Podcasts about Cancer immunotherapy

In today's episode, we had the pleasure of speaking with Elizabeth Mittendorf, MD, PhD, MHCM, the 2026 president-elect of ASCO. Dr Mittendorf is the Robert and Karen Hale Distinguished Chair in Surgical Oncology and the vice chair for research in the Department of Surgery at the Brigham and Women's Hospital; co-leader of the Breast Program and director of the Breast Immuno-Oncology Program at the Dana-Farber Brigham Cancer Center; co-leader of the Parker Institute for Cancer Immunotherapy at the Dana-Farber Cancer Institute; and a professor of surgery at Harvard Medical School, all in Boston, Massachusetts.  In our exclusive interview, Dr Mittendorf discussed her priorities for advancing oncology practice and improving patient outcomes during her presidency. These include multidisciplinary cancer care, workforce well-being, leveraging artificial intelligence to enhance efficiency, and addressing global cancer care. She also emphasized the importance of mentorship and sponsorship for early career professionals, highlighting her personal experience with multiple mentors and her commitment to supporting the next generation of oncology professionals. 

Poolbeg Pharma CEO Jeremy Skillington joined Steve Darling from Proactive to announce a significant milestone in the company's clinical development strategy: the U.S. Food and Drug Administration has granted Orphan Drug Designation to POLB 001, Poolbeg's innovative oral therapy aimed at preventing Cytokine Release Syndrome caused by T-cell engager bispecific antibody immunotherapies. POLB 001, an oral small molecule inhibitor of the IL-1 receptor, is designed to modulate the inflammatory response without suppressing the underlying anti-cancer immune activation. The FDA's Orphan Drug Designation recognizes the potential of POLB 001 to address a rare but serious medical condition, affecting fewer than 200,000 individuals annually in the United States. This designation confers a range of developmental and commercial incentives including seven years of U.S. market exclusivity post-approval, waiver of certain FDA fees, such as the Prescription Drug User Fee Act or PDUFA application fees and others. The company plans to initiate a Phase 2a clinical trial in the second half of 2025, marking the next step in evaluating POLB 001's efficacy and safety in a controlled setting. Poolbeg anticipates completing interim analysis in the first half of 2026, with topline data expected in the second half of 2026. With the Orphan Drug Designation in hand, Poolbeg is now well-positioned to advance discussions with potential partners and stakeholders as it progresses toward its clinical milestones. #proactiveinvestors #poolbegpharma #aim #polb #OrphanDrug #POLB001 #FDAApproval #CytokineReleaseSyndrome #CancerTherapy #BiotechNews #Immunotherapy #ClinicalTrials #PharmaInvesting

Send us a textDr. Samir Khleif, MD is CEO of Georgiamune ( https://www.georgiamune.com/team ), a private, science and discovery clinical stage immunotherapeutic biotechnology company focused on reprogramming immune signaling pathways to redirect the immune system to fight diseases.  Dr. Khleif is a pioneer in the field of immunotherapy. He is a medical oncologist, immunologist, innovator, and entrepreneur, as well as a transformational executive in health care and biomedical research.Prior to becoming CEO of Georgiamune, Dr. Khleif served in different academic and leadership positions. He was a National Cancer Institute (NCI)/National Institutes of Health (NIH) scientist and Chief of the NCI Cancer Vaccine Section, where he led the development of pioneering immune-oncology and cancer vaccines into clinical trials. As a national and international academic leader, and detailed by the US government, he served as the founding director and CEO of the King Hussein Cancer Center ( https://www.khcc.jo/en ) in Amman, Jordan, where he led the development of the largest cancer center in the MENA region. He also served as the director of the Georgia Cancer Center, the state cancer center, at Augusta University. He is currently a biomedical scholar and holds a professorship at Georgetown University Medical School.Dr. Khleif also served as a Special Assistant to the Commissioner of the FDA, leading the FDA's Critical Path Initiative for Oncology. He is a member of the board of directors of Ayala Pharmaceuticals and Emerald Biopharmaceutics, and served as a member of the scientific advisory board of more than 20 biotechnology and pharmaceutical companies.Dr. Khleif is an international KOL in immunology and immunotherapy. He has served on many national committees, including the Scientific Advisory Board of the Biden Cancer Initiative, as chair of the Immunotherapy Committee for NRG, and as a member of the NCI Cooperative Group. He currently serves as an advisor for the Parker Institute for Cancer Immunotherapy. Dr. Khleif is an editor of three books, the author of hundreds of peer-reviewed scientific research articles, and a prolific inventor with more than 150 patents issued or pending in the field of immunology and immunotherapy.Dr. Khleif received his medical degree at the University of Jordan, Amman Jordan. He completed his residency in Internal Medicine at the Medical College of Ohio and his fellowship in Medical Oncology at the National Cancer Institute (NCI) in Bethesda, Maryland.#SamirKhleif #Georgiamune #Immunotherapy #KingHusseinCancerCenter #CriticalPathInitiative #FDA #Tregs #RegulatoryTCells #Cancer #Oncology #CheckpointInhibitors #ImmuneEscapeMechanisms #DualFunctioningAntibody #Autoimmune #ProgressPotentialAndPossibilities #IraPastor #Podcast #Podcaster #Podcasting #ViralPodcast #STEM #Innovation #Science #Technology #ResearchSupport the show

A patient beats grim cancer survival rates. Learn about the immunotherapy and other strategies that give people hope. Plus, we discuss survivor's guilt when you defy the odds.

“The most effective therapies for solid tumors are also the most toxic — and we need to fix that,” says Dr. John Connolly, chief scientific officer of the Parker Institute for Cancer Immunotherapy. In this episode of the Vanguards of Health Care podcast, Connolly tells Bloomberg Intelligence pharmaceutical analyst Sam Fazeli why managing toxicity is the key to unlocking CAR-T’s potential in solid tumors. They explore the rise of in vivo cell therapies, evolving views on the tumor microenvironment and why foundational cancer vaccines may shape the future of all immunotherapy. Connolly also shares the clinical trials he’s watching closely, the ones that could flip the script on cancer care.See omnystudio.com/listener for privacy information.

In this episode of the Veterinary Cancer Pioneers Podcast, host Dr. Rachel Venable welcomes Dr. Mark Mamula, an immunologist and professor at Yale University School of Medicine, to discuss his groundbreaking work in canine cancer immunotherapy. Dr. Mamula shares how his background in autoimmune diseases led him to develop an experimental vaccine targeting EGFR and HER2 proteins in dogs with cancer. He explains the science behind this therapy, its clinical trial progress, and its potential to improve survival outcomes for cancers such as osteosarcoma and hemangiosarcoma. They also explore the challenges of bringing new therapies to veterinary medicine, the role of combination treatments, and the importance of accessible, cost-effective options for pet owners. Tune in for an insightful conversation on the evolving landscape of canine cancer treatment and the promising future of immunotherapy.

In this episode of the Onc Now Podcast, host Jonathan Sackier is joined by Heather McArthur, Associate Professor in the Department of Medicine at University of Texas, UT Southwestern Medical Center, USA. They discuss recent advancements in breast cancer immunotherapy and the future of personalised care.  Timestamps:    00:00 - Introduction  01:20 - Transformative breakthroughs in immunotherapy  03:51 - Communicating new research to the public  05:48 - Racial disparities in cancer screenings  07:22 - Unmet needs in treating triple-negative breast cancer  11:48 - Genomic profiling and molecular pathways   13:30 - Barriers to personalised treatment plans  15:09 - Designing and conducting large-scale, international trials  19:16 - Optoacoustic imaging in cancer  22:52 - The ‘first' cell and the heterogeneity of breast tumours  25:21 – Heather's three wishes for healthcare 

Daniel Laheru , MD, is the Professor of Oncology and Co-Director of Skip Viragh Center for Pancreatic Cancer Research at the Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins Hospital. He holds the Ian MacMillian Professorship in Clinical Pancreatic Cancer Research. Dr. Laheru has developed a vaccine along with Dr. Elizabeth Jaffee, that supercharges the immune system and causes immune cells, which tend to be tolerant of cancer, to seek out and kill pancreatic cancer cells throughout the body. He is a Member of the Miller-Coulson Academy of Clinical Excellence, Member of Bloomberg-Kimmel Institute for Cancer Immunotherapy, and Associated Director of the Institute for Convergence Science.  “There's no job that's insignificant here. Whatever you're doing, you need to do it to the best of your abilities.” A monumental lesson from Dr. Daniel Laheru's parents taught him to notice the janitor who moves by silently in the corner, the nurse who works overtime without appreciation, and the security guard who passes a silent glance at every passerby. In this episode of The Medicine Mentors, Dr. Daniel Laheru explains recognizing the interconnected nature of every person's role in the infrastructure of medicine, instilling gratitude in our practice, and paying it back by paying it forward. Pearls of Wisdom:   1. Enjoy the time that you're a student because you'll wonder what you did with all your time after. The future is entirely open to you, the ceiling is what you make it. 2. I'm happy doing what I'm doing right now, and if I can do this five years from now, I'll be ecstatic.  3. The fellows, residents, and medical students are the lifeblood of the institution and the next generation so don't be shy about asking somebody if they have time to meet with you.  4. A good mentor is like a parent in the sense that they put your goals ahead of their own. My mentor really saw my future before I was able to understand it for myself. 5. The little things in the course of a day actually make a big difference. Thanking and appreciating someone goes a long way. 

BUFFALO, NY - December 3, 2024 – A new #review was #published in Oncotarget's Volume 15 on November 22, 2024, entitled “Mesenchymal stem cells - the secret agents of cancer immunotherapy: Promises, challenges, and surprising twists." Authored by Theia Minev, Shani Balbuena, Jaya Mini Gill, Francesco M. Marincola, Santosh Kesari, and Feng Lin from CureScience Institute, Sonata Therapeutics, and Pacific Neuroscience Institute and Providence Saint John's Health Center, this review explores the potential role of mesenchymal stem cells (MSCs) in cancer treatment. These stem cells can naturally target tumors and deliver therapeutic agents directly to cancer cells, potentially improving treatment outcomes while reducing side effects commonly associated with traditional therapies like chemotherapy. However, the authors also note significant challenges, pointing out that under certain conditions, MSCs may unintentionally promote tumor growth, highlighting the need for careful therapeutic design. MSCs are cells that can develop in different types of tissues, such as bone, fat, or cartilage, and act as natural repair agents. What makes them particularly special is their ability to respond to biological signals, like inflammation, which is often present in cancer. This enables them to locate tumors, and once there, they can deliver cancer treatments directly to the affected area. Clinical trials are already investigating MSC-based treatments for cancers such as brain tumors, melanoma, and ovarian cancer. Some results are promising, showing that MSCs can effectively deliver treatments and boost the immune system's fight against cancer. However, other trials have also revealed the complexities of MSC behavior, including variability in their effects and the potential to create conditions that support tumor growth. “This variability may be due to the tumor immune microenvironment's effects, where immune cells are inhibited by various factors, creating a conducive environment for tumor growth.” The authors also suggest that “Developing personalized MSC therapies tailored to the specific characteristics of a patient's tumor and immune system could enhance the efficacy and safety of MSC-based treatments.” Achieving this requires a deeper understanding of how MSCs interact with cancer cells and their surrounding environment. In conclusion, this review highlights both the potential and challenges of (MSCs in cancer therapy. With ongoing research and technological advancements, MSCs could become a key component of personalized cancer treatments, offering new hope for patients worldwide. DOI - https://doi.org/10.18632/oncotarget.28672 Correspondence to - Feng Lin - flin@curescience.org Video short - https://www.youtube.com/watch?v=Wwc3zDDitlc Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Faron Pharmaceuticals Limited (AIM:FARN) CEO Dr Juho Jalkanen talked with Proactive's Stephen about the significant fast-track designation awarded to their cancer immunotherapy, bexmarilimab, by the UK's Medicines and Healthcare products Regulatory Agency (MHRA). This milestone aligns with prior FDA acknowledgments, marking critical progress in addressing relapsed refractory Myelodysplastic Syndrome (r/r MDS). Faron also announced MHRA approval to expand its BEXMAB trial to UK sites. Jalkanen explained, “UK is like a second home for us,” emphasising the importance of extending treatment access to UK patients. He also detailed how the Innovation Passport streamlines regulatory interactions, rolling submissions, and early drug access opportunities. Looking ahead, Dr. Jalkanen shared that a confirmatory Phase 3 study is being planned for high-risk MDS patients globally, in collaboration with major regulatory authorities. The global trial underscores the company's dedication to delivering groundbreaking therapies to patients in need. For more insightful interviews, visit Proactive's YouTube channel. Don't forget to like this video, subscribe, and turn on notifications for updates! #faronpharmaceuticals #CancerImmunotherapy #Bexmarilimab #MDSResearch #BiotechInnovation #ClinicalTrials #MHRA #FDAApproval #GlobalHealthcare #ProactiveInvestors #invest #investing #investment #investor #stockmarket #stocks #stock #stockmarketnews

Dr. Ryan Augustin and Dr. Jason Luke discuss neoadjuvant immunotherapy and the importance of multidisciplinary team coordination, promising new TIL therapy for advanced melanoma, and the emerging role of CD3 engagers in treatment strategies. TRANSCRIPT Dr. Ryan Augustin: Hello, I'm Dr. Ryan Augustin, your guest host of the ASCO Daily News Podcast today. I'm a medical oncology fellow at Mayo Clinic in Rochester, Minnesota. Joining me today is Dr. Jason Luke, an associate professor of medicine and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh Hillman Cancer Center. I had the privilege of working as a postdoc in Jason's translational bioinformatics lab, where we investigated mechanisms of resistance to immunotherapy in melanoma and other cancers.  Today, we'll be discussing 3 important topics, including neoadjuvant immunotherapy and the importance of multidisciplinary team coordination, the impact and practical considerations for incorporating TIL therapy into melanoma, and the current and future use of CD3 engagers in both uveal and cutaneous melanoma.  You'll find our full disclosures in the transcript of this episode.  Jason, it's great to have this opportunity to speak with you today. Dr. Jason Luke: Absolutely. Thanks, Ryan. It's great to see you. Dr. Ryan Augustin: So, to kick things off, Jason, we, of course, have seen tremendous advances in cancer immunotherapy, not only in metastatic disease but also the perioperative setting. Recent data have shown that the use of neoadjuvant therapy can provide not only critical prognostic information but can also help individualize post-resection treatment strategies and potentially even eliminate adjuvant therapy altogether in patients who achieve a pathologic, complete response. This signifies a conceptual shift in oncology with the goal of curing patients with immunotherapy. In triple-negative breast cancer, the KEYNOTE-522 regimen with pembrolizumab is standard of care. In non-small cell lung cancer, there are now four FDA approved chemo-IO regimens in both the neoadjuvant and perioperative settings. And, of course, in melanoma, starting with SWOG S1801 utilizing pembro mono therapy, and now with combined CTLA-4 PD-1 blockade based on results from the NADINA trial, neoadjuvant IO is the new standard of care in high-risk, resectable melanoma. It's important to highlight this because whereas other tumor types have more mature multidisciplinary care, for example, patients with breast cancer are reviewed by the whole team in every center, and every patient with lung cancer certainly benefits from multidisciplinary care conferences, that's not always the case with melanoma, given the relative frequency of cases compared to other tumor types.  Jason, would you say that we have now moved into an era where the integration of a multidisciplinary team and melanoma needs to be prioritized. And why is it important to have multidisciplinary team coordination from the onset of a patient's diagnosis? Dr. Jason Luke: Well, I think those are great questions, Ryan, and I think they really speak to the movement in our field and the great success that we've had integrating systemic therapy, particularly immunotherapy, into our treatment paradigms. And so, before answering your question directly, I would add even a little bit more color, which is to note that over the last few years, we've additionally seen the development of adjuvant therapy into stages of melanoma that, historically speaking, were considered low-risk, and medical oncologists might not even see the patient. To that, I'm speaking specifically about the stage 2B and 2C approvals for adjuvant anti-PD-1 with pembrolizumab or nivolumab. So this has been an emerging complication.  Classically, patients are diagnosed with melanoma by either their primary care doctor or a dermatologist. Again, classically, the next step was referral to a surgeon who had removed the primary lesion, with discussion around nodal evaluation as well. And that paradigm has really changed now, where I think integration of medical oncology input early on in the evaluation of the appropriate treatment plan for patients with melanoma is quite a pressing issue now, both because we have FDA approvals for therapeutics that can reduce risk of recurrence, and whether or not to pursue those makes a big difference to the patient for discussion early on.  And, moreover, the use of systemic therapies now, prior to surgery, of course, then, of course, requires the involvement of medical oncology. And just for an emphasis point on this, it's classically the case, for good reason, that surgeons complete their surgery and then feel confident to tell the patient, “Well, we got it all, and you're just in really good shape.” And while I understand where that's coming from, that often leaves aside the risk of recurrence. So you can have the most perfect surgery in the world and yet still be at very high risk of recurrence. And so it's commonly the case that we get patients referred to us after surgery who think they're just in totally good shape, quite surprised to find out that, in fact, they might have a 20% to 50% risk of recurrence. And so that's where this multidisciplinary integration for patient management really does make a big difference.  And so I would really emphasize the point you were making before, which is that we need multidisciplinary teams of med onc with derm, with surgery early on, to discuss “What are the treatment plans going to be for patients?” And that's true for neoadjuvant therapy, so, for palpable stage 3, where we might give checkpoint inhibitors or combinations before surgery. But it's true even in any reasonably high-risk melanoma, and I would argue in that state, anything more than stage 1 should be discussed as a group, because that communication strategy with the patient is so important from first principles, so that they have an expectation of what it's going to look like as they are followed out over time. And so we're emphasizing this point because I think it's mostly the case at most hospitals that there isn't a cutaneous oncology disease management meeting, and I think there needs to be.  It's important to point out that usually the surgeons that do this kind of surgery are actually either the GI surgeons who do colon cancer or the breast surgeons. And so, given that melanoma, it's not the most common kind of cancer, it could easily be integrated into the existing disease review groups to review these cases. And I think that's the point we really want to emphasize now. I think we're not going to belabor the data so much, but there are enormous advantages to either perioperative or adjuvant systemic therapy in melanoma. We're talking about risk reduction of more than 50%, 50-75% risk reduction. It's essential that we make sure we optimally offer that to patients. And, of course, patients will choose what they think is best for their care. But we need to message to them in a way that they can understand what the risks and benefits of those treatments are and then are well set up to understand what that treatment might look like and what their expectations would be out over time.  So I think this is a great art of medicine place to start. Instead of belaboring just the details of the trial to say, let's think about how we take care of our patients and how we communicate with them on first principles so that we can make the most out of the treatments that we do have available. Dr. Ryan Augustin: That's great, Jason. Very insightful points. Thank you.  So, shifting gears now, I'd also like to ask you a little bit about TIL therapy in melanoma. So our listeners will be aware that TIL is a promising new approach for treating advanced melanoma and leverages the power of a patient's cytotoxic T cells to attack cancer cells. While we've known about the potential of this therapy for some time, based on pioneering work at the NCI, this therapy is now FDA approved under the brand AMTAGVI (Lifileucel) from Iovance Biotherapeutics, making it the first cellular therapy to be approved for a solid tumor. Now, I know TIL therapy has been administered at your institution, Jason, for several years now, under trial status primarily for uveal melanoma using an in-house processing. But for many cancer centers, the only experience with cellular therapy has come under the domain of malignant hematology with CAR T administration. At our institution, for example, we have only recently started administering TIL therapy for melanoma, which has required a tremendous multidisciplinary effort among outpatient oncology, critical care, and an inpatient hematology service that has expertise in cytokine release syndrome.  Jason, where do you see TIL therapy fitting into the metastatic space? Which patients do you think are truly candidates for this intensive therapy? And what other practical or logistical considerations do you think we should keep in mind moving forward? Dr. Jason Luke: Well, thanks for raising this. I think the approval of lifileucel, which is the scientific name for the TIL product that's on the market now. It really is a shift, a landscape shift in oncology, and we're starting in melanoma again, as seems to be commonly the case in drug development. But it's really important to understand that this is a conceptually different kind of treatment, and therefore, it does require different considerations. Starting first with data and then actualization, maybe secondarily, when we see across the accelerated approval package that led to this being available, we quote patients that the response rate is likely in the range of 30%, maybe slightly lower than that, but a meaningful 25% to 30% response rate, and that most of those patients that do have response, it seems to be quite durable, meaning patients have been followed up to four years, and almost all the responders are still in response. And that's a really powerful thing to be able to tell a patient, particularly if the patient has already proceeded through multiple lines of prior standard therapy. So this is a very, very promising therapy.  Now, it is a complicated therapy as well. And so you highlighted that to do this, you have to have a tumor that's amenable for resection, a multidisciplinary team that has done a surgery to remove the tumor, sent it off to the company. They then need to process the TIL out of the tumor and then build them up into a personalized cell product, bring it back, you have to lympho-deplete the patient, re-introduce this TIL. So this is a process that, in the standard of care setting under best circumstances, takes roughly six weeks. So how to get that done in a timely fashion, I think, is evolving within our paradigms. But I think it is very important for people who practice in settings where this isn't already available to realize that referring patients for this should be a strong consideration. And thinking about how you could build your multidisciplinary team in a way to be able to facilitate this process, I think is going to be important, because this concept of TIL is relevant to other solid tumors as well. It's not approved yet in others, but we kind of assume eventually it probably will be. And so I think, thinking through this, how could it work, how do you refer patients is very important.  Now, coming back to the science, who should we treat with this? Well, of course, it's now an air quotes “standard of care option”, so really it ought to be available to anybody. I will note that currently, the capacity across the country to make these products is not really adequate to treat all the patients that we'd want. But who would we optimally want to treat, of course, would be people who have retained a good performance status after first line therapy, people who have tumors that are easily removable and who have not manifested a really rapid disease progression course, because then, of course, that six-week timeline probably doesn't make sense. The other really interesting data point out of the clinical trials so far is it has looked like the patients who got the least amount of benefit from anti-PD-1 immunotherapy, in other words, who progressed immediately without any kind of sustained response, those patients seem to have the best response to TILs, and that's actually sort of a great biomarker. So, this drug works the best for the population of patients where checkpoint inhibitors were not effective. And so as you think about who those patients might be in your practice, as you're listening, I think prioritizing it for primary progression on anti PD-1, again and giving it ahead thought about how would you get the patient through this process or referred to this process very quickly is really important because that lag time is a problem. Patients who have melanoma tend to progress reasonably quickly, and six weeks can be a long time in melanoma land. So, thinking ahead and building those processes is going to be important moving into the future Dr. Ryan Augustin: Definitely appreciate those practical considerations. Jason, thank you.  Moving on to our final topic, I was hoping to discuss the use of immune cell engagers in melanoma. So, similar to CAR T therapy, bispecific T-cell engagers, or BiTEs, as they're commonly known, are standard of care in refractory myeloma and lymphoma. But these antibodies engaging CD-3 on T cells and a tumor specific antigen on cancer cells are relatively new in the solid tumor space. Tarlatamab, which is a DLL-3 and CD-3 bispecific antibody, was recently approved in refractory small cell lung cancer, and, of course, tebentafusp, an HLA-directed CD-3 T cell engager was approved in uveal melanoma in 2022. Both T and NK cell engaging therapies are now offering hope in cancers where there has historically been little to offer. However, similar to our discussion with TIL therapy, bispecifics can lead to CRS and neurotoxicity, which require considerable logistical support and care coordination.  Jason, I was wondering if you could briefly discuss the current landscape of immune cell engagers in melanoma and how soon we may see these therapies enter the treatment paradigm for cutaneous disease. Dr. Jason Luke: I think it is an exciting, novel treatment strategy that I think we will only see emerge more and more. You alluded to the approval of tebentafusp in uveal melanoma, and those trials were, over the course of a decade, where those of us in solid tumor land learned how to manage cytokine release syndrome or the impact of these C3 bispecifics, in a way that we weren't used to. And what I'll caution people is that CRS, as this term, it sounds very scary because people have heard of patients that, of course, had difficult outcomes and hematological malignancies, but it's a spectrum of side effects. And so, when we think about tebentafusp, which is the approved molecule, really what we see is a lot of rash because GP100, the other tumor antigen target, is in the skin. So, patients get a rash, and then people do get fevers, but it's pretty rare to get more than that. So really what you have to have is the capacity to monitor patients for 12 hours, but it's really not more scary than that. So it really just requires treating a few people to kind of get used to these kinds of symptoms, because they're not the full-on ICU level CRS that we see with, say, CAR T-cells.  But where is the field going? Well, there's a second CD3 bispecific called brenetafusp that targets the molecule PRAME, that's in a phase 3 clinical trial now for frontline cutaneous melanoma. And tebentafusp is also being evaluated in cutaneous melanoma for refractory disease. So, it's very possible that these could be very commonly used for cutaneous melanoma, moving into, say, a two-to-four-year time horizon. And so therefore, getting used to what are these side effects, how do you manage them in an ambulatory practice for solid tumor, etc., is going to be something everyone's going to have to learn how to deal with, but I don't think it should be something that people should be afraid of.  One thing that we've seen with these molecules so far is that their kinetics of treatment effect do look slightly different than what we see with more classic oncology therapies. These drugs have a long-term benefit but doesn't always manifest as disease regression. So, we commonly see patients will have stable disease, meaning their tumor stops growing, but we don't see that it shrank a lot, but that can turn into a very meaningful long-term benefit. So that's something that we're also, as a community, going to have to get used to. It may not be the case we see tumors shrink dramatically upfront, but rather we can actually follow people with good quality- of-life over a longer period of time.  Where is the field going? You mentioned tarlatamab in small cell lung cancer, and I think we're only going to see more of these as appropriate tumor antigens are identified in different tumors. And then the other piece is these CD3 engagers generally rely upon some kind of engagement with a T cell, whether CD3 engagers, and so they can be TCR or T-cell receptor-based therapies, although they can be also SCFV-based. But that then requires new biomarkers, because TCR therapy requires HLA restriction. So, understanding that now we're going to need to profile patients based on their germline in addition to the genomics of the tumor. And those two things are separate. But I would argue at this point, basically everybody with cutaneous melanoma should be being profiled for HLA-A(*)0201, which is the major T-cell receptor HLA haplotype that we would be looking for, because whether or not you can get access immediately to tebentafusp, but therefore clinical trials will become more and more important.  Finally, in that T-cell receptor vein, there are also T cell receptor-transduced T cells, which are also becoming of relevance in the oncology community and people listening will be aware in synovial sarcoma of the first approval for a TCR-transduced T cell with afamitresgene autoleucel. And in melanoma, we similarly have TCR-transduced T cells that are coming forward in clinical trials into phase 3, the IMA203 PRAME-directed molecule particularly. And leveraging our prior conversation about TILs, we're going to have more and more cellular based therapies coming forward, which is going to make it important to understand what are the biomarkers that go with those, what are the side effect profiles of these, and how do you build your practice in a way that you can optimally get your patients access to all of these different treatments, because it will become more logistically complicated, kind of as more of these therapies come online over the next, like we said, two to four years kind of time horizon. So, it's very exciting, but there is more to do, both logistically and scientifically. Dr. Ryan Augustin: That's excellent. Thanks, Jason, and thank you so much for sharing your great insight with us today on the ASCO Daily News Podcast. Dr. Jason Luke: Thanks so much for the opportunity. Dr. Ryan Augustin: And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode, and you can follow Dr. Luke on X, formerly known as Twitter, @jasonlukemd. And you can find me, @RyanAugustinMD. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today's speakers: @ryanaugustinmd Dr. Jason Luke @jasonlukemd   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures: Dr. Ryan Augustin: No relationships to disclose Dr. Jason Luke: Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

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If you only listen to one show this year make it this one! With Producer Sean leaving early for INTERGEO, DD was joined this week by Peta Cox for this heartfelt and inspiring story. Our guest was Claire Masikewich. Claire is a seasoned marketing and communications professional at GeoVerra with a passion for advocacy that transcends her corporate career.  In May 2023, Claire's career paused when her five-year-old daughter was diagnosed with stage 4 neuroblastoma, a rare and aggressive pediatric cancer. This life-altering event ignited a new purpose: using her marketing expertise to raise awareness and advocate for more research in the severely underfunded area of pediatric cancer. Claire's story is not only one of professional success but also of personal resilience. She has faced and overcome challenges with anxiety and depression, which once felt overwhelming. Yet, with her daughter's diagnosis, Claire channeled her strength and transformed her pain into purpose, becoming a fierce advocate while navigating her daughter's treatment. By August 2024, just before Childhood Cancer Awareness Month, the Strong Like Sloane Foundation—named in honor of her daughter—became an official charitable organization in Alberta. Since launching fundraising efforts in October 2023, the foundation has raised over $155,000 for pediatric cancer research at Calgary's Riddell Centre for Cancer Immunotherapy.  Claire is a testament to the power of resilience, personal growth, and the unwavering love of a parent. Her life's journey is an inspiration to all who face personal challenges and a reminder that, with determination and support, we can find strength and light even in the most difficult of circumstances. "You don't know what you're capable of until you're asked to be capable." Music by Zach Bryan!

Join us each week as we do a quick review of three compelling stories from the pharma world — one good, one bad and one ugly. Up this week:   The good — Roche snags FDA nod for subcutaneous cancer immunotherapy  The bad — Moderna to cut R&D expenses by $1.1B  The ugly — Teva reaches $80M opioid settlement with Baltimore 

Elizabeth Jaffee, MD, is an internationally recognized expert in cancer immunology and pancreatic cancer. She is the Deputy Director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Co-director of the Skip Viragh Center for Pancreatic Cancer and Associate Director of the Bloomberg Kimmel Institute for Cancer Immunotherapy. Her research focuses on developing novel immunotherapies for the treatment and prevention of pancreatic cancer. Dr. Jaffee is a past president of AACR. She has served on a number of committees at the National Cancer Institute including the Co-chair of the Biden Moonshot Blue Ribbon Panel which identified high research priorities for the NCI. “You can be an amazing scientist, but what's most important is that whatever you do in science has implications for the patient.” From being inspired by Dr. Marie Curie's biography as a child to now becoming one of the leading names in pancreatic cancer research internationally, Dr. Elizabeth Jaffee helps us re-focus on the patient and our role as ‘physician' scientists. Tune in to this episode of The Medicine Mentors as we journey with Dr. Jaffee to connect the science with the patient. Pearls of Wisdom:   1. Regardless of the direction we take in our professional journey, we have to keep the implications of our actions and research focused on our patients and how we can help them. 2. While leadership is a forefront activity and mentorship an educational activity, both can be thought of as similar in that you're helping someone become the best version of themselves. That means taking into account each individual's strengths and weaknesses and tailoring that to the intended outcome. 3. Don't have just one mentor. It's futile hoping that one person can teach you everything you'll need to know. Find a network of individuals that can help you, which starts by putting yourself out there as someone who wants to do more and wants help.  

In this episode, Dr. Jill O'Donnell-Tormey, CEO and Director of Scientific Affairs at the Cancer Research Institute (CRI), discusses the fascinating history of cancer immunotherapy, recent breakthroughs, and the potential role of focused ultrasound in enhancing immunotherapy treatments. The conversation explores current challenges and opportunities in cancer immunotherapy, including the need for personalized treatment approaches and the promising potential of combining immunotherapy with other modalities like focused ultrasound. Dr. O'Donnell-Tormey explains key concepts such as checkpoint inhibitors and CAR T-cell therapy, making complex ideas accessible to listeners. Listeners will gain valuable insights into the collaborative efforts between CRI and the Focused Ultrasound Foundation, learning how this partnership is driving innovation in cancer treatment. Dr. O'Donnell-Tormey also reflects on her career achievements and the evolving landscape of cancer research. This episode offers a unique opportunity to learn from a leading expert in the field, providing a deeper understanding of the latest advancements in cancer immunotherapy and the potential for innovative technologies like focused ultrasound to improve treatment outcomes for cancer patients. For more information about CRI visit cancerresearch.org SHOW TRANSCRIPT ---------------------------- QUESTIONS? Email podcast@fusfoundation.org if you have a question or comment about the show, or if you would you like to connect about future guest appearances.  Email info@fusfoundation.org if you have questions about focused ultrasound or the Foundation.  FUSF SOCIAL MEDIA LinkedIn X Facebook Instagram TikTok YouTube FUSF WEBSITE https://www.fusfoundation.org SIGN UP FOR OUR FREE NEWSLETTER https://www.fusfoundation.org/newsletter-signup/ READ THE LATEST NEWSLETTER https://www.fusfoundation.org/the-foundation/news-media/newsletter/ DOWNLOAD "THE TUMOR" BY JOHN GRISHAM (FREE E-BOOK) https://www.fusfoundation.org/read-the-tumor-by-john-grisham/

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

For more than three decades, Dr. Lewis Lanier has researched natural killer (NK) cells and their innate and adaptive responses to pathogens and cancer. The Parker Institute for Cancer Immunotherapy's Chief Scientific Officer John Connolly, PhD, kicks off the first season of From Bench to Fireside™ in conversation with Distinguished Professor Emeritus at University of California, San Francisco and former Center Director for the PICI Center at UCSF. Together, they share insights on the progress of NK cell biology, reflect on Dr. Lanier's role in helping to shape PICI's mission, and the impact of cultivating collaborations in both academia and industry.++From Bench to Fireside™ is a new podcast from the Parker Institute for Cancer Immunotherapy (PICI) that takes you from behind the lab bench to the frontiers of cancer research. Each episode features an interview with members of the PICI Network, pioneers in cancer immunotherapy and leaders at world-renowned cancer research institutions. Throughout the conversations, these experts weigh in on the potential of the human immune system to target and eradicate cancer cells, from the latest breakthroughs in immuno-oncology to their impact on patients. Along the way, they unpack the hurdles encountered and the opportunities that lie ahead.Tune in to hear from scientific leaders who stand at the forefront of developing breakthrough immune therapies with the goal of turning all cancers into curable diseases.From Bench to Fireside™ is produced by the Parker Institute for Cancer Immunotherapy. Follow PICI on LinkedIn , X @parkerici or visit parkerici.org.

This episode of “From Bench to Fireside” is a special one for PICI that marks a network expansion with Weill Cornell Medicine joining as our newest PICI Center. The partnership will build upon PICI's work to accelerate research efforts in cancer immunotherapy and represents an expansion for PICI on the East Coast. Dr. Jedd D. Wolchok, the Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and newly appointed Director for the PICI Center at Weill Cornell Medicine, talks with PICI Chief Scientific Officer John Connolly, PhD, to discuss the new cancer immuno-oncology research center in NYC.Dr. Wolchok, who previously served as PICI Center Director at Memorial Sloan Kettering Cancer Center (MSKCC), shares his vision for the PICI Center at Weill Cornell, ideas for integrating clinical research and cancer care to improve access for diverse populations, ambitions to accelerate cancer immunotherapy research, and a two-decade exploration of the immune system's interaction with cancer. He also dives into challenges targeting checkpoint inhibitors, advancements in manufacturing cell therapies, personalized cancer vaccines, and the potential of engineered cytokines in next-gen immunotherapies.Get ready to go from bench to fireside with Dr. Jedd Wolchok as he shares his bold vision for the future of the field.++From Bench to Fireside™ is a podcast from the Parker Institute for Cancer Immunotherapy (PICI) that takes you from behind the lab bench to the frontiers of cancer research. Each episode features an interview with members of the PICI Network, pioneers in cancer immunotherapy and leaders at world-renowned cancer research institutions. Throughout the conversations, these experts weigh in on the potential of the human immune system to target and eradicate cancer cells, from the latest breakthroughs in immuno-oncology to their impact on patients. Along the way, they unpack the hurdles encountered and the opportunities that lie ahead.Tune in to hear from scientific leaders who stand at the forefront of developing breakthrough immune therapies with the goal of turning all cancers into curable diseases.From Bench to Fireside™ is produced by the Parker Institute for Cancer Immunotherapy. Follow PICI on ⁠LinkedIn⁠, X ⁠@parkerici⁠ or visit ⁠www.parkerici.org⁠.

In this episode, pioneering researcher Crystal Mackall, MD, Director for the PICI Center at Stanford Medicine, talks through what led to her contributions to cancer immunotherapy, including her point of view on tackling challenging problems like pediatric cancers. Dr. Mackall has dedicated her career to harnessing the immune system to treat cancer and was among a notable handful that helped conduct some of the first cancer immunotherapy clinical trials in the early 90s. She and PICI CSO John Connolly, PhD, explore what engineered “serial killer” T cells have to do with future treatments, the challenges of toxicity and partnering with the FDA to gain confidence in academia, all while getting into the crucial role that mentorship plays in fostering the next generation of scientific innovators.Get ready to go from bench to fireside with an eye-opening look at the past, present and future of cancer immunotherapy, as informed by Dr. Mackall's cutting-edge scientific experiences.++From Bench to Fireside™ is a new podcast from the Parker Institute for Cancer Immunotherapy (PICI) that takes you from behind the lab bench to the frontiers of cancer research. Each episode features an interview with members of the PICI Network, pioneers in cancer immunotherapy and leaders at world-renowned cancer research institutions. Throughout the conversations, these experts weigh in on the potential of the human immune system to target and eradicate cancer cells, from the latest breakthroughs in immuno-oncology to their impact on patients. Along the way, they unpack the hurdles encountered and the opportunities that lie ahead.Tune in to hear from scientific leaders who stand at the forefront of developing breakthrough immune therapies with the goal of turning all cancers into curable diseases. From Bench to Fireside™ is produced by the Parker Institute for Cancer Immunotherapy. Follow PICI on ⁠LinkedIn⁠, X ⁠@parkerici⁠ or visit ⁠www.parkerici.org⁠.

Introducing From Bench to Fireside™, a new podcast from the Parker Institute for Cancer Immunotherapy (PICI) that takes you from behind the lab bench to the frontiers of cancer research. Hosted by PICI Chief Scientific Officer John Connolly, each episode features an interview with members of the PICI Network, pioneers in cancer immunotherapy and leaders at world-renowned cancer research institutions. Throughout the conversations, these experts weigh in on the potential of the human immune system to target and eradicate cancer cells, from the latest breakthroughs in immuno-oncology to their impact on patients. Along the way, they unpack the hurdles encountered and opportunities ahead. Tune in to hear from scientific leaders who stand at the forefront of developing breakthrough immune therapies with the goal to turn all cancers into curable diseases. From Bench to Fireside™ is produced by the Parker Institute for Cancer Immunotherapy. Follow us on ⁠LinkedIn⁠, X ⁠@parkerici⁠ or visit ⁠www.parkerici.org⁠.

Dr. Diwakar Davar and Dr. Jason Luke discuss key abstracts from the 2024 ASCO Annual Meeting that explore triplet therapy in advanced melanoma, TIL cell therapy in immune checkpoint inhibitor–naive patients, and other novel approaches that could shape the future of immunotherapy in melanoma and beyond.  TRANSCRIPT Dr. Diwakar Davar: Hello and welcome to the ASCO Daily News Podcast. I am your guest host, Dr. Diwakar Davar. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I'm delighted to have my friend and colleague, Dr. Jason Luke, on the podcast today to discuss key abstracts in melanoma and immunotherapy that will be featured and highlighted at the 2024 ASCO Annual Meeting. Dr. Luke is an associate professor of medicine, the director of the Cancer Immunotherapeutic Center, as well as the associate director for clinical research at the University of Pittsburgh's Hillman Cancer Center.  You will find our full disclosures in the transcript of this episode.  Jason, as always, it's a pleasure to have you on this podcast to hear your key insights on trials in the immunotherapy space and melanoma development paradigm, and to have you back on this podcast to highlight some of this work.  Dr. Jason Luke: Thanks so much for the opportunity to participate. I always enjoy this heading into ASCO.  Dr. Diwakar Davar: We're going to go ahead and talk about three abstracts in the melanoma space, and we will be starting with Abstract 9504. Abstract 9504 essentially is the RELATIVITY-048 study. It describes the efficacy and safety of the triplet nivolumab, relatlimab, and ipilimumab regimen in advanced PD-1 naive melanoma. So in this abstract highlighted by Dr. Ascierto and colleagues, they report on the results of this phase 2 trial in this setting. By way of background, PD-1 inhibitors and immune checkpoint inhibitors starting in PD-1 and CTLA-4, as well as PD-1 and LAG-3, are all FDA-approved on the basis of several pivotal phase 3 trials, including KEYNOTE-006, CheckMate-066, CheckMate-067, and most recently, RELATIVITY-047. Jason, can you briefly summarize for this audience what we know about each of these drugs, at least the two combinations that we have at this time?  Dr. Jason Luke: For sure. And of course, these anti PD-1 agents, became a backbone in oncology and in melanoma dating back to more than 10 years ago now, that response rates in the treatment-naive setting to anti PD-1 with either pembrolizumab or nivolumab are roughly in the range of mid-30s to high-40s. And we've seen clinical trials adding on second agents. You alluded to them with the seminal study being CheckMate-067, where we combined a PD-1 antibody and CTLA-4 antibody or nivo + ipi. And there the response rate was increased to approximately 56%. And more recently, we have data combining PD-1 inhibitors with anti-LAG-3. So that's nivolumab and relatlimab. Now, in that trial, RELATIVITY-047, the overall response rate was described as 43%. And so that sounds, on a first pass, like a lower number, of course, than what we heard for nivolumab and ipilimumab. We have to be cautious, however, that the cross-trial comparison between those studies is somewhat fraught due to different patient populations and different study design. So I think most of us think that the response rate or the long-term outcomes between PD-1, CTLA-4, and PD-1 LAG-3 are probably roughly similar, albeit that, of course, we have much better or much longer follow up for the nivo + ipi combo.  The one other caveat to this, of course then, is that the side effect profile of these two combinations is distinct, where the incidence of high-grade immune-related adverse events is going to be roughly half with nivolumab and relatlimab, a combination of what you would see with the nivolumab and ipilimumab. So that has caused a lot of us to try to think about where we would use these different combinations. But we do see that all of these treatments can land a durable long-term response in the subset of patients that do have an initial treatment benefit. The landmark, I think, for the field has been the 7-and-a-half-year median overall survival that we've seen with PD-1 plus CTLA-4, nivo + ipi; of course, we don't have such long-term follow up for PD-1 and LAG-3. But I think that's the setting for thinking about the rationale for combining a triplet regimen of PD-1, CTLA-4, and LAG-3. Dr. Diwakar Davar: So, Jason, in your mind, given the difference in the disparity and durability of the responses for the 067 regimen of nivo-ipi, and the RELATIVITY-047 regiment of nivo-rela, what is the standard of care in the U.S., and how does it change in the rest of the world, knowing that nivo-rela is not necessarily approved in all jurisdictions? Dr. Jason Luke: So this is a major complication in our field, is that there is perhaps not complete agreement across the world in terms of what the frontline standard of care should be. I think most United States investigators, or those of us that really treat melanoma most of the time, would suggest that a combination regimen, given the enhanced response rate and longer-term outcomes, should be the consideration for the majority of patients. In fact, in my practice, it's hard to think of who I would treat with a monotherapy PD-1 approach in the PD-1 naive setting. So either nivo + ipi or nivo + rela. As you alluded to however, in other regulatory settings throughout the world, combinations might not actually even be approved at this point. So PD-1 monotherapy would be the backbone of that setting. It does set up some complications when you think about a comparator arm; say you were going to look at various combinations, probably PD-1 monotherapy would be the worldwide comparator. You have to understand though, in the United States, I think that that's a less attractive option. Dr. Diwakar Davar: So in RELATIVITY-047, Dr. Ascierto and his colleagues are looking at generating a triplet. And in this case, they looked at this in the context of frontline metastatic melanoma, 46 patients. Very interestingly, the dose of ipilimumab studied here was 1 mg/kg through 8 weeks, not the 3 mg/kg every three weeks times four doses using 067, or even the low dose ipilimumab regimen that you studied in the second line setting, which was 1 mg/kg every 3 weeks for 4 doses. So let's talk about the results and specifically the implications of potentially studying lower doses of ipi. Dr. Jason Luke: I appreciate you raising that point. I think it's really important as we think about this dataset because this triplet regimen is not by any means the only version of a triplet that could be developed using these agents. So just to give the high-level numbers from the abstract, we see from these data that the overall response rate is described as 59% and 78%, a disease control rate with patients having an unreached link. So duration of response of unreached, and then the progression-free survival at about 5 months. So those are really interesting data. But as was alluded to, it's not totally clear to me that that's the best that we could do with this regimen.   Now, you alluded to this low-dose ipilimumab schedule at 1 mg/kg every 8 weeks, and it's really important to note that we have no benchmark for that regimen in melanoma oncology. And in fact, the one study that used that regimen, which was the adjuvant study of nivolumab and ipilimumab, known as CheckMate915, is in fact the only immune checkpoint inhibitor study in melanoma oncology that was actually negative. That study noted no benefit to adding ipilimumab at 1 mg/kg every 8 weeks on top of nivolumab, again, the adjuvant setting. So it's a little bit curious to then understand what it means in this study to have that amount of ipilimumab added to the rela-nivo backbone. And that manifests in a few different ways. We see the response rate here at 59%. Again, if you compare that just against the standard nivo + ipi dosing schedule, it's about the same. So is that really an advantage to having the triplet as compared to just doing standard nivo + ipi?   We do see that it manifests in a slightly lower rate of grade 3/4 immune-related adverse events, at 39%. That's a little bit lower than what we'd expect for standard nivo + ipi. But again, I think that that emphasizes to me the possibility that some efficacy was left on the table by using this very low dose ipilimumab regimen. I think that's really a concern. It's not clear to me that these triplet data really differentiate from what we'd expect with the already approved regimen of nivo + ipi. Therefore, it makes it difficult to think about how would we really want to move this regimen forward, or should there be more work done about dose and schedule to optimize how we might want to do this?  Dr. Diwakar Davar: As far as triplet therapy in the context of frontline metastatic melanoma, meaning triplet immune therapy, because there are at least several targeted therapy triplets that are FDA-approved, [but] not necessarily widely utilized. How would you summarize the future for triplet therapy? Do you think it's potentially attractive? Do you think it's very attractive with some caveats? Dr. Jason Luke: Well, I think it's attractive, and we have 3 independently active agents. And so I do think it's a priority for the field to try to figure out how we could optimize the therapy. We've had such a revolution in melanoma oncology, talking about 7.5-year median survival from CheckMate-067, but that still implies that 7.5 years, half the patients have passed away. There's more to do here. And so I do think it should be a priority to sort this out. I guess I would be cautious, though, about advancing this regimen directly to a phase 3 trial because it doesn't seem clear to me that this is optimized in terms of what the outcome could be. If we're willing to tolerate higher rates of toxicity from other dose schedules of nivo-ipi alone, then I think we should do a little bit more here to potentially explore the space that might be possible to increase that overall response rate a little more without getting into a completely exaggerated toxicity profile that would be unacceptable. So, I do think it's exciting, but there's possibly more to do before really think about going big time with this. Dr. Diwakar Davar: Great. So now we'll switch gears and move from frontline metastatic melanoma to the second line and beyond looking at a new agent and contextualizing the effects of that actually in the frontline settings. So Abstract 9505 describes the efficacy and safety of lifileucel, which is essentially autologous tumor-infiltrating lymphocyte cell therapies, also known as TIL, in combination with pembrolizumab in patients with ICI naive, so not necessarily pretreated, but ICI naive metastatic or unresectable melanoma. This is data from the IOV-COM-202 Cohort 1A oral abstract presented by Dr. Thomas and colleagues. In this abstract, Dr. Thomas and colleagues are presenting data from the 1A cohort, which is the phase 2 portion of the frontline trial that is evaluating autologous TIL with pembro in checkpoint inhibited naive metastatic melanoma.  By way of background, TIL is FDA approved on the basis of several cohorts from a phase 2 trial. The data has been presented multiple times now by Drs. Sarli, Chesney, and multiple colleagues of ours. And essentially autologous TIL, which is generated from a surgical procedure in which a patient undergoes a surgery to extract a tumor from which T cells are then grown after ex vivo expansion and rapid expansion protocol. The entire procedure was essentially pioneered by several colleagues at the NCI, primarily Dr. Steve Rosenberg, and this approach produces objective response rates of approximately 31% to 36%. And the most recent publication demonstrated that at median follow up of approximately 2 years, the median duration of response was not reached. The median OS was about 14 months and PFS was about 4 months or so. So, can you contextualize the results of the abstract in the frontline setting? And then we'll talk a little bit about where we think this is going to go. Dr. Jason Luke: So I think this is a timely study given the recent approval. And in the abstract presented here, we see an early data cut from the PD-1 naive study, as you alluded to. So here we had 22 patients and distributed across various states of advanced melanoma. Ten out of the 22 had M1C, but there also were smatterings of earlier M1A and M1B at 18.2% and 9.1%. So this is important, as we think who the treatment population is that's going to be optimized with a TIL procedure. The median sum of diameters, meaning how much tumor burden the patients have, was about 5.5cm, and I'll note that that's a relatively modest amount of tumor burden, albeit not that unusual for an early-stage trial. So of the patients that participated, 8 had BRAF mutations so that's 36%. That's not that high, but it's reasonable. And I think the important overlying number, the response rate so far in the study, with about 17 months of follow up, was 63.6%, and that includes 22% or 23% having complete response. So those are interesting data.  And another point that was made in the abstract, which we've all seen, is that responses to TIL, all of immunotherapy but especially TIL, do seem to mature over time, meaning they deepen over time. So it's possible the response rate could go up some extent as we watch this study advance. So I think these are exciting data on some level. Also, a 63.6% response rate sounds pretty impressive, but we do have to put that in the context of a double checkpoint blockade, which we just got done discussing, gives you almost a 60% response rate, 59% response rate. So then the question really is: Is it worth the amount of effort that we could go into generating a TIL product in a treatment naive patient, and put them through the lymphodepletion that is associated with TIL and the high dose interleukin 2 treatment that accompanies the reinfusion of the TIL, if you're going to get a response rate that's roughly the same as what you would get if you gave them off the shelf nivo plus ipilimumab?  At this point it's a little bit hard to know the answer to that question. I think it could be possible that the answer is yes, because we don't know exactly which populations or patients are most likely to benefit from each of these therapies. And if it could be teased out who's not going to benefit to nivo + ipi from the get-go, then of course, we would want to offer them a therapy that has that frontline potential, durable, long-term response. But I have to say, on a one-to-one with TIL therapy, you get a lot of toxicity initially with the treatment; with nivo + ipi on the back end, you get a fair amount of toxicity with the treatment. How are we going to judge those two things? And I think we probably need a larger dataset to really have a good handle on that.  So these are interesting early data, but it's not totally clear to me that even if this holds up all the way through the trial, and we're going to talk about the design of the registration trial here in a second, a 60% response rate on its own without further biomarker stratification is a little bit hard for me to see in clinical practice why we would want to do that, given we can already just go off the shelf and give checkpoint inhibitors. Dr. Diwakar Davar: So that brings us to TILVANCE-301. So TILVANCE is a phase 3 trial. It's a registration intent trial by our Iovance colleagues evaluating the pembro-TIL regimen versus pembrolizumab alone. So in this phase 3 trial, approximately 670 patients will be randomized to either arm A, which is lifileucel + pembro. And in this arm A, patients are going to be getting lifileucel with the tumor resection, non-myeloablative lymphoid depletion, the lifileucel and abbreviated course of high-dose IL-2, and thereafter, continued pembro for the study mandated duration versus arm B, where patients will be getting just pembrolizumab monotherapy per label. Arm B patients, per the design, may cross over to receive TIL monotherapy at the time of central-blinded, radiology-confirmed disease progression.   The study design otherwise is fairly routine and, per most of our registration trials these days, patients have actually been permitted to receive neoadjuvant and adjuvant therapy, including checkpoint inhibitors, as long as the receipt of the therapy was more than 6 months prior to the inclusion of the patient in that registration trial. The dual primary efficacy endpoints as stated are BICR-assessed objective response rate as well as PFS, and the key secondary endpoint is overall survival.   So Jason, what are your thoughts on the study design and potentially the regulatory implications, particularly given, one, the control arm of pembro monotherapy, and two, the role of TIL crossover to receive TIL monotherapy at the time of BICR mandated progression for arm B? Dr. Jason Luke: So this goes to a few points that we've touched on already in the discussion here. When we think about the primary endpoints for this study, with one of them being overall response rate, one has to assume that that's a given that they would get that. I feel like that's a low bar. And we go back to that cross-trial comparison. If their results end up being that the response rates are about 60%, I don't know that that differentiates necessarily from what's already available in the field with combination immune checkpoint blockade. For the purposes of the study that would mean it's a positive study, so I think that would probably be good. But again, the comparator to pembrolizumab monotherapy, I think some of us would argue, isn't really consistent with what we would do with a patient in our clinic. So it's not that it's bad per se, but I think there's going to be a whole lot of cross-trial comparison. So if the study is positive, that would be good for getting the drug available. It's still a bit hard though, based on the preliminary data that I've seen, to imagine how this would have uptake in terms of utilization as a frontline therapy.  You alluded to the crossover, and I think there, the assumption is that patients who get TIL therapy as a second line perhaps would have an attenuated benefit. But I'm not sure that's really true. It certainly looks from the data that we have, like the patients who benefit most from TIL are going to be those who didn't respond to anti PD-1 in the front line. So I'm not sure how much difference there's going to be between first- and second-line TIL therapy, but those data will kind of wait to be seen. So I think it's an important study. Of course, the accelerated approval of TIL as a later line therapy is dependent on this trial being positive. So there is some risk that if this trial ended up not being positive, that that could have regulatory implications on the utility or availability of TILs, a subsequent line therapy. But all of these, I guess we'll have to wait to see the results. We do hope for a positive trial here, although I think it'll be nuanced to sort of interpret those data given that pembrolizumab monotherapy control arm.  Dr. Diwakar Davar: Fantastic. So we've learned a lot about TIL, both its use in the second-line setting and this very exciting but potentially risky frontline trial that is ongoing at some centers in the United States and certainly a lot of ex-U.S. enrollment.   So we'll now pivot to a related product which actually belongs to a much larger class of agents that are antigen specific T-cell therapies in a variety of different formats. And that is Abstract 9507, which is the “Phase 1 safety and efficacy of IMC-F106C, a PRAME × CD3 ImmTAC bispecific, in post-checkpoint cutaneous melanoma (CM).” Now, in this abstract, Dr. Omid Hamid and colleagues reported the results of this phase 1 trial. As a disclosure, I'm an investigator and the last author on this manuscript. Jason, it would be important for our audience, for us to maybe firstly, outline the PRAME as a target, and then the ImmTAC as a platform prior to discussing these results. So let's start with the target PRAME, which I think is a target that you know well. So why don't you start with the target and we'll talk a little bit about that and then the platform? Dr. Jason Luke: Yeah, so I think for the audience, being aware of PRAME, or the Preferentially Expressed Antigen in Melanoma, is going to be quite important moving into the future. So PRAME as a therapeutic target is a cancer testis antigen that's overexpressed in tumor tissues. And of course the name has melanoma in it, but it's not uniquely present in melanoma. So the expression patterns of PRAME as a target are very high in melanoma. So in cutaneous disease, this is upwards of almost 100%, somewhere between 95% and 100%, in metastatic melanoma tissues. And PRAME has several different roles on a molecular level, although I don't think for our purposes here, it's so much important to be aware of them, but rather that this is a very highly expressed target, which then can make it attractive for using T cell receptor-based therapies. And so in the case we're talking about here on the ImmTAC platform, that's a CD3 PRAME×CD3 bispecific approach. But of course there are other approaches that can also be taken, such as TCR T cells that directly go after PRAME itself. Dr. Diwakar Davar: Let's now talk about the platform and how it differs from some of the other antigen targeting platforms that you have just alluded to. I think the Immtac platform is basically a fusion protein comprising engineered TCRs with a CD3 specific short chain variable fragment. And then the engineered TCR therefore binds antigens in an HLA dependent fashion. But you know quite a lot about some of these alternative platforms, and I think it'll be important to contextualize for the audience the difference between ImmTAC, which is a prototype drug that is already approved in the context of tebentafusp. But how does this differ from some of the other more nuanced platforms, such as the Immatics TCR or TCR platform and TScan TCRT nanoplasmonic platform.  Dr. Jason Luke: Right. So the ImmTAC platform as alluded to is already approved on the market with tebentafusp, which is the gp100-CD3 bispecific molecule. And the advantage of that approach is infusion off the shelf of a drug. The downside of it is that it is a weekly dosing strategy as it stands now. And there are some complicated disease kinetics associated with treatment response, which we'll come back to in the context of the PRAME bispecific. Those are, in contrast with T-cell receptor-transduced T cells, as an alternative strategy, which is a form of adopted cell transfer. So we just got done talking about TIL therapy, which of course, is trying to take lymphocytes out of the tumor and grow them up and then give them back. Here with TCR-transduced T cells, we're talking about taking leukopak from the blood and then using different transfection approaches to try to insert into the lymphocytes of the patient a T cell receptor that recognizes to a certain cancer antigen, in this case, PRAME.  So you alluded to a couple of different companies that have different platforms to do this. Immatics has a molecule called IMA 203, for which there have been data disclosed in the past year, again showing some very interesting responses in patients who have highly refractory melanoma. That process, though, again, does require lymphodepletion before you reinfuse the cells. Again, in contrast, the ImmTAC, which is an off the shelf revenue administer, there you have to make the product and then bring the patient back, lymphodeplete, and give the cells back. Immatics platform uses a viral transfection vector. The T scan approach that you alluded to before uses an approach of a mixed system on multiple HLA backgrounds to try to get past HLA-A*02:01 only, and in this case, uses a plasmid-based transfection syndrome that perhaps can be more broadly utilized given the lack of a lentiviral vector.   So this is a complicated area of technology that starts to get into immune engineering, and I think for the purposes of this discussion, we don't want to belabor it. But both of these technologies, talking about the CD3 bispecific with the off the shelf aspect of it and the adoptive cell transfer, each of these using a T cell receptor-based therapy to try to go after PRAME, I think have very high upsides, and I think we'll initially see it in melanoma over the next year or so. But this is likely to be relevant to multiple tumor types beyond melanoma.  Dr. Diwakar Davar: So let's discuss the results of this phase 1 trial. IMC-F106C, like all other ImmTAC, is administered intravenously and does require step-up dosing. You alluded to the fact that the tebentafusp was approved, and it's one of those drugs that is fortunately otherwise administered weekly, which can be difficult for the patient and requires at least the patient spend the first 3 doses overnight under some kind of monitoring, whether it's in the hospital or extended outpatient monitoring, for at least 23 hours. The efficacy of this agent and this platform appears to be surprising in that you tend to see a relatively low RECIST response rate. We'll have you comment a little bit on why that is the case and what may be the role of ctDNA, as opposed to conventional RECIST in assessing response.   At least in this trial, they mandated pre-testing, but did not require it for study enrollment. And pre-positivity was defined using immunohistochemistry with a relatively low H-score of 1%. And the molecular response definition was a 0.5 log or a 68% ctDNA reduction just prior to the first imaging assessment. So how do you contextualize the results? But maybe before you talk a little bit about the results, the ctDNA aspect, that was a recent publication by Drs. Rich Carvajal, Alex Shoushtari, and I think you are also involved in that.  Dr. Jason Luke: So, I think an interesting observation around tebentafusp has been that ctDNA may be a better predictor of long-term outcomes. And how you define ctDNA response is still something that the field is grappling with, albeit that I think is going to be an important consideration as we think about these novel therapies, these ImmTACs and other CD3 engagers moving into the future. But for the purposes of the abstract here, we see that in the population of patients treated, there were 46 patients with cutaneous melanoma. The majority got monotherapy with IMC-F106C, and that's the PRAME bispecific. So 40 patients that got monotherapy and six who got a combination with checkpoint inhibitor. All these patients had prior treatment with immunotherapy, and most of them had PD-1 and CTLA-4 antibody with a small spanner that also had BRAF inhibitors.  In terms of that PRAME testing that you alluded to, based on the immunohistochemistry H-score greater than 1%, 35 out of 40 patients were positive, so they defined 5 as negative. And we could come back if we have time, but there are other ways to do PRAME testing as well that I think may become unique for different agents, maybe an important biomarker. In the data, 31 out of the 46 patients were RECIST evaluable. The outcomes of those patients were to note that the response rate was 13%, which was four partial responses. But 35% of patients had tumor regression with a disease control rate at 65%. It was clear that there was an enrichment by PRAME positivity for both progression free and overall survival. So those patients who had obvious positivity essentially had a doubling of the PFS and more than the doubling of the OS, 2.1 to 4.1 months for TFS and landmark OS, 40% to 94%. So I think these are quite intriguing data.  It does suggest that for the vast majority of patients, we do see some induction of the antitumor effect, albeit that RECIST might undercall the effect. And so this may become another area where the ctDNA monitoring might be able to help us to understand who is likely to have really long-term benefit from this therapy. And given the number of emerging treatments that we have for melanoma, we might be able to really focus in on that group of patients in terms of optimizing how we would use this drug moving into the future. Dr. Diwakar Davar: So you talked about a response rate, and at first glance, this response rate is a little underwhelming. We're talking about 4 out of 31 RECIST evaluable patients, 13%. So it's in the double digits, but barely. So how enthusiastic are you about the results? How does it contrast with at least the publicly known data from other brain targeting approaches, such as the IMA203 agent, understanding that while they may be all targeting somewhat the same target, they are actually extraordinarily different platforms. One's off the shelf, one's highly customized. How do you contextualize the results? How would it contrast with other cellular approaches?  Dr. Jason Luke: I think it's important, again, to emphasize the point you made, which is that they're very different kinds of treatments. So even though they both target PRAME, they're going to be differently useful, and they could be quite useful for different groups of patients. And so here we see that there is a subfraction of patients who are deriving long-term benefit. And we commonly have an argument in our field about, is overall response rate really a useful monitor that describes a patient-centric outcome? While, of course, patients like to know their tumors are shrinking, what they want the most is for the tumors not to get worse and for them not to pass away from cancer. So I think I'm enthusiastic about these results, but emphasizing the point that we need to better understand who is going to benefit the most from this CD3 bispecific PRAME approach and how we're going to be able to harness that into long term benefit for patients because there's no doubt that an off the shelf therapy has a high degree of value relative to adoptive cell transfer, which sort of requires a big wind up.   So when you say, what does it contrast with? Well, the data for IMA203 has shown more than a 50% response rate in patients with more than 5 lines of therapy for metastatic disease. That really looks quite exciting. And several of those patients are now out for quite an extended period, meaning 2 years or more given only a single dose of IMA203. But again, the caveat being, you have to make the cell product for the patient, and that takes time. You lymphodeplete the patient, not all patients can tolerate that in the refractory disease setting, and then they have to be able to tolerate the reinfusion of the cells. And so this drug, IMC-F106C, looks very promising. Moving into the earlier phase trial that we'll talk about, I think the TCR T cell program has a lot of upsides for patients, especially with refractory disease. And so I think these two different approaches are really on parallel tracks. They both target PRAME, but I don't think they necessarily need to be compared one to one, as if they're going to go head-to-head with each other. Dr. Diwakar Davar: So now we'll talk a little bit about the frontline setting, because on the basis of some of these results, Immunocore is now exploring IMC-F106C frontline melanoma. This trial is actually being presented as a trial in progress at this meeting by Georgina Long and colleagues. Some of us are co-authors in that abstract. And in this study, HLA-A*02:01 positive patients with advanced unresectable melanoma will be randomized one to one to the combination of IMC-F106C, which actually, I think after this meeting will be known as bre-ni in combination with nivolumab versus nivolumab regimens, which will either be nivo or nivo-rela, investigators choice and likely dependent on region. So what do you think of the challenge of this trial? We talked about some of the challenges of the TILVANCE trial earlier. But what is going to be the challenge of this trial and in this setting, particularly given the response rates that we've seen so far? Dr. Jason Luke: Yeah, so, similar to comments we had before, thinking about what the optimal control arm is for a study like this is difficult, and so that'll be important as we think about interpreting the results. One has to assume for the purpose of this conversation that it is a positive trial, and that adding the PRAME bispecific theory does lead to an improvement in progression free survival relative to those in checkpoint alone approaches. And I think the magnitude of that difference is going to be of some relevance. And then I think importantly, also figure out who needs this treatment and who's going to benefit long term are going to be really important considerations.  We alluded to how this drug requires an intensive dosing period at the get go, and so telling patients that they need to come in weekly or bi-weekly initially for some number of weeks before they switch to a longer-term intermittent regimen, that comes with real world considerations for patients, their families, their finances, etc. So the benefit has to be clearly obvious that makes it worthwhile doing that, again, because a default could be giving drugs that we've had for 10 years with the nivolumab and ipilimumab. So there's going to be a lot of cross-trial comparison that is going to necessarily have to take place here to think about what these results really mean in the context of other available therapies.  I think the study is reasonable to do. I think this is a very active agent. There's no doubt there's a subset of patients who seem to benefit a lot from it. And I would just emphasize the point that that's probably going to be the most important thing to really drill down on is under the assumption there's a positive trial, we need to know who those people are so we could optimize giving this kind of a treatment to them. Dr. Diwakar Davar: I guess one important point to underscore what Jason said about potential predictive biomarkers, I think as part of the presentation, Dr. Hamid and colleagues will be talking about a candidate predictive biomarker of this agent, which is potentially class specific and not necessarily agent specific of a T cell signature that potentially could define patients who are more likely to benefit from this agent.  So, Jason, as always, thank you for sharing your expertise and insights with the team today. We certainly look forward to catching up again for our wrap up episode after the annual meeting where we'll talk about some of the data that we could not talk about, particularly the late breaking abstracts and other key advances that will shape the future of, certainly the field of immunotherapy and melanoma, potentially the field of cancer immunotherapy at large. Dr. Jason Luke: Oh, thanks very much for the opportunity. Dr. Diwakar Davar: And thank you to our listeners today. You'll find the links to the abstracts discussed today in the transcript of this episode. And finally, if you value the insights that you hear on this podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. So thank you, and we'll see you soon.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today's speakers:   Dr. Diwakar Davar   @diwakardavar   Dr. Jason Luke   @jasonlukemd      Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:       Dr. Diwakar Davar:     Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences    Consulting or Advisory Role: Instil Bio, Vedanta Biosciences    Consulting or Advisory Role (Immediate family member): Shionogi    Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences    Research Funding (Inst.): Zucero Therapeutics    Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy       Dr. Jason Luke:    Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX    Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine    Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure    Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)    Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio      

Dr Bernardo Goulart (US Food and Drug Administration) discusses his paper on correlations of response rate and progression-free survival with overall survival in immunotherapy trials for metastatic non-small-cell lung cancer.Read the full article:https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00040-8/fulltext?dgcid=buzzsprout_icw_podcast_generic_lanoncContinue this conversation on social!Follow us today at...https://twitter.com/thelancet & https://Twitter.com/TheLancetOncolhttps://instagram.com/thelancetgrouphttps://facebook.com/thelancetmedicaljournalhttps://linkedIn.com/company/the-lancethttps://youtube.com/thelancettv

More than half of U.S. households include pets, but there has been a lack of medical treatments developed specifically for small animals. Biotech companies are working to change that with new treatment options that both borrow from and, potentially, advance human health discoveries.Follow us on LinkedIn, X, Facebook and Instagram. Visit us at https://www.bio.org/

Marcel van den Brink, MD,  is the Head and Alan N. Houghton Chair of the Division of Hematologic Oncology at Memorial Sloan Kettering Cancer Center. He is internationally renowned for his work in the field of bone marrow transplantation, the gut microbiome, and immunotherapy. He is also the Co-Director of the Parker Institute for Cancer Immunotherapy and Chairman of the Board of DKMS, an international nonprofit organization devoted to bone marrow donor registration. He is a recipient of numerous prestigious awards and is a member of the American Society for Clinical Investigation and he has been elected to the Royal Netherlands Academy of Arts and Sciences for his contributions in the field of hematologic malignancies. “Finding solutions is often as simple as shutting up and listening to what people formulate as the problem and what they have thought of as the answer. Without fail, I'm surprised that they've got something better than I could have come up with.” Join us in this episode of The Medicine Mentors where Chairman of Heme Malignancies at MSKCC, Dr. Marcel van den Brink, shares tips of effective leadership. Tune in as we learn about the five-minute ‘no talking, only listening' rule at the start of meetings and why the best leaders find comfort in not knowing everything. Pearls of Wisdom:   1. We will be leaders before we know it, and the simple formula of leadership is listening. When we conduct meetings, all we have to do is be quiet for the first five minutes and listen. 2. To know when we are ready to move on to the next stage, the next level, we have to know what we don't know, that is, do we know how to prioritize what matters, and if not, are we ready to seek help for it? 3. Failure and success often follow a 9:1 ratio, and so, to increase our chances of success, we should try our hands in different endeavors to see where we can truly shine. 4. Just like listening is the pathway to leadership, respect is the pathway to teamwork, and we should be mindful of it in our day-to-day interactions.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC information, and to apply for credit, please visit us at PeerView.com/GZR865. CME/MOC credit will be available until February 14, 2025.PATHway to Decoding the Impact of Cancer Immunotherapy: Latest Advances in Biomarker Testing and Pathologic Response Assessment In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresCo-Chair/PlannerKurt A. Schalper, MD, PhD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; Agenus Inc.; AstraZeneca; Bristol Myers Squibb; CDR-Life Inc.; Clinica Alemana de Santiago; EMD Serono Inc.; F.Hoffmann-La Roche; Genmab A/S; Indaptus Therapeutics; Janssen Pharmaceuticals, Inc.; Merck Sharpe & Dohme; Moderna, Inc.; Molecular Templates, Inc.; OnCusp Therapeutics; Parthenon/Incendia Therapeutics; Repertoire Therapeutics; Sanofi; Sensei Biotherapeutics; Shattuck Labs, Inc.; and Takeda Pharmaceutical Company Limited.Grant/Research Support from Akoya Biosciences; AstraZeneca; Boehringer Ingelheim; Bristol Myers Squibb; F. Hoffmann-La Roche; Lilly; Merck Sharpe & Dohme; Ribon Therapeutics; Surface Oncology; Takeda Pharmaceutical Company Limited; and Tesaro Inc./GSK.Speakers Bureau participant with Bristol Myers Squibb; Fluidigm Corporation; Genmab A/S; Merck & Co., Inc.; Sanofi; and Takeda Pharmaceutical Company Limited.Co-Chair/PlannerVamsidhar Velcheti, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Bristol Myers Squibb; Galvanize Therapeutics, Inc.; GSK; Merck & Co., Inc.; Novocure; TAIHO ONCOLOGY, INC.; and Takeda Pharmaceutical Company Limited.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC information, and to apply for credit, please visit us at PeerView.com/GZR865. CME/MOC credit will be available until February 14, 2025.PATHway to Decoding the Impact of Cancer Immunotherapy: Latest Advances in Biomarker Testing and Pathologic Response Assessment In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresCo-Chair/PlannerKurt A. Schalper, MD, PhD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; Agenus Inc.; AstraZeneca; Bristol Myers Squibb; CDR-Life Inc.; Clinica Alemana de Santiago; EMD Serono Inc.; F.Hoffmann-La Roche; Genmab A/S; Indaptus Therapeutics; Janssen Pharmaceuticals, Inc.; Merck Sharpe & Dohme; Moderna, Inc.; Molecular Templates, Inc.; OnCusp Therapeutics; Parthenon/Incendia Therapeutics; Repertoire Therapeutics; Sanofi; Sensei Biotherapeutics; Shattuck Labs, Inc.; and Takeda Pharmaceutical Company Limited.Grant/Research Support from Akoya Biosciences; AstraZeneca; Boehringer Ingelheim; Bristol Myers Squibb; F. Hoffmann-La Roche; Lilly; Merck Sharpe & Dohme; Ribon Therapeutics; Surface Oncology; Takeda Pharmaceutical Company Limited; and Tesaro Inc./GSK.Speakers Bureau participant with Bristol Myers Squibb; Fluidigm Corporation; Genmab A/S; Merck & Co., Inc.; Sanofi; and Takeda Pharmaceutical Company Limited.Co-Chair/PlannerVamsidhar Velcheti, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Bristol Myers Squibb; Galvanize Therapeutics, Inc.; GSK; Merck & Co., Inc.; Novocure; TAIHO ONCOLOGY, INC.; and Takeda Pharmaceutical Company Limited.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC information, and to apply for credit, please visit us at PeerView.com/GZR865. CME/MOC credit will be available until February 14, 2025.PATHway to Decoding the Impact of Cancer Immunotherapy: Latest Advances in Biomarker Testing and Pathologic Response Assessment In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresCo-Chair/PlannerKurt A. Schalper, MD, PhD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AbbVie Inc.; Agenus Inc.; AstraZeneca; Bristol Myers Squibb; CDR-Life Inc.; Clinica Alemana de Santiago; EMD Serono Inc.; F.Hoffmann-La Roche; Genmab A/S; Indaptus Therapeutics; Janssen Pharmaceuticals, Inc.; Merck Sharpe & Dohme; Moderna, Inc.; Molecular Templates, Inc.; OnCusp Therapeutics; Parthenon/Incendia Therapeutics; Repertoire Therapeutics; Sanofi; Sensei Biotherapeutics; Shattuck Labs, Inc.; and Takeda Pharmaceutical Company Limited.Grant/Research Support from Akoya Biosciences; AstraZeneca; Boehringer Ingelheim; Bristol Myers Squibb; F. Hoffmann-La Roche; Lilly; Merck Sharpe & Dohme; Ribon Therapeutics; Surface Oncology; Takeda Pharmaceutical Company Limited; and Tesaro Inc./GSK.Speakers Bureau participant with Bristol Myers Squibb; Fluidigm Corporation; Genmab A/S; Merck & Co., Inc.; Sanofi; and Takeda Pharmaceutical Company Limited.Co-Chair/PlannerVamsidhar Velcheti, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Bristol Myers Squibb; Galvanize Therapeutics, Inc.; GSK; Merck & Co., Inc.; Novocure; TAIHO ONCOLOGY, INC.; and Takeda Pharmaceutical Company Limited.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/AAU865. CME/MOC/AAPA/IPCE credit will be available until February 18, 2025.Calibrating Care Across the HCC Continuum: Guidance on Delivering Effective Care With Modern Immunotherapy and Targeted Approaches In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and Blue Faery: The Adrienne Wilson Liver Cancer Association. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis educational activity is supported through independent educational grants from AstraZeneca, Eisai Inc., Exelixis, Inc., Merck & Co., Inc., and Novocure, Inc.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresChair/PlannerGhassan Abou-Alfa, MD, MBA, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Autem Therapeutics; Berry Genomics; BioNTech; Boehringer Ingelheim Pharmaceuticals, Inc.; Bristol Myers Squibb; Eisai Inc.; Exelixis, Inc.; F. Hoffmann-La Roche Ltd/Genentech, Inc.; Incyte; Ipsen Biopharmaceuticals, Inc.; Merck & Co., Inc.; Merus; Neogene Therapeutics; NewBridge Pharmaceuticals; Novartis Pharmaceuticals Corporation; Servier Laboratories; Tempus; Vector; and Yiviva.Grant/Research Support from Agenus Inc.; Arcus Biosciences, Inc.; AstraZeneca; BioNTech; Bristol Myers Squibb; Elicio Therapeutics Inc; F. Hoffmann-La Roche Ltd/Genentech, Inc.; Helsinn Healthcare SA; Parker Institute for Cancer Immunotherapy; Pertzye; Puma Biotechnology, Inc.; QED Therapeutics; and Yiviva.Faculty/PlannerAnthony El-Khoueiry, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Exelixis, Inc.; F. Hoffmann-La Roche AG/Genentech, Inc.; Merck & Co., Inc.; Qurient; and Senti Biosciences.Grant/Research Support from Astex Pharmaceuticals; AstraZeneca; Auransa Inc.; and Fulgent Pharma.Faculty/PlannerAhmed Omar Kaseb, MD, CMQ, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for Bristol Myers Squibb; Eisai Inc.; Exelixis, Inc.; Genentech, Inc.; Merck & Co., Inc.; and Pfizer.Grant/Research Support from Bristol Myers Squibb; Eisai Inc.; Exelixis, Inc.; Genentech, Inc.; Merck & Co., Inc.; Pfizer; and Tvardi Therapeutics.Faculty/PlannerStacey M. Stein, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Eisai Inc.; Exelixis, Inc.; and Genentech, Inc.Data Safety Monitoring Board for Aethlon Medical, Inc.and Genentech, Inc.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.PlannerAndrea Wilson WoodsPresident & Founder, Blue FaeryAndrea Wilson Woods has a financial interest/relationship or affiliation in the form of:Consultant for AstraZeneca and Humanise Health.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/AAU865. CME/MOC/AAPA/IPCE credit will be available until February 18, 2025.Calibrating Care Across the HCC Continuum: Guidance on Delivering Effective Care With Modern Immunotherapy and Targeted Approaches In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and Blue Faery: The Adrienne Wilson Liver Cancer Association. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis educational activity is supported through independent educational grants from AstraZeneca, Eisai Inc., Exelixis, Inc., Merck & Co., Inc., and Novocure, Inc.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresChair/PlannerGhassan Abou-Alfa, MD, MBA, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Autem Therapeutics; Berry Genomics; BioNTech; Boehringer Ingelheim Pharmaceuticals, Inc.; Bristol Myers Squibb; Eisai Inc.; Exelixis, Inc.; F. Hoffmann-La Roche Ltd/Genentech, Inc.; Incyte; Ipsen Biopharmaceuticals, Inc.; Merck & Co., Inc.; Merus; Neogene Therapeutics; NewBridge Pharmaceuticals; Novartis Pharmaceuticals Corporation; Servier Laboratories; Tempus; Vector; and Yiviva.Grant/Research Support from Agenus Inc.; Arcus Biosciences, Inc.; AstraZeneca; BioNTech; Bristol Myers Squibb; Elicio Therapeutics Inc; F. Hoffmann-La Roche Ltd/Genentech, Inc.; Helsinn Healthcare SA; Parker Institute for Cancer Immunotherapy; Pertzye; Puma Biotechnology, Inc.; QED Therapeutics; and Yiviva.Faculty/PlannerAnthony El-Khoueiry, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Exelixis, Inc.; F. Hoffmann-La Roche AG/Genentech, Inc.; Merck & Co., Inc.; Qurient; and Senti Biosciences.Grant/Research Support from Astex Pharmaceuticals; AstraZeneca; Auransa Inc.; and Fulgent Pharma.Faculty/PlannerAhmed Omar Kaseb, MD, CMQ, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for Bristol Myers Squibb; Eisai Inc.; Exelixis, Inc.; Genentech, Inc.; Merck & Co., Inc.; and Pfizer.Grant/Research Support from Bristol Myers Squibb; Eisai Inc.; Exelixis, Inc.; Genentech, Inc.; Merck & Co., Inc.; Pfizer; and Tvardi Therapeutics.Faculty/PlannerStacey M. Stein, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Eisai Inc.; Exelixis, Inc.; and Genentech, Inc.Data Safety Monitoring Board for Aethlon Medical, Inc.and Genentech, Inc.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.PlannerAndrea Wilson WoodsPresident & Founder, Blue FaeryAndrea Wilson Woods has a financial interest/relationship or affiliation in the form of:Consultant for AstraZeneca and Humanise Health.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/AAU865. CME/MOC/AAPA/IPCE credit will be available until February 18, 2025.Calibrating Care Across the HCC Continuum: Guidance on Delivering Effective Care With Modern Immunotherapy and Targeted Approaches In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and Blue Faery: The Adrienne Wilson Liver Cancer Association. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis educational activity is supported through independent educational grants from AstraZeneca, Eisai Inc., Exelixis, Inc., Merck & Co., Inc., and Novocure, Inc.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresChair/PlannerGhassan Abou-Alfa, MD, MBA, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Autem Therapeutics; Berry Genomics; BioNTech; Boehringer Ingelheim Pharmaceuticals, Inc.; Bristol Myers Squibb; Eisai Inc.; Exelixis, Inc.; F. Hoffmann-La Roche Ltd/Genentech, Inc.; Incyte; Ipsen Biopharmaceuticals, Inc.; Merck & Co., Inc.; Merus; Neogene Therapeutics; NewBridge Pharmaceuticals; Novartis Pharmaceuticals Corporation; Servier Laboratories; Tempus; Vector; and Yiviva.Grant/Research Support from Agenus Inc.; Arcus Biosciences, Inc.; AstraZeneca; BioNTech; Bristol Myers Squibb; Elicio Therapeutics Inc; F. Hoffmann-La Roche Ltd/Genentech, Inc.; Helsinn Healthcare SA; Parker Institute for Cancer Immunotherapy; Pertzye; Puma Biotechnology, Inc.; QED Therapeutics; and Yiviva.Faculty/PlannerAnthony El-Khoueiry, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Exelixis, Inc.; F. Hoffmann-La Roche AG/Genentech, Inc.; Merck & Co., Inc.; Qurient; and Senti Biosciences.Grant/Research Support from Astex Pharmaceuticals; AstraZeneca; Auransa Inc.; and Fulgent Pharma.Faculty/PlannerAhmed Omar Kaseb, MD, CMQ, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for Bristol Myers Squibb; Eisai Inc.; Exelixis, Inc.; Genentech, Inc.; Merck & Co., Inc.; and Pfizer.Grant/Research Support from Bristol Myers Squibb; Eisai Inc.; Exelixis, Inc.; Genentech, Inc.; Merck & Co., Inc.; Pfizer; and Tvardi Therapeutics.Faculty/PlannerStacey M. Stein, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Eisai Inc.; Exelixis, Inc.; and Genentech, Inc.Data Safety Monitoring Board for Aethlon Medical, Inc.and Genentech, Inc.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.PlannerAndrea Wilson WoodsPresident & Founder, Blue FaeryAndrea Wilson Woods has a financial interest/relationship or affiliation in the form of:Consultant for AstraZeneca and Humanise Health.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/AAU865. CME/MOC/AAPA/IPCE credit will be available until February 18, 2025.Calibrating Care Across the HCC Continuum: Guidance on Delivering Effective Care With Modern Immunotherapy and Targeted Approaches In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and Blue Faery: The Adrienne Wilson Liver Cancer Association. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis educational activity is supported through independent educational grants from AstraZeneca, Eisai Inc., Exelixis, Inc., Merck & Co., Inc., and Novocure, Inc.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresChair/PlannerGhassan Abou-Alfa, MD, MBA, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Autem Therapeutics; Berry Genomics; BioNTech; Boehringer Ingelheim Pharmaceuticals, Inc.; Bristol Myers Squibb; Eisai Inc.; Exelixis, Inc.; F. Hoffmann-La Roche Ltd/Genentech, Inc.; Incyte; Ipsen Biopharmaceuticals, Inc.; Merck & Co., Inc.; Merus; Neogene Therapeutics; NewBridge Pharmaceuticals; Novartis Pharmaceuticals Corporation; Servier Laboratories; Tempus; Vector; and Yiviva.Grant/Research Support from Agenus Inc.; Arcus Biosciences, Inc.; AstraZeneca; BioNTech; Bristol Myers Squibb; Elicio Therapeutics Inc; F. Hoffmann-La Roche Ltd/Genentech, Inc.; Helsinn Healthcare SA; Parker Institute for Cancer Immunotherapy; Pertzye; Puma Biotechnology, Inc.; QED Therapeutics; and Yiviva.Faculty/PlannerAnthony El-Khoueiry, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Exelixis, Inc.; F. Hoffmann-La Roche AG/Genentech, Inc.; Merck & Co., Inc.; Qurient; and Senti Biosciences.Grant/Research Support from Astex Pharmaceuticals; AstraZeneca; Auransa Inc.; and Fulgent Pharma.Faculty/PlannerAhmed Omar Kaseb, MD, CMQ, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for Bristol Myers Squibb; Eisai Inc.; Exelixis, Inc.; Genentech, Inc.; Merck & Co., Inc.; and Pfizer.Grant/Research Support from Bristol Myers Squibb; Eisai Inc.; Exelixis, Inc.; Genentech, Inc.; Merck & Co., Inc.; Pfizer; and Tvardi Therapeutics.Faculty/PlannerStacey M. Stein, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Eisai Inc.; Exelixis, Inc.; and Genentech, Inc.Data Safety Monitoring Board for Aethlon Medical, Inc.and Genentech, Inc.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.PlannerAndrea Wilson WoodsPresident & Founder, Blue FaeryAndrea Wilson Woods has a financial interest/relationship or affiliation in the form of:Consultant for AstraZeneca and Humanise Health.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/AAU865. CME/MOC/AAPA/IPCE credit will be available until February 18, 2025.Calibrating Care Across the HCC Continuum: Guidance on Delivering Effective Care With Modern Immunotherapy and Targeted Approaches In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and Blue Faery: The Adrienne Wilson Liver Cancer Association. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis educational activity is supported through independent educational grants from AstraZeneca, Eisai Inc., Exelixis, Inc., Merck & Co., Inc., and Novocure, Inc.Disclosure PolicyAll relevant conflicts of interest have been mitigated prior to the commencement of the activity.Faculty/Planner DisclosuresChair/PlannerGhassan Abou-Alfa, MD, MBA, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Autem Therapeutics; Berry Genomics; BioNTech; Boehringer Ingelheim Pharmaceuticals, Inc.; Bristol Myers Squibb; Eisai Inc.; Exelixis, Inc.; F. Hoffmann-La Roche Ltd/Genentech, Inc.; Incyte; Ipsen Biopharmaceuticals, Inc.; Merck & Co., Inc.; Merus; Neogene Therapeutics; NewBridge Pharmaceuticals; Novartis Pharmaceuticals Corporation; Servier Laboratories; Tempus; Vector; and Yiviva.Grant/Research Support from Agenus Inc.; Arcus Biosciences, Inc.; AstraZeneca; BioNTech; Bristol Myers Squibb; Elicio Therapeutics Inc; F. Hoffmann-La Roche Ltd/Genentech, Inc.; Helsinn Healthcare SA; Parker Institute for Cancer Immunotherapy; Pertzye; Puma Biotechnology, Inc.; QED Therapeutics; and Yiviva.Faculty/PlannerAnthony El-Khoueiry, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Exelixis, Inc.; F. Hoffmann-La Roche AG/Genentech, Inc.; Merck & Co., Inc.; Qurient; and Senti Biosciences.Grant/Research Support from Astex Pharmaceuticals; AstraZeneca; Auransa Inc.; and Fulgent Pharma.Faculty/PlannerAhmed Omar Kaseb, MD, CMQ, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for Bristol Myers Squibb; Eisai Inc.; Exelixis, Inc.; Genentech, Inc.; Merck & Co., Inc.; and Pfizer.Grant/Research Support from Bristol Myers Squibb; Eisai Inc.; Exelixis, Inc.; Genentech, Inc.; Merck & Co., Inc.; Pfizer; and Tvardi Therapeutics.Faculty/PlannerStacey M. Stein, MD, has a financial interest/relationship or affiliation in the form of:Consultant and/or Advisor for AstraZeneca; Eisai Inc.; Exelixis, Inc.; and Genentech, Inc.Data Safety Monitoring Board for Aethlon Medical, Inc.and Genentech, Inc.Planning Committee and Reviewer DisclosuresPlanners, independent reviewers, and staff of PVI, PeerView Institute for Medical Education, do not have any relevant financial relationships related to this CE activity unless listed below.PlannerAndrea Wilson WoodsPresident & Founder, Blue FaeryAndrea Wilson Woods has a financial interest/relationship or affiliation in the form of:Consultant for AstraZeneca and Humanise Health.

A new study published in the journal Nature details breakthrough T-cell immunotherapy research from Northwestern Medicine. In this episode, Jaehyuk Choi, MD, PhD, senior author of the paper, explains how a gene mutation found in T-cells of patients with lymphoma could hold the key to a potent cancer-fighting immunotherapy for solid tumor cancers, which account for 90 percent of all cancers. 

A discussion of the neurological complications of systemic cancer treatments, with Drs. Kevin Yan and Mary Barden.Note: This podcast is intended solely as an educational tool for learners, especially neurology residents. The contents should not be interpreted as medical advice.Further Reading:Taylor JW. Neurologic Complications of Conventional Chemotherapy and Radiation Therapy. Continuum (Minneap Minn). 2023 Dec 1;29(6):1809-1826. doi: 10.1212/CON.0000000000001358. PMID: 38085899.Wang N. Neurologic Complications of Cancer Immunotherapy. Continuum (Minneap Minn). 2023 Dec 1;29(6):1827-1843. doi: 10.1212/CON.0000000000001362. PMID: 38085900.

One of the most amazing successes in the battle against cancer over the last two decades has been the introduction of antibody drugs that harness the body's own immune system to kill tumor cells. Finding those drugs may sound like a biology problem rather than a machine learning or a big-data problem. But actually, these days, it's both. Harry's guest this week is Leonard Wossnig, who's the chief technology officer for a UK company called LabGenius. The company uses a combination of synthetic biology, high-throughput assays, and machine learning to hunt for new drugs within a subclass of antibody medicines called T cell engagers that, loosely speaking, can grab tumor cells with one end and then grab tumor-killing T cells from the bloodstream with the other end. And Wossnig says the key to the whole thing is having the best data possible—meaning, data about their candidate T cell engagers and how specifically they bind to their targets in the lab assays. LabGenius has built an automated platform called EVA that runs experiment after experiment and uses active learning to zero in on T cell engagers with just the right ability to bind to their intended targets. One of the big takeaways from the interview is that companies that want to use AI to speed up drug discovery need the biggest, cleanest, and most consistent data sets possible.For a full transcript of this episode, please visit our episode page at http://www.glorikian.com/podcast Please rate and review The Harry Glorikian Show on Apple Podcasts or Spotify! Here's how to do that on Apple Podcasts:1. Open the Podcasts app on your iPhone, iPad, or Mac. 2. Navigate to The Harry Glorikian Show podcast. You can find it by searching for it or selecting it from your library. Just note that you'll have to go to the series page which shows all the episodes, not just the page for a single episode.3. Scroll down to find the subhead titled "Ratings & Reviews."4. Under one of the highlighted reviews, select "Write a Review."5. Next, select a star rating at the top — you have the option of choosing between one and five stars. 6. Using the text box at the top, write a title for your review. Then, in the lower text box, write your review. Your review can be up to 300 words long.7. Once you've finished, select "Send" or "Save" in the top-right corner. 8. If you've never left a podcast review before, enter a nickname. Your nickname will be displayed next to any reviews you leave from here on out. 9. After selecting a nickname, tap OK. Your review may not be immediately visible.On Spotify, the process is similar. Open the Spotify app, navigate to The Harry Glorikian Show, tap the three dots, then tap "Rate Show." Thanks!

Rob Knight, Ph.D., delves into the incredible world of our gut microbiome and its potential impact on our health, particularly its role in conditions like autism. By examining various dietary strategies and their effects on the gut, Knight reveals the remarkable potential of tailored diets in managing health conditions, offering hope for new, more accessible treatments. Moreover, Knight discusses the complex relationship between probiotics, their benefits, and potential risks, highlighting the importance of evidence-based choices. Knight underlines the crucial link between our diet, our gut, and our overall health, shedding light on the exciting future of microbiome-focused interventions in medicine. For parents, caregivers, and anyone interested in improving their health, this lecture provides valuable insights into how the foods we eat can be harnessed to nurture a healthier gut and, in turn, a healthier life. Series: "Autism Tree Project Annual Neuroscience Conference" [Health and Medicine] [Science] [Show ID: 39165]

Rob Knight, Ph.D., delves into the incredible world of our gut microbiome and its potential impact on our health, particularly its role in conditions like autism. By examining various dietary strategies and their effects on the gut, Knight reveals the remarkable potential of tailored diets in managing health conditions, offering hope for new, more accessible treatments. Moreover, Knight discusses the complex relationship between probiotics, their benefits, and potential risks, highlighting the importance of evidence-based choices. Knight underlines the crucial link between our diet, our gut, and our overall health, shedding light on the exciting future of microbiome-focused interventions in medicine. For parents, caregivers, and anyone interested in improving their health, this lecture provides valuable insights into how the foods we eat can be harnessed to nurture a healthier gut and, in turn, a healthier life. Series: "Autism Tree Project Annual Neuroscience Conference" [Health and Medicine] [Science] [Show ID: 39165]

Rob Knight, Ph.D., delves into the incredible world of our gut microbiome and its potential impact on our health, particularly its role in conditions like autism. By examining various dietary strategies and their effects on the gut, Knight reveals the remarkable potential of tailored diets in managing health conditions, offering hope for new, more accessible treatments. Moreover, Knight discusses the complex relationship between probiotics, their benefits, and potential risks, highlighting the importance of evidence-based choices. Knight underlines the crucial link between our diet, our gut, and our overall health, shedding light on the exciting future of microbiome-focused interventions in medicine. For parents, caregivers, and anyone interested in improving their health, this lecture provides valuable insights into how the foods we eat can be harnessed to nurture a healthier gut and, in turn, a healthier life. Series: "Autism Tree Project Annual Neuroscience Conference" [Health and Medicine] [Science] [Show ID: 39165]

Rob Knight, Ph.D., delves into the incredible world of our gut microbiome and its potential impact on our health, particularly its role in conditions like autism. By examining various dietary strategies and their effects on the gut, Knight reveals the remarkable potential of tailored diets in managing health conditions, offering hope for new, more accessible treatments. Moreover, Knight discusses the complex relationship between probiotics, their benefits, and potential risks, highlighting the importance of evidence-based choices. Knight underlines the crucial link between our diet, our gut, and our overall health, shedding light on the exciting future of microbiome-focused interventions in medicine. For parents, caregivers, and anyone interested in improving their health, this lecture provides valuable insights into how the foods we eat can be harnessed to nurture a healthier gut and, in turn, a healthier life. Series: "Autism Tree Project Annual Neuroscience Conference" [Health and Medicine] [Science] [Show ID: 39165]

Rob Knight, Ph.D., delves into the incredible world of our gut microbiome and its potential impact on our health, particularly its role in conditions like autism. By examining various dietary strategies and their effects on the gut, Knight reveals the remarkable potential of tailored diets in managing health conditions, offering hope for new, more accessible treatments. Moreover, Knight discusses the complex relationship between probiotics, their benefits, and potential risks, highlighting the importance of evidence-based choices. Knight underlines the crucial link between our diet, our gut, and our overall health, shedding light on the exciting future of microbiome-focused interventions in medicine. For parents, caregivers, and anyone interested in improving their health, this lecture provides valuable insights into how the foods we eat can be harnessed to nurture a healthier gut and, in turn, a healthier life. Series: "Autism Tree Project Annual Neuroscience Conference" [Health and Medicine] [Science] [Show ID: 39165]

In conversation with Carl H. June, MD, Director of the Center for Cellular Immunotherapies, University of Pennsylvania Siddhartha Mukherjee won the 2011 Pulitzer Prize for nonfiction for The Emperor of All Maladies, a ''meticulously researched, panoramic history'' (The Boston Globe) of humankind's fight against cancer. It was awarded the PEN/E.O. Wilson Literary Science Writing Award, was named to numerous media outlets' ''Best of the Year'' lists, and was adapted by Ken Burns into a PBS documentary. Mukherjee is also the author of the No. 1 New York Times bestseller The Gene: An Intimate History. An assistant professor of medicine at Columbia University and a staff cancer physician at the New York-Presbyterian/Columbia University Irving Medical Center, he is a physician and researcher whose laboratory focuses on discovering new cancer drugs. His articles and commentary have been published in such places as Nature, New England Journal of Medicine, The New York Times, and The New Republic. In The Song of the Cell, Mukherjee takes readers through the centuries-spanning quest to understand cells, the tiny self-contained units that make up all life. Carl June is the Richard W. Vague Professor in Immunotherapy in the Department of Pathology and Laboratory Medicine at the University of Pennsylvania. He is also the director of the Center for Cellular Immunotherapies at the Perelman School of Medicine and director of the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania. Acclaimed for his research into the treatment of leukemia, he has published more than 350 medical papers and has received numerous awards and honors. Because you love Author Events, please make a donation to keep our podcasts free for everyone. THANK YOU! (recorded 10/5/2023)

Immunotherapy has revolutionized the therapy landscape of non-small cell lung cancer, significantly prolonging the overall survival of advanced-stage patients. We hear from both doctors and patients about the importance of Immunotherapy research. Dr. Smith will discuss her research advancements, thanks to LCFA funding, and what needs to be done for research in the future. In this inspiring Hope With Answers: Living With Lung Cancer episode, host Diane Mulligan sits down with Lysa Buonanno, a remarkable individual who has defied the odds and thrived while living with lung cancer. Lysa's story serves as a beacon of hope for others facing similar challenges, showcasing the power of research and the impact of donations in extending lives. Lysa, who has been on chemotherapy for five years, candidly shares her journey, acknowledging the difficult days but emphasizing the importance of living life to the fullest. She highlights the role of research in providing her with the opportunity to enjoy her life. And she encourages listeners to support lung cancer research, no matter the size of their donation. Lysa's message resonates deeply, reminding us that every dollar counts and contributes to future breakthroughs. Guests: Dr. Kellie Smith, Associate Professor of Oncology at the Bloomberg Kimmel Institute for Cancer Immunotherapy at Johns Hopkins.  Lysa Buonanno is living with lung cancer and is a tireless advocate for Lung Cancer Foundation of America. Resources: Breakthroughs in Lung Cancer Detection & Treatment Landscape of Immuno-Oncology Drug Development Dr. Smith's Research in Immunotherapy for lung cancer Show Notes | Transcript | View Video

Creatine is a supplement that every single person out there can benefit from. No matter your age, size, health status, or activity level.  Let's address every common concern and question that most people have about creatine. I'm going to give you all of the information to ease your mind and hopefully, you'll become a lifelong fan of this beneficial supplement. I'm not even selling it. So don't worry there's no sales pitch at the end. I truly just want you to do whatever you can to optimize your health for overall strength and longevity.  In this episode:  • Creatine monohydrate vs. creatine HCL • Does creatine cause bloating or weight gain? • Does creatine cause hair loss? • Does creatine cause muscle cramps? • Creatine and bipolar disorder • Creatine and non-athletic lifestyle benefits  • Creatine and athletic benefits • Dosing recommendations  • Is creatine loading necessary? PubMed Links: Creatine supplementation and cognitive performance in elderly individuals  https://pubmed.ncbi.nlm.nih.gov/17828627/ Creatine supplementation for older adults: Focus on sarcopenia, osteoporosis, frailty, and Cachexia: https://pubmed.ncbi.nlm.nih.gov/35688360/ Creatine in T Cell Antitumor Immunity and Cancer Immunotherapy: https://pubmed.ncbi.nlm.nih.gov/34067957/    Creatine electrolyte supplement improves anaerobic power and strength: a randomized double-blind control study: https://www.tandfonline.com/doi/full/10.1186/s12970-019-0291-x Creatine Supplementation in Women's Health: A Lifespan Perspective: https://www.mdpi.com/2072-6643/13/3/877  To sum it all up, creatine is safe, effective, and everyone should strongly consider using it throughout any stage of life. It aids in brain health, athletic performance, muscle health, bone health, sleep quality, and mood. And these are facts that have been proven over and over by legitimate scientific studies.  Don't get hung up on the brand. Just look for a label that says creatine monohydrate. I highly recommend this product not just for performance but also for longevity, optimizing aging, and protecting health through the lifecycle.  If you enjoyed this, share it on social media, tag FitFizz and let me know your favorite part. Send it your loved ones and get them on some creatine!  Thank you so much for listening! I'm Kelly Wilson, your health concierge, and until next time, breathe, stay strong, and always celebrate victory! Website: fitfizzstudio.com Social: @fitfizz

Dr. Greg Delgoffe is an Associate Professor at the University of Pittsburgh. His lab studies the intersection of metabolism and immunity in cancer. He talks about the metabolism of immune cells in cancer and the effects of nutrients in the tumor microenvironment.

Taking us to the cutting edge of the new frontier of medicine, a visionary biotechnologist and a pathbreaking researcher show how we can optimize our health in ways that were previously unimaginable. We are on the cusp of a major transformation in healthcare—yet few people know it. At top hospitals and a few innovative health-tech startups, scientists are working closely with patients to dramatically extend their “healthspan”—the number of healthy years before disease sets in. In The Age of Scientific Wellness, two visionary leaders of this revolution in health take us on a thrilling journey to this new frontier of medicine. Today, most doctors wait for clinical symptoms to appear before they act, and the ten most commonly prescribed medications confer little or no benefit to most people taking them. Leroy Hood and Nathan Price argue that we must move beyond this reactive, hit-or-miss approach to usher in real precision health—a form of highly personalized care they call “scientific wellness.” Using information gleaned from our blood and genes and tapping into the data revolution made possible by AI, doctors can catch the onset of disease years before symptoms arise, revolutionizing prevention. Current applications have shown startling results: diabetes reversed, cancers eliminated, Alzheimer's avoided, and autoimmune conditions kept at bay. This is not a future fantasy: it is already happening, but only for a few patients and at a high cost. It's time to make this gold standard of care more widely available. Inspiring in its possibilities, and radical in its conclusions, The Age of Scientific Wellness shares actionable insights to help you chart a course to a longer, healthier, and more fulfilling life. Dr. Leroy Hood is a world-renowned scientist and recipient of the National Medal of Science in 2011. Dr. Hood co-founded the Institute for Systems Biology (ISB) in 2000, served as its first President from 2000-2017 and is a Professor and Chief Strategy Officer. In 2022, Dr. Hood started Phenome Health, a non-profit dedicated to delivering value through health innovation. Dr. Nathan Price is CEO of Onegevity, a division of Thorne HealthTech. He is also an (on leave) Professor at the Institute for Systems Biology, where he and Lee Hood co-direct the Hood-Price Lab for Systems Biomedicine. Additionally, Dr. Price is an affiliate faculty at the University of Washington in the Departments of Bioengineering, Computer Science & Engineering, and Molecular & Cellular Biology. In 2019, he was selected by the National Academy of Medicine as one of their 10 Emerging Leaders in Health and Medicine. Dr. Jim Heath is President and Professor at Institute for Systems Biology in Seattle. Heath also has the position of Professor of Molecular and Medical Pharmacology at UCLA. Formerly, he directed the National Cancer Institute-funded NSB Cancer Center, was the Elizabeth W. Gilloon Professor of Chemistry at Caltech, and served as co-director of the Parker Institute for Cancer Immunotherapy at UCLA until 2017. Presented by Town Hall Seattle and the Institute of Systems Biology. The Age of Scientific Wellness: Why the Future of Medicine Is Personalized, Predictive, Data-Rich, and in Your Hands Third Place Books

