Podcasts about PFS

Jun 23, 2024 – In today's Lifetime Planning health segment, host Jim Puplava, President of Financial Sense Wealth Managment, speaks with Roger Rasmussen, author of Finding Fenbendazole: My Unexpected Path Through Cancer, in a thought-provoking...

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Jun 19, 2025 – A demographic storm is brewing, and its impact on the economy and society could be more profound than anyone expects. Demographic expert Bradley Schurman joins Cris Sheridan to discuss rapid demographic changes impacting...

A plethora of recent updates: -Pembrolizumab (perioperative) in head & neck cancer (Keynote-689) -Prostate cancer updates on cabozantinib/atezolizumab (yes, really) and talazoparib -Pirtobrutinib improves PFS in CLL -Zanubrutinib has a new dosage form on the way -Another mitomycin product approved with "reverse thermal properties" -A new regimen for FL of tafasitamab/rituximab/lenalidomide -A comparison of the new ROS1-inhibitor, taltrectenib, compared to other 1st-line treatment options

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

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Dr. John Sweetenham shares highlights from Day 2 of the 2025 ASCO Annual Meeting, including new data on the treatment of ER+/HER2-negative breast cancer and potentially practice-changing results for patients with cutaneous squamous cell carcinoma at high risk of recurrence.  Transcript Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, your host of the ASCO Daily News Podcast, welcoming you to our special coverage of the 2025 ASCO Annual Meeting. Today, I'll be bringing you my takeaways on selected abstracts from Day 2 of the Meeting. My disclosures are available in the transcript of this episode.  Today's selection features important, new data on the treatment of ER-positive, HER2-negative breast cancer, the use of tumor treating fields in combination with chemotherapy for locally advanced pancreatic cancer, and potentially practice-changing results for patients with cutaneous squamous cell carcinoma at high-risk of recurrence.  Our first selected abstract is LBA1000. This important phase 3 study was presented by Dr. Erika Hamilton from the Sarah Cannon Research Institute in Nashville and evaluated the use of a novel agent, vepdegestrant, in patients with ER-positive/HER2-negative breast cancer, which had progressed after first-line endocrine therapy. Vepdegestrant is a selective oral PROTAC estrogen receptor degrader, which targets wild-type and mutant estrogen receptor through a novel mechanism of action which directly harnesses the ubiquitin-proteasome system to degrade ER. It has potential advantages over fulvestrant, a selective ER degrader which has to be administered intramuscularly and has limited benefit in patients who progress after endocrine therapy plus a CDK4/6 inhibitor.  Building on the encouraging results from the initial phase 1/2 study of vepdegestrant, Dr. Hamilton reported results from the VERITAC-2 global phase 3 trial, comparing this agent with fulvestrant. The patients in the study had already received treatment with hormone therapy and a CDK inhibitor and were randomly assigned to receive treatment with either vepdegestrant (313 patients) or fulvestrant (311 patients). The vepdegestrant was taken orally each day, while the fulvestrant was given intramuscularly on days 1 and 15 of the first cycle of treatment and day 1 of each subsequent treatment cycle. Patients were stratified by the presence of wild-type ER or ESR1 mutation. A total of 43.3% of patients had ESR1 mutations; 136 of those were in the vepdegestrant group and 134 in the fulvestrant group.   For patients with ESR1 mutations, vepdegestrant significantly increased progression-free survival compared with fulvestrant. For patients who received vepdegestrant, the median PFS was 5 months versus 2.1 months for those who received fulvestrant. The clinical benefit rate was 42.1% in the vepdegestrant group vs. 20.2% in the fulvestrant group. The overall response rate was 18.6% in the vepdegestrant group compared with only 4% in the fulvestrant group.  The PFS and response benefits of vepdegestrant were largely restricted to the population with ESR1 mutations. Overall survival data are currently immature. The safety profile was favorable, with fewer than 5% of patients having dose reductions or discontinuation due to toxicity. The most frequent toxicities were fatigue, nausea, and elevated transaminases.  