – that we can bring promising medicines to our patients in a really expedited timeline, obviously without compromising their safety.  We now know that cancer vaccines have entered a new, or maybe I should say, renewed era of promise. And it's holding promise on many fronts, Pedro, if I may. It's very exciting in the area of molecular residual disease. In other words, a setting where the cancer is treated definitively by surgery or radiation, plus adjuvant treatment. And we know some patients will relapse because we know they're at high risk. And now we also have different ways to detect these microscopic risks, such as by ctDNA, circulating tumor DNA, or biomarkers. And we know that having some therapeutic that can eradicate these cancers at such microscopic levels would be very attractive, especially with low toxicity, and I think cancer vaccine is such a candidate. And of course, we can even look further into the future of using such treatment in cancer prevention, especially in those with high risk of developing cancer, for example, those with hereditary syndromes like lynch syndrome. We're not there yet, but I think it holds that promise.   So I think, going back to your original question, if we can develop such a therapeutic that is showing promise in a very short period of time, it brings the timeline and the hope to a much shorter timeframe to really deliver to our patients in a very timely manner while safeguarding all the important parts, such as safety and tolerability. Dr. Pedro Barata: Wow, those are such important points. I couldn't agree with you, more. It's really exciting. As I think through this, and as I was reading through your piece, I was thinking it would be great if you could highlight some of the novel approaches to personalized neoantigen vaccine development that are driving progress in this space. Dr. Lillian Siu: Absolutely. And during the session, Dr. Weber spoke about the neoantigen vaccine, and he's a pioneer in this space. So I can only try to iterate some of the points he had delivered during his talk. Neoantigen is a very exciting space for immunologists because we know that tumors express these neoantigens. Many of these are unique antigens that are only expressed in tumors, so-called tumor specific antigens, that we can use as our targets, including vaccines, but not limited to vaccines. And with these altered sequences in DNA in different forms, they could be mutations and splice alterations, etc. We expect that we have modified proteins that are expressed by tumor cells, and these become targets for our drug development of vaccines. And now we can have very specific strategies, very sophisticated algorithms to figure out which neoantigens are more so called immunogenic, more likely to stimulate or activate the immune system, and they can be recognized by T cells. So leveraging this knowledge and technology, we have been able to develop especially mRNA vaccines that are deliverable to our patients through different mechanisms, for example, in lipopeptides, etc., so that we can deliver to the patients in a safe way, such that we can use it to deliver vaccines, such as in the MRD setting that I mentioned earlier, as well as in the advanced disease setting. So Dr. Weber, in his presentation, highlighted one of such vaccines that have been tested in a randomized controlled trial that is KEYNOTE-942, which randomized 157 patients to the mRNA vaccine plus pembrolizumab versus pembrolizumab alone in patients with advanced melanoma. This is a vaccine against 34 mutated neoantigens, and it showed a significant difference in the recurrence free survival with a hazard ratio of 0.56. And if you look at the 18-month relapse free survival rate, it was 78.6% versus 62.2%. Obviously, these are still fairly early data and numbers are still small. I think we would definitely look forward to the randomized phase 3 study of neoantigen vaccine in melanoma and other cancers. Dr. Pedro Barata: No, absolutely. And I agree, it's really exciting. Dr. Weber did a fantastic job going through some of that data. So let me ask you Dr. Siu, as you think about this cancer vaccine field, what are the limitations that you'd highlight when you think about cancer vaccine development? What challenges do you encounter, obstacles do you encounter?  Dr. Lillian Siu: There are many, many potential challenges. And to some extent, that's probably why cancer vaccine development has been somewhat slow for the many decades until more recently. We know first of all; the target has to be recognized. So we need immunogenic targets. So I think a lot of the effort has been put into trying to understand which antigens expressed by cancer cells are immunogenic, able to activate the immune system. They're obviously assay based methods. You're going to try and see if you can ex vivo stimulate immune cells on dishes and models, etc. But we need to also develop in silico computerized algorithms, and now with AI, I think that makes it even more tangible and exciting that we can actually understand through a large number of neoantigens or other antigens, whether we can choose the ones that are most likely going to actually stimulate T cells to be activated. And I think that is one area that there is a lot of interest in development, how to really develop ways to select out the most attractive antigens.   