Podcasts about dmmr

Listen to ASCO's Journal of Clinical Oncology Art of Oncology article, "A Whipple of Choice” by Dr. Carl Forsberg, who is an Assistant Professor of Strategy and History at Air Force War College. The article is followed by an interview with Forsberg and host Dr. Mikkael Sekeres. Dr Forsberg shares his experience with an uncommon cancer treated by a new therapy for which no directly relevant data were available. Transcript Narrator: A Whipple of Choice, by C. W. Forsberg, PDH I sat across from a hepatobiliary surgeon on a gray October afternoon. “To be frank,” he told me, “we don't know what to recommend in your case. So we default to being conservative. That means a Whipple surgery, even though there are no data showing it will improve your outcome.” The assessment surprised me, diverging from my expectation that doctors provide clear recommendations. Yet the surgeon's willingness to structure our conversation around the ambiguity of the case was immensely clarifying. With a few words he cut through the frustrations that had characterized previous discussions with other physicians. I grasped that with an uncommon cancer treated by a novel therapy with no directly relevant data, I faced a radical choice. My situation that afternoon was worlds away from where I was 5 months earlier, when I was diagnosed with presumed pancreatic cancer at the age of 35. An early scan was suspicious for peritoneal metastasis. The implications seemed obvious. I prepared myself for the inevitable, facing my fate stoically except in those moments when I lingered next to my young son and daughter as they drifted to sleep. Contemplating my death when they were still so vulnerable, I wept. Then the specter of death retreated. Further tests revealed no metastasis. New doctors believed the tumor was duodenal and not pancreatic. More importantly, the tumor tested as deficient mismatch repair (dMMR), predictable in a Lynch syndrome carrier like me. In the 7 years since I was treated for an earlier colon cancer, immune checkpoint inhibitor (ICI) immunotherapy had revolutionized treatment of dMMR and high microsatellite instability tumors. One oncologist walked me through a series of recent studies that showed extraordinary responses to ICI therapy in locally advanced colon and rectal tumors with these biomarkers.1-4 He expressed optimism that my cancer could have a similar response. I embarked on a 24-week course of nivolumab and ipilimumab. After 6 weeks of therapy, a computed tomography (CT) scan showed a significant reduction in tumor size. My health rebounded as the tumor receded. This miraculous escape, however, was bound by the specter of a Whipple surgery, vaguely promised 6 months into my treatment. At the internationally renowned center where I was diagnosed and began treatment with astonishing efficiency, neither oncologists nor surgeons entertained the possibility of a surgery-sparing approach. “In a young, healthy patient like you we would absolutely recommend a Whipple,” my first oncologist told me. A second oncologist repeated that assessment. When asked if immunotherapy could provide a definitive cure, he replied that “if the tumor disappeared we could have that conversation.” My charismatic surgeon exuded confidence that I would sail through the procedure: “You are in excellent health and fitness—it will be a delicious surgery for me.” Momentum carried me forward in the belief that surgery was out of my hands. Four months into treatment, I was jolted into the realization that a Whipple was a choice. I transferred my infusions to a cancer center nearer my home, where I saw a third oncologist, who was nearly my age. On a sunny afternoon, 2 months into our relationship, he suggested I think about a watch-and-wait approach that continued ICI therapy with the aim of avoiding surgery. “Is that an option?” I asked, taken aback. “This is a life-changing surgery,” he responded. “You should consider it.” He arranged a meeting for me with his colleague, the hepatobiliary surgeon who clarified that “there are no data showing that surgery will improve your outcome.” How should patients and physicians make decisions in the absence of data? My previous experience with cancer offered little help. When I was diagnosed with colon cancer at the age of 28, doctors made clear recommendations based on clear evidence. I marched through surgery and never second-guessed my choices. A watch-and-wait approach made sense to me based on theory and extrapolation. Could duodenal tumors treated by ICIs behave that differently from colorectal cancers, for which data existed to make a watch-and-wait approach appear reasonable? The hepatobiliary surgeon at the regional cancer center told me, “I could make a theoretical argument either way and leave you walking out of here convinced. But we simply don't know.” His comment reflects modern medicine's strict empiricism, but it foreclosed further discussion of the scientific questions involved and pushed the decision into the realm of personal values. Facing this dilemma, my family situation drove me toward surgery despite my intuition that immunotherapy could provide a definitive cure. The night before I scheduled my Whipple procedure, I wrote in my journal that “in the face of radical uncertainty one must resort to basic values—and my priority is to survive for my children. A maimed, weakened father is without doubt better than no father at all.” To be sure, these last lines were written with some bravado. Only after the surgery did I viscerally grasp that the Whipple was a permanent maiming of the GI system. My doubts lingered after I scheduled surgery, and I had a final conversation with the young oncologist at the cancer center near my home. We discussed a watch-and-wait approach. A small mass remained on CT scans, but that was common even when tumors achieved a pathological complete response.5 Another positron emission tomography scan could provide more information but could not rule out the persistence of lingering cancer cells. I expressed my low risk tolerance given my personal circumstances. We sat across from one another, two fathers with young children. My oncologist was expecting his second child in a week. He was silent for moments before responding “I would recommend surgery in your situation.” Perhaps I was projecting, but I felt the two of us were in the same situation: both wanting a watch-and-wait approach, both intuitively believing in it, but both held back by a sense of parental responsibility. My post-surgery pathology revealed a pathological complete response. CT scans and circulating tumor DNA tests in the past year have shown no evidence of disease. This is an exceptional outcome. Yet in the year since my Whipple, I have been sickened by my lack of gratitude for my good fortune, driven by a difficult recovery and a sense that my surgery had been superfluous. Following surgery, I faced complications of which I had been warned, such as a pancreatic fistula, delayed gastric emptying, and pancreatic enzyme insufficiency. There were still more problems that I did not anticipate, including, among others, stenoses of arteries and veins due to intraabdominal hematomas, persistent anemia, and the loss of 25% of my body weight. Collectively, they added up to an enduringly dysfunctional GI system and a lingering frailty. I was particularly embittered to have chosen surgery to mitigate the risk that my children would lose their father, only to find that surgery prevented me from being the robust father I once was. Of course, had I deferred surgery and seen the tumor grow inoperable or metastasize between scans, my remorse would have been incalculably deeper. But should medical decisions be based on contemplation of the most catastrophic consequences, whatever their likelihood? With hindsight, it became difficult not to re-examine the assumptions behind my decision. Too often, my dialogue with my doctors was impeