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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

Dr. Nimish Mohile and Dr. Jaishri Blakeley share the new rapid recommendation update to the therapy for diffuse astrocytic and oligodendroglial tumors in adults guideline. They review the evidence from the INDIGO trial that prompted this update, and how to incorporate the use of vorasidenib into clinical practice. They discuss the importance of molecular testing, particularly for IDH1 or IDH2 mutations and outstanding questions for treatment of patients with oligodendrogliomas and astrocytomas. Read the latest update, “Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline Rapid Recommendation Update.” Transcript This guideline, clinical tools, and resources are available at http://www.asco.org/neurooncology-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in Journal of Clinical Oncology.   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. Jaishri Blakeley from Johns Hopkins University School of Medicine and Dr. Nimish Mohile from the Department of Neurology and Wilmot Cancer Institute at the University of Rochester Medical Center, co-chairs on “Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: American Society of Clinical Oncology-Society for Neuro-Oncology Guideline Rapid Recommendation Update.”  Thank you for being here today, Dr. Blakeley and Dr. Mohile.  Dr. Jaishri Blakeley: Thank you.  Dr. Nimish Mohile: Thank you for having us.  Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Blakeley and Dr. Mohile who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.   So then, to jump into the content here, Dr. Mohile, could you start us off by describing what prompted this rapid update to the ASCO-SNO therapy for diffuse astrocytic and oligodendroglial tumors in adults guideline, which was previously published in 2021?  Dr. Nimish Mohile: Yeah. So the key reason for this update is the publication of a study in 2023. And this was a study called the INDIGO study that looked at a new class of therapies, something called IDH inhibitors. And in this study with a drug called vorasidenib, changed how we think about the treatment of oligodendrogliomas and astrocytomas, so particularly the grade 2 oligodendrogliomas and grade 2 astrocytomas. Because of the results of that study, we decided that we needed to do an update to inform clinicians about some of these changes and how we might approach these tumors differently today.  Brittany Harvey: Great. I appreciate that background. So then, based off the new data from the INDIGO study, what are the updated and new recommendations from the expert panel?  Dr. Nimish Mohile: So the key findings from the INDIGO study involved people who had grade 2 astrocytomas and grade 2 oligodendrogliomas. And in the setting after surgery, they were treated with vorasidenib, and what they found is that this delayed the time to next intervention. And the key aspect of that is that it delayed when we could start radiation and chemotherapy in these patients.   So what we did in the guidelines is that for both low grade oligodendrogliomas and low grade astrocytomas, we added one additional guideline statement. Our previous guideline in 2021 offered the options for observation or treatment with radiation and chemotherapy. And now in this guideline, we have options for observation, treatment with vorasidenib in those in whom we feel it is safe to defer radiation and chemotherapy, and then treatment with radiation and chemotherapy. So we've added in an additional option here. And the key message of the guideline is really on how, as clinicians, we think about using the vorasidenib and what the ideal setting for using the vorasidenib is.  Brittany Harvey: Excellent. It's great to hear about this new option for patients. So then you were just talking about how we think about who to offer this IDH inhibitor to. So, Dr. Blakeley, what should clinicians know as they implement these new recommendations into practice?  Dr. Jaishri Blakeley: Yes. So, first and foremost, let's go back to 2021, and a key note from those guidelines was the importance of molecular testing. And at that point, the importance of molecular testing, which in large part was focused on IDH1 or IDH2 mutations, was prognostic. We could say there's a difference in an IDH1 mutant astrocytoma and an IDH1 wild type astrocytoma, but we didn't have a specific therapeutic recommendation attached to that, like Dr. Mohile just said. And the big shift here is now we have a specific therapeutic for that population with IDH1 or IDH2 mutant glioma.   So for clinicians, we hope that they've been getting molecular testing on newly diagnosed glioma already, but now there's an additional motivation to do so because it may change your treatment plan in the right circumstance. So since the publication of the phase III INDIGO study that Dr. Mohile mentioned, and the FDA approval of vorasidenib, if you meet the specified criteria in the clinical trial - which the guidelines point out is a little different than what's on the FDA label, so clinicians might want to dig into that a little bit - then there is a treatment option that is new and different than combined chemoradiation or radiation alone or observation.  Brittany Harvey: I appreciate those clarifications there.   So then also, Dr. Blakeley, how does this update impact patients with astrocytic or oligodendroglial tumors?  Dr. Jaishri Blakeley: So first, patients also should know if they have IDH mutant gliomas. And this update only applies to people with IDH1/2 mutant glioma. Perhaps, we're not sure, it might only apply to people who are in the newly or newly-ish diagnosed category because the INDIGO study required that people were within the first five years of their surgical diagnosis and had not had other treatment. So there are a lot of people who have astrocytoma or oligodendroglioma who may or may not know their IDH1/2 status and may have already had another therapy - this update doesn't apply to them. We hope that future research will teach us about that. This update is for people who are newly diagnosed and just starting the journey to figure out the best therapy. It does say that if you do have that IDH1/2 alteration in your tumor, there is a drug therapy that is different from the drug therapies we would offer gliomas that do not have the IDH1/2 mutation.  Brittany Harvey: Absolutely. I think both that emphasis on molecular testing is very important and also thinking about that study inclusion criteria and how it impacts who's eligible for this treatment.   So then finally, Dr. Mohile, what are the outstanding questions about vorasidenib or other interventions for gliomas in adults?  Dr. Nimish Mohile: I think the key question for clinicians is exactly who we're going to use this in. The challenges with inclusion criteria in clinical trials is they don't actually always match what we're seeing in the clinic. And I think it brings up the question of, in low grade oligodendrogliomas which we think of as very slow growing tumors, do we have the option outside of the strict inclusion criteria to use that drug in other settings? I think it brings up the question for some clinicians in some of the higher grade tumors, in the grade 3 tumors, we don't yet have data in that area and our guideline doesn't address that. But I think some will be asking what the clinical activity of vorasidenib is in that setting. There are some suggestions that the IDH inhibitors may impact seizure control, and I think that that's data that we're continuing to wait on.   So I think that there's several outstanding questions there that we will have answers for hopefully in the next several years. I think the big question that we don't have an answer for and that will take a long time to know is whether the addition of vorasidenib in this setting actually improves how long people live. And given how long people with low grade oligodendrogliomas and low grade astrocytomas live today, we probably won't have an answer to that question for more than a decade.  Brittany Harvey: Definitely. We'll look forward to these ongoing developments and eventually longer term data on overall survival on these agents.   So, I want to thank you both so much for your work to rapidly include this information from this new trial. And thank you for your time today, Dr. Blakeley and Dr. Mohile.  Dr. Jaishri Blakeley: Thank you so much.  Dr. Nimish Mohile: Thank you Brittany.  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/neurooncology-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. 

Welcome to the Oncology Brothers podcast! In this episode, Drs. Rohit and Rahul Gosain are joined by Dr. Ghassan Abou-Alfa, a medical oncologist specializing in the hepatobiliary space at Memorial Sloan Kettering. Together, they explored the current treatment landscape of biliary tract cancer, focusing on the advancements in HER2-driven therapies.   Key topics discussed included: • The evolution of treatment options for biliary tract cancer, including chemotherapy and immunotherapy. • The significance of genetic testing, including IDH1 mutations, FGFR alterations, and HER2 status. • The role of multidisciplinary collaboration in managing hepatobiliary cancers. • Insights into the latest clinical trials and emerging therapies for HER2-positive biliary tract cancer.   Join us as we delve into the complexities of biliary tract cancer and the promising developments in HER2-targeted treatments. Don't forget to check out our next episode, where we will take a deeper dive into the data surrounding HER2 therapies and discuss management strategies for common side effects.   YouTube: https://youtu.be/pGiU7JJGNOc   Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/   Subscribe to stay updated on the latest in oncology! #OncologyBrothers #BiliaryTractCancer #HER2 #CancerTreatment #MedicalOncology #CME #Podcast