I would also want to highlight that the platforms, which is how we deliver the vaccine, can also pose significant challenges. For example, vaccines can be delivered using peptide-based formulation, cell-based formulation, nucleic acids and viral vectors. For some of these formulations, for example, the peptides very often are restricted to HLA. They can be rapidly degraded in the body, such that they become not really visible to the T cells anymore. Some of the formulations can be very complex. For example, the cell-base; it may need to have cells isolated from patients, cultured, stored and transported to the site of delivery, which can be very complex. For some of the nucleic acid vaccines, they can have very low transfection efficiency. It could be at risk for also having, for example, DNA vaccines integrated into the host genome. And then lastly, there's also the immune suppressive environment in the TME, such that it does not really have the effect when you give it repeatedly. It becomes attenuated and no longer effective. So these are some of the challenges associated with cancer vaccines.  Dr. Pedro Barata: Thank you for that summary. I think it's really important for folks out there, including researchers getting into this field, to be aware of potential obstacles they might encounter.  So let me ask you the opposite question as we see more compelling preclinical and clinical data emerging in this field of vaccine development, what is really exciting you the most about the newest technologies that are shaping the future of cancer vaccines, in your opinion?  Dr. Lillian Siu: I think one I want to highlight is the immune-modulatory vaccine that Dr. Svane, Dr. Inge Marie Svane had presented during the presentation at ASCO. This is a completely different strategy from the neoantigen vaccine. It targets antigens in the tumor microenvironment. And we know that in the tumor microenvironment, we have tumor cells, we have immune cells, and there are many types of cell types, including, for example, macrophages, cancer associated fibroblasts, regulatory T cells, etc. And using these particular cell types, we know that we can really develop vaccines that can stimulate the body's immune system to attenuate, to downgrade some of the negative factors in the tumor microenvironment. And this is what Dr. Svane and her group is trying to do. For example, they have an IDO vaccine that is able to actually target these antigens in the tumor microenvironment, and by that, not just suppressing the negative forces, so to speak, but also activate T cells to help attack cancer cells. I think that's a very interesting area. Very early promise has been seen already in non-small cell lung cancer in early phase trials using the immune-modulatory vaccine.  But going back to your question, what kind of advances; I mentioned earlier about having novel ways to select our antigens that are most immunogenic. There are many algorithms that are being developed, and I think we can try and leverage that kind of knowledge from artificial intelligence, machine learning. So I think that's definitely very exciting. There are also new vaccine platforms coming out. For example, there's recent data using modification of peptides, so called amphiphile vaccines, that already show very early promise in colorectal cancer, microsatellite status, colorectal cancer, as well as in pancreatic cancer in the molecular residual disease setting, where these long peptide vaccines targeting KRAS mutants together with adjuvant oligonucleotide DNA, combined together, can actually be given to patients and reduce the chance of cancer relapse in patients with resected colorectal cancer, as well as pancreatic cancer, with endpoints such as ctDNA or biomarker being downregulated. I think that's a very exciting example. Another very exciting example is cell-based vaccines that are being developed in Europe by the NKI Netherlands Cancer Institute Group, where they are looking at plasmacytoid dendritic cells that are loaded with peptides from different tumor associated antigens and then given to patients, which, again, in non-small cell lung cancer, together with pembrolizumab, has yielded very high response rate. And we will almost certainly see more trials coming out using that particular platform with the dendritic cells. So that's just some of the examples of exciting things that are happening in the vaccine field. Dr. Pedro Barata: Thank you. I'm wondering if you can share with our listeners about what really are the existing guidelines for using these new tools for discovery, methods of treatment, and perhaps optimizing patient selection to access trials.  