The authors concluded that oral vepdegestrant demonstrates statistically significant and clinically meaningful improvement in progression-free survival compared with fulvestrant in this group of patients with ESR1-mutated ER+/HER2- advanced breast cancer who have progressed after endocrine therapy and a CDK inhibitor. Patients with recurrent disease in this context are now routinely tested for ESR1 mutations, and this agent is for sure a potential treatment option for them.  The next study on today's episode, LBA4005, reports on the use of tumor treatment fields for patients with locally advanced pancreatic cancer. Tumor treatment fields are electric fields which disrupt cell division and may also induce an enhanced immune response, using a non-invasive portable device attached to the skin, and are already approved for the treatment of some cancers, including GBM and non-small cell lung cancer. A previous phase 2 trial, PANOVA-2, confirmed the feasibility and safety of using this approach in combination with gemcitabine plus or minus nabpaclitaxel in pancreatic cancer. In today's presentation, Dr. Vincent Picozzi from the Virginia Mason Medical Center in Seattle presented the results of the PANOVA-3 trial, a phase 3 study comparing gemcitabine and nabpaclitaxel with the same chemotherapy plus tumor treatment fields in patients with locally advanced pancreatic adenocarcinoma.  Five hundred and seventy-one eligible patients were enrolled in the study with a total of 405 (198 in the treatment field group and 207 in the standard arm) comprising the modified intent- to-treat population. The duration of chemotherapy treatment was comparable in both study arms, and patients receiving treatment fields had a median exposure of almost 27 weeks.  Statistically significant improvements were observed for several study endpoints, including overall survival (a median of 16.2 versus 14.2 months), distant PFS (at 13.9 versus 11.5 months) and pain-free survival (at 15.2 versus 9.1 months), all in favor of the treatment fields arm. Although quality of life data were not reported in detail, the authors noted a significant improvement in global health status in the treatment fields arm. Safety data showed a higher level of skin adverse events in the treatment fields arm but were otherwise as expected for the GnP combination.  These are quite remarkable results which add to the growing evidence base for tumor treatment fields and are particularly compelling in this patient group given the substantial improvement in pain-free survival. It will be especially interesting to see the mature analysis of the quality-of-life endpoints in a subsequent report.  The final selection today is Abstract 6001, which describes the C-POST trial, a phase 3 trial of adjuvant cemiplimab versus placebo in patients with high-risk cutaneous squamous cell carcinoma of the skin. This study was presented by Dr. Danny Rischin from the Peter MacCallum Cancer Centre in Melbourne, Australia.   Although surgical resection with or without adjuvant radiation is curative in 90% of patients with cutaneous squamous cell carcinoma, high-risk features, including nodal disease, skin and subcutaneous metastases, perineural invasion and bone involvement, predict for an inferior prognosis.  Cemiplimab, a PD-1 targeting antibody is standard therapy for patients with locally advanced or metastatic disease who are not candidates for curative surgical resection or radiation therapy, with an overall response rate of almost 50%.  The C-POST study evaluated the use of cemiplimab as adjuvant therapy following surgery and radiation in high-risk patients, compared with placebo. Treatment was administered at 3-week intervals for 12 weeks, and then 6-week intervals for a further 36 weeks, with a primary endpoint of disease-free survival. Four hundred and fifteen patients were randomized in the study, 209 to cemiplimab and 206 to placebo. With median follow-up at 24 months, Dr. Rischin reported a highly significant improvement in disease-free survival for the cemiplimab arm, 49.4 months for placebo versus not reached for cemiplimab, with improvements also observed in the rates of locoregional recurrence and distant recurrence at 80% and 60% reductions, respectively. No new safety signals were observed.  This study is potentially practice-changing and provides strong evidence that cemiplimab should be considered the new standard of care in this clinical context.  Thanks for listening today and join me again tomorrow to hear more top takeaways from ASCO25. 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  