    Drs. Diwakar Davar and Jason Luke discuss KEYNOTE-716, KEYNOTE-942, RELATIVITY-047, and other key advances in melanoma, including the promise of mRNA vaccines in melanoma and potentially other cancers, as well exciting advances in neoadjuvant therapies across malignancies featured at the 2023 ASCO Annual Meeting. TRANSCRIPT  Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh Hillman Cancer Center. I'm delighted to have my colleague and good friend Dr. Jason Luke on the podcast today to discuss some practice-changing studies and other advances in immunotherapy that were featured at the 2023 ASCO Annual Meeting. Dr. Luke is an associate professor of medicine, the director of the Cancer Immunotherapy Center, as well as the associate director of clinical research at the University of Pittsburgh's Hillman Cancer Center.     You can find both of our disclosures in the transcript of this episode, and disclosures of all guests on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.   Jason, there was a lot of exciting data in the immunotherapy space highlighted at the Annual Meeting, and it's great to have you back on the podcast to discuss some of this work.   Dr. Jason Luke: Thanks for having me.    Dr. Diwakar Davar: So, the abstracts that we had selected have several key themes. We'll be covering some of the early advances in melanoma in the stage 2 and stage 2B/C space with KEYNOTE-716. I think this is a study that you know a little bit about seeing you are the presenting author and the principal investigator for the study, as well as the pivotal KEYNOTE-942 trial. And then going on to themes with using third-generation checkpoints, neoadjuvant therapy in non-small-cell lung cancer, and cutaneous squamous cell carcinoma.    But we'll start with KEYNOTE-716. So, this is LBA9505, the study which evaluated pembrolizumab versus placebo as adjuvant therapy in stage 2B and stage 2C melanoma patient population for which historically there was no real effective therapy other than remotely interferon. And these are the final results of the DMFS analysis from this phase 3 trial. So, Jason, what are your thoughts about this, and can you contextualize the results relative to the recent publication?   Dr. Jason Luke: Thanks. I think the important point to level set on this was just a few years ago; this was a population of patients that we didn't treat in clinic. In fact, sometimes they weren't even referred to medical oncology for evaluation. And that was despite the fact that we knew from historical data that the risk of melanoma-specific survival, death from melanoma, was just as high for this population of patients as it was for the patients with stage 3 melanoma, where obviously adjuvant immunotherapy has been a standard for quite some time. And so we launched this clinical trial, KEYNOTE-716. It was a global, randomized phase 3 study of almost 1,000 patients, randomizing patients to either get pembrolizumab or placebo. Importantly, these patients being those with deep primary lesions, stage 2B and 2C with negative sentinel lymph node evaluation.    People will recall that this study hit its primary endpoint on the first protocol-specified analysis at a year. And what we updated at ASCO this year was the final analysis of distant metastasis-free survival. Obviously, an important secondary endpoint because if patients eventually going to develop metastatic disease and pass away, it's the distant metastasis that we worry about. And what we saw in this trial with a landmark 36-month follow-up median of 39 months was that the benefit was increasing. In other words, the magnitude of the hazard ratio change was increasing over time as would be expected, such that at this analysis there was a 41% reduction in the risk of distant metastasis for patients treated with pembrolizumab versus placebo. And we saw a consistent benefit in the recurrence-free survival also out through that same period of time and importantly no change in the safety summary with of course the adverse event profile of pembrolizumab being what it is and well understood across oncology.    So I think these are very important data because they really kind of set the stage for the field. It is now the case that at least discussing adjuvant therapy for patients with stage 2B and 2C is the standard of care; it should be offered to all the patients. Of course, it's always a risk-benefit about whether or not patients want to pursue adjuvant therapy versus consideration of treatment at the time of recurrence. But in my clinic at least, many patients do prefer to try to eliminate the possibility of recurrence and distant metastasis as much as possible.    So I think these are very important data because they really level set the field for what to expect in this population of patients and then they also start to set the table for what's going to come after this. And that's going to be sort of the next step in our conversation here because the next generation of adjuvant studies in melanoma are now going to think about all of melanoma in the adjuvant setting as really one entity, starting from stage 2B going all the way through stage 4 resected. And that'll be relevant actually as we talk about the next abstract that will come in this discussion.   Dr. Diwakar Davar: Just to underscore, positive RFS data, positive DMFS data, and now this therapy has currently got regulatory approval in this investigation and is approved in the United States and certainly in Europe and Australia. One interesting point that we will probably have to contend with, and some of the listeners may be thinking about, is overall survival. So the last adjuvant study that demonstrated overall survival benefit was actually ipilimumab, and increasingly, the Illuminati in melanoma do not believe that we will ever see OS benefit in this disease going forward, even though it has to be an endpoint in all registration phase 3 trials. So, Jason, what are your thoughts about whether or not we'll have a positive OS readout, and even if we don't, why this is still a very important advance in this disease at this time?   Dr. Jason Luke: Your points are well taken. I think it's unclear, probably trending towards unlikely, that we would see an overall survival advantage in this trial given that we have not seen that in the stage 3 adjuvant studies. Now people can debate if, whether or not overall survival is the only meaningful endpoint for patients. I personally do not believe that's true. And to me, preventing recurrence has a value in and of itself, whether or not that's connected to overall survival. And part of the reason that I say that is that for an average patient, the median patient on a trial, of course, we can tell them treatment now, treatment later. It's a wash when you look at the overall study. And yet at the same time, for an individual person who's facing melanoma or cancer, generally they're not going to be the average patient; they're going to be one patient. And it's very possible they could end up with the type of recurrence that in fact is not highly treatable at that time.     So I think that's really the nuance that goes into those adjuvant discussions. The regulatory endpoints have been recurrence in melanoma for a long time. And I think it's important that patients understand the pros and the cons of each. The complexity in adjuvant therapy and neoadjuvant therapy is you don't necessarily know that you had to have it. You're only really going to know whether or not it didn't work if you recur later on. But to me and in my clinic, most patients are willing and interested to want to pursue those therapies in the perioperative setting to try to reduce the possibility of ever developing metastatic disease.    Dr. Diwakar Davar: Excellent. So I think key advance [is] positive DMFS data to add to the earlier reported RFS data and truly practice-changing.     So, moving on to the next study, LBA9503. This is the phase 2 trial of the Moderna vaccine. This is the trial that almost every medical oncologist knows intimately or has been called about by either the press or patients. So what is this study? This essentially is a phase 2 trial evaluating the personalized cancer vaccine PCV Moderna, made by Moderna, the mRNA vaccine, that is being studied in combination with anti-PD-1 pembrolizumab in the stage 3 BCD and stage 4 resected setting. And so there are really two very interesting results here because this is an update of the RFS data that was presented at AACR earlier this year, which was positive. What are your takes on the DMFS results, and maybe a quick blurb on how is this vaccine generated for those who may not be aware of this particular platform?    Dr. Jason Luke: Yeah, certainly. So this individualized neo-antigen therapy, as we're now calling it, is a technology platform that allows us to develop an individualized treatment for each patient based on their own cancer. So taking the actual tumor specimen, whole exome sequencing is performed to try to identify changes in the DNA, and then through a reasonably complex bioinformatic pipeline, those mutations that are likely to generate proteins that can be bound within class 1 MHC molecules are then identified in the computer and then synthesized with an mRNA, very similar to the way that the COVID vaccines were made. And then that becomes the actual drug.    So in the clinical trial, which was KEYNOTE-942, about 160 patients were randomized 2 to 1 to receive either pembrolizumab for a year as per standard adjuvant therapy but then with the addition of the individualized neoantigen therapy starting with dose 3 and throughout the rest of the year versus the control arm of pembrolizumab as the standard of care. As you mentioned, the recurrence-free survival were highly positive in this trial when it was first presented earlier this year, and at the updated ASCO we see the 18-month RFS in which the hazard ratio continues to be maintained. But I think most impressively is that distant metastasis-free survival, where we saw an even greater advantage for distant metastasis-free survival – hazard ratio here being 0.35. And so that's a huge advantage for distant metastasis-free survival in this population of patients.     And very interestingly in the clinical trial, when you follow the Kaplan-Meier plots, what you see over time is that they overlap almost the entire first year. And it's really at about a year, basically after the vaccine has had time to kick in and these neoantigens have been identified, that we then start to see the separation of the curve, which looks very flat over time. And so I think this is a very, very exciting kind of technology platform and very exciting results because there was minimal increase in toxicity – just at the site of the local injection – for the addition of the individualized neoantigen therapy.    And beyond that, hypothetically, this is not necessarily just a melanoma thing. So, of course, based on these phase 2 results, a phase 3 clinical trial called KEYNOTE-V940 is going to be launching later this year to compare pembrolizumab versus pembrolizumab plus this V940 individualized neoantigen therapy. And we're very, very excited in the field to see what those results will look like because the concept here is you could really, really enhance adjuvant therapy with this kind of an approach. Meanwhile, we're just about to talk in a little bit about all the exciting things happening in the neoadjuvant space as well. And with no increase in toxicity, obviously, that looks really good.    Suffice it to say that this technology is not specific to melanoma but rather could be applied almost to any cancer where we think about an adjuvant therapy platform. So I think the results are very, very exciting. It is a phase 2 study and it does have some caveats about not being the largest study and some other things, but you can't help but be impressed by the data that have been presented here so far.   Dr. Diwakar Davar: One important plug, I guess, in addition to that is that you mentioned that there's data using the platform in other diseases. And one really exciting paper that came out recently was Dr. Vinod Balachandran's paper; for those who haven't read it, it's in Nature, and really in a very provocative proof of concept study, they studied the platform, the vaccine plus checkpoint inhibitor therapy plus chemotherapy in a highly adverse tumor patient population. So these are patients with resectable pancreatic cancer who had the vaccine generated from pancreatic cancer that was resected after Whipple surgery. And extraordinarily, out of the 16 patients who had immune responses, 8 of them did not have relapse at a median follow-up of almost a year and a half, which is really quite extraordinary given the lack of really any effective drug outside of chemotherapy in that setting.     So, the point that you're making regarding the benefit of this therapy, suggesting that it could potentially be extended to not just melanoma, potentially other tumors such as highly immunogenic tumors, and potentially even nonimmunogenic tumors such as pancreatic cancer, really suggests that this is going to be a very exciting landscape. And potentially this area, adjuvant therapy and neoadjuvant therapy, like we'll talk about, is potentially an area in which other drugs and potentially combinations will be developed.    So next, we will be discussing 3 abstracts evaluating the theme of combinations, and these abstracts are 9501, 9502, and 4010. Abstract 9501 is an evaluation of the combination of fianlimab and cemiplimab anti-LAG-3 and anti-PD-1, respectively, in advanced melanoma, specifically focusing on the post-PD-1 experience in this disease by Dr. Omid Hamid. 9502 is the updated 2-year survival results from RELATIVITY-047, which evaluated nivolumab and relatlimab against nivolumab alone in frontline metastatic melanoma. And Abstract 4010 are the results from the MORPHEUS platform study, specifically looking at tiragolumab and atezolizumab in patients with advanced unresectable HCC.    But focusing on 9501 and 9502, Jason, what do you make of the combination of fianlimab and cemiplimab post-PD-1 setting?   Dr. Jason Luke: I think the data look very intriguing for this second combination of PD-1 and LAG-3 combination. When nivolumab and relatlimab, the approved LAG-3 inhibitor, kind of burst on the scene a couple of years ago, it was somewhat to the surprise of a lot of people in the community who had really come to think that while PD-1 and CTLA-4 were core molecules for therapeutics and cancer, that we just weren't ever really going to see something else come along in checkpoint blockade. And so nivo and rela got approved. We'll talk about them again in a second. But the data now coming forward for another PD-1 LAG-3 combination, again with cemiplimab PD-1 and fianlimab LAG-3, looks very, very promising.    So in Abstract 9501, they updated a phase 1 expansion cohort, phase 2 cohort looking at patients across the various different settings. And whereas in the treatment naive frontline metastatic setting they had previously described about a 63% response rate, they saw a similar level of response rate in patients who had previously gotten adjuvant anti-PD-1, had a period of time off treatment, and then were treated again. And that was reassuring because it suggested that this is still an active combination even with prior exposure to IO in the past.     Now, the thing that I found to be the most interesting about this combination was whereas with nivo and rela, at least from the RELATIVITY-047 phase 3 trial, it looked like there was less benefit in some of the high-risk population cohorts, at least for this combination in early testing for cemi and fian; like we talk about it sometimes, we saw there was a high response rate even in patients with liver metastases and some other high-risk features. And so I think this combination looks quite potent, and I'm very excited to see what the data will look like. I think it's very unlikely we'll ever actually get a randomized trial of two PD-1 LAG-3 combinations against each other. But suffice it to say that the data we've seen so far for fianlimab LAG-3 with cemiplimab PD-1 looks very intriguing. It certainly justifies the frontline metastatic phase 3 and the adjuvant phase 3 trials that are already in planning or ongoing.   Dr. Diwakar Davar: So one thing to consider is on the RELATIVITY-020 trial – the early trial that was led by Dr. Ascierto that really took a long time to read out – the response rate in patients with prior checkpoint inhibitor therapy was quite low. In fact, the data was quite surprising, as you'd mentioned that we had even seen this movement in the frontline setting because the response rate by BICR was only about 12%. So do you feel like the 2 LAG-3 inhibitors are fundamentally different? And if so, can you speculate as to why that might be? Again, with the caveat to the fact that these are very early data and we don't have enough information. And maybe we can also talk a little bit about the 2 pending trials that are ongoing in the advanced and adjuvant therapy landscapes perspective.   Dr. Jason Luke: I think we don't have enough data yet to truly understand whether or not they're really different. The trials that have been run so far are so different that it's hard to compare things back and forth. You can notice that the dose, the milligram dosage of fianlimab in terms of anti-LAG-3 is quite a bit higher, like a log fold higher almost than with relatlimab. And so there's some question of whether or not just merely more drug-blocking LAG-3 might in fact be more efficacious relative to the dose that's approved for relatlimab in melanoma. But beyond that, I think the data hold up very well for this new combination, again noting all the caveats about cross-trial comparison to, say, it looks to be at least as potent, possibly more potent than the relatlimab combination. But again, I think probably we need to see the data from randomized trials and how that fits into the landscape when the trials actually read out because there's a lot of things going on in melanoma that are likely to change between now and then.   Dr. Diwakar Davar: So just to draw people's attention, there are actually 2 ongoing pivotal phase 3 trials: fian plus cemi versus pembro in patients with advanced metastatic and locally advanced, previously untreated melanoma, as well as an adjuvant trial of the combination against pembrolizumab. Again, highly high-risk resected melanoma. These trials are ongoing. We don't have the results yet and we are looking forward to them.    Now, 9502, a 2-year RELATIVITY-047 result presented by Dr. Hussein Tawbi.    Dr. Jason Luke: So this is the study we were just alluding to before, the randomized phase 3 study of nivolumab versus nivolumab plus for relatlimab. To me, the most useful data sort of updating with this two-year survival follow-up is to show the maintenance of benefit between the 2 arms. And so, consistent with what we saw with nivolumab and ipilimumab, there seems to be a persistent delta between the arms for both progression-free and for overall survival out over that extended period of time, where we can see with that updated data now, at 2 years, that it's 52% of patients still alive on the relatlimab combo versus 42 with nivolumab. And it does seem like this is probably a higher-risk population of patients than participated in CheckMate-067.    So it's a little bit difficult to compare the landmarks except to notice that that difference between the control and experimental groups is consistent over a long period of time and that there were no new safety signals either, and so that was also reassuring. To me, the most interesting nugget of data in the abstract, though, is to look at what happened to patients after they were on the first-line treatment. So one of the big questions in our field is really “If patients get nivolumab and relatlimab upfront, what should they get after that?” Should they then get nivo plus ipi, or vice versa? And I think we don't have an answer clearly to that question just yet.    There was an important letter to the editor of the New England Journal now going on about a year ago by Alex Menzies and colleagues that suggested that the use of ipilimumab was attenuated, the utility of it, after a prior exposure to nivolumab plus relatlimab. They quoted a response rate on the order of only about 10% for patients who got an ipilimumab-containing regimen after initial LAG-3. In the data from Hussein Tawbi at ASCO, however, in a small number of patients, caveat, the response rate was more in sort of the low 20% range, 22% to 25%. And so that would be a much more meaningful and important sort of consideration. If we do have independent activity, then lining up sequential therapies and the toxicities associated with each will become increasingly important as we think about how to maximize these kinds of treatments for our patients, but important longer-term data to show that the benefit is holding up and it's safe, and some new insights into what to do after progression on one of these regimens.    Dr. Diwakar Davar: So, pivoting slightly to combinations, we are going to be discussing a combination of TIGIT plus checkpoints. So tiragolumab is the FC-active TIGIT inhibitor from Regeneron-Roche and this is currently in multiple pivotal phase 3 trials, several of which have been negative, including SKYSCRAPER-01 in non-small cell lung cancer and SKYSCRAPER-03 in small cell lung cancer. The MORPHEUS platform trial essentially is a platform study evaluating multiple different combinations, in this case in liver cancer. And so we have a very interesting Abstract 4010, which is giving us an early readout of the evaluation of tiragolumab plus atezolizumab along with bevacizumab in unresectable, locally advanced or metastatic hepatocellular carcinoma giving us a result that is a little different from what we had seen from the prior negative results of TIGIT. So Jason, what do you make of these early results in the advanced HCC setting?   Dr. Jason Luke: I think these are cautiously intriguing results to really highlight the point is the third checkpoint possibly being LAG-3, now a fourth checkpoint maybe with TIGIT, but with all the caveats that you talked about. In this study, the flow is that there's a continuously accruing control arm which in hepatocellular carcinoma is a combination of atezolizumab plus bevacizumab, and then other arms are added where you add in a third agent. In this case, it's the anti-TIGIT tiragolumab. And in an intriguing fashion, the response rate to the triplet was 42.5% compared to the doublet which was only 11%. So that's a pretty big difference in this population.     Now, it wasn't the largest study, only 58 patients, but it was a randomized clinical trial. And so I think those data really make people kind of open their eyes again. It's worth a little bit of a caveat here that HCC is an unusual cancer in that what is deemed to be unresectable and therefore amendable to systemic therapy is a moving target and that requires multidisciplinary evaluation of patients. And so I think a larger number of patients would really be needed to fully understand this. But certainly, a fourfold increase in the benefit or in terms of response rate looks quite intriguing.    I think the other piece of this is to be just cautious a little bit was when the initial data in non-small cell lung cancer in the CITYSCAPE study came forward, and they looked roughly sort of like this: There was more than a doubling in the PFS and the response rate, which is what triggered all of those phase 3 studies. So to me, this is enough to continue to be very interested in TIGIT as a therapeutic target. And there are many phase 3 trials already ongoing. And so I think, I'm cautiously optimistic that some of those actually will be positive and we could see more movement around TIGIT becoming a standard of care agent.    Dr. Diwakar Davar: To your point about TIGIT being an interesting target, recent data looking at the neoadjuvant landscape in melanoma from Merck, with Merck, also FC-active TIGIT and also some data from authors looking at that TIGIT also presented in this case at ASCO specifically from the ARC-7 study. So very interesting target. Several pivotal trials have been announced. Do you know of any trials that are ongoing in the adjuvant setting in other diseases?   Dr. Jason Luke: Well, as you alluded to, the vibostolimab data in melanoma for TIGIT in the neoadjuvant setting was interesting. And in fact, that has been enough to trigger a global, randomized phase 3 adjuvant study of pembrolizumab and vibostolimab versus pembrolizumab in melanoma. And that sort of takes us back to the beginning of our discussion here, building on the KEYNOTE-716 data. So, yes, TIGIT will be moving forward in the adjuvant space in melanoma and obviously at a static setting for several different tumor types with a PD-1 or PD-L1 backbone.   Dr. Diwakar Davar: So now pivoting towards neoadjuvant therapy and non-small cell lung cancer. The standard of care in this setting was established by the CheckMate-816 trial that essentially established nivolumab plus chemotherapy in the setting of resectable non-small cell lung carcinoma path. Response rate in this setting is approximately 21%. And we have several studies that are essentially looking at novel combinations or in this case, different PD-1 inhibitors in this setting. So Abstract 8500 essentially looked at nivolumab plus relatlimab from a NEOpredict-Lung trial. Jason, do you want to tell us a little bit about this?    Dr. Jason Luke: Yes, I think this is a very interesting study and that this is sort of our first peek at targeting LAG-3 in the context of lung cancer. So obviously we talked about LAG-3 for melanoma. Although the audience is probably aware that there have been neoadjuvant data for LAG-3 with relatlimab in melanoma that substantiated the phase 3 data for the metastatic setting. So one of the questions as we start to apply the LAG-3 in other diseases would be, “Do we see it hold up in both metastatic disease and in the neoadjuvant space?” But in this study, while there were no changes in the safety profile; it didn't impact on whether or not patients could have surgery. There really didn't look to be a big difference in this study between nivolumab and nivolumab plus relatlimab, with the major pathologic response as you alluded to right around 30% for both arms.    Now, it wasn't really the biggest study, but that's certainly quite a bit in contrast with what we've seen in melanoma, where with a PD-1 inhibitor you get again 25%-30%, but with adding on LAG-3, that pushes you up closer to 60%. So I think these were very interesting data that probably put a little bit of an eyebrow raise to say, “Well, let's see what happens in the metastatic setting in lung cancer with the addition of relatlimab LAG-3 on top of a PD-1.” I think it might not be quite so straightforward as what we saw in melanoma, but we'll look forward to those results because those phase 3 trials in metastatic lung cancer should be maturing sometime in the next year or two.   Dr. Diwakar Davar: The theme of neoadjuvant therapy non-small lung cancer, LBA100, which has again previously been discussed in an episode of this podcast by Dr. Jack West and Dr. Velcheti is KEYNOTE-671. And this is a study essentially that looked at pembrolizumab or placebo with platinum-based chemotherapy doublet and followed by resection. So again, a direct parallel to CheckMate-816. What do you make of the results that were reported by our colleagues in this setting, Jason?   Dr. Jason Luke: So not to rehash this, because our colleagues in the lung cancer group have already discussed this at length and obviously they're experts in that disease, but we'll just note that there was a threefold increase in major pathologic response, which turned into a major advantage for event-free survival. And so I think this is at least the third PD-1, PD-L1 combination regimen for neoadjuvant lung cancer that looks very, very promising. It certainly, to me, seems like neoadjuvant consideration really should be the standard of care already moving forward.   To me, what the big question that is left with is “Do we still need the adjuvant component after we give the neoadjuvant?” So, some of the trials are including neoadjuvant and adjuvant, some of them are only neoadjuvant. And I think that's going to be a really important question as we move into the future, both in terms of what is that contribution of the adjuvant component, and then again, going back to earlier in our discussion here, if there could be a major advantage to adding individualized neoantigen therapy, maybe it is important to have both. But I think that's one of the big questions we have to get teased out by the field over the next couple of years.   Dr. Diwakar Davar: And finally pivoting towards cutaneous squamous cell carcinoma. We have 2 abstracts discussing perioperative therapy. So cutaneous squamous cell carcinoma is a high-TMB tumor. The median tumor mutation burden in this disease is threefold that of melanoma. This is a disease in which checkpoint inhibitor therapy is approved as a single agent both with pembrolizumab and cemiplimab on the basis of nonrandomized phase 2 trials. And increasingly, there has been early development in the perioperative setting. The first data in this space came from our colleague Dr. Gross at MD Anderson, who reported in a small, nonrandomized phase 2 trial of 20 patients, a path CR rate with two cycles of cemiplimab at approximately 50%.    A larger multi-institutional phase 2 trial demonstrated that a longer duration of perioperative therapy of four cycles or 3 months of cemiplimab did not particularly improve the path response rates. The response rates were similar at approximately 50% as well. And what we have right now are 2 other trials. The first is the MATISSE trial, Abstract 9507 ,that evaluated nivolumab or nivolumab plus epilimumab in this disease. And the other one was the NEO-CESQ trial, or Abstract 9576, that evaluated neoadjuvant plus adjuvant therapy that's cemiplimab in the high-risk patient population. So we're starting with 9507. Jason, what do you make of the ipi and ipi-nivo data reported in this setting?   Dr. Jason Luke: So I think this is a really interesting study because I think part of the intent is the clinical aspect of how you manage patients with cutaneous squamous cell carcinoma. For those that don't do cutaneous oncology, many of these patients have the development of lesions, which can be actually quite difficult to resect in a way that's not otherwise mutilating or cosmetically quite problematic. And that was part of the impetus for this trial where, again, they looked at either monotherapy PD-1 or a PD-1 plus CTLA-4, and they saw great success. As was predicted based on the other data that you alluded to, response rates are more than 50% near 60%, with actually a substantial number of patients on the trial actually refusing to have surgery after they received their neoadjuvant therapy because they were so certain that they had had a good outcome.    So I think these data are quite reassuring in the context of all of this emerging data around cutaneous squamous cell carcinoma. We'll talk about this NEO-CESQ trial in just a second, but I think it really is emerging to be the standard of care very soon for the use of perioperative PD-1 for cutaneous squamous cell.   Dr. Diwakar Davar: What do you feel about the dose and schedule of checkpoint inhibitor therapy used here? So the dose of ipilimumab used was ipi-1 and not ipi-3, and they waited 4 weeks. So when patients only got two cycles of Q2 weekly nivo, and one cycle of ipilimumab, do you think the responses would have been deeper if they'd waited longer?   Dr. Jason Luke: I think it is possible that they might have been deeper, although I'm not totally sure about that. One of the other abstracts we're not directly mentioning here was a study in Merkel cell carcinoma which suggested that in fact, adding ipi and that also highly immuno-oncology-responsive tumor type did not add to the response rate. So I'm not totally sure about that. I think rather what would be most interesting here is sort of the sort of next generation of biomarker work.    As part of their presentation, the MATISSE trial team showed gene expression profiling that really strongly identified which patients were going to do well on the trial. And I think that's probably eventually going to be how we need to think about this. There are patients in the neoadjuvant setting who are going to do really well with anti-PD-1 alone. And then for those who aren't, that's where we probably really need to think about do we need combos, how long to give the treatment, etc. And I think we're really only on the cusp in the beginning of this, which is exciting as we think about moving into the future.    Dr. Diwakar Davar: Certainly, many combinations are being evaluated in this space and we are very excited for the data that it's about to hopefully come in the next couple of months to years.    So the NEO-CESQ – it's quite a puzzle as to how to pronounce this acronym – and this evaluated cemiplimab in the high-risk setting. So it's worthwhile noting that Dr. Gross's first trial looked at high-risk stage 2, 3, and 4 disease. So the context of cutaneous squamous cell carcinoma that's node-positive disease and distant metastatic disease that is in one location or patients with node-positive disease invention. And his multi-institutional cemiplimab trial of four cycles evaluated included patients with stage 2, 3, and 4 disease.    So here in a study just in stage 3 and 4 diseases, Dr. Ascierto reported the results of 2 cycles of cemiplimab and importantly, these patients had both the neoadjuvant and the adjuvant portion of cemiplimab. So, Jason, you mentioned earlier that one of the key aspects that we start thinking about neoadjuvant therapy is exactly how much do you need. Do you need both the pre-surgical therapy and the post-surgical therapy? Is the presurgical therapy enough? After all, neoadjuvant response equals cure. How much benefit are you getting from post-surgical portions? So what do you make of the results that they've seen here and what is the impact? How do you think we'll be disentangling the impact of the neoadjuvant and the adjuvant portion of the immunotherapy upon response and survival?    Dr. Jason Luke: So just to leverage those comments, I think these data are reassuring because in this higher-risk group of patients, they saw excellent outcomes very similar to what Gross et al had previously reported. So that's good. To your question about how we are going to disentangle this adjuvant versus non-adjuvant question, there's a trial in melanoma called the NADINA trial which is ongoing now in which the use of the adjuvant therapy is actually risk-adapted. So after patients have an initial neoadjuvant treatment they're evaluated, and if they have had a pathologic complete response, they're actually going to stop that treatment and they're not going to give the neoadjuvant therapy. And so I think obviously it's a slightly different disease, but those kinds of data, I think, will be very meaningful to help us sort this out.    And I'm not sure whether or not in cutaneous squamous we would need a different trial than in melanoma, although I think in a different tumor, maybe like, say, lung cancer, you probably would need a dedicated study to try to look at that because I think just the responsiveness to checkpoint blockade is going to vary quite a bit once you get outside of cutaneous oncology. But to summarize, reassuring that a similar pathologic response rate, and I think this question of adjuvant or nonadjuvant, I think that's the next question we've got to answer in the field.    Dr. Diwakar Davar: We have now come to the end of our back-and-forth discussion on these very, very exciting abstracts. So Jason, thank you for highlighting these advances and for engaging in a robust discussion.    Dr. Jason Luke: Thanks for having me.    Dr. Diwakar Davar: And thank you to our listeners today for taking the time to listen to this podcast. You will find the links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear in the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.    Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Follow today's speakers:   Dr. Diwakar Davar   @diwakardavar   Dr. Jason Luke   @jasonlukemd      Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:      Dr. Diwakar Davar:     Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences    Consulting or Advisory Role: Instil Bio, Vedanta Biosciences    Consulting or Advisory Role (Immediate family member): Shionogi    Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences    Research Funding (Inst.): Zucero Therapeutics    Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy    Dr. Jason Luke:      Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical , Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX    Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine    Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure    Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)    Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio        

We speak to Simblified fan (!) and microbiologist Avraneel Paul on a whole bunch of things related to what happens inside our body! Viruses and bacteria, how vaccines work, how those WBC badasses keep us safe, and so on. Along the way, we also speak about exciting advancements like CRISPR, and explore philosophical questions like whether Covid has changed the field... And what a day in the life of a scientist looks like. There's loads of trivia, loads of simblification and a few bad jokes as well in this two-part episode. We hope you like it and have renewed appreciation for scientists (and your body!) after it! Add one part news, one part bad jokes, one part Wikipedia research, one part cult references from spending too much time on the internet, one part Wodehouse quotes, and one part quality puns, and you get Simblified. A weekly podcast to help you appear smarter, to an audience that knows no less! Your four hosts - Chuck, Naren, Srikeit, and Tony attempt to deconstruct topics with humor (conditions apply). Fans of the show have described it as "fun conversations with relatable folks", "irreverent humor", "the funniest thing to come out of Malad West" and "if I give you a good review will you please let me go". Started in 2016 as a creative outlet, Simblified now has over 300 episodes, including some live ones, and some with guests who are much smarter than the hosts. Welcome to the world of Simblified! You can contact the hosts on: Chuck: http://twitter.com/chuck_gopal  / http://instagram.com/chuckofalltrades Naren: http://twitter.com/shenoyn  / http://instagram.com/shenoynv Tony: http://twitter.com/notytony  / http://instagram.com/notytony Srikeit: http://twitter.com/srikeit  / http://instagram.com/srikeitSee omnystudio.com/listener for privacy information.

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