Dr. John Sweetenham and Dr. James Foran discuss the evolving treatment landscape in acute myeloid leukemia, including new targeted therapies, advances in immunotherapy, and the current role for allogeneic transplantation. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast. There has been steady progress in the therapies for acute myeloid leukemia (AML) in recent years, largely based on an increasing understanding of the molecular mechanisms which underlie the disease. On today's episode, we'll be discussing the evolving treatment landscape in AML. We'll explore risk group stratification, new targeted therapies, advances in immunotherapy for AML, and also a little about the current role for allogenic transplantation in this disease.  I'm delighted to welcome Dr. James Foran to this discussion. Dr. Foran is a professor of medicine and chair of the Myeloid Malignancies and Blood and Marrow Transplant Disease Group at the Mayo Clinic Comprehensive Cancer Center. He's based in Jacksonville, Florida.  Our full disclosures are available in the transcript of this episode.  James, it's great to have you join us on the podcast today, and thanks so much for being here. Dr. James Foran: I'm delighted and thank you for the invitation. Thank you very much. Dr. John Sweetenham: Sure, James, let's get right into it. So, our understanding of the molecular mechanisms underlying AML has resulted not only in new methods for risk stratification in this disease, which have added refinement to cytogenetics, but also has resulted in the development of many new targeted agents. Understanding that this is a complex area of investigation, and our time is somewhat limited, can you give us a high-level update on the current state of the art in terms of how risk factors are being used for treatment selection now? Dr. James Foran: Absolutely. I think in the past, you know, we had things broken down pretty simply into make a diagnosis based on morphology, do cytogenetics, break patients into the groups of those who were more likely to benefit from therapy – so-called favorable risk – those where the intensive therapies were less likely to work – so-called poor adverse risk, and then this large intermediate group that really had variable outcomes, some better, some worse. And for a long time, the progress was in just identifying new subtle cytogenetic risk groups. And then, late 1990s, we began to understand that FLT3 mutations or NRAS mutations may be more adverse than others that came along. In the first part of this millennium, in the, you know, 2000-2010 range, a lot of work was being done to understand better or worse risk factors with single genes. The ability to do multiplex PCR, and then more recently NGS platforms, have allowed us to really look at many genes and identify many mutations in patients. At the beginning that was used just to sort of refine – who did a little better, who did a little worse with intensive therapy – helped us decide who may benefit more from an allogeneic transplanter for whom that would not be necessary.  But the good news is that really, we're now starting to target those mutations. One of the first molecularly targeted treatments in leukemia was FLT3 mutations, where we knew they were adverse. Then along came targeted treatments. I was involved in some of those early studies looking at sunitinib, sorafenib, more recently midostaurin, now quizartinib, FDA approved, and gilteritinib in the relapse refractory setting.  So we're moving into a state where we're not just refining prognosis, we're identifying targets. You know, it's been slow progress, but definite incremental progress in terms of outcomes by looking for FLT3 mutations, then looking for IDH mutations, and more recently, mutations involving NPM1 or rearrangement of what we used to call the MLL gene, now the lysine methyltransferase 2A or KMT2A rearrangement, where we now have targets. And it's not just for refinement of prognosis, but now we're identifying therapeutic targets for patients and ways to even look for measurable residual disease which is impacting our care. Dr. John Sweetenham: That's great, James. And I'm going to expand on that theme just a little bit and perhaps ask you to elaborate a little bit more on how the introduction of these new therapies have specifically impacted frontline therapy. And a couple of ancillary questions maybe to go along with that: First of all, is ‘7+3' a standard therapy for anybody in 2025? And maybe secondly, you know, could you comment also maybe briefly on older patients with AML and how you think maybe the treatment landscape is changing for them compared with, say, 5 or 10 years ago? Dr. James Foran: I'll start with the therapy and then work my way back. So we've had ‘7+3' cytarabine daunorubicin or cytarabine anthracycline since 1976, and we're still using it as the backbone of our intensive therapy. There is still an important role for it, particularly in younger or fitter patients, and particularly for those with intermediate or favorable risk genetic groups or cytogenetic risk groups just because we achieve high rates of remission. Our 30-day induction mortality rates are lower now than they were 10 and 20 years ago. Our supportive care is better. And we still have a busy inpatient hospital service here at Mayo Florida and my colleagues in Rochester and Arizona as well giving intensive therapy. So that remains the backbone of curative therapy for younger adults. We are trying to be a little more discriminating about who we administer that to. We are trying to add targeted agents. We know from, now, two different randomized trials that the addition of a FLT3 inhibitor, either midostaurin or more recently quizartinib, has a survival advantage in patients with a FLT3 mutation, or for quizartinib, a FLT3/ITD mutation. And so yes, ‘7+3' remains important.  Off protocol for somebody who just comes in with acute leukemia in a 40-year-old or 30-year-old or even early 60s and fit, we would still be considering ‘7+3' therapy and then waiting for an expedited gene mutation panel and an expedited cytogenetics panel to come back to help us discriminate is that a patient for whom we should be giving a FLT3 inhibitor? I think there's a little more nuance about when we do a day 14 bone marrow, do they really matter as much anymore? I still do them. Some of my colleagues find them less important. But we're still giving intensive therapy. We're still giving high-dose ARA-C consolidation for younger patients who achieve complete remission.  In older adults, it's a different story. You know, it was only in the early part of the 2000s – 2004, 2007 range – where we really got buy-in from randomized studies that low-dose therapy was better than no therapy. There was a lot of nihilism before then about therapy for older adults, especially over age 75. We know that low-dose ARA-C is better than nothing. It looked like azacitidine was better than ARA-C or at least equivalent or slightly better. But with the advent of venetoclax it was a game changer. I ran a national randomized study of intensive therapy in AML. It was the last national randomized study of intensive therapy in older patients right before venetoclax got approved. And we were very excited about our results, and we thought we had some really interesting clinical results. And suddenly that's a little bit obsolete in patients over 70 and particularly over age 75 because of the high remission rates with azacytidine venetoclax or hypomethylating agents, so-called HMAs and venetoclax and the survival advantage. Now, it's not a home run for everybody. We quote 60% to 70% remission rates, but it's a little different based on your cytogenetics and your mutation profile. You have to continue on therapy so it's continuous treatment. It's not with curative intent, although there are some people with long-term remission in it. And the median survival went from 10 months to 15 months. So home run? No, but definitely improved remissions, meaningful for patients off transfusions and better survival. So right now it's hard to find an older adult who you wouldn't give azacitidine and venetoclax or something similar, decitabine, for instance, and venetoclax, unless somebody really was moribund or had very poor performance status or some reason not to. And so ‘7+3' is still relevant in younger adults. We're trying to get better results with ‘7+3' by adding targeted agents and azacitine and venetoclax in older adults.  I think the area of controversy, I guess there are two of them, is what to do in that overlap age between 60 and 75. Should people in that age still get intensive therapy, which we've used for years – the VIALE-A trial of aza-venetoclax was age 75 plus – or with cardiac comorbidities? And I think if you're 68 or 72, many of us are starting to bias towards aza-venetoclax as generally being better tolerated, generally being more outpatient, generally being slow and steady way to get a remission. And it doesn't stop you from going to transplant for somebody who might still be a candidate.  The other area of controversy is somebody under 60 who has adverse cytogenetics where we don't do very well with ‘7+3,' we still give it and we might do just as well with decitabine venetoclax. A lot of us feel that there's equipoise in the 60 to 75 group where we really can ask a question of a randomized study. Retrospective studies might suggest that intensive therapy is a little better, but there are now a couple of randomized studies happening saying, “Can we replace ‘7+3' in that intermediate age with aza-venetoclax?” And for younger adults similarly, we're looking to see how we apply that technology. Those are the areas where we're really trying to investigate what's optimal for patients and that's going to require randomized trials. Dr. John Sweetenham: Oh, that's great, thank you. And I'll just extend that question a little bit more, particularly with respect to the new targeted therapies. How much are they impacting the treatment of these patients in the relapse and refractory setting now? Dr. James Foran: Oh, they're definitely impacting it. When I trained and probably when you trained, AML was still a medical emergency. But that was the thing that you admitted to the hospital immediately, you started therapy immediately. The rule was always that's the one thing that brings the fellow and the consultant in at night to see that new patient on a Friday or Saturday. Now, we'll still admit a patient for monitoring, but we try not to start therapy for the first three or five or seven days if they're stable, until we get those genetics and those genomics back, because it helps us discriminate what therapy to pursue. And certainly, with FLT3 mutations, especially FLT3/ITD mutations, we're adding FLT3 inhibitors and we're seeing a survival advantage. Now, on the surface, that survival advantage is in the range of 7% or 10%. But if you then pursue an allogeneic transplant in first remission, you're taking disease where we used to see 30%, 40% long-term survival, maybe less, and you're pushing that to 60%, 70% in some studies. And so we're now taking a disease that– I don't want to get off topic and talk about Ph+ ALL. But that's a disease where we're actually a little excited. We have a target now, and it used to be something really adverse and now we can do a lot for it and a lot about it.  The other mutations, it's a little more subtle. Now, who knew until 2010 that a mutation in a sugar metabolism gene, in isocitrate dehydrogenase, or IDH was going to be so important, or even that it existed. We know that IDH1 and IDH2 mutations are still a minority of AML, certainly less than 10% to 15%, maybe overall. But we're able to target those with specific IDH1 and IDH2 inhibitors. We get single-agent responses. There are now two approved IDH1 inhibitors on the market. We don't yet have the randomized data that adding those to intensive therapy is better, but we're getting a very strong hint that it might be better in older adults who have an IDH mutation, maybe adding those is helpful and maybe adding those to low-intensity therapy is helpful. Those studies are ongoing, and we're also trying with low-intensity treatments to add these agents and get higher remission rates, deeper remissions, longer remissions. I think a lot of work has to be done to delineate the safety of that and the long-term efficacy. But we're getting hints it's better, so I think it is impacting.  The other area it's impacting is when you pick up adverse mutations and those have crept into our classification systems like an ASXL1 mutation or RUNX1 mutation for instance, or some of the secondary AML mutations like BCOR and others, where that's helping us discriminate intermediate-risk patients who we think aren't going to do as well and really helping us select a group who's more likely to get benefit from allogeneic transplant or for whom at least our cure rates without allo transplant are low. And so I think it's impacting a lot. Dr. John Sweetenham: Great. And I'm going to pick up now, if I may, on a couple of things that you've just mentioned and continue the theme of the relapsed and refractory setting. We've started to see some reports which have looked at the role of immune strategies for patients with AML, in particular CAR T or NK cells. Can you comment a little on this and let us know whether you think either these two strategies or other immune strategies are likely to have a significant role in AML in the future? Dr. James Foran: They are, but I think we're still a step behind finding the right target or the right way to do it. If you think of allogeneic transplantation as the definitive immune therapy, and we know for adverse AML we can improve survival rates and cure rates with an allotransplant, then we know inherently that immune therapy matters. And so how do we do what they've done in large cell lymphoma or in CD19 targeting for B cell malignancies? How do we bring that to acute myeloid leukemia? There have been a number of efforts. There have been at least 50 trials looking at different targets. CD33, CD123, CD7, others, CLL-1. So, there have been a number of different trials looking at how to bind a CAR T or a CAR T construct that can be active. And we have hints of efficacy. There was kind of a provocative paper in the New England Journal of Medicine a year ago in April of last year from a Chinese group that looked at a CD7-based CAR T and it was 10 patients, but they used CD7 positive acute leukemia, AML or ALL and had a CD7-targeted CAR T and they actually incorporated that with a haploidentical transplant and they had really high remission rates. People tolerated it quite well. It was provocative. It hasn't yet been reproduced on a larger scale, but the strong hints that the strategy is going to work.  Now, CD33 is a little tricky to have a CAR T when CD33 is expressed on normal hematopoietic cells. CD123 likewise. That's been something where there's, I think, still promise, but we've struggled to find the trials that make that work. Right now, there's a lot of interest in leveraging NK cells and looking, for a couple of reasons, but NK cells are attractive and NK cell markers might be attractive targets. NK cells might have similar degrees of immune efficacy. It's speculative, but they are likely to have less cytokine release syndrome and less neurotoxicity than you see with CAR T. And so it's kind of attractive to leverage that. We have had some ongoing trials looking at it with bispecifics and there certainly are trials looking at it with CAR NK-based strategies. One of the antigens that people looked at is the NK group 2D. NK group 2D or NKG2D is overexpressed in AML and its ligands overexpressed. And so that's a particular potential target. So, John, it's happening and we're looking for the hints of efficacy that could then drive a pivotal trial to get something approved.  One of the other areas is not restricting yourself just to a single antigen. For instance, there is a compound that's looking at a multi-tumor-associated antigen-specific T-cell therapy, looking at multiple antigens in AML that could be overexpressed. And there were some hints of activity and efficacy and actually a new trial looking at a so-called multi-tumor associated antigen-specific T cell therapy. So without getting into specific conflicts of interest or trials, I do think that's an exciting area and an evolving area, but still an investigational area. I'll stop there and say that we're excited about it. A lot of work's going there, but I'm not quite sure which direction the field's going to pivot to there. I think that's going to take us some time to sort out. Dr. John Sweetenham: Yeah, absolutely. But as you say, exciting area and I guess continue to watch this space for now.  So you've mentioned allogeneic stem cell transplants two or three times during this discussion. Recognizing that we don't have an imatinib for AML, which has kind of pushed transplant a long way further back in the treatment algorithm, can you comment a little on, you know, whether you think the role of stem cell transplantation is changing in AML or whether it remains pretty much as it was maybe 10 years ago? Dr. James Foran: By the way, I love that you use imatinib as an introduction because that was 6 TKIs ago, and it tells you the evolution in CML and you know, now we're looking at myristoyl pocket as a target, and so on. That's a great way to sort of show you the evolution of the field.  Allogeneic transplant, it remains a core treatment for AML, and I think we're getting much smarter and much better about learning how to use it. And I'm just going to introduce the topic of measurable residual disease to tell you about that. So I am a little bit of a believer. Part of my job is I support our allogeneic transplant program, although my focus is acute myeloid leukemia, and I've trained in transplant and done it for years and did a transplant fellowship and all that. I'm much more interested in finding people who don't need a transplant than people who do. So I'm sort of looking for where can we move away from it. But it still has a core role. I'll sidestep and tell you there was an MDS trial that looked at intermediate or high-risk MDS and the role of allogeneic transplant that shows that you about double your survival. It was a BMT CTN trial published several years ago that showed you about double your three-year survival if you can find a donor within three months and get to a transplant within six months. And so it just tells you the value of allotransplant and myeloid malignancy in general. In AML we continue to use it for adverse risk disease – TP53 is its own category, I can talk about that separately – but adverse risk AML otherwise, or for patients who don't achieve a really good remission. And I still teach our fellows that an allotransplant decreases your risk of relapse by about 50%. That's still true, but you have to have a group of patients who are at high enough risk of relapse to merit the non-relapse mortality and the chronic graft versus host disease that comes with it. Now, our outcomes with transplant are better because we're better at preventing graft versus host disease with the newer strategies such as post-transplant cyclophosphamide. There are now new FDA-approved drugs for acute and chronic graft versus host disease, ruxolitinib, belumosudil, axatilimab now. So we have better ways of treating it, but we still want to be discriminating about who should get it.  And it's not just a single-minded one-size-fits-all. We learned from the MORPHO study that was published in the JCO last year that if you have FLIT3-positive AML, FLIT3/IDT-positive AML, where we would have said from retrospective studies that your post-transplant survival is 60% give or take, as opposed to 15% or 20% without it, that we can discriminate who should or shouldn't get a transplant. Now that trial was a little bit nuanced because it did not meet its primary endpoint, but it had an embedded randomization based upon MRD status and they used a very sensitive test of measurable residual disease. They used a commercial assay by Invivoscribe that could look at the presence of a FLT3/ITD in the level of 10 to the minus 5th or 10 to the minus 6th. And if you were MRD-negative and you went through a transplant, you didn't seem to get an advantage versus not. That was of maintenance with gilteritinib, I'll just sort of put that on there. But it's telling us more about who should get a transplant and who shouldn't and who should get maintenance after transplant and who shouldn't.  A really compelling study a year ago from I don't know what to call the British group now, we used to call them the MRC and then the NCRI. I'm not quite sure what to call their studies at the moment. But Dr. Jad Othman did a retrospective study a year ago that looked at patients who had NPM1 mutation, the most common mutation AML, and looked to see if you were MRD positive or MRD negative, what the impact of a transplant was. And if you're MRD negative there was not an advantage of a transplant, whereas if you're MRD positive there was. And when they stratified that by having a FLT3 mutation that cracked. If you had a FLT3 mutation at diagnosis but your NPM1 was negative in remission, it was hard to show an advantage of a transplant. So I think we're getting much more discriminating about who should or should not get a transplant by MRD testing for NPM1 and that includes the patients who have a concomitant FLT3 mutation. And we're really trying to learn more and more. Do we really need to be doing transplants in those who are MRD-negative? If you have adverse risk genetics and you're MRD-negative, I'll really need good data to tell me not to do a transplant, but I suspect bit by bit, we'll get that data. And we're looking to see if that's really the case there, too. So measurable residual disease testing is helping us discriminate, but there is still a core role of allogeneic transplant. And to reassure you, compared to, I think your allotransplant days were some time ago if I'm right. Dr. John Sweetenham: Yes. Dr. James Foran: Yeah. Well, compared to when you were doing transplants, they're better now and better for patients now. And we get people through graft versus host disease better, and we prevent it better. Dr. John Sweetenham: That's a great answer, James. Thanks for that. It really does help to put it in context, and I think it also leads us on very nicely into what's going to be my final question for you today and perhaps the trickiest, in a way. I think that everything you've told us today really emphasizes the fact that the complexity of AML treatment has increased, primarily because of an improved understanding of the molecular landscape of the disease. And it's a complicated area now. So do you have any thoughts on what type of clinical environment patients with AML should be evaluated and treated in in 2025? Dr. James Foran: Yeah, I want to give you a kind of a cautious answer to that because, you know, I'm a leukemia doctor. I work at a leukemia center and it's what we focus on. And we really pride ourselves on our outcomes and our diagnostics and our clinical trials and so on. I am very aware that the very best oncologists in America work in private practice and work in community practice or in networks, not necessarily at an academic site. And I also know they have a much harder job than I have. They have to know lung cancer, which is molecularly as complicated now as leukemia, and they have to know about breast cancer and things that I don't even know how to spell anymore. So it's not a question of competence or knowledge. It's a question of infrastructure. I'll also put a little caveat saying that I have been taught by Rich Stone at Dana-Farber, where I did a fellowship a long time ago, and believe Rich is right, that I see different patients than the community oncologists see with AML, they're seeing different people. But with that caveat, I think the first thing is you really want to make sure you've got access to excellence, specialized hematopathology, that you can get expedited cytogenetics and NGS testing results back. There was a new drug, approved just a few months ago, actually, for relapsed AML with a KMT2A rearrangement, revumenib. We didn't talk about the menin inhibitors. I'll mention them in just a second. That's a huge area of expansion and growth for us. But they're not found on NGS platforms. And normal cytogenetics might miss a KMT2A-rearrangement. And we're actually going back to FISH panels, believe it or not, on AML, to try to identify who has a KMT2A-rearrangement. And so you really want to make sure you can access the diagnostic platforms for that.  I think the National Referral Labs do an excellent job. Not always a really fast job, but an excellent job. At my institution, I get NGS results back within three days or four days. We just have an expedited platform. Not everybody has that. So that's the key, is you have to be able to make the diagnosis, trust the pathologist, get expedited results. And then it's the question of trying to access the targeted medications because a lot of them are not carried in hospital on formulary or take time to go through an insurance approval process. So that's its own little headache, getting venetoclax, getting gilteritinib, getting an IDH1 inhibitor in first line, if that's what you're going for. And so I think that requires some infrastructure. We have case managers and nurses who really expedite that and help us with it, but that's a lot of work. The other piece of the puzzle is that we're still with AML in the first month and maybe even the second month. We make everybody worse before we make them better. And you have to have really good blood bank support. I can give an outpatient platelet transfusion or red cell transfusion seven days a week. We're just built for that. That's harder to do if you're in a community hospital and you have to be collaborating with a local blood bank. And that's not always dead easy for somebody in practice. So with those caveats, I do find that my colleagues in community practice do a really good job making the diagnosis, starting people on therapy, asking for help. I think the real thing is to be able to have a regional leukemia center that you can collaborate with, connect with, text, call to make sure that you're finding the right patients who need the next level of diagnostics, clinical trial, transplant consults, to really get the best results.  There was some data at ASH a couple of years ago that looked at – the American Society of Hematology and ASCOs had similar reports – that looked at how do we do in academic centers versus community practice for keeping people on therapy. And on average, people were more likely to get six cycles of therapy instead of three cycles of therapy with azacitidine venetoclax at an academic center. Now, maybe it's different patients and maybe they had different cytogenetics and so on, but I think you have to be patient, I think you have to collaborate. But you can treat those patients in the community as long as you've got the infrastructure in place. And we've learned with virtual medicine, with Zoom and other platforms that we can deliver virtual care more effectively with the pandemic and beyond. So I think we're trying to offer virtual consults or virtual support for patients so they can stay in their home, stay in their community, stay with their oncologists, but still get access to excellent diagnostics and supportive care and transplant consults, and so on. I hope that's a reasonable answer to that question. It's a bit of a nuanced answer, which is, I think there's an important role of a leukemia center, and I think there's a really fundamental role of keeping somebody in the community they live in, and how we collaborate is the key to that. And we've spent a lot of time and effort working with the oncologists in our community to try to accomplish that.  John, I want to say two other things. I didn't mention in the molecular platforms that NPM1 mutations, we can now target those on clinical trials with menin inhibitors. We know that NPM1 signals through the Hoxa9/Meis1 pathway. We know that similar pathways are important in KMT2A rearrangements. We know that there are some other rare leukemias like those with NUP98 rearrangement. We can target those with menin inhibitors. The first menin inhibitor, revuminib, was approved by the FDA for KMT2A. We have others going to the FDA later this year for NPM1. There are now pivotal trials and advanced expanded phase 1/2 studies that are showing 30% response rates. And we're looking to see can we add those into the first-line therapy. So, we're finding more targets.  I'll say one last thing about molecular medicine. I know I'm a little off topic here, but I always told patients that getting AML was kind of like being struck by lightning. It's not something you did. Now, obviously, there are risk factors for AML, smoking or obesity or certain farm environments, or radioactive exposures and so on. But bit by bit, we're starting to learn about who's predisposed to AML genetically. We've identified really just in the last five or eight years that DDX41 mutations can be germline half the time. And you always think germline mutations are going to cause AML in a younger patient, but the median age is 60 to 70 just like other AMLs. They actually might do pretty well once they get AML. We've reported that in several papers. And so we're trying to understand who that has a RUNX1 mutation needs germline testing, who with a DDX41 needs germline testing. And we're trying to actually come up with a cleaner pathway for germline testing in patients to really understand predisposition, to help with donor selection, to help with family counseling. So I think those are other areas where a leukemia center can contribute for somebody in who's community practice to understand genomic or genetic complexity in these patients. And we're starting to develop the databases that support that. Dr. John Sweetenham: Yeah, great. Thanks, James. I loved your answer about the clinical environment too. And I know from a patient-centric perspective that I know that patients would certainly appreciate the fact that we're in a situation now where the folks taking care of them will make every effort to keep them close to home if they possibly can.  I want to thank you, James, for an incredible review of a very complex subject and I think you did a great job. I think we all will have learned a lot. And thanks again for being willing to share your insights with us today on the ASCO Daily News Podcast. Dr. James Foran: John, it's my pleasure. And as you know, I'll do anything for a latte, so no problem at all. Dr. John Sweetenham: Okay. I owe you one, so thank you for that.  And thank you to our listeners for your time today. You'll find links to the studies we've discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:  Dr. John Sweetenham  Dr. James Foran 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. James Foran: Stock and Other Ownership Interests: Aurinia Pharmaceuticals Consulting or Advisory Role: Peerview, CTI BioPharma Corp, Remix Therapeutics, Cardinal Health, Medscape, Syndax, Autolus Therapeutics Research Funding (Inst.): Chordia Therapeutics, Abbvie, Actinium Pharmaceuticals, Kura Oncology, Sellas Life Sciences, Novartis, Roivant, Celgene/Bristol-Myers Squibb, Astellas Pharma, SERVIER Travel, Accommodations, Expenses: Peerview