Dr. Lillian Siu: To be honest, the latest guideline that was published from the FDA that I can find is almost 13 years ago in 2011. So I think it is time for a new guidance, or at least a draft guidance, to give some additional support and guidance in terms of what to do with these new treatments from the FDA and perhaps other regulatory agencies as well. I think we're now entering a very exciting time that cancer vaccines are no longer an ineffective therapeutic. It is now showing evidence of efficacy, not just in the advanced setting, but also in the molecular residual disease setting. There're so many questions to be answered, like how to develop these trials in early disease; what's the end point? Can we incorporate them into the neoadjuvant setting, and if so, how do we give these drugs before surgery, and do we give them maintenance after surgery? I think guidance from the regulatory authorities would be extremely helpful and informative to guide academic groups as well as the pharmaceutical sector to develop these agents in the right way. Dr. Pedro Barata: Dr. Siu, this is a fantastic summary, and we certainly are on the cusp of a new dawn of discovery and development in cancer vaccines, and super interesting to hear from you talking about it. Before letting you go, do you have any final thoughts that you'd like to share with the listeners, with all of us about this topic? Dr. Lillian Siu: I think as a drug developer like you are, I'm extremely excited because we now have yet another way to leverage the host immunity as a cancer therapeutic, and it is going to be opening a new door to combination therapy because we can imagine combining these treatments with other immunotherapeutics such as bispecific molecules such as CAR Ts and even vaccine plus vaccine combination is feasible. That came up actually during the session as a question from the audience. Can we combine neoantigen vaccines and immune-modulatory vaccines together? And both of our speakers who presented felt that it was possible. Obviously, we have to understand the sequence question and the endpoints question, but the fact that it opens a new door to combinatorial therapy, not just with immunotherapeutics, but perhaps with other therapeutics as well, antibody drug conjugates, etc., really, I think, is very exciting for this field to become further explored.  I mentioned earlier in the podcast that the whole area of cancer prevention is something that we have not been tapping into for the last decade with vaccines because it has not been very effective. Viral vaccines, of course, HPV and other vaccines targeting viruses, but targeting cancer cells is not something we have been successful using vaccines to prevent cancer from developing. I think we would be very interested to see if this will become a reality in the next decade. I think we would start off with patients with high risk of developing cancers such as, as I mentioned earlier, those with lynch syndrome, those harboring BRCA alterations, for example. Can we use these vaccines to actually prevent the cancers from developing in such high-risk individuals? I think the field is definitely open to that consideration.  Dr. Pedro Barata: Definitely. And I'd like to thank you, Dr. Siu, for sharing these great insights with us today on the ASCO Daily News Podcast. Dr. Lillian Siu: Thank you so much for your time.  Dr. Pedro Barata: And thank you to all the listeners for your time today. You'll find a link to the article discussed today in the transcript of this episode, and I encourage you to check out the 2024 ASCO Educational Book. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. So again, thank you so much for your time and see you soon.   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. Pedro Barata  @PBarataMD  Dr. Lillian Siu  @lillian_siu   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures:    Dr. Pedro Barata: Honoraria: UroToday  Consulting or Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, AVEO, Dendreon  Speakers' Bureau (Inst): Caris Life Sciences, Bayer, Pfizer/Astellas  Research Funding (Inst.): Blueearth, AVEO, Pfizer, Merck    Dr. Lillian Siu:  Leadership (Immediate family member): Treadwell Therapeutics  Stock and Other Ownership Interests (Immediate family member): Agios   Consulting or Advisory Role: Merck, AstraZeneca/MedImmune, Roche, Voronoi Inc., Oncorus, GSK, Seattle Genetics, Arvinas, Navire, Janpix, Relay Therapeutics, Daiichi Sankyo/UCB Japan, Janssen, Research Funding (Institution): Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Bayer, Amgen, Astellas Pharma, Shattuck Labs, Symphogen, Avid, Mirati Therapeutics, Karyopharm Therapeutics, Amgen