JCO Editorial Fellow Dr. Peter Li and JCO Associate Editor Dr. Andrew Ko discuss the ASCO 25 Simultaneous Publication paper "Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III Randomized LEAP-015 Study." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Peter Li: Hello, everyone, and welcome to our 2025 ASCO Annual Meeting Series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Peter Li, JCO Editorial Fellow, and I'm joined by Dr. Andrew Ko, JCO Associate Editor, to discuss the Journal of Clinical Oncology article and abstract presentation "Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III Randomized LEAP-015 Study." Now, let's start off with the relevance of this article. Andrew, can you please explain this to our listeners? Dr. Andrew Ko: Sure. Thanks, Peter. So, this was a very large international study evaluating the combination of lenvatinib and pembrolizumab. And just for context, that combination has been approved for use in other solid tumor types. It's FDA approved for renal cell carcinoma, for example, and endometrial carcinoma. But this study was looking specifically at this combination together with a chemotherapy backbone - so either FOLFOX or CAPOX - and comparing that to what at the time was a standard of care, which was just standard chemotherapy by itself. So, this very large study was intending to look at this particular novel combination. And we can get into some of the nuances of this study because the way that the experimental, the combination arm, was designed was perhaps a little bit more on the unusual side and led to maybe some imbalance in terms of how we think about the respective arms. Dr. Peter Li: Okay. We can definitely talk more about that as we go on. So, what are some of the key results of this study, and how do you think this will impact practice in the future? Dr. Andrew Ko: That's a good question. Technically, it was not a positive study. Well, it was positive in the sense that the co-primary endpoints - which included both progression-free survival and overall survival - so, progression-free survival, it did technically meet its endpoint, both in terms of the overall population and the preplanned subgroup analysis of patients who had a PD-L1 CPS of greater than or equal to 1. So, there was a PFS benefit with the experimental combination - the lenvatinib, pembrolizumab, plus chemotherapy - compared to chemotherapy alone. I will say the benefit was on the more modest side. So, if you even look at the medians, it was not a marked difference. If you look at the hazard ratios, they did meet statistical significance. On the other hand, this did not translate into a benefit for overall survival. So, when you ask, "Well, is this going to inform practice?" I'd have to say no. It highlights, I think, that JCO does want to publish articles that aren't necessarily going to be practice-changing, but that I think offer a lot of insights into trial design and important aspects of investigating novel treatments, even if they don't end up moving the needle in routine clinical practice. Dr. Peter Li: I totally agree with you. I mean, it was significant in terms of progression-free survival, but again, not clinically significant. And then overall survival, the interventional arm actually appeared to do slightly worse overall. Can you make some comments on the strengths and the weaknesses of this study, and where do you see us going from here? Dr. Andrew Ko: So, I think a couple of things worth highlighting in this study, very well designed, more than 800 patients in total. So, first of all, as I mentioned at the beginning, the combination was a little bit unique in terms of patients enrolled to the experimental arm got the combination of lenvatinib, pembrolizumab, together with chemotherapy for a very finite duration. So, that period of chemotherapy they received was only three months. And per protocol, patients then just segued to, quote unquote “maintenance treatment” with just the lenvatinib and pembrolizumab combination. Whereas patients on the control arm, meaning chemotherapy alone, would continue chemotherapy basically in perpetuity until their disease progressed or intolerable toxicity. So, there really was an imbalance in terms of, if you think that chemotherapy or continuing chemotherapy beyond that initial three-month period of time may be significant, that could have had some impact on the robustness or the efficacy of the experimental arm. There were some other aspects in terms of perhaps some differences in the rates of post-progression treatment, in other words, patients going on to receive second-line treatment. I think the other very relevant aspect, Peter, in this study was that the control arm - and no fault of the investigators - but the control arm at the time the study was ongoing just consisted of chemotherapy, FOLFOX CAPOX, by itself, without an immune checkpoint inhibitor, right? And we clearly know, based on results of several large phase III studies, and it's now in standard clinical practice, that we routinely use chemotherapy plus an immune checkpoint inhibitor. Certainly for patients with CPS PD-1/PD-L1 scores that are, well, you could argue greater than 1, or perhaps greater than 5 or 10. But the point being that the control arm of the study probably doesn't reflect what is currently used in clinical practice. And that's just always a challenge in clinical trial design, right? That when a study is designed and when it rolls out, you're always at risk in a rapidly changing and moving field that the standard of care may evolve during the lifetime of that particular trial, which is what I think you see in LEAP-015. Dr. Peter Li: Totally understand. And the survival we see from this study is also roughly similar to the combination of immuno-chemotherapy that is the standard of care today, which is, the authors mentioned, 12 to 14 months. Thank you so much, Andrew, for your input and for speaking about the JCO article "Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III Randomized LEAP-015 Study." Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. 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.

JCO Editorial Fellow Dr. Ece Cali Daylan and JCO Associate Editor Dr. Grant McArthur discuss the ASCO 2025 Simultaneous Publication paper "A Phase II (Alliance A091802) Randomized Trial of Avelumab Plus Cetuximab vs. Avelumab Alone in Advanced Cutaneous Squamous Cell Carcinoma (cSCC)." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Ece Cali: Hello, and welcome to our 2025 ASCO Annual Meeting series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Ece Cali, and I'm joined by JCO Associate Editor Dr. Grant McArthur. Today, we will discuss Journal of Clinical Oncology article and abstract presentation "A Phase II Randomized Trial of Avelumab Plus Cetuximab Versus Avelumab Alone in Advanced Cutaneous Squamous Cell Carcinoma." Let's start with a brief overview of the clinical trial. This is a randomized phase II trial that compared avelumab plus cetuximab to avelumab in PD-1/PD-L1 antibody-naive patients with advanced cutaneous squamous cell carcinoma. This is a cooperative group study conducted in the United States. Sixty patients were randomized one-to-one and stratified by PD-L1 and HIV status. The primary endpoint was progression-free survival. Patients on the cetuximab plus avelumab arm had a median PFS of 11.1 months, while patients on the avelumab arm had a median PFS of 3 months, corresponding to a hazard ratio of 0.48 with a p-value of 0.018. Grade III or higher treatment-related adverse events occurred in 48% of the patients on the combination arm versus 21% of patients on the avelumab arm. Dr. McArthur, can you please explain to our listeners how you interpret this data? Dr. Grant McArthur: These results are very important because they provide proof of concept for inhibiting PD-L1 as a target when combined with EGFR, so inhibiting PD-L1 with avelumab and inhibiting EGFR with cetuximab, in a randomized trial with a very significant impact in terms of efficacy. So, what this does is it provides proof of concept for inhibiting those targets in cutaneous squamous cell carcinoma of the skin. Avelumab is not approved for cutaneous squamous cell carcinoma of the skin, and so further studies would need to be done, particularly asking the question about combination with the approved PD-1 agents cemiplimab and pembrolizumab. Dr. Ece Cali: I still find the difference in median PFS with various PD-1/PD-L1 inhibitors striking in this context. In this trial, avelumab, as you mentioned, the PD-L1 inhibitor, demonstrated a median PFS of 3 months, whereas PD-1 inhibitors cemiplimab and pembrolizumab have demonstrated longer median PFS in other trials. So, what are some potential reasons for this, and do you think this difference impacts the interpretation of the results here? Dr. Grant McArthur: So, the obvious reason for the differences is that avelumab targets PD-L1, where pembrolizumab and cemiplimab inhibit PD-1, so there could be simply a difference in the target to explain those differences in progression-free survival. However, as you point out, cross-trial comparisons, one has to do with caution because you can, in different phase II studies, enroll different patient populations, which would impact the progression-free survival. So, we have to be cautious about that interpretation. However, given that cemiplimab and pembrolizumab are the approved agents, I think they are the logical ones for further clinical development. Nonetheless, this is still a very important proof-of-concept trial showing that there is a strong clinical signal when you combine EGFR inhibition with inhibition of PD-L1 versus PD-L1 alone. Dr. Ece Cali: I want to highlight some of the safety data presented in this trial as well. The treatment discontinuation rate due to adverse events was much higher in the combination arm, reaching 31% compared to the 14% in the single-agent avelumab arm. The most common grade III adverse events were infusion reaction, rash, and diarrhea in the combination arm. So, these adverse events may affect patients' quality of life significantly. So, what are your thoughts on this, Dr. McArthur? Dr. Grant McArthur: So, the safety data is important. What we're seeing is safety related to each individual agent. So, we have diarrhea and skin rash from the cetuximab, and the infusion reactions is a common toxicity of avelumab. I think what's important, given this is proof of concept inhibiting these targets going forward to further studies, is that agents such as cemiplimab and pembrolizumab have a very low infusion reaction rate. So, the treatment discontinuations due to infusion reaction are unlikely to be an issue with cemiplimab and pembrolizumab when further clinical trials are done. Of course, there is still the issue of diarrhea and skin rash. Now, that can be managed in many patients with EGFR inhibition, you know. However, one would have to await safety data from a significant patient cohort with a combination of cetuximab with either cemiplimab or pembrolizumab, of course, to assess the clinical impact of those safety signals. But I would expect there to be definitely rash and diarrhea as predominant toxicities with those other combinations as well. Dr. Ece Cali: And lastly, I think we touched upon this a little bit, but how do you think this trial impacts the clinical practice, and what are some outstanding questions that need to be addressed in this field in light of the data from this trial? Dr. Grant McArthur: So, the most important outstanding question is - of course, we've already alluded to in our conversation - regarding using anti-PD-1 agents such as pembrolizumab or cemiplimab. So, that needs to be undertaken. Clearly, a randomized trial would be required combining cetuximab with those agents because they are quite active as single agents with impressive response rates and PFS. So, that is the way forward. There's other important clinical questions as well, though. So, patients that get locally aggressive or metastatic cutaneous squamous cell carcinoma of the skin are often immunosuppressed. And so, we do need data in patients that are immunosuppressed, either due to treatment of immune-related disorders - and also organ transplantation. We see a lot of cutaneous squamous cell carcinoma in organ transplant patients. So, these are important patient subsets that would also need to be investigated in further clinical development. However, overall, you know, this is a strong signal, hazard ratio of less than 0.5, and very worthy of further investigation in randomized trials of inhibiting these targets. Dr. Ece Cali: This was a great discussion. Thank you so much for your insight, Dr. McArthur, for speaking about the JCO article "A Phase II Randomized Trial of Avelumab Plus Cetuximab Versus Avelumab Alone in Advanced Cutaneous Squamous Cell Carcinoma." Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. 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.

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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 

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In this JCO Precision Oncology Article Insights episode, Jiasen He summarizes "Predictive Impact of Tumor Mutational Burden on Real-World Outcomes of First-Line Immune Checkpoint Inhibition in Metastatic Melanoma” by Dr. Miles C. Andrews, et al. published on June 07, 2024. Transcript The guest on this podcast episode has no disclosures to declare. Jiasen He: Hello and welcome to the JCO Precision Oncology Article Insights. I'm your host, Jiasen, and today we'll be discussing the JCO Precision Oncology article, "Predictive Impact of Tumor Mutational Burden on Real-World Outcomes of First-Line Immune Checkpoint Inhibition in Metastatic Melanoma," by Dr. Miles C. Andrews and colleagues. This study was supported by Foundation Medicine, a for-profit company that conducts FDA-regulated molecular diagnostics, including assays used to measure tumor mutational burdens, or TMB, as described in this article. Immune checkpoint inhibitor (ICI) therapy has become a cornerstone in the treatment of metastatic melanoma. They work by activating the patient's own immune system, representing a fundamentally different approach from traditional chemotherapy. Several biomarkers have emerged as promising tools to predict ICI therapy response, and TMB is one of the most extensively studied. TMB is defined as the number of somatic mutations per megabase of an interrogated genome sequence. In the KEYNOTE-158 study, patients with high TMB showed better response rates and longer progression-free survival compared to those with low TMB, which led to the FDA tumor-agnostic approval of TMB as a biomarker to guide ICI therapy. In this manuscript, Dr. Andrews and colleagues set out to answer an important question: does TMB predict outcomes of ICI therapy in real-world patients with advanced melanoma? To explore this, they analyzed de-identified data from the nationwide Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB). To be included, patients needed to have had at least two visits to a Flatiron Health clinic and a Foundation Medicine Comprehensive Genomic Profiling report. Eligible patients had received first-line treatment with either monotherapy (nivolumab or pembrolizumab) or dual therapy with the combination of ipilimumab and nivolumab for metastatic melanoma. They also needed a tissue-based TMB score from either the FoundationOne or FoundationOne CDx genomic test. For this study, TMB less than 10 mutations per megabase was considered low TMB; TMB equal to or more than 10 mutations per megabase was considered high TMB; and TMB equal to or more than 20 mutations per megabase was considered very high TMB. Of the 497 patients in the final cohort, 29% had low TMB, while 71% had high TMB, and 50% had very high TMB. The authors observed that patients with very high TMB were more often male, had BRAF wild-type tumors, and were more likely to receive anti-PD-1 monotherapy. This group also had tumors more commonly sampled from brain and lung metastases. Patients with high TMB but not very high TMB were more likely to carry the BRAF V600K mutation and were least likely to have lung metastases. Meanwhile, those with low TMB tended to be younger and had disease limited to non-visceral sites. As expected, the presence of ultraviolet mutation signatures, a known driver of melanoma, was strongly associated with TMB. UV signatures were found in just 18% of the low TMB group, but in 89% of the high TMB and 93% of the very high TMB group. High TMB was found to be prognostic of improved real-world progression-free survival (PFS) and overall survival (OS) in patients receiving both monotherapy and dual immune checkpoint inhibitors, even after adjusting for other established prognostic factors. Interestingly, in the low TMB group, overall survival was likely confounded by the availability of effective second-line targeted therapy, particularly for BRAF-mutant patients. These patients had better outcomes compared to their BRAF wild-type counterparts, likely reflecting a greater reliance on salvage therapy in low TMB patients who derived less benefit from first-line immunotherapy. The authors then further examined the ICI outcomes using stepwise TMB thresholds, with TMB less than 10 as low, 10 to 19 as high, and equal to or more than 20 as very high. For those receiving ICI monotherapy, both PFS and OS were highest in the very high TMB group, followed by the high TMB group, and lowest in the low TMB group. However, in patients treated with dual ICI therapy, the results diverged. While low TMB patients still had the poorest outcomes, those with high TMB (mutations 10 to 19 per megabase) had better PFS and overall survival than those with very high TMB (mutations equal to or more than 20 per megabase). The authors then conducted exploratory multivariable modeling, showing that among very high TMB patients with BRAF mutations, dual ICI therapy was associated with a significantly higher hazard ratio compared to monotherapy. They concluded that dual ICI may not benefit, and could even harm, patients with very high TMB, whereas those with TMB between 10 and 20 mutations per megabase may get more from the intensified regimen. Importantly, as the authors stated in the manuscript, we need to note that in this cohort, very high TMB patients were more likely to have brain metastases at treatment initiation, be male, and lack BRAF V600E/K mutations—all factors associated with poorer prognosis. This might partially explain inferior outcomes to dual ICI in very high TMB patients, as patients were not randomly assigned to therapy in this retrospective, real-world study. As such, these findings should be interpreted with caution and validated in future studies. In summary, this study showed that in a real-world setting, high tumor mutational burden predicts better outcomes with immune checkpoint inhibitor therapy in patients with advanced melanoma. Interestingly, the authors found that dual ICI therapy may offer no added benefit for patients with very high TMB compared to ICI monotherapy. However, this was a retrospective, non-randomized study, and the cohorts were imbalanced for some known risk factors, which could confound outcomes. As a result, these findings should be interpreted with caution and will need to be validated in future prospective studies. 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.

May 27, 2025 – What's in store for the 2025 US economy in the second half of this year? In a thought-provoking discussion with FS Insider's Cris Sheridan, Alpine Macro's David Abramson suggests a second-half slowdown but one that...

Newcore Gold continues to deliver wide mineralized zones and shallow high-grade intercepts at its Enchi Gold Project in Ghana, while now pivoting to aggressive resource expansion drilling.   In this company update, Luke Alexander, President and CEO of Newcore Gold (TSX.V:NCAU - OTCQX:NCAUF), joins us to discuss progress on the company's ongoing 35,000-meter drill program. Since our last interview in March, four drill result press releases have been issued, showcasing consistent gold mineralization, wide intercepts, and signs of resource expansion beyond existing pit shells.   Luke outlines: Over 20,000 meters of drilling results released to date, with highlights including 2.25 g/t over 56m and 4.4 g/t over 24m at the Boin deposit. Ongoing conversion-focused drilling, now largely completed, is expected to significantly improve the upcoming resource update and PFS. The remaining 15,000 meters are targeting step-out and deeper holes, testing strike extensions and high-grade feeder zones that could further scale the project. Drilling is now extending mineralization beyond existing pit boundaries, potentially widening and deepening the resource base. The company is fully funded through the current drill program and PFS, with up to $30 million in projected cash including in-the-money warrant proceeds. We also touch on investor sentiment and strategic direction. With 55% institutional ownership, Newcore is focused on delivering a construction-ready project while advancing exploration upside across a district-scale gold trend.   Have follow-up questions for Luke? Send them in and we'll include them in future interviews. Fleck@kereport.com  Click here to visit the Newcore Gold website.  

May 26, 2025 – In today's Lifetime Planning segment of the Financial Sense Newshour, Jim Puplava and Bill Harris, author of The Investment Tax Guide: How to Slash Your Taxes, explore ten tax-saving strategies, from 401(k) optimization and asset...

May 23, 2025 – Markets are choppy, headlines are driving wild swings, and policy shifts seem to dictate every move. But is this just noise, or are deeper trends at play? Mish Schneider of MarketGauge joins Jim Puplava to challenge bullish...