In a conversation with CancerNetwork®, Shewetal Mehta, PhD, spoke about her research team's focuses in moving novel brain cancer therapies down the pipeline as part of an early phase clinical trials program at the Ivy Brain Tumor Center. Mehta, the deputy director and pre-clinical core leader at the Ivy Brain Tumor Center of Barrow Neurological Institute in Phoenix, Arizona, underscored a scientifically rigorous, patient-driven philosophy that drives her team members to deliver timely answers to those with brain cancer via work in a clinical lab and a pre-clinical arm. This collaboration helps identify therapeutic agents that may demonstrate activity in the brain while determining patient populations who are suitable to enroll on clinical trials. As part of her institution's early phase trial program, Mehta specifically highlighted work associated with a phase 0/1 clinical trial (NCT06072586) evaluating BDTX-1535, a brain-penetrant fourth-generation EGFR inhibitor, for those with recurrent high-grade glioma harboring oncogenic EGFR alterations or fusions.1 Investigators are incorporating liquid biopsy, sampling cerebrospinal fluid from patients on treatment to monitor potential evolutions or changes in brain tumors. Regarding biomarker testing, Mehta described the roles that gene sequencing and immunohistochemistry can play in identifying targetable alterations in patients with brain cancer. She mentioned vorasidenib (Voranigo), which received approval from the FDA in August 2024, as an example of a targeted therapy that may be suitable for use in patients who are found to have actionable IDH mutations. “Over the last year, we've seen that we were capable of not just doing these early phase clinical trials [but of entering] this phase of moving drugs into phase 3 [studies]. That's exciting,” Mehta stated regarding her outlook on the current state of brain cancer treatment. “Right now, we are excited about these new classes of agents that are within the space, like the proteolysis targeting chimeras, protein degraders, and antibody-drug conjugates, which have shown amazing promise in the rest of the oncology space.” References 1.        Study of BDTX-1535 in recurrent high-grade glioma (HGG) participants with EGFR alterations or fusions. ClinicalTrials.gov. Updated January 15, 2025. Accessed January 15, 2025. https://tinyurl.com/m6kwr2b3 2.        FDA approves vorasidenib for grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation. News release. FDA. August 6, 2024. Accessed January 20, 2025. https://tinyurl.com/25r9fkvy

Dr. Horbinski sits down with me to discuss the complexities of brain tumors and how his work in the Feinberg School of Medicine lab is looking into mutIDH1 and how it dramatically alters the glioma's micro-environmental landscape by preventing the thrombosis-necrosis phenomenon that is characteristic of IDH1 wild-type gliomas. Furthermore, mutIDH1 increases the risk of seizures in patients. He explains why his team's work may improve diagnostic and prognostic accuracy. For methylation profiling patient care and information, please send samples to: Northwestern Department of Pathology. Season Sponsors: GammaTile Therapy Imvax Inc.   Episode Sponsors: Highmark BlueCross BlueShield of WNY Mimivax Inc.

This week Jonathan is joined by Joshua Zeidner, Associate Professor of Medicine, University of North Carolina School of Medicine, USA. Together, they discuss findings from recent research and treatment options for acute myeloid leukaemia and myelodysplastic syndrome. Timestamps:     (00:00)- Introduction    (01:57)- Joshua's love for the New York Giants  (04:28)- Treatment outcomes in IDH1 and IDH2-mutated acute myeloid leukaemia (AML)  (08:05)- Safety and efficacy of new agents in AML  (17:00)- Treatments for patients with AML with a TP53 mutation  (22:02)- Reliance on transfusion in myelodysplastic syndrome (MDS)  (25:44)- The time from research lab to bedside in drugs to treat AML and MDS  (30:50)- Joshua's three wishes for healthcare   (35:13)- Outro   

El Dr. Javier Martín Broto, oncólogo médico del Hospital Universitario Fundación Jiménez Díaz en Madrid, España, presenta un resumen de los estudios que considera más relevantes en el ámbito de sarcomas expuestos durante el Congreso de ESMO 2024. EREMIS: estudio fase II que evaluó el uso de regorafenib como terapia de mantenimiento en sarcomas de partes blandas. Este diseño incluyó pacientes que recibieron previamente seis ciclos de quimioterapia basada en doxorrubicina y lograron al menos una estabilización o una respuesta objetiva. GEIS-52: estudio fase II, el cual es parte de una investigación impulsada por el grupo español de investigación en sarcomas que explora la combinación de sunitinib y nivolumab en pacientes con sarcoma de tejidos blandos. C-800-01: estudio fase I que evaluó botensilimab más balstilimab en una de las cohortes de angiosarcomas y sarcomas. Multisarc: estudio fase II/III, aleatorizado de medicina de precisión en sarcomas avanzados de tejidos blandos para la identificación de alteraciones genéticas accionables. Estudio que evalúa lenvatinib frente a placebo en pacientes con tumores del estroma gastrointestinal en progresión, específicamente en aquellos que han progresado después de recibir al menos tratamientos previos con imatinib y sunitinib. Estudio que analiza olverembatinib en tumores del estroma gastrointestinal de tipo wall type con deficiencia de SDH. En este estudio olverembatinib muestra una actividad superior a la observada con regorafenib y sunitinib en términos de supervivencia libre de progresión. AXAGIST: estudio fase II que evalúa la combinación de avelumab (un inhibidor de PD-L1) y axitinib (un inhibidor de VEGFR) en pacientes con tumores del estroma gastrointestinal avanzados o metastásicos que han progresado después de terapias estándar. 1721MO: estudio que evalua la seguridad y eficacia de olutasidenib, un inhibidor de la mutación IDH1, para el tratamiento del condrosarcoma con mutación IDH1 recurrente/recidivante o localmente avanzado o metastásico. MOTION: estudio fase III, aleatorizado, controlado con placebo y doble ciego de vimseltinib (DCC-3014) para el tratamiento del tumor de células gigantes tenosinoviales.     Fecha de grabación: 10 de octubre de 2024.                            Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente.

El Dr. Elias Ortega Chahla, oncólogo clínico del Instituto de Oncología Ángel H. Roffo en Buenos Aires, Argentina, presenta un resumen de los estudios que considera más relevantes en el ámbito de tumores del sistema nervioso central expuestos durante el Congreso de ESMO 2024. Abstract 440O: estudio en humanos de la vacuna contra el cáncer basada en ARNm CVGBM en pacientes con glioblastoma no metilado MGMT (O-6-metilguanina-ADN metiltransferasa) recién diagnosticado y resecado quirúrgicamente: primeros resultados de la fase de aumento de dosis. Abstract 443O: estudio perioperatorio, abierto de un solo brazo para evaluar la viabilidad, la farmacocinética y la farmacodinamia del tratamiento con safusidenib después de la biopsia y antes de la resección quirúrgica en pacientes con glioma con mutación IDH1 que no han recibido radioterapia ni quimioterapia. Abstract 444O: el objetivo de este estudio fue evaluar el impacto pronóstico de las deleciones heterocigóticas de CDKN2A/B en astrocitomas y oligodendrogliomas de bajo grado con mutación IDH. GLORIA: estudio fase I/II de un solo brazo con aumento de dosis de NOX-A12 en combinación con irradiación en pacientes con glioblastoma de primera línea inoperable o parcialmente resecado con promotor MGMT no metilado con un grupo de expansión de múltiples brazos. Abstract 451: estudio fase Ib/II el cual evalúa GLAS-DHIV, un inhibidor oral que está siendo investigado principalmente en combinación con otros tratamientos como temozolomida en el contexto de glioblastoma de recién diagnóstico. Fecha de grabación: 26 de septiembre de 2024.                      Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente.

In today's episode, supported by Servier Pharmaceuticals, we had the pleasure of speaking with Jennie W. Taylor, MD, MPH, about the FDA approval of vorasidenib (Voranigo) for patients with IDH-positive grade 2 astrocytoma or oligodendroglioma. Dr Taylor is an associate professor of clinical neurology at the University of California, San Francisco (UCSF), as well as the community engagement liaison in the Neurologic Oncology Program at the UCSF Helen Diller Family Comprehensive Cancer Center. On August 6, 2024, the FDA approved vorasidenib for the treatment of adult and pediatric patients at least 12 years of age with grade 2 astrocytoma or oligodendroglioma harboring susceptible IDH1 or IDH2 mutations who have previously undergone surgery including biopsy, sub-total resection, or gross total resection. This regulatory decision was backed by findings from the phase 3 INDIGO trial (NCY04164901), in which, at a median follow-up of 14.0 months (interquartile range [IQR], 10.1-17.9), vorasidenib (n = 168) produced a median progression-free survival of 27.7 months (95% CI, 17.0-not estimated) vs 11.1 months (95% CI, 11.0-13.7) in the placebo arm (n = 163) at a median follow-up of 14.3 months (IQR, 10.0-18.1; HR, 0.39; 95% CI, 0.27-0.56; P < .001). In our exclusive interview, Dr Taylor discussed the significance of this approval, key data from INDIGO, and where vorasidenib fits into the astrocytoma or oligodendroglioma treatment paradigms.

In this episode, we discuss the history of venetoclax in AML, along with key clinical trials that have shaped its current use in AML. Here are the trials discussed in this episode: 1. VIALE-A study: https://www.nejm.org/doi/full/10.1056/NEJMoa20129712. 10 day Decitabine plus venetoclax for ND AML https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(20)30210-6/abstract3. Genetic Risk Stratification and Outcomes with AML treated with venetoclax and azacitidine https://ashpublications-org.proxy.library.vanderbilt.edu/blood/article/doi/10.1182/blood.2024024944/517355/Genetic-Risk-Stratification-and-Outcomes-Among4. Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations https://ashpublications-org.proxy.library.vanderbilt.edu/blood/article/doi/10.1182/blood.2024025409/517356/Genetic-risk-classification-for-adults-with-AML5. AGILE study: Ivosidenib and azacitidine in IDH1-mutated AML https://www.nejm.org/doi/full/10.1056/NEJMoa21173446. MRD response and prognosis in treatment naïve AML with AZA/VEN https://ascopubs.org/doi/10.1200/JCO.21.01546?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed7. Monocytic subclone confer resistance to venetoclax-based therapy in patients with AML https://aacrjournals.org/cancerdiscovery/article/10/4/536/2403/Monocytic-Subclones-Confer-Resistance-to8. VEN/DEC vs 7+3 https://ashpublications.org/blood/article/142/Supplement%201/970/503790/Comparing-the-Efficacy-and-Safety-of-Venetoclax9. FILO study: Outcomes of AML  https://onlinelibrary.wiley.com/doi/10.1002/ajh.2741710. Treatment-free remission after ceasing venetoclax-based therapy in patients with AML https://ashpublications-org.proxy.library.vanderbilt.edu/bloodadvances/article/6/13/3879/485175/Treatment-free-remission-after-ceasing-venetoclax11. Targeting molecular MRD and low-blast relapse in AML with Venetoclax and LDAC (VALDAC) https://ascopubs-org.proxy.library.vanderbilt.edu/doi/10.1200/JCO.23.01599?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed12. INTERCEPT trial: https://ashpublications.org/blood/article/140/Supplement%201/3341/492722/ALLG-AMLM26-Phase-1B-2-Study-Investigating-Novel

Featuring slide presentations and related discussion from Dr Lipika Goyal, Dr James J Harding, Dr Milind Javle and Dr Robin K (Katie) Kelley, including the following topics: Current Role of Immunotherapeutic Strategies for Advanced Biliary Tract Cancers (BTCs) — Dr Kelley (0:00) Case: A man in his late 60s with advanced distal cholangiocarcinoma treated with the TOPAZ-1 regimen (13:27) Case: A woman in her early 70s with recurrent gallbladder cancer with biliary obstruction (15:56) Targeting FGFR and IDH Alterations for Advanced BTCs — Dr Goyal (35:00) Case: A woman in her late 30s with FGFR2 fusion-positive intrahepatic cholangiocarcinoma (ICC) (54:25) Case: A man in his late 60s with cholangiocarcinoma metastases to liver and bone (1:01:33) Case: A woman in her 60s with ICC with an IDH1 mutation (1:10:05) Emerging Role of HER2-Targeted Therapy for Advanced BTCs — Dr Harding (1:21:15) Case: A man in his early 40s with cholangiocarcinoma metastatic to the appendix (1:57:25) New Directions in the Management of BTCs — Dr Javle (2:01:09) CME information and select publications

In this episode, listen to Professor Eunice S. Wang, MD, share her clinical insights and takeaways on new data for acute myeloid leukemia (AML) presented at the 2024 ASCO annual meeting and the EHA 2024 Congress including:Data from the prospective, single-center phase Ib/II study of FLAG-IDA plus venetoclax in newly diagnosed or relapsed/refractory AML Phase I/II study of oral decitabine/cedazuridine with venetoclax and gilteritinib in patients with newly diagnosed and relapsed/refractory FLT3-mutant AMLA retrospective comparison of abbreviated course 7+7 vs standard HMA plus venetoclax doublet in older/unfit patients with newly diagnosed AML Multisite randomized trial of a collaborative palliative and oncology care model for patients with AML and myelodysplastic syndromes (MDS) receiving nonintensive therapyFinal 5-year results from the phase II pivotal cohort of olutasidenib for IDH1-mutated AML Post hoc analyses of outcomes in patients with AML and MDS-related changes who received oral azacitidine maintenance therapy in the phase III QUAZAR AML-001 studyFirst-in-human phase I/II of the menin-MLL inhibitor DSP-5336 in patients with R/R acute leukemia: updated results from the dose escalation phase A phase Ib study of the menin-KMT2A inhibitor bleximenib in combination with venetoclax and azacitidine in R/R AML with alterations in KMT2A or NPM1 Program faculty:Eunice S. Wang, MDChief, Leukemia and Benign Hematology ServiceProfessor of OncologyRoswell Park Comprehensive Cancer CenterBuffalo, New YorkCourtney DiNardo, MD, MSCEProfessor of MedicineDepartment of LeukemiaMD Anderson Cancer CenterHouston, TexasResources:To download the slides associated with this podcast discussion, please visit the program page:https://bit.ly/4bvJGij