Healthcare Unfiltered
ASCO Updates in Lung Cancer With Balazs Halmos and Lecia Sequist

Healthcare Unfiltered

Play Episode Listen Later Jul 9, 2024 53:13


Drs. Balazs Halmos and Lecia Sequist delve into the groundbreaking updates from the 2024 ASCO Annual Meeting. With Chadi, they reveal game-changing insights on EGFR-mutated lung cancer from the LAURA trial, small-cell lung cancer upgrades from the ADRIATIC trial, important revelations in ALK mutation research, innovative combination therapies, ctDNA results from the ADAURA trial, and conclude with the relevance of the KRYSTAL-12 study. Check out Chadi's website for all Healthcare Unfiltered episodes and other content. www.chadinabhan.com/ Watch all Healthcare Unfiltered episodes on YouTube. www.youtube.com/channel/UCjiJPTpIJdIiukcq0UaMFsA

Oncology Brothers
GU Cancer ASCO 2024 Practice Changing Highlights - Discussion with Dr. Toni Choueiri

Oncology Brothers

Play Episode Listen Later Jun 20, 2024 21:24


Welcome to another insightful episode of the Oncology Brothers podcast! In this episode, hosts Drs. Rahul and Rohit Gosain are joined by Dr. Toni Choueiri, a GU Medical Oncologist from Dana-Farber Cancer Institute, to discuss key abstracts from ASCO 2024. They delve into topics such as the impact of the EV302 study on metastatic bladder cancer, the potential role of ctDNA as a biomarker in bladder cancer, real-world data on metastatic RCC, and the PSMA-4 study in prostate cancer. The discussion covers patient-reported outcomes, treatment strategies, and the evolving landscape of oncology care. Tune in to gain valuable insights into the latest advancements in oncology and how they are shaping the standard of care for patients. Don't miss out on this engaging conversation with experts in the field. Subscribe to the Oncology Brothers podcast for more updates from the world of oncology. Website: http://www.oncbrothers.com/ Twitter: https://twitter.com/oncbrothers Contact us at info@oncbrothers.com

The Uromigos
ASCO24: The role of ctDNA in the TheraP trial (LuPSMA vs cabazitaxel in CRPC)

The Uromigos

Play Episode Listen Later Jun 2, 2024 22:16


Alex Wyatt describes the predictive resistance of ctDNA fraction at baseline in predicting outcome.

BackTable ENT
Ep. 172 HPV and Oropharyngeal Cancer: Evolving Insights and Implications with Dr. Mihir Patel

BackTable ENT

Play Episode Listen Later May 21, 2024 66:39


In this episode, Dr. Mihir Patel, Professor of Otolaryngology at Emory University and expert in Transoral Robotic Surgery (TORS), discusses HPV-positive head and neck cancer with host Dr. Ashley Agan. --- CHECK OUT OUR SPONSOR Medtronic ENT https://www.medtronic.com/us-en/healthcare-professionals/medical-specialties/ear-nose-throat.html?cmpid=Vanity_URL_MIX_medtronicent-com_202212_US_EN_NS_ENT_FY23 --- SYNPOSIS Dr. Patel opens by briefly sharing his journey to head & neck surgery, and, more specifically, expertise in TORS. After, Dr. Patel explains the epidemiology and pathophysiology of HPV-caused cancers, which frequently present as painless neck masses. Then, Dr. Patel describes workup and treatment of these cancers. He shares surgical strategies, paying special attention to cases of unknown primary lesions. He underscores the importance of collaboration with medical and radiation oncologists, particularly given the rapid pace of treatment innovation. Finally, Dr. Agan and Dr. Patel examine how increased HPV vaccine uptake could drastically lower the burden of this disease in the coming decades. --- TIMESTAMPS 00:00 - Introduction 05:26 - The Evolution of HPV-Related Oropharyngeal Cancer Treatment 17:26 - Contemporary Diagnostics for Head & Neck Cancer 24:39 - Surgical Strategies for Unknown Primary Lesions 38:15 - The Role of ctDNA in Cancer Management 46:10 - Advancements in HPV-Driven Cancer Treatment 53:30 - The Future of Cancer Screening and Vaccination 01:01:54 - Vaccination: A Tool for Cancer Prevention --- RESOURCES Medtronic ENT: https://www.medtronic.com/us-en/healthcare-professionals/products/ear-nose-throat.html Dr. Mihir Patel's Emory University Profile: https://winshipcancer.emory.edu/bios/faculty/patel-mihir-r.html AVOID Trial: https://pubmed.ncbi.nlm.nih.gov/31785337/