May 23, 2025 – Financial Sense interviews Merdith Whitney who warns that ‘over 52% of American households already went through a recession' and that the real economy is far more fragile than headline numbers suggest. She warns that unemployment...

May 22, 2025 – Both gold and silver have seen strong moves this year. Gold is up 25% year-to-date at a little over $3,300 an ounce and silver is up 14% at just over $33 an ounce. Given ongoing concerns over US debt and geopolitical uncertainty...

May 21, 2025 – Today on FS Insider, Laurent Lequeu, author of Macro Butler, discusses soaring US debt refinancing needs—$7T in 2025—forcing Treasury yields higher amid persistent “velcro” inflation and waning foreign demand, especially post-Trump trade shifts...

May 19, 2025 – Curious about career paths beyond college? Jim Puplava and Doug Crawford discuss the growing appeal and advantages of trade schools versus traditional college. As college costs soar and skilled trades like electricians, plumbers...

May 16, 2025 – Art Hill, Chief Technical Strategist at TrendInvestorPro.com, discusses the stock market's dramatic V-shaped recovery with Jim Puplava after a steep April plunge triggered by Liberation Day. Hill's breadth indicators signaled...

May 16, 2025 – In a riveting discussion with Jim Puplava, real estate investor and economist George Karahalios unveils the seismic shifts rocking America's economy. His prophetic 2007 article warned of U.S. defeat in the global currency war...

May 14, 2025 – What do the latest U.S.-China trade negotiations mean for markets, the economy, and your investments? Dr. Ed Yardeni, President and Chief Investment Strategist at Yardeni Research, discusses recent developments in U.S.-China trade...

May 13, 2025 – Market cycles may be nearing a turning point, according to Avi Gilburt, co-founder of ElliottWaveTrader.net, who recently shared his contrarian outlook on stocks, gold, and the US dollar. He believes the US stock market is...

May 12, 2025 – As college costs soar and the job market transforms, Jim Puplava interviews Rob Franek, editor-in-chief of The Princeton Review, on how families can navigate the challenges of higher education. They discuss the current state of...

May 9, 2025 – Can investors outpace volatility in a year of global headlines and shifting trends? David Keller, Chief Investment Strategist at Sierra Alpha Research, joins Jim Puplava on Financial Sense Newshour to analyze current market dynamics...

May 9, 2025 – Political risk expert and author of Bear Traps Report Larry McDonald joins Jim Puplava to discuss his latest book, How to Listen When Markets Speak: Risks, Myths, and Investment Opportunities in a Radically Reshaped Economy...

May 8, 2025 – Discover why Invictus Research's Mike Singleton is urging caution, even as economic data looks strong and the S&P 500 rallies. In this insightful interview, Singleton explains his shift from a bullish to a deflationary outlook...

May 6, 2025 – Are tariffs throwing the U.S. economy into chaos, or is there a hidden opportunity amidst the uncertainty? Peter Boockvar, author of the widely read Boock Report, joins Cris Sheridan to discuss the current US economic outlook...

May 5, 2025 – How can families afford college without drowning in debt? In today's Lifetime Planning episode of the Financial Sense Newshour, Jim Puplava and Crystal Colbert discuss some of the most important factors and considerations...

May 2, 2025 – Stocks have recently rallied, but Jim Welsh at Macro Tides believes the market is still in a prolonged correction or early bear market, with risks of retesting recent lows. Next, Jim Puplava and Robert Rapier discuss falling oil prices...

May 2, 2025 – In today's Smart Macro segment, Chris Puplava, Chief Investment Officer at Financial Sense Wealth Management, analyzes the credit markets amid recent stock market volatility. He notes a divergence, as credit markets...

May 1, 2025 – In part 2 of today's interview, Satyajit Das warns of a looming financial crisis, likening the global economy to a frail patient, crippled by high debt and weak growth. He critiques the US's miscalculated trade policies, predicting tariffs...

May 1, 2025 – FS Insider speaks with Satyajit Das, a former banker and author of numerous books, who contends that the global economy is entering a period of heightened risk, characterized by a combination of slowing growth, evolving trade policies...

Apr 30, 2025 – Curious about where the global trade war is headed—and who the winners and losers might be? In this timely interview, Variant Perception's macro strategist Jonathan Petersen joins Financial Sense to break down the real...