JCO PO author Dr. Jun Gong shares insights into his JCO PO articles, “Phase II Study of Erdafitinib in Patients with Tumors with FGFR Amplifications: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol K1" and “Phase II Study of Erdafitinib in Patients with Tumors with FGFR Mutations or Fusions: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol K2”. Host Dr. Rafeh Naqash and Dr. Gong discuss the limited activity of FGFR inhibition in solid tumors with FGFR amplifications and mutations or fusions in this NCI-MATCH phase II trial. TRANSCRIPT  Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the Stevenson Cancer Center at the University of Oklahoma.  Today, we are excited to be joined by Dr. Jun Gong, Associate Professor in the Division of Medical Oncology at Cedars-Sinai Medical Center and lead author of the JCO Precision Oncology article entitled "Phase II Study of Erdafitinib in Patients with Tumors Harboring FGFR Amplifications: Results from the NCI-MATCH ECOG-ACRIN Trial EAY131 Subprotocol K1" and "Phase II Study of Erdafitinib in Patients with Tumors with FGFR Mutations or Fusions: Results from the NCI-MATCH ECOG-ACRIN Trial EAY131 Subprotocol K2."   Our guest's disclosures will be linked in the transcript.   Dr. Gong, welcome to our podcast and thank you for joining us.  Dr. Jun Gong: Thank you, Dr. Naqash and JCO Precision Oncology for having me. Dr. Rafeh Naqash: We are excited to be discussing some interesting aspects that you have led and published on from the NCI-MATCH trial. We were trying to understand from a background perspective, since this master protocol has been going on for quite some time, could you give us a little bit of background for the sake of our listeners on what the NCI-MATCH is and what were the specific objectives for these two subprotocols?  Dr. Jun Gong: Yes, of course, Dr. Naqash. So, as you may all know, the importance of targeted therapies in the current era of precision oncology. And on that backdrop, the NCI-MATCH was a national multicenter study designed essentially to look for signals of efficacy across various solid tumor and hematologic malignancy types, with a focus on specific mutations. The master protocol is unique in that there are several arms to the trial, each targeting a specific potential targetable alteration using available agents in cancer today. Dr. Rafeh Naqash: Excellent. Thank you for that background. I know this master protocol has been going on for quite some time with different subprotocols. I believe some of them are immunotherapy-based. Also, you've led two important subprotocols, which are the FGFR amplification and the FGFR mutation or fusion. There are some differences, from what I gather, in responses for the fusions versus the amplifications or mutations versus the amplifications. Could you first delve into the first paper of the fusions, and describe what were the tumor types? As you mentioned in the paper, some tumors were excluded. What was the reason for the exclusion of some of those tumor types? Why did you want to study the fusions and mutations versus the amplifications separately? What was the background for that? Could you highlight some of those points for us? Dr. Jun Gong: Firstly, as a kind of a more background, FGFR has been a recognizable target for a couple of tumor types. And if you look at the broad landscape of FGFR alterations, they occur in about 5%-10% of cancers, with the majority being FGFR amplifications actually, and mutations and rearrangements following second and third respectively in most commonly identified alterations. With that being said, FGFR mutations and rearrangements have already been established in a couple of tumor types. Actually, the first FDA approval for an oral FGFR inhibitor was erdafitinib, which was the agent used in both of these back-to-back trials. However, erdafitinib was first approved in urothelial carcinoma, and since then, there has been an explosion in oral FGFR inhibitors targeting fusions and mutations in other cancer types, such as cholangiocarcinoma.   More recently, there was even an FDA approval in a myeloid malignancy as well. So, we used erdafitinib, being that it was the first FDA-approved, orally available agent to target this alteration. We conducted the two back-to-back studies in recognition that although rearrangements and mutations have already been established in certain tumor types, we were more interested in looking at the more common FGFR alteration, that being amplifications. However, the efficacy in that was a little unknown, and so these two separate subprotocols were developed: K2, which was to look at FGFR mutations and fusions in tumor types, excluding urothelial carcinoma, to look if there was a signal of efficacy beyond currently FDA-approved indications, and amplification as a separate cohort. Dr. Rafeh Naqash: That's a very good explanation of why you concentrated on the tumor types in these protocols.  Now, going back to subprotocol K1, could you tell us what were some of the tumor types that you did include, and what was the sample size, and what was the hypothesis for the sample size as a meaningful level of activity that you wanted to see and would have potentially led to a bigger, broader trial? Dr. Jun Gong: So, subprotocol K1 was the arm investigating erdafitinib in those with FGFR amplifications, and these were predefined on the NCI-MATCH protocol, looking at FGFR 1, 2, 3, and 4 amplifications essentially. These were allowed to have local testing through a local CLIA-certified assay, but then they needed to be confirmed on a central assay, which is the NCI-MATCH Oncomine assay. These statistics are uniform for the NCI-MATCH trials, and the goal was at least 31 patients, with the hypothesis that if the response rate was 16% or more, this was considered a signal of activity. However, there was an additional protocol specific requirement in that if the sample size was fewer than 31 patients, then the primary efficacy population would be assessed against a null hypothesis overall response rate of 5%. Meaning that if there were less than 31 subjects, an overall response rate of greater than 5% would be defined as positive. Again, the NCI-MATCH was uniform. Secondary objectives included progression-free survival, overall survival, and safety and toxicity. With that being said, K1 originally began accrual. The NCI-MATCH actually launched in 2015, but in the subprotocol K1, 35 patients were initially enrolled in the study. If you go down the eligibility criteria, however, a lot of these patients dropped out due to a lack of central tumor confirmation and various reasons. Ultimately, 18 patients were included in the pre-specified primary efficacy cohort. Dr. Rafeh Naqash: Thank you. I did see for subprotocol K1, you mostly had stable disease in a couple of patients, no responses, and I think one individual with breast cancer had a prolonged stable disease.   Now, from an FGFR amplification standpoint, did you or were you able to correlate - again, this is not objective responses, it's not a partial response or a complete response - was there any correlation from the level of amplification to the duration of stable disease?  Dr. Jun Gong: That's actually the core of our discussion about why K1, despite a variety basket of solid tumor types, somewhere, preclinical data had suggested FGFR amplifications could be targeted, that K1 was ultimately a negative trial with a 0% response rate. We dive in that although we included as an eligibility criteria a copy number variation of seven as the threshold for amplification, we realized that if you look at some of the literature out there, that even in the FGFR 1 and 2 amplification cohorts, where these are the more common cohorts of amplified tumor types that have been targeted, you really needed a high level of amplification, more than 99% of tumor cells being amplified in the previous studies, to actually generate a response.  The thought was that we assumed that FGFR amplification would lead to protein expression and dependence on FGFR signaling, providing sensitivity to FGFR inhibition. However, we realized that there is a certain degree where a high level of amplification needs to happen, and it may not be for all FGFR amplifications. We looked into the literature that FGFR 1 and 2 were the more commonly studied FGFR amplifications. FGFR 1, if you actually look at the amplicon structure, it tends to amplify a lot of other genes because it's such a huge amplicon structure. But FGFR 2 is shorter and centered on just FGFR 2 with a few other genes co-amplified. So, actually in the literature, they've already been seeing that maybe FGFR 2 amplification tumors are more readily targetable based on the robustness of evidence, rather than FGFR 1. But across all of these, the higher the level of amplification, seems the more targetable. Dr. Rafeh Naqash: Those are interesting discussions around protein expression on the tumor that could imply therapeutic vulnerability. So I've always thought about it, whether trials like NCI-MATCH trials or ASCO TAPUR, for example, would be perhaps more informative if, on a secondary analysis standpoint, proteomics is something that could be done on the tumor tissue, because similar to NCI-MATCH, ASCO TAPUR has other sub protocols where some of these mutations or amplifications don't necessarily result in antitumor responses. But I think from a biology standpoint, as you mentioned, a certain amplification might correspond to RNA expression and that might correspond to protein expression, which is downstream. So looking at that would be something interesting. Have you planned for something like that on these tumor specimens? If you have biobanked any of those specimens. Dr. Jun Gong: I think that's a great future direction. And I know you, Dr. Naqash, being involved in so many cooperative trials, I think it is possible, but it really depends on good trial planning from the onset. When designing such massive trials like this, I think the more important thing is if your trials are negative, but they are informative for the field to go back and have these postdoc available biobanks that you said. And I think having it integrated firstly, is way more efficient than to have kind of an amendment kind of going through halfway or when the trial is started. That could be a little bit more logistically difficult.  Dr. Rafeh Naqash: I completely agree. And you mentioned corporate groups, I think we've been discussing, and I'm pretty sure you have also, there's a lot to be learned from clinical trials that are negative. We often, in the academic or non-academic setting, end up not publishing some of those negative results, pharma or corporate group based studies. And I think the resources, the specimens, and the negative results could correlate to some other novel findings if some of those exploratory analyses are done in the appropriate manner.   Now, going to the drug itself or the erdafitinib here, it's a pan-FGFR inhibitor. Is that something that you think is a limitation in the drug development space? I do early phase trials, and I'm pretty sure you do a lot of these basket early phase trials. Is that something that you feel is a limitation when you have a drug that targets different mutations or different protein changes of the same gene or different amplifications? Could that be a reason why something like this doesn't necessarily work because it doesn't have as much specificity against the isoform as one might need to inhibit the downstream kinase activation?  Dr. Jun Gong: That is also a great point. The NCI-MATCH sub protocol K1 and K2 used erdafitinib, which was the first FDA-approved FGFR inhibitor. But as many of the listeners and yourself may know, there have been newer iterations in next-generation development of the FGFR inhibitors. And it's very fascinating, the tyrosine kinase inhibitors, with each iteration, you seem to have a little more potency and the ability to bypass some of the resistance mutations, almost paralleling the lung cancer space, where we kind of follow that, and they've been kind of the pioneers in that space. And to your point, yes, we consider– the NCI-MATCH was developed nearly a decade ago, and the available agents at that time, would it have changed the findings if we used a kind of a newer generation or more potent FGFR inhibitor? It's possible, I think, especially in the K1 cohort with the amplifications. We even suggested in the discussion of the paper future directions, is that one way to kind of bypass the amplification issue is to use more potent and specific FGFR inhibitors. And so I think it's very possible that you highlight this point.  Dr. Rafeh Naqash: And for the sake of our listeners, Jun, especially trainees, could you highlight what are currently some of the FDA-approved FGFR inhibitors, and what tumor types are they currently approved in?  Dr. Jun Gong: The first one, as we have hinted, was in treatment of refractory, essentially urothelial carcinoma with FGFR mutations and rearrangements, mainly 2 and 3. And this is where oral erdafitinib was approved. And it's interesting, I kind of teach my fellows and our health staff that erdafitinib is interesting in that its FDA label insert requires a starting dose of about 8 milligrams daily, and it's a 28-day cycle. But during the first 14 days, we're really looking at the serum phosphate levels. If they are within a certain level, if they are within 5.5 to 7, for example, you continue the current dose. But if they are less than 5.5, the FDA label actually mandates that you increase it to 9 milligrams oral daily, continuously. This is biologically logical to me. FGFR is located to the renal tubules, and so this is a major phosphate kind of metabolism pathway here. And so you're using that as a surrogate, essentially, if the right dosing is achieved. And so that's unique.  And then the subsequent kind of FGFR inhibitors that came about, you had a couple in cholangiocarcinoma, where, unlike urothelial carcinoma, where it's about 30% of the time, you'll find the FGFR alterations of target. It's about half of that 15% in cholangiocarcinoma, and it's mainly intrahepatic cholangiocarcinoma in that sense. And here you have pemigatinib, which is one of the FGFR inhibitors approved for cholangiocarcinoma. And then you also had infragatinib, which is approved. But however, infigratinib eventually had their FDA label culled. It was withdrawn by the company, I think it was in 2022. And then more recently, you had even a more potent FGFR inhibitor in cholangio approved and futibatinib. It's interesting that with these more later generations of FGFR inhibitors, they do show a correlation with phosphate levels, but they don't have that specific kind of dosing early on in the first cycle, like erdafitinib. And so it's interesting to see that with the later generations, you're seeing more potency as well. Dr. Rafeh Naqash: Thank you for that overview, which I'm sure most of the trainees appreciate since this is an up and coming field in the space of precision medicine, especially FGFR. From a side-effect profile standpoint, you mentioned phosphate issues. Do you think that is a drug class effect here, or is that an FGFR receptor subtype effect, depending on which FGFR receptor, 1 or 2 or 3, that is being targeted?  Dr. Jun Gong: I do think this is a class effect that you'll see across a lot of the trials where phosphorus elevations or decreases are going to be probably your most common treatment-related adverse event. And I actually emphasize this is probably one of the most trickier side effects of this class, where we're almost having to have to monitor the phosphorus levels pretty routinely, pretty closely. And you also have other class effects on the nails. There's some rare retinal ocular toxicities that's unique to the FGFR class as well. And so it's a very exciting class of compounds, but it does require some close monitoring of some unique class effects as you've hinted. Dr. Rafeh Naqash: Based on the results from your K1 sub protocol, are FGFR inhibitors still the approach within, let's say, within cholangio or urothelial with FGFR amplifications? Is that still something that has been established and seen from a clinical response standpoint? Dr. Jun Gong: The FDA approvals are really for mutations and fusions. So this K1 sub protocol, essentially, I think provides one answer that we've been all wondering about for the longest time, “Hey, could amplifications be targeted as well?” Unfortunately, we didn't include urothelial carcinomas in this study because of the FDA approval. But from a kind of a basket solid tumor perspective, I think this really dampens the enthusiasm. As of right now, it really is fusions and mutations that are targetable. Amplifications need further investigation before becoming established in solid tumors. Dr. Rafeh Naqash: Going to the discussion with the second K2 protocol, which is mutations and fusions, can you highlight again which tumor types there where you saw some clinical outcomes that you saw and any unique insights on certain mutations or protein changes that were a little more relevant than some others?  Dr. Jun Gong: Sure. So this is the parallel study to K1, in that now we are looking at fusions and mutations of FGFR1, 2, 3, and 4. And essentially, we, again, excluded those with urothelial carcinoma, given the FDA approval for erdafitinib in this trial. The trial actually opened then the FDA approvals for the FGFR inhibitors for cholangiocarcinoma happened. So this trial didn't really exclude those with FGFR mutated or rearranged cholangiocarcinoma as well. If you look at the breakdown of the cohort in K2, you saw a good mix of breast cancers or a couple of gynecologic malignancies. There were a couple of head and neck cancers. There were several brain tumors as well. There was one lung cancer. There were four noted intrahepatic cholangiocarcinomas. Again, we could not exclude those due to the fact that the trial had opened and was accruing when the FGFR inhibitors approved for cholangiocarcinoma happened. Similar design, with a phase II, single-arm, open-label of erdafitinib, and again, the same statistical design was implemented in that if it's higher than 31 patients, 16% overall response rate was a primary endpoint goal. If it was less than that, it was against the 5% overall response rate.   And here in K2, 35 patients were enrolled and 25 patients were ultimately included in the primary efficacy analysis. So because it was fewer than 31 in the primary efficacy cohort, it followed the NCI-MATCH to be specified with a primary endpoint goal of 5% or higher. And here, in a heavily pre-treated cohort of more than 50% of subjects who have received prior than 3 or higher lines of therapy, overall response rate essentially confirmed was 16% with the p value of 0.034, which met the positivity cutoff of 5%. However, an additional seven patients experienced stable disease as best confirmed response. And it's important to note that four of these were grade IV glioblastomas with prolonged progression-free survival. So ultimately, this trial was positive in reading the endpoint that outside of urothelial carcinoma, could FGFR inhibition be pursued in other tumor types that had FGFR rearrangements or fusions? Dr. Rafeh Naqash: You mentioned glioblastoma, which is an area of huge unmet need. Do you think a trial like this as an upfront approach in glioblastoma, perhaps maybe after Temodar, could be a more meaningful way using the strongest, more precise therapy earlier on when there are certain mechanisms that inhibition of which would result in anti-tumor responses? Do you think doing this earlier on rather than second, third, fourth line would be more intriguing in some ways?  Dr. Jun Gong: I think you've hit upon several key points there. Firstly, just a high unmet need in glioblastomas, in general. And then to us, although it was a stable disease it was quite noticeable that four of these occurred in IDH1 and 2 wild-type brain tumors. We kind of discussed that in the discussion as well. And of these, we actually realized that in the pre-clinical and other published literatures space that for some reason, IDH1 and wild-type tended to have more FGFR alterations, while 0% were found in IDH1 and 2 mutant high grade gliomas. So I think there is something hypothesis generating coming out of this study as well even though there were stable disease. And that you may be selecting for– We may be able to have future studies to select for a specific niche of glioblastomas. And as to your point, Dr. Naqash, I think  if we can have a design trial looking for these specific molecular subsets, I think it's wide open for trials of this nature in the first line, second line, or refractory space. Even piggybacking into cholangiocarcinoma, you see, they're now looking at these in the neoadjuvant and adjuvant space as well. So I think we can identify the subset - it's wide open out there. Dr. Rafeh Naqash: I completely agree. I remember my program director a few years back when immunotherapy was in the metastatic setting, it was very exciting. He gave a talk in which he said "Early, earlier, earliest," and the more early, the better it seems. So I'm guessing that it's probably something similar for precision medicine-based approaches like targeting FGFR perhaps earlier.   So what is next for some of these two studies, or these ideas that have come out of these two studies? Are you trying to develop something subsequently, or is NCI-MATCH looking at it from a certain perspective? Or what would you want to do as a next step, ideally if you had the funding and the pharma support? Dr. Jun Gong: That's the million dollar question. So just from the broad strokes, I think what these two back to back papers and studies comment is that amplifications may not be the more targetable of FGFR subset, but there is avenue for improvement there and further investigation. FGFR fusions and mutations however seem to go along with what we know in some of the FDA approved types now. Now the next step is in the area of precision oncology is could we expand the label indications now to other subtypes with FGFR fusions and mutations. And this is I think following precedent. You and the audience may know that there are a lot of different tumor agnostic approvals now for both immunotherapy and other targeted therapy types. So I think the goal of this study was to provide momentum for, perhaps, advancements into a tumor agnostic indication for FGFR inhibitors.  And we do cite in the K2 manuscript the results of a phase II study that was also published around the time we were writing the study up. It was the phase II RAGNAR study. And that enrolled patients, again, with FGFR fusions and mutations. And that trial was positive, too. That one was a larger study of 217 subjects. We highlight some differences in study populations as to why maybe the difference in responders were detected. Both were positive studies. It was reassuring that the overall survival impulse studies were about the same. And again, I think they don't compete. I rather think they complement each other in providing this body of evidence that  may meet- at one point, the FDA should be approached with this evidence for a tumor agnostic mutation so that more patients with this subset could be benefitting.  Dr. Rafeh Naqash: Excellent. Thank you so much, Jun.  Now, could you tell us briefly what your background is, where you've trained, and your interests, and how you balance clinical research with some of your personal interests?  Dr. Jun Gong: Sure. Thank you for that interest. I did my training in medical school in New York. I went to New York Medical College. And then I did my residency at Cedars-Sinai for medicine. And I went to City of Hope for fellowship where I was trained in GU by Dr. Monty Powell who maybe you folks are familiar with. And my GI training was with Dr. Fakih at City of Hope. And since then I returned back to Cedars-Sinai where I serve as a dual GI/GU focused medical oncologist. I do clinical trials in both and translational science, really focused on targeting tumor metabolism in both as well. My advice to the listeners and trainees and I tell my own fellows this, I think it's very rare now unless you're in phase I to do a dual focus. So I actually emphasized to my trainees that the more focused you can be, the better. Unless you are going into phase I, for example. With that, you can hone in, develop your craft. But then again, I have known several mentors who do multiple tumor types. But I think the more traditional mechanism is to focus as much as you can is my advice for the listeners.  Dr. Rafeh Naqash: Thank you again, Jun, for all those interesting scientific and personal insights. We appreciate you and working with JCO Precision Oncology for both of your manuscripts. This is the first time we have ever invited a lead author for two manuscripts at the same time. It's always good to be the first in something, and I learned a lot and hopefully, our audience would have learned a lot. Dr. Jun Gong: Thank you, Dr. Naqash, for having me. It was a pleasure speaking with you and the crew. Dr. Rafeh Naqash: Thank you.   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, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Drs. Shaalan Beg and Aparna Parikh discuss the role of ctDNA as a powerful prognostic biomarker for GI cancers, along with its impact on risk stratification and the detection of recurrence. They highlight key studies in ctDNA that were featured at the 2024 ASCO GI Cancers Symposium, including COBRA, GALAXY, and BESPOKE in CRC, as well as the promise of ctDNA testing in the preoperative detection of iCCA. TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Shaalan Beg, your guest host for the ASCO Daily News Podcast today. I am an adjunct associate professor at UT Southwestern's Harold Simmons Comprehensive Cancer Center in Dallas. On today's episode, we will be discussing the emergence of circulating tumor DNA (ctDNA) technology in GI cancers. I am delighted to be joined by Dr. Aparna Parikh, an assistant professor of medicine at Harvard University and the director for colorectal medical oncology at the Massachusetts General Hospital Cancer Center, where she also serves as the medical director of the Young Adult Colorectal Cancer Center. Dr. Parikh will share her insights on key research on this hot topic in GI oncology that was featured at the recent ASCO Gastrointestinal Cancers Symposium.  Our full disclosures are available in the transcripts of this episode, and disclosures related to all episodes of the podcast are available at asco.org/DNpod.  Dr. Parikh, it's great to have you on the podcast today. Dr. Aparna Parikh: Thanks so much, Dr. Beg.  Dr. Shaalan Beg: In recent years, it has become evident that liquid biopsy and other emerging ctDNA technologies are changing how we treat GI cancers, and colorectal cancer (CRC) is in the forefront of this space. Before we dive into key studies, can you briefly highlight for our listeners how ctDNA is advancing the field and how it can influence the care that we deliver to our patients in the future? Dr. Aparna Parikh: Absolutely, ctDNA is certainly a hot topic. What we have learned over the years is that ctDNA has emerged across many solid tumor types as one of the most powerful, if not the most powerful, prognostic biomarker we have to date. ctDNA has improved risk stratification. We have learned a lot about the role in what is called minimal or molecular residual disease in patients with early-stage disease, and ctDNA being a biomarker of recurrence for those patients, with ctDNA, we have a better understanding of tumoral heterogeneity, both spatially and temporally, getting a better glimpse of what is happening in a given patient with multiple metastases, as well as genomic evolution of tumors over time. So certainly many, many roles and areas where ctDNA is emerging. Dr. Shaalan Beg: This was a hot topic at the 2024 ASCO GI Cancers Symposium, and we're going to take a deep dive into some of the abstracts that were presented. Let's start with the COBRA study, which is the NRG-GI005. That was Abstract 5 at the ASCO GI Cancers Symposium, and the GALAXY study, which was Abstract 6 at the symposium. So, the COBRA study reported results of ctDNA as a predictive biomarker in adjuvant chemotherapy for people with colon cancer. At a high level, it was a negative study, but there are some important lessons for us to learn. Similarly, in the GALAXY study, investigators from Japan presented an updated analysis on the correlation of ctDNA dynamics with outcomes in colorectal cancer with minimal residual disease. How do you synthesize all this information and help the listeners understand our current state for ctDNA applications in colorectal cancer? Dr. Aparna Parikh: Yeah. Let's take the COBRA study first. Let's talk a little bit about the design of COBRA. COBRA was intended to look at patients that were resected, stage 2 colorectal cancer patients, or colon cancer patients who were 2A. These are patients where the treating physician would, at the outset, decide that there was no adjuvant chemotherapy indicated. These are patients where active surveillance would be entirely appropriate as the standard of care. Patients were randomized to arm 1, which was active surveillance, or randomized to arm 2, which was assay-directed therapy. If there were ctDNA positive in arm 2, then they were given chemotherapy, FOLFOX or CAPOX. And if they were “ctDNA not detected,” then they would also go on to active surveillance.   And so, the plan was that nearly 1,500 patients are to be recruited, and at the time of this data cut, they had around 630-some patients. The primary objective was to look at the clearance rates of ctDNA between the ctDNA-positive cohorts, remember, the chemotherapy and the active surveillance cohorts at 6 months. They had around a 5% detection rate of ctDNA patients. Ultimately, that was around 16 patients. The reason that the study shut down was that what they found was that in the surveillance arm, the arm that was not getting any treatment, they had a ctDNA clearance of 43% versus 11% in the chemotherapy arm. They had an interim analysis to look at the clearance rate between the 2 arms, and what was surprising to the investigators and the community was what was happening in terms of clearance. Why do we have a 43% clearance rate in patients that were not getting anything? And so, because of that, the study was shut down as it did not meet its prespecified interim look at clearance in those 2 arms.   Many things came up in terms of learnings from COBRA. Number one was the characteristics of the assay. And so, you take an assay in a low-risk patient population that has a fixed specificity, and when your baseline prevalence of recurrence is so low, for example, in low-risk stage 2 patients, your composite predictive value is very susceptible to small changes in that specificity. And so, your PPV is going to be a lot lower in a low-risk patient population than a higher-risk patient population. The COBRA study used an older version of a tumor-uninformed assay, so it definitely called into question some characteristics of the assay. Is one-time-point clearance sufficient, and is that the right endpoint? We have seen now, including the GALAXY study that we'll talk about here, previously reported just spontaneous clearance happening in 5%, 10% of patients. The question with that spontaneous clearance is: Was it actually clearance, or was chemotherapy just perhaps in a low ctDNA shedding state? Are you just suppressing the ctDNA below the level of limited detection?  And then in this study, the clearance draw was actually done in the chemotherapy arm right before the last cycle of chemotherapy, again to that point of, are you just suppressing the ctDNA with chemotherapy? There is also stochastic sampling error that can happen in patients with very low residual tumor volume. So, I think this is a disappointing study in the sense that it is still a really important question. There are still 2A patients that recur, but maybe [this was] not the right test, or maybe single-time-point testing wasn't enough. And so, lots of lessons to be learned from this study in terms of test and design, but hopefully more to come. I think certainly stage 2 patients remain an area where I think, hopefully, ctDNA still plays a factor for those patients.  Dr. Shaalan Beg: And how was the patient population for the GALAXY study? That was Abstract 6, compared to the COBRA study. Could you summarize those findings for us?  Dr. Aparna Parikh: Yeah, so GALAXY was part of a large study in Japan that includes an observational cohort plus therapeutic cohorts as well. And so, GALAXY was just further reporting of the observational cohort. So unlike COBRA, which is a low-risk, stage 2 study that was actually asking that interventional question: Can you use it to guide therapy? The GALAXY and the updated GALAXY just continues to show more clinical validity data rather than clinical utility data. And it was nearly 3,000 patients, pan stages. Again, the lion's share were stage 2 and 3 patients, but there were also stage 1 and stage 4 patients as well. And what they showed was that ctDNA is undoubtedly prognostic. They showed very consistent Kaplan-Meier curves, which we've seen time and time again, where if you're ctDNA-positive, you don't do as well.  What they showed was, not surprisingly, with longer-term follow-up – this is 24-month follow up, so longer-term follow up than was published in their paper last year – was that when you test at one time point, so landmark testing, the sensitivity of detecting recurrence was around 48%, and that fell from the publication last year which was around 58%, 59%, which is not surprising as you follow more people. I think single time point testing soon after surgery may miss those late recurrences, but it's still prognostic and showed a specificity of around 94%.   They also continued to show that if you continued to test with serial testing, your sensitivity improves, but what was really interesting and new, what they presented this time, was a clearance analysis. And showing, again, comparable to COBRA, in many ways, in the sense that clearance can be a little bit finicky, especially at one time point, is what they showed is that patients who had sustained clearance, and these are patients that had at least two time points with their ctDNA remained to be negative, they did very well. But if you had transient clearance, and again, the definition was a little bit broad, at least having one negative and then one positive, those patients ultimately, at 24 months, the curves came together with the no clearance curve. So initially, they did better than the people that didn't have any clearance. But if you transiently cleared at two years, the curves came back together.   And what was interesting is that in those patients that sort of transiently clear by 9 to 12 months, 80% of those are actually having a rapid return of ctDNA. And so this begs the question of was chemotherapy just suppressing that ctDNA or maybe if you have a better test you could have actually improved it.  These were some of the updated, interesting learnings from GALAXY, which remains incredibly prognostic. And then the concept of clearance, which I think we have to look into a little bit more as a field, and understanding that maybe just one time point clearance isn't sufficient.  Dr. Shaalan Beg: Yeah, and one of the most important applications for ctDNA can be its ability to inform adjuvant chemotherapy. Its ability to not only identify more people who may benefit from chemotherapy, but maybe even identify people who don't need chemotherapy. And along those lines, Abstract 9, the BESPOKE study, looked to understand the role of ctDNA-based detection of molecular residual disease to inform adjuvant therapy for stage 2 and 3 colorectal cancer. And they presented interim data at the GI ASCO this year. What were your takeaways from this study? Dr. Aparna Parikh: Exactly. Beyond the prognostic implications, I think what was really interesting was that there was the initial data looking at the benefit of adjuvant chemotherapy. So, what they did was they said, “Okay. We're going to take the MRD-positive patients and look at the benefit of adjuvant chemotherapy and then the benefit of adjuvant chemotherapy in the MRD-negative patients.” And again, remember, this is a prospective observational study, so it's not looking at negative and positive to guide therapy, but it's just looking prospectively and observationally at how those patients are doing. But what they showed again is that indeed, in the adjuvant chemotherapy group, the benefit of adjuvant chemotherapy again with the follow-up to date on the study was different in the MRD-positive patients.  First of all, I guess taking a step back, the DFS in the ctDNA-negative patients at 2 years was very good. So negative patients had over 98% 2-year DFS in both the adjuvant chemotherapy and observational group. And there was no real difference between adjuvant or not. But in the positive patients, not surprisingly, the DFS was worse. But what was reassuring to see is that you can make an impact with adjuvant chemotherapy in the positive patients. And the difference in DFS between the positive and negative patients, with adjuvant or not, was 42% versus 12.5%, in the observational patients. So, it is benefitting the patients who are positive so it does give us more data that, again, at least in the positive patients, you may be able to reverse the recurrences there with adjuvant chemotherapy. And maybe if you're negative, eventually, we'll get to a point of de-escalation of care. Again, keeping in mind the kinds of sensitivity limitations as well.  Dr. Shaalan Beg: Wonderful. And one of the other malignancies in the GI space where precision therapies and molecular biomarkers are making a huge difference are intrahepatic cholangiocarcinoma. Genomic profiling using ctDNA is increasingly being used in this population to inform precision oncology approaches and determine mechanisms of resistance to targeted therapies as well. In Abstract 528, investigators looked at the role of preoperative ctDNA testing for resectable intrahepatic cholangiocarcinoma. What are your thoughts on that study?  Dr. Aparna Parikh: Yeah, it's such an important area, as you mentioned, in the metastatic space – FGFR, IDH1, all these alterations that are emerging in intrahepatic cholangios. This was a very small study, it was preoperative, and so the tumor was intact, and around 14 patients. They used a tumor-informed approach just for detection and quantification of ctDNA. So this was not a study that was looking at a next-generation sequencing approach where you're going to actually be able to detect the alterations, but it's actually looking for the detection and quantification of ctDNA rather than genomic characterizations. And patients had about a month or so where they had their baseline blood detected. And I think what was reassuring to say was that ctDNA was actually detected in all the patients with the primary tumor intact, except for one patient who was a very low-risk stage 1A patient. There was some correlation, against a small number of patients, between the concentration of ctDNA in patients that had the lower stage and then the higher stage groups. Small numbers were actually hard to characterize and correlate with recurrence or mortality, but at least, some correlation with pathologic tumor size, they were able to because it was a bespoke panel and you're sampling the tissue and then looking in the blood, IDH1 and 2 were mutations that were tracked based on the genomic profiling and a couple of the patients were able to have their IDH mutations tracked.  So it gives us a sense, a little bit, that ctDNA, we know has a lot of variable shedding across disease states and tumor locations, but gives us some promise that it is reliably detected with the tumor-informed approach, at least preoperatively in cholangios. So may again open some more opportunities for MRD testing in cholangiocarcinoma as well.  Dr. Shaalan Beg: Thank you. That's a wonderful review of ctDNA applications in gastrointestinal cancers from the 2024 ASCO GI Cancers Symposium. Thank you, Dr. Parikh, for sharing your valuable insights with us on the podcast today. Dr. Aparna Parikh: Thank you so much for having me. Dr. Shaalan Beg: Thank you to our listeners for your time today. You'll find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclaimer: The purpose of this podcast is to educate and 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. Aparna Parikh @aparna1024   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals   Dr. Aparna Parikh: Consulting or Advisory Role (An Immediate Family Member): PMV Consulting or Advisory Role: Checkmate Pharmaceuticals, Guardant Health, Foundation Medicine, Abbvie, Value Analytics Labs, Bayer, Taiho Oncology, Delcath, Seagen, CVS, SAGA Diagnostics, Scarce, Illumina, UpToDate, Takeda, AstraZeneca, Takeda, Pfizer, Kahr, Xilio Therapeutics, Sirtex Research Funding: PMV Pharma, Erasca, Inc, Syndax Research Funding (Institution): Bristol-Myers Squibb, Genentech, Guardant Health, Array, Eli Lilly, Novartis Pharmaceuticals UK Ltd., PureTech, Mirati Therapeutics, Daiichi Sankyo, Karkinos Other Relationship: C2i Genomics, Xgenomes, Parithera, Cadex