Behind The Knife: The Surgery Podcast
Journal Review in Hepatobiliary Surgery: ctDNA & Colorectal Liver Metastasis

Behind The Knife: The Surgery Podcast

Play Episode Listen Later May 2, 2024 34:33


Circulating tumor DNA, more commonly referred to as ctDNA, has emerged as an attractive and potentially highly sensitive biomarker for patients with colorectal cancer. But what exactly is ctDNA, does it have any prognostic value for patients with colorectal liver metastasis, and how can it be incorporated into the management of said patients? In this episode from the HPB team at Behind the Knife, listen in on the discussion about ctDNA and its role in the perioperative management of colorectal liver metastasis.   Hosts Anish J. Jain MD (@anishjayjain) is a T32 Research Fellow at the University of Texas MD Anderson Cancer Center within the Department of Surgical Oncology. Timothy E. Newhook MD, FACS (@timnewhook19) is an Assistant Professor within the Department of Surgical Oncology. He is also the associate program director of the HPB fellowship at the University of Texas MD Anderson Cancer Center.  Jean-Nicolas Vauthey MD, FACS (@VautheyMD) is Professor of Surgery and Chief of the HPB Section, as well as the Dallas/Fort Worth Living Legend Chair of Cancer Research in the Department of Surgical Oncology at The University of Texas MD Anderson Cancer Center Learning Objectives: -Develop an understanding of what circulating tumor DNA (ctDNA) is.  -Develop an understanding of what makes ctDNA unique from other “tumor markers” like CEA. -Develop an understanding of the prognostic value of ctDNA for colorectal liver metastasis (CRLM).  -Develop an understanding of the current role of ctDNA in the perioperative treatment of patients with CRLM. -Develop an understanding of how ctDNA can be incorporated into future treatment algorithms for patients undergoing hepatic resection for CRLM. Papers Referenced (in the order they were mentioned in the episode): 1)    Newhook TE, Overman MJ, Chun YS, et al. Prospective Study of Perioperative Circulating Tumor DNA Dynamics in Patients Undergoing Hepatectomy for Colorectal Liver Metastases. Ann Surg. 2023;277(5):813-820. https://pubmed.ncbi.nlm.nih.gov/35797554/ 2)    Nishioka Y, Chun YS, Overman MJ, et al. Effect of Co-mutation of RAS and TP53 on Postoperative ctDNA Detection and Early Recurrence after Hepatectomy for Colorectal Liver Metastases. J Am Coll Surg. 2022;234(4):474-483. https://pubmed.ncbi.nlm.nih.gov/35290266/ Please visit https://behindtheknife.org to access other high-yield surgical education podcasts, videos and more.   If you liked this episode, check out our recent episodes here: https://app.behindtheknife.org/listen

The Fellow on Call
Episode 101: Colorectal Cancer Series, Pt. 3 - Adjuvant Therapy in Stage II Colon Cancer and ctDNA

The Fellow on Call

Play Episode Listen Later May 1, 2024


In this week's episode, we discuss the management of stage II colon adenocarcinoma, which is defined by a lack of nodal involvement and invasion through the muscularis layer of the colon. If you have not done so already, be sure to check out episode 099 (overview of colorectal cancer) and episode 100 for stage III colon cancer, as we will building on concepts discussed already. Content: - Is there a role for adjuvant chemotherapy in stage II colon cancer patients? - What is the impact on MSI/MMR testing in stage II colon cancer patients? - Is there a role for evaluating circulating tumor DNA (ctDNA) in colon cancer patients? - Is there a role for immunotherapy in the adjuvant setting?** Want to review the show notes for this episode and others? Check out our website: https://www.thefellowoncall.com/our-episodesLove what you hear? Tell a friend and leave a review on our podcast streaming platforms!Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google Podcast