References FEMS Microbiol Rev.1998. Oct;22(4):255-75 Discoveries(Craiova). 2017 Jul-Sep; 5(3): e77. J Cell Mol Med. 2015 Jul; 19(7): 1427–1440. Oncogene. 2017 Mar 23; 36(12): 1607–1618. Bach, JS. 1742. Kunst der Fuge , BWV 1080; Marta Czech https://youtu.be/p1Sq1HOYglU?si=2GMF7kf3dLW4rr2O Lennon and MCartney.1968. "Martha my Dear" https://youtu.be/RXawa90YU2s?si=dUPDtTdm4UqrgWit --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support

Featuring perspectives from Dr Richard M Stone, including the following topics:  • Introduction: ASH 2023 Update — Key Oral Presentations (0:00) • Case: A woman in her early 90s with dementia who presented with anemia and was diagnosed with low-risk myelodysplastic syndromes (MDS) with ring sideroblasts, now receiving luspatercept — Eric H Lee, MD, PhD (9:09) • Case: An African American woman in her early 60s with high-risk del(5q) MDS who receives oral decitabine/cedazuridine — Henna Malik, MD (26:05) • Case: A man in his late 60s with therapy-related acute myeloid leukemia (AML) with a FLT3-ITD mutation — Rebecca L Olin, MD, MSCE (34:49) • Case: A woman in her early 70s with PMH of inflammatory breast cancer diagnosed with FLT3-ITD AML who achieved a complete response (CR) with azacitidine/venetoclax, followed by gilteritinib maintenance for 2 years — Zanetta S Lamar, MD (40:43) • Case: A man in his mid 30s who presents with pathologic spinal fracture, is diagnosed with myeloid sarcoma and receives induction CLAG-M with CR followed by consolidation high-dose cytarabine — Anna Halpern, MD (43:56) • Case: A man in his mid 80s with MDS, complex cytogenetics and a TP53 mutation treated with azacitidine/venetoclax — Neil Morganstein, MD (46:40) • Case: A woman in her early 70s with newly diagnosed, poor-risk AML, ineligible for intensive chemotherapy (ECOG PS 2) who receives a hypomethylating agent/venetoclax — Amany R Keruakous, MD, MS (49:56) • Case: A man in his early 70s with relapsed AML (SRSF2, IDH1, ASXL1 mutations) after azacitidine/venetoclax, now receiving ivosidenib — Dr Halpern (55:23)   CME information and select publications  

Dr DiNardo discusses the the FDA approval of ivosidenib for patients with relapsed/refractory IDH1-mutant myelodysplastic syndromes, the unique mechanism of action of ivosidenib, and key efficacy and safety findings from the AG120-C-001 trial.

Featuring perspectives from Dr Gail J Roboz, including the following topics: Introduction (0:00) Case: A man in his early 50s presents with fatigue and pancytopenia; bone marrow shows myelodysplastic syndromes (MDS) with 11% blasts; normal FISH MDS panel; next-generation sequencing shows BCOR, RUNX1 and UTAF1 mutations; normal metaphase cytogenetics — Warren S Brenner, MD (10:12) Case: An African American woman in her early 60s with high-risk MDS receives oral decitabine/cedazuridine — Henna Malik, MD (16:39) Case: A woman in her early 70s with anemia and low-grade MDS with ring sideroblasts experiences a poor response to erythropoietin and is now on luspatercept — Neil Morganstein, MD (22:15) Case: A woman in her early 60s with newly diagnosed acute myeloid leukemia (AML) and a FLT3-ITD mutation receives 7 + 3 induction with midostaurin induction, consolidation, allogeneic transplant and maintenance — Amany R Keruakous, MD, MS (35:23) Case: A man in his mid 60s with AML and an IDH1 mutation receives venetoclax/azacitidine/ivosidenib — Rebecca L Olin, MD, MSCE (53:23) Case: A woman in her late 30s with refractory leiomyosarcoma develops anthracycline-related secondary AML with an IDH2 mutation and is unable to obtain foundation funding assistance for enasidenib copays — Eric H Lee, MD, PhD (56:48) CME information and select publications

Check out our free downloads at nascentmc.com: Implementing AMA Style – 8 Things to Get Right in Your Next Project Needs Assessments – 7 Essentials for Getting Funded Working With Your Medical Writer – 8 Ways to Get the Most out of Them See the full write ups for today's episode at nascentmc.com/podcast Here are the highlights: ·       Loqtorzi (toripalimab-tpzi) has received FDA approval for the treatment of nasopharyngeal carcinoma, both in combination with chemotherapy and as a monotherapy, demonstrating significant improvements in progression-free survival and overall survival. ·       Vabysmo (faricimab-svoa) has been approved by the FDA as a treatment for macular edema following retinal vein occlusion, showing early and sustained vision improvement in patients, with a generally well-tolerated safety profile. ·       Omvoh (mirikizumab-mrkz) has gained FDA approval for the treatment of moderate-to-severe active ulcerative colitis, offering a targeted approach to address inflammation in this chronic inflammatory bowel disease. ·       Agamree (vamorolone) oral suspension has been approved by the FDA as a novel corticosteroid treatment for Duchenne muscular dystrophy, demonstrating efficacy in improving muscle function with a favorable safety profile. ·       Tibsovo (ivosidenib) has received FDA approval for adult patients with relapsed/refractory myelodysplastic syndromes carrying an IDH1 mutation, offering a potential treatment option for this specific group. ·       The FDA is reviewing AstraZeneca's application to allow patients or caregivers to self-administer FluMist Quadrivalent, potentially becoming the first self-administered flu vaccine, with a decision expected in the first quarter of 2024.  Intro and outro music Garden Of Love by Pk jazz Collective

Featuring perspectives from Dr Naval Daver, including the following topics: Introduction: Biology, Classification, p53, Magrolimab (0:00) Case: A man in his early 70s with acute myeloid leukemia (AML) with a TP53 mutation, myelodysplastic syndromes (MDS)-related changes and complex cytogenetics who received CPX-351receives azacitidine/venetoclax and is now in palliative care — Anna Halpern, MD (9:06) Case: A woman in her late 50s with multiple comorbidities and FLT3-ITD-positive AML who experienced disease progression on azacitidine/venetoclax now receives gilteritinib — Bhavana (Tina) Bhatnagar, DO (17:01) Case: A woman in her early 70s with AML with FLT3-ITD and IDH1 mutations receives a hypomethylating agent with ivosidenib — Amany R Keruakous, MD, MS (29:10) Case: A man in his early 60s with newly diagnosed MDS with ring sideroblasts receives oral decitabine/cedazuridine — Khuda Dad Khan, MD, PhD (33:54) Case: A man in his mid 60s presents with copper deficiency and ring sideroblasts; genetic analysis reveals SF3B1 and DNMT3A mutations — Rachel J Cook, MD (42:25) Case: A woman in her early 70s with a history of extensively treated follicular lymphoma develops AML and receives CPX-351 — Ranju Gupta, MD (46:05) Case: A woman in her late 70s with newly diagnosed AML receives decitabine/venetoclax with concurrent voriconazole — Rebecca L Olin, MD, MSCE (51:05) Case: A woman in her late 90s is diagnosed with multiple myeloma and del(5q) MDS — Erik Rupard, MD (54:26) Journal Club with Dr Daver (57:28) CME information and select publications

In this episode, we discuss the diagnosis and management/monitoring of Clonal Cytopenias of Unknown Significance (CCUS) with Dr. Uma Borate. We also discuss the emerging data on risk stratification and key trials in this space that are currently ongoing. Here are the shownotes:1. CCUS and risk of transformation to myeloid neoplasms:https://www.sciencedirect.com/science/article/pii/S0006497121013471 2. Prediction of risk for myeloid neoplasms in clonal hematopoiesis:https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200310 3. CHRS risk score:http://www.chrsapp.com 4. Germline predisposition to clonal hematopoiesis: https://www.sciencedirect.com/science/article/abs/pii/S0145212623006094?via%3Dihubhttps://www.nature.com/articles/s41586-020-2819-2 5. Cancer therapy shapes the fitness landscape of clonal hematopoiesis:https://www.nature.com/articles/s41588-020-00710-0 6. Canakinumab for the prevention of progression to cancer in patients with Clonal Cytopenias of Unknown Significance, IMPACT Study:https://clinicaltrials.gov/study/NCT05641831?cond=CCUS%20Clonal%20Cytopenia%20of%20Undetermined%20Significance&rank=3 7. Ivosidenib in patients with CCUS and mutations in IDH1:https://classic.clinicaltrials.gov/ct2/show/NCT05030441https://sites.wustl.edu/pimm/

Dr. Ingo K. Mellinghoff discusses his paper, "Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma". Show references: https://pubmed.ncbi.nlm.nih.gov/37272516/

Featuring perspectives from Dr Anthony El-Khoueiry, Dr Robin K (Katie) Kelley and Prof Arndt Vogel, includingthe following topics: Hepatocellular Carcinoma (HCC) Introduction (0:00) Adjuvant therapy for HCC (1:47) First-line systemic therapy for advanced/metastatic HCC (10:36) Management of HCC in the second-line setting and beyond (18:27) Biliary Tract Cancers (BTCs) First-line systemic therapy for metastatic BTCs (26:41) Management of metastatic cholangiocarcinoma with FGFR fusions/rearrangements (35:16) Management of metastatic cholangiocarcinoma with IDH1 mutations  (43:54) Management of metastatic HER2-positive BTC (48:47) CME information and select publications

Listen to this live interview recorded by Oncology Data Advisor at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting with Timothy Cloughesy, MD!

References Free Radical Biology and Medicine 2014. Volume 71, June.Pages 1-15 J Mol Endocrinol. 2020 Nov; 65(4): R77–R90. REDOX and Cholesterol metabolism lectures-Dr Guerra --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message

References Cancers (Basel). 2019 May; 11(5): 678. Oncogene.2017 Mar 23; 36(12): 1607–1618 Dr Guerra's annotated lecture notes from graduate biochemistry course(s) --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message

Go online to PeerView.com/GFT860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Oncology nurse professionals play a particularly important role in providing high-quality and increasingly personalized care to patients with acute myeloid leukemia (AML)—but how current are you with the “real-world” practice of nursing care in AML? Find out in this activity, featuring an oncology nurse's expert overview of nursing principles that can be used to modernize care and optimize the use of innovative targeted therapies (such as FLT3, IDH1/2, and BCL-2 inhibitors) across the treatment continuum. Upon completion of this activity, participants should be better able to: Recognize clinical symptoms, patient-related factors, and molecular/genetic features that influence AML treatment decisions and prognosis; Summarize efficacy and safety evidence related to novel targeted and epigenetic options for the management of newly diagnosed AML, postremission disease, and the relapsed/refractory setting; Educate patients with AML about therapeutic choices with novel agent classes, treatment expectations, dosing and adherence, and safety considerations; and Manage adverse events experienced by patients with AML receiving novel targeted and epigenetic options as part of their care.

Go online to PeerView.com/GFT860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Oncology nurse professionals play a particularly important role in providing high-quality and increasingly personalized care to patients with acute myeloid leukemia (AML)—but how current are you with the “real-world” practice of nursing care in AML? Find out in this activity, featuring an oncology nurse's expert overview of nursing principles that can be used to modernize care and optimize the use of innovative targeted therapies (such as FLT3, IDH1/2, and BCL-2 inhibitors) across the treatment continuum. Upon completion of this activity, participants should be better able to: Recognize clinical symptoms, patient-related factors, and molecular/genetic features that influence AML treatment decisions and prognosis; Summarize efficacy and safety evidence related to novel targeted and epigenetic options for the management of newly diagnosed AML, postremission disease, and the relapsed/refractory setting; Educate patients with AML about therapeutic choices with novel agent classes, treatment expectations, dosing and adherence, and safety considerations; and Manage adverse events experienced by patients with AML receiving novel targeted and epigenetic options as part of their care.

Go online to PeerView.com/GFT860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Oncology nurse professionals play a particularly important role in providing high-quality and increasingly personalized care to patients with acute myeloid leukemia (AML)—but how current are you with the “real-world” practice of nursing care in AML? Find out in this activity, featuring an oncology nurse's expert overview of nursing principles that can be used to modernize care and optimize the use of innovative targeted therapies (such as FLT3, IDH1/2, and BCL-2 inhibitors) across the treatment continuum. Upon completion of this activity, participants should be better able to: Recognize clinical symptoms, patient-related factors, and molecular/genetic features that influence AML treatment decisions and prognosis; Summarize efficacy and safety evidence related to novel targeted and epigenetic options for the management of newly diagnosed AML, postremission disease, and the relapsed/refractory setting; Educate patients with AML about therapeutic choices with novel agent classes, treatment expectations, dosing and adherence, and safety considerations; and Manage adverse events experienced by patients with AML receiving novel targeted and epigenetic options as part of their care.

Go online to PeerView.com/GFT860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Oncology nurse professionals play a particularly important role in providing high-quality and increasingly personalized care to patients with acute myeloid leukemia (AML)—but how current are you with the “real-world” practice of nursing care in AML? Find out in this activity, featuring an oncology nurse's expert overview of nursing principles that can be used to modernize care and optimize the use of innovative targeted therapies (such as FLT3, IDH1/2, and BCL-2 inhibitors) across the treatment continuum. Upon completion of this activity, participants should be better able to: Recognize clinical symptoms, patient-related factors, and molecular/genetic features that influence AML treatment decisions and prognosis; Summarize efficacy and safety evidence related to novel targeted and epigenetic options for the management of newly diagnosed AML, postremission disease, and the relapsed/refractory setting; Educate patients with AML about therapeutic choices with novel agent classes, treatment expectations, dosing and adherence, and safety considerations; and Manage adverse events experienced by patients with AML receiving novel targeted and epigenetic options as part of their care.

Go online to PeerView.com/GFT860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Oncology nurse professionals play a particularly important role in providing high-quality and increasingly personalized care to patients with acute myeloid leukemia (AML)—but how current are you with the “real-world” practice of nursing care in AML? Find out in this activity, featuring an oncology nurse's expert overview of nursing principles that can be used to modernize care and optimize the use of innovative targeted therapies (such as FLT3, IDH1/2, and BCL-2 inhibitors) across the treatment continuum. Upon completion of this activity, participants should be better able to: Recognize clinical symptoms, patient-related factors, and molecular/genetic features that influence AML treatment decisions and prognosis; Summarize efficacy and safety evidence related to novel targeted and epigenetic options for the management of newly diagnosed AML, postremission disease, and the relapsed/refractory setting; Educate patients with AML about therapeutic choices with novel agent classes, treatment expectations, dosing and adherence, and safety considerations; and Manage adverse events experienced by patients with AML receiving novel targeted and epigenetic options as part of their care.

Go online to PeerView.com/GFT860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Oncology nurse professionals play a particularly important role in providing high-quality and increasingly personalized care to patients with acute myeloid leukemia (AML)—but how current are you with the “real-world” practice of nursing care in AML? Find out in this activity, featuring an oncology nurse's expert overview of nursing principles that can be used to modernize care and optimize the use of innovative targeted therapies (such as FLT3, IDH1/2, and BCL-2 inhibitors) across the treatment continuum. Upon completion of this activity, participants should be better able to: Recognize clinical symptoms, patient-related factors, and molecular/genetic features that influence AML treatment decisions and prognosis; Summarize efficacy and safety evidence related to novel targeted and epigenetic options for the management of newly diagnosed AML, postremission disease, and the relapsed/refractory setting; Educate patients with AML about therapeutic choices with novel agent classes, treatment expectations, dosing and adherence, and safety considerations; and Manage adverse events experienced by patients with AML receiving novel targeted and epigenetic options as part of their care.

Go online to PeerView.com/XSA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Are you ready to leverage the benefits of the wide range of newly approved therapeutics that are revolutionizing patient care in AML? Find out in this “Clinical Consults” activity based on a recording at the 2023 USCAP Annual Meeting. A pathologist and a hematologist-oncologist team up to discuss how modern diagnostic techniques can lead to better, more collaborative, personalized care using novel therapeutics to manage challenging AML cases (including in high-risk and mutation-defined AML) and use cases to illustrate diagnostic testing techniques and how pathology and hem-onc can collaborate on treatment decision-making. Watch this video activity today and hear how pathologists and hematologist-oncologists can team up for better outcomes! Upon completion of this activity, participants should be better able to: Discuss the cytogenetic and histopathologic features that enable diagnosis and influence prognosis of different AML subtypes, including secondary AML/AML-MRC or FLT3, IDH1/2, or TP53-mutated disease; Select appropriate molecular/pathology tests to establish a diagnosis of AML or a specific AML subtype and collect relevant information for subsequent treatment decisions; Summarize current evidence supporting innovative cytotoxic, targeted, and immunotherapy strategies in different AML subtypes, including high-risk and mutation-defined disease; and Facilitate the integration of novel therapeutics into team treatment plans informed by baseline test results, including for patients with secondary AML/AML-MRC or FLT3, IDH1/2, or TP53-mutated AML.

Go online to PeerView.com/XSA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Are you ready to leverage the benefits of the wide range of newly approved therapeutics that are revolutionizing patient care in AML? Find out in this “Clinical Consults” activity based on a recording at the 2023 USCAP Annual Meeting. A pathologist and a hematologist-oncologist team up to discuss how modern diagnostic techniques can lead to better, more collaborative, personalized care using novel therapeutics to manage challenging AML cases (including in high-risk and mutation-defined AML) and use cases to illustrate diagnostic testing techniques and how pathology and hem-onc can collaborate on treatment decision-making. Watch this video activity today and hear how pathologists and hematologist-oncologists can team up for better outcomes! Upon completion of this activity, participants should be better able to: Discuss the cytogenetic and histopathologic features that enable diagnosis and influence prognosis of different AML subtypes, including secondary AML/AML-MRC or FLT3, IDH1/2, or TP53-mutated disease; Select appropriate molecular/pathology tests to establish a diagnosis of AML or a specific AML subtype and collect relevant information for subsequent treatment decisions; Summarize current evidence supporting innovative cytotoxic, targeted, and immunotherapy strategies in different AML subtypes, including high-risk and mutation-defined disease; and Facilitate the integration of novel therapeutics into team treatment plans informed by baseline test results, including for patients with secondary AML/AML-MRC or FLT3, IDH1/2, or TP53-mutated AML.

Go online to PeerView.com/XSA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Are you ready to leverage the benefits of the wide range of newly approved therapeutics that are revolutionizing patient care in AML? Find out in this “Clinical Consults” activity based on a recording at the 2023 USCAP Annual Meeting. A pathologist and a hematologist-oncologist team up to discuss how modern diagnostic techniques can lead to better, more collaborative, personalized care using novel therapeutics to manage challenging AML cases (including in high-risk and mutation-defined AML) and use cases to illustrate diagnostic testing techniques and how pathology and hem-onc can collaborate on treatment decision-making. Watch this video activity today and hear how pathologists and hematologist-oncologists can team up for better outcomes! Upon completion of this activity, participants should be better able to: Discuss the cytogenetic and histopathologic features that enable diagnosis and influence prognosis of different AML subtypes, including secondary AML/AML-MRC or FLT3, IDH1/2, or TP53-mutated disease; Select appropriate molecular/pathology tests to establish a diagnosis of AML or a specific AML subtype and collect relevant information for subsequent treatment decisions; Summarize current evidence supporting innovative cytotoxic, targeted, and immunotherapy strategies in different AML subtypes, including high-risk and mutation-defined disease; and Facilitate the integration of novel therapeutics into team treatment plans informed by baseline test results, including for patients with secondary AML/AML-MRC or FLT3, IDH1/2, or TP53-mutated AML.

Go online to PeerView.com/XSA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Are you ready to leverage the benefits of the wide range of newly approved therapeutics that are revolutionizing patient care in AML? Find out in this “Clinical Consults” activity based on a recording at the 2023 USCAP Annual Meeting. A pathologist and a hematologist-oncologist team up to discuss how modern diagnostic techniques can lead to better, more collaborative, personalized care using novel therapeutics to manage challenging AML cases (including in high-risk and mutation-defined AML) and use cases to illustrate diagnostic testing techniques and how pathology and hem-onc can collaborate on treatment decision-making. Watch this video activity today and hear how pathologists and hematologist-oncologists can team up for better outcomes! Upon completion of this activity, participants should be better able to: Discuss the cytogenetic and histopathologic features that enable diagnosis and influence prognosis of different AML subtypes, including secondary AML/AML-MRC or FLT3, IDH1/2, or TP53-mutated disease; Select appropriate molecular/pathology tests to establish a diagnosis of AML or a specific AML subtype and collect relevant information for subsequent treatment decisions; Summarize current evidence supporting innovative cytotoxic, targeted, and immunotherapy strategies in different AML subtypes, including high-risk and mutation-defined disease; and Facilitate the integration of novel therapeutics into team treatment plans informed by baseline test results, including for patients with secondary AML/AML-MRC or FLT3, IDH1/2, or TP53-mutated AML.

Go online to PeerView.com/XSA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Are you ready to leverage the benefits of the wide range of newly approved therapeutics that are revolutionizing patient care in AML? Find out in this “Clinical Consults” activity based on a recording at the 2023 USCAP Annual Meeting. A pathologist and a hematologist-oncologist team up to discuss how modern diagnostic techniques can lead to better, more collaborative, personalized care using novel therapeutics to manage challenging AML cases (including in high-risk and mutation-defined AML) and use cases to illustrate diagnostic testing techniques and how pathology and hem-onc can collaborate on treatment decision-making. Watch this video activity today and hear how pathologists and hematologist-oncologists can team up for better outcomes! Upon completion of this activity, participants should be better able to: Discuss the cytogenetic and histopathologic features that enable diagnosis and influence prognosis of different AML subtypes, including secondary AML/AML-MRC or FLT3, IDH1/2, or TP53-mutated disease; Select appropriate molecular/pathology tests to establish a diagnosis of AML or a specific AML subtype and collect relevant information for subsequent treatment decisions; Summarize current evidence supporting innovative cytotoxic, targeted, and immunotherapy strategies in different AML subtypes, including high-risk and mutation-defined disease; and Facilitate the integration of novel therapeutics into team treatment plans informed by baseline test results, including for patients with secondary AML/AML-MRC or FLT3, IDH1/2, or TP53-mutated AML.

Go online to PeerView.com/XSA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Are you ready to leverage the benefits of the wide range of newly approved therapeutics that are revolutionizing patient care in AML? Find out in this “Clinical Consults” activity based on a recording at the 2023 USCAP Annual Meeting. A pathologist and a hematologist-oncologist team up to discuss how modern diagnostic techniques can lead to better, more collaborative, personalized care using novel therapeutics to manage challenging AML cases (including in high-risk and mutation-defined AML) and use cases to illustrate diagnostic testing techniques and how pathology and hem-onc can collaborate on treatment decision-making. Watch this video activity today and hear how pathologists and hematologist-oncologists can team up for better outcomes! Upon completion of this activity, participants should be better able to: Discuss the cytogenetic and histopathologic features that enable diagnosis and influence prognosis of different AML subtypes, including secondary AML/AML-MRC or FLT3, IDH1/2, or TP53-mutated disease; Select appropriate molecular/pathology tests to establish a diagnosis of AML or a specific AML subtype and collect relevant information for subsequent treatment decisions; Summarize current evidence supporting innovative cytotoxic, targeted, and immunotherapy strategies in different AML subtypes, including high-risk and mutation-defined disease; and Facilitate the integration of novel therapeutics into team treatment plans informed by baseline test results, including for patients with secondary AML/AML-MRC or FLT3, IDH1/2, or TP53-mutated AML.

Rong He, M.D., explains how Mayo Clinic Laboratories' IDHQ test speeds therapeutic decision making for adults with acute myeloid leukemia, or AML. The standalone assay yields faster results than next generation sequencing.(00:32) Would you provide a brief background of yourself? (01:42) Could you give an overview of the IDHQ test? (02:25) Is there anything more you'd like to touch on about the droplet digital PCR approach and high sensitivity? (03:09) Why are IDH1 and IDH2 important in disease diagnosis, prognosis, or therapeutic management? (05:00) Is there anything else you'd like to say about this particular assay? (06:56) Would you describe the specific group of patients where testing is recommended?

Featuring perspectives from Dr Richard Finn, Dr Lipika Goyal and Prof Arndt Vogel, moderated by Dr Katie Kelley, including the following topics: •      First-Line Treatment for Advanced Hepatocellular Carcinoma (HCC) — Dr Finn  o   Introduction (0:00) o   Case: A man in his early 70s with newly diagnosed metastatic HCC receives atezolizumab/bevacizumab — Warren S Brenner, MD (2:27)) o   Case: A woman in her late 50s with a history of hepatitis C and chronic kidney disease on dialysis with localized HCC after surgical resection; patient developed metastatic disease 10 months later — Liudmila N Schafer, MD (6:48) o   Faculty presentation: Dr Finn (11:47) •      Selection and Sequencing of Therapies for Relapsed/Refractory HCC — Dr Kelley  o   Case: A man in his mid 60s with metastatic HCC and a medical history of hepatitis C develops interstitial lung disease on atezolizumab/bevacizumab — Priya Rudolph, MD (21:48) o   Cases: A man in his late 60s with post-transplant recurrence develops metastatic HCC and receives lenvatinib followed by cabozantinib followed by regorafenib and a man in his late 70s with metastatic HCC after treatment with atezolizumab/bevacizumab, lenvatinib and currently cabozantinib — Lionel A Kankeu Fonkoua, MD and Susmitha Apuri, MD (26:58) o   Faculty presentation: Dr Kelley (35:56) •      Current and Future Role of Immunotherapy in the Treatment of Advanced Biliary Tract Cancers (BTCs) — Prof Vogel  o   Case: A woman in her mid 70s with metastatic cholangiocarcinoma who received first-line gemcitabine/cisplatin with durvalumab — Dr Brenner (45:40) o   Case: A man in his early 70s with localized cholangiocarcinoma deemed potentially resectable with tumor response — Jeremy Lorber, MD (50:23) o   Faculty presentation: Dr Vogel (55:10) •      Integration of Targeted Therapy into the Management of Advanced BTCs — Dr Goyal  o   Cases: A woman in her late 70s with intrahepatic cholangiocarcinoma considered unresectable — an FGFR2-KIAA1598 fusion was detected on NGS and a man in his early 60s with metastatic cholangiocarcinoma with severe muscle pain on pemigatinib — Dr Fonkoua and Joseph Martins, MD (1:06:18) o   Cases: A man in his early 50s with recurrent metastatic cholangiocarcinoma with a BRAF V600E mutation treated with dabrafenib/trametinib and a woman in her mid 60s with cholangiocarcinoma with an IDH1 mutation receives ivosidenib — Farshid Dayyani, MD, PhD and Niyati A Nathwani, MD (1:12:26) o   Faculty presentation: Dr Goyal (1:19:08) CME information and select publications

Featuring perspectives from Dr Richard Stone, including the following topics: Current and future trends in the care of patients with acute myeloid leukemia (AML) (0:00) Management of AML with IDH1/2 and FLT3 mutations (17:28) Advances in the treatment of high-risk AML (29:42) Emerging data with novel therapies for AML with targetable mutations (36:53) Hematopoietic stem cell transplantation as a treatment option for patients with relapsed or refractory AML (51:15) Advances in the care of patients with myelodysplastic syndromes (56:19) CME information and select publications

Listen to a soundcast of the December 1, 2022, FDA approval of Rezlidhia (olutasidenib) for relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation.

Tumor-Infiltrating Lymphocytes (TILs) getting closer to entering practice. Updated survival results published from DESTINY-Breast03 (T-DXd vs. T-DM1). A new IDH1 inhibitor, olutasidenib, is FDA-approved for relapsed or refractory AML.

Here are the links for everything discussed in Episode 87. Times are also below so feel free to skip around and get to the updates that interest you.  (1:08) Approval of Hemgenix for Hemophilia B (4:45) Rebyota approved for recurrence of CDiff infection (9:39) New approval for AML with IDH1 mutation - Rezlidhia CDC website for COVID information - get boosted!FDA monkeypox response websiteConnect with The Rx Daily Dose:Twitter      Instagram      YouTube      Linkedin       WebsiteEmail: therxdailydose@gmail.comConnect with Ian Parnigoni PharmD. on social media:Twitter       Instagram       Linkedin  ★ Support this podcast on Patreon ★

JCO PO author Dr. Mark Yarchoan, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, shares research on the four distinct subsets of biliary tract cancers (BTCs) and their varying immune responses and mutations. Dr. Naqash and Dr. Yarchoan discuss the article's study of intrahepatic cholangiocarcinoma [IHC], extrahepatic cholangiocarcinoma, and gallbladder cancer. Click here to read the article! Dr. Naqash: Welcome to ASCO's JCO Precision Oncology Conversations where we bring you the highlights and overview of precision oncology. Episodes will feature engaging conversations with authors of clinically relevant and highly impactful and significant JCO PO articles. These articles can be accessed at ascopubs.org/journals/po. Hi, I am Dr. Rafeh Naqash, Assistant Professor of Medicine at Oklahoma University Stephenson Cancer Center, where I focus on Phase I clinical trials and lung cancer. You're listening to JCO Precision Oncology Conversations podcast. Today, I will be talking with Dr. Mark Yarchoan about his recent paper, Clinical, Genomic, and Transcriptomic Data Profiling of Biliary Tract Cancer Reveals Subtype-Specific Immune Signatures. Dr. Yarchoan is an Associate Professor of Medicine in the GI Medical Oncology branch at the Johns Hopkins, Sydney Kimmel Comprehensive Cancer Center. Full disclosure for our guests will be linked in the show notes and can be found on the article's publication page. Dr. Yarchoan, thank you so much for joining us today. Dr. Yarchoan: Thank you for having me. Dr. Naqash: For the sake of our listeners, Mark, could you tell us about your professional background and your research interests? Dr. Yarchoan: Sure. I'm a medical oncologist by training focused on hepatobiliary malignancies at the Johns Hopkins Hospital, a co-director of Liver Multidisciplinary Clinic, and I'm interested in novel immunotherapeutic approaches to treating liver cancers. Dr. Naqash: That is definitely an unmet need, which we're going to talk about more as we discuss your paper. Again, for the sake of our listeners, before we take a deeper dive into the published paper, could you provide us a one-minute overview of the main findings from your manuscript that was published in JCO Precision Oncology? Dr. Yarchoan: Absolutely. So, we looked at the molecular subtypes of cholangiocarcinoma. So, there are essentially two common forms of liver cancer. There's hepatocellular carcinoma and biliary tract cancers, also sometimes called cholangiocarcinomas. Cholangiocarcinomas are the rarer of the two types of liver cancer and we know that cholangiocarcinoma's not really one cancer, it's a number of different cancers that all anatomically start within the bile ducts of the liver. And what we did working with a number of different collaborators and then also, with Tempus, which is a major molecular profiling company, is we looked at the landscape of mutations that occur in cholangiocarcinoma, and then tried to correlate these mutations with features of the tumor immune microenvironment using RNA data from the same tumors. Dr. Naqash: Thank you so much. So, again, being a thoracic oncologist myself, we have a lot of excitement associated with immune checkpoint alone or immune checkpoint in combination with chemotherapy, similar to what has been seen in some of the upper GI cancers in the last couple of years. Now, before you started this paper or this work with Tempus, what was known about the landscape of biliary tract cancers and what have been the standard approaches of management for advanced biliary tract cancers? Dr. Yarchoan: You know, many of us who treat biliary tract cancers have joked for years that we treat the lung cancer of the GI cancer world because so many of these cancers have actionable molecular alterations. I think that's something that has been known for a long time. Over the last couple of years, for the first time, we have multiple drug approvals in cholangiocarcinoma for molecularly defined subsets of disease. So, for example, we have now inhibitors of FGFR2 that have been approved for FGFR2 fusions or rearrangements. We have an IDH1 inhibitor approved for cholangiocarcinoma. There are some tumor agnostic approvals like for BRAF and NTRK, all of which we do occasionally find in biliary tract cancer. So, you know I think it's been known for a long time that looking for molecular alterations is fruitful in cholangiocarcinoma. You often find these things and these cancers often respond to these agents. I think what is unique here is we've taken this knowledge and first of all, this is the largest series of biliary tract cancer that has ever been profiled to our knowledge, and other profiling efforts have been international. But we know that biliary tract cancer in Southeast Asia can sometimes be different from what we see here in the U.S. because there, those cancers are often caused by liver flukes, which we don't tend to see as much in the U.S. So, the genetics can be somewhat different. And finally, I think what is unique about our paper is that we have actually correlated these molecular differences, these molecular drivers of cholangiocarcinoma. And we've correlated these drivers with the RNA from the same tumor to really understand when you have a tumor that is for example, FGFR2 fusion or rearrangement, what is typically found in the immune microenvironment from that same tumor. Dr. Naqash: Thank you for that explanation. Now, going back to why biliary tract cancer's potentially not as responsive to immune checkpoint inhibitors as some of the other GI-based tumors — pancreatic cancer, as you very well know, has a certain tumor microenvironment associated with presence of fibroblasts and other immunosuppressive macrophages that result in lack of response to immunotherapy-based combinations. What is unique in biliary tract cancers, as you've nicely explained in the discussion or your introduction, that based on Keynote-158, the response rates have generally been in the range of 2 to 10%. So, what is unique here that results in tumors being not so responsive to immunotherapy-based combinations? Dr. Yarchoan: Yeah, biliary tract cancers tend to be fairly immune resistant cancers. As you mentioned, the response rate to single agent anti PD-1 immunotherapy is probably in a range of about 5 to 10% in most studies. We do have new data now from the TOPAZ-1 study, this is a randomized first line study of Gemcitabine Platinum with or without durvalumab, which is a PDL1 inhibitor where the addition of durvalumab did modestly improve survival. So, there is some activity for immunotherapy, but it's quite low as you mentioned. And again, I think that we're still learning why this is, but cholangiocarcinoma tends to have, number one, a very low tumor mutation burden. So, the total number of mutations, which is a surrogate for the number of neoantigens that the immune system can see tends to be low. But also, when we look at the immune microenvironment at these cancers, we tend to find relatively low numbers of effector T cells in the microenvironment, which are an anti-tumor subset. We tend to find high numbers of immunosuppressive cell types, M2 macrophages and T regulatory cells. And these tumors also tend to have a lot of stroma which can impede the immune system coming in. So, the two major accesses that can determine immune sensitivity, the mutational burden in the immune cells, and the microenvironment, both point to an immune suppressed tumor type. Dr. Naqash:  Totally agree. And I think that's why findings that you describe in this paper have a lot of relevance to precision medicine and how we can approach biliary tract cancers, not just anatomically but also from a molecular standpoint. Going back to lung cancer analogy, small cell lung cancer until a few years back was considered one entity and now, it is three to four different entities based on some transcriptional factors which determine how patients respond. And I believe there is something similar going on here like you described. So, now taking a deeper dive into the paper, you did mutational signature analysis clustering, and then you also assessed RNA. What would some of the mutation-specific findings associated with whether tumors were intrahepatic or extrahepatic gallbladder in this manuscript? Dr. Yarchoan: Sure. So, we, as you mentioned, did some cluster analysis looking at the driver mutations in cholangiocarcinoma. And what we found were essentially, there appeared to be four distinct subsets of these cancers. One subset which has been reported in other similar cluster analyses, including an international cluster analysis; one subset really appears to be driven by FGFR2 fusions or rearrangements and is entirely an intrahepatic cholangiocarcinoma subset. And we found that this subset tended to have the lowest immune infiltration of any of the four subsets that we looked at. A second subset, which we called mutational cluster three, was both intrahepatic and extrahepatic disease. And the most common mutation was really in CDKN2A or N2B. The second cluster that we looked at, clusters 1, 2, 3, 4 — I think is one of the most interesting clusters. And this is a cluster that was enriched for genes that seemed to alter the epigenome of the tumor. So, for example, IDH1 mutations, which we know result in an oncometabolite 2HG were common in the subset also ARID1A and PBRM1 were common. And then finally, the largest subset of all were the tumors that had frequent mutations in KRAS, TP53 among other mutations. We found that this was the most inflamed cluster, had the highest PD-L1 expression, slightly enriched in the extrahepatic subset versus intrahepatic subset. Dr. Naqash: Definitely interesting findings based on the cluster analysis and the mutations in each cluster. Going to cluster one where you have found that TP53, ATM, et cetera, mutations are commonly altered genes, are you suggesting based on some of this work that the immune inflamed tumor microenvironment could potentially be linked to TP53, which is cell cycle checkpoint, which when altered could result in higher DNA damage similarly with ATM being in the DNA damage pathway. Could that be a potential explanation for why these alterations are resulting in a hot tumor immune microenvironment? Dr. Yarchoan: Certainly, could be. You know, obviously, we can't prove that. This was correlative, but I think that would certainly explain what we found. Dr. Naqash: And again, going back to cluster four with FGFR2 and BAP1 alterations, which had the lowest PD-L1 and lowest immune microenvironment inflammatory signature, is that potentially a cluster that you think would most commonly benefit from targeted therapies rather than immune checkpoint-based therapies? Dr. Yarchoan: That's our hypothesis here. This was a subgroup that appeared to be non-inflamed, had a low mutational burden. Genomically, I would call this a stupid cancer in the sense that there's a very powerful driver mutation and not a whole lot else going on here. It seems like the sort of tumor that may benefit from targeted therapy. I think what we don't know, and one of the questions that immediately comes out of this work is, is FGFR2 itself immunosuppressive and that's why we don't find a lot of immune cells. And if so, it raises the question whether these sort of cluster four tumors would benefit from a combination approach of targeted therapy plus immunotherapy. And so, I think that's an open question, something that we hope to look into. Dr. Naqash: Definitely, leads to potential subsequent work in this field to expand more on these findings. Now, going back to some of the other important findings in your paper, you described actionable biomarkers in the biliary tract cancers based on proven trials with specific therapies. One of the questions that I had was you take TMB ≥10 as a potentially actionable biomarker. Is that true for biliary tract cancers? Because there's data from different groups showing that different TMB cutoffs have different meaning for different types of tumors. So, is 10 a cutoff where you are reasonably comfortable in saying that potentially, single agent immunotherapy may work and TMB here is predictive of outcomes, or do you think a higher TMB is probably more relevant in these cancers that are generally not immune responsive? Dr. Yarchoan: Yeah, the approval for pembrolizumab in high TMB tumors has been controversial. I think probably more controversial than it should be. But Keynote-158, which was sort of a prospectively analyzed study of pembrolizumab and multiple tumor histologies, actually included biliary tract cancers. And the response rate in that study for biliary tract cancer in the TMB high group again, small numbers of patients but, was consistent with pembrolizumab being very active. I have to say in my own clinic, I've had some absolutely spectacular responses for high TMB biliary tract cancer, and so I tend to believe the data. I've actually had complete responses. I've had patients downstage to surgery who went on single agent anti PD-1. So, I think this is an important group of patients and I think it is a group that we shouldn't miss for biliary tract cancer. Dr. Naqash: Definitely agree with you. All of us strive as medical oncologists to get some of those complete responses that don't come often very commonly or easily. But it's always nice to see those responses and individuals especially with these biomarker-specific tumors with high TMB or high PD-L1. Now, other findings from your paper, you describe mutual exclusivity of two mutations in a certain subgroup, which was TP53 and BAP1. Could you explain the clinical relevance or the molecular significance of these mutually exclusive mutations and what they might mean in the context of this tumor? Dr. Yarchoan:The short answer is these were clearly in different immune subsets and different molecular subsets. Again, the TP53 belonged to what we called cluster one. Usually, went with KRAS, was more common in extrahepatic disease. The BAP1 mutations tended to go along with FGFR2 fusions or rearrangements, was intrahepatic. But exactly why these were mutually exclusive, why was it not evolutionarily advantageous for tumors to have both of these things at once? You know, I think remains an unanswered question. There's certainly a hypothesis for why the tumor wouldn't need both, but I don't know. Dr. Naqash:  And you also looked at PD-L1 and tumor mutational burden across the biliary tract tumor subtypes. Could you tell us more about some of those findings? Dr. Yarchoan: Yeah, for sure. I mean, I think our cluster one, which again was the most inflamed cluster, had more KRAS, more TP53 — not surprisingly seemed to have the most immune infiltration, the highest PD-L1 expression in a trend towards a higher tumor mutation burden as well. Not totally surprising. I don't want to over-interpret that finding though because we've looked now at the prospective data from TOPAZ-1 where patients got GemCis with or without durvalumab. As a matter of fact, PD-L1 was not a very strong predictor for durvalumab benefit in that study. So, I wouldn't over-interpret the trend towards higher PD-L1 expression in that subset. It may not be very clinically actionable. Dr. Naqash:  Sure. Now, another finding is the TMB comparisons across the biliary tract cancer subtypes. And to me, it seemed like the TMB, median TMB, was slightly different but not significantly different that may not necessarily have a huge clinical relevance. Do you agree with that? What are your thoughts on that side? Dr. Yarchoan: We're in an era now where we just get TMB at an individual patient level. So, I don't think we're going to be relying on cluster analysis to figure out a patient's TMB. So, I don't think it's necessarily clinically actionable. I do think there were some findings here that are interesting from a research perspective. For example, ARID1A was associated with a higher tumor mutation burden; something that's been reported in other tumor types and that's certainly interesting and something that should be followed up on, I think, from a research standpoint. Dr. Naqash: Excellent. Now, last figure that I came across, which was again, very interesting, was that you analyze association between all the different mutations and different immune gene signatures. And it seemed based on the figure that TP53, again, stood out when you correlated with PD-L1 or CDA T cell or other immune inflammatory gene signatures. Is there something going on with TP53 here that you think is potentially relevant co-mutation in this tumor, which could lead to some novel therapeutic combination approaches? Dr. Yarchoan: Yeah, I don't want to over-interpret our work, but I agree, it's very interesting and this is a topic that is being investigated in many tumor types because TP53 is something that appears in many tumors including the ones that you treat. So, I think this is particularly relevant because we have a bunch of TP53 targeted therapies coming down the pike. How those will modulate the tumor immune microenvironment is an interesting topic. So, maybe just for sake of discussion, are you finding the same thing in lung cancer and what's the thought process in lung cancer now? Dr. Naqash:  Yes, again, very interesting question. So, we actually had some data last year that we presented in the context of lung cancer in STK11, which is again, commonly found in pancreatic and biliary cancers also. And we saw TP53 co-mutated tumors had a very high immune inflammatory gene signature with all the different aspects of immune infiltration or Interferon gamma upregulation (IFN-γ). So, likely, our assessment was that this was potentially linked to the cell cycle aspect and higher neoantigens for DNA damage. So, something common probably going on here in this tumor type as well as you mentioned. So, one of the other things that I came across, which is interesting and I've come across a patient actually a few years back with cholangiocarcinoma, but that was associated with a liver fluke. The tumors that you assess using the Tempus database obviously, were from North America and did not have Asian patients. And from my understanding, TOPAZ-1 did include a decent number of patients from Asia. So, have you looked at or is there a potential reason to believe that liver fluke-associated tumors may have a higher inflammatory signature or has there been any data in comparing liver fluke versus non-liver fluke-associated biliary tract tumors to see what could be the genomic transcriptomic differences there? Dr. Yarchoan: Yeah, as you mentioned, our study was purely for North American patients. It's not that there were no Asian patients. There certainly were Asian patients, including patients who may have been born in Southeast Asia but immigrated here. There have been other analyses of the molecular landscape of biliary tract cancer that were international and included more patients from Asia, including a paper in Cancer Discovery a couple of years ago that I think is worth reading. Overall, I think there is some data that this subgroup of patients may have a unique tumor immune microenvironment and unique mutational landscape. We tend to find more for two in these patients. They do tend to be, I think, a little more inflamed, have more PD-L1 expression. Interestingly, in the TOPAZ-1 study, which again, was the prospective study of durvalumab, there appeared to be more benefit to durvalumab in patients in Asia than patients in the West. And it does raise the question whether that could be mediated in part by this liver fluke ideology. So, again, certainly not a settled question, but something interesting that should be followed up on. Dr. Naqash:Definitely interesting. I would again like to thank you Dr. Yarchoan and your team for this excellent work and sharing all your thoughts with us today, and giving us more insights into biliary tract cancers. On behalf of JCO PO, I'd like to thank you for considering JCO PO as the final destination for this interesting work, and hopefully, you consider JCO PO for future work as well. Dr. Yarchoan: Well, thank you for highlighting our work and for the opportunity to publish, and thanks for this discussion. Dr. Naqash: Absolutely. It's been a pleasure talking to you today, and hopefully, our audience will find this conversation equally intriguing and interesting. Thank you for listening to JCO Precision Oncology Conversations. You can find all our shows, including this one at asco.org/podcasts or wherever you get your podcasts. To stay up to date, be sure to follow and share JCO PO content on Twitter. Our Twitter handle is @JCOPO_ASCO. All JCO PO articles and series can be found at ascopubs.org/journals/po.   Voiceover:  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 Mark Yarchoan  Consulting or Advisory Role: Eisai, Exelixis, AstraZeneca, Genentech/Roche, Replimune, Hepion Pharmaceuticals  Research Funding: Bristol Myers Squibb (Inst), Merck (Inst), Exelixis (Inst), Incyte (Inst)   Guest Bio Dr. Mark Yarchoan, MD, is a medical oncologist focused on hepatobiliary malignancies at the Johns Hopkins Hospital and co-director of Liver Multidisciplinary Clinic.

Featuring an interview with Professor Juan Valle, including the following topics: Immunotherapy for patients with biliary tract cancers (BTCs) (0:00) Etiology and presentation of and recent advances in the management of cholangiocarcinoma (4:18) Targeting FGFR alterations in cholangiocarcinoma and other BTCs (12:47) Spectrum and management of toxicities associated with FGFR inhibitors (19:33) Targeting driver mutations beyond FGFR (28:16) Case: A man in his early 60s with intrahepatic cholangiocarcinoma, an FGFR2 fusion and an IDH1 R132C mutation (35:53) Case: A woman in her early 60s with intrahepatic cholangiocarcinoma and an IDH1 mutation that did not respond to third-line ivosidenib (41:49) Case: A woman in her early 60s with gallbladder cancer who received first-line chemotherapy with pembrolizumab (46:15) CME information and select publications

Featuring perspectives from Dr Melissa Johnson, including the following topics: Introduction: KRAS in Lung Cancer (0:00) Case: A woman in her early 60s with adenocarcinoma of the lung and a ROS1 fusion, with bone, brain and leptomeningeal metastases — Gigi Chen, MD (15:52) Case: A man in his late 50s with Stage IVa lung cancer and malignant pleural effusion and a BRAF V600E mutation (PD-L1 60%) — Jiaxin (Jason) Niu, MD, PhD (22:28) Case: A woman in her mid 60s with adenocarcinoma of the lung, a solitary brain metastasis and an ALK fusion — Neil Morganstein, MD (29:33) Case: A woman in her early 50s with metastatic adenocarcinoma of the lung and a RET mutation (PD-L1 TPS 40%) — Rao Mushtaq, MD (36:42) Case: A woman in her early 70s with Stage IV lung adenocarcinoma and malignant pleural effusion and NRG1 fusion — Dr Niu (41:45) Case: A man in his late 60s with metastatic squamous cell carcinoma of the lung with an IDH1 mutation — Sulfi Ibrahim, MD (51:08) MET Exon 14 and HER2 Mutations (54:07) CME information and select publications

Featuring articles on restricted calories and eating times in weight loss, asthma therapy in Black and Latinx adults, ivosidenib in IDH1-mutated acute myeloid leukemia, vaccine boost effects on protection against omicron, and fighting cardiac fibrosis with CAR T cells; a review article on early-onset colorectal cancer; a case report of a woman with transient ischemic attack and mitral valve masses; and Perspective articles on a change in the leading cause of death among U.S. children, on strengthening the Medicaid Reentry Act, and on Covid-19's devastating effect on tuberculosis care.

Featuring perspectives from Dr Rebecca Olin, including the following topics: Introduction: Journal Club with Rebecca L Olin, MD, MSCE — Evaluation of the older patient with acute myeloid leukemia (AML) (0:00) Case: A woman in her late 80s with transfusion-dependent AML secondary to myelodysplastic syndrome — Raman Sood, MD (7:52) Case: A frail man in his mid 70s with newly diagnosed poor-risk AML with FLT3-ITD and IDH1 mutations — Amany R Keruakous, MD, MS (12:46) Case: A woman in her late 60s with relapsed AML and a FLT3-ITD mutation — Prashant Sharma, MD (18:23) Case: A man in his late 50s with AML receives 7 + 3 induction prior to discovery of complex cytogenetics — Rachel J Cook, MD (22:04) ASH 2021 review — Part 1 (25:07) Case: A man in his early 70s with relapsed AML and an IDH2 mutation — Erik J Rupard, MD (29:13) Case: A man in his late 50s with therapy-related AML and an IDH2 mutation — Bhavana (Tina) Bhatnagar, DO (32:28) Case: A woman in her mid 40s with newly diagnosed poor-risk AML and an ejection fraction of 35% — Dr Keruakous (32:28) ASH 2021 review — Part 2 (39:28) Faculty survey (58:32) CME information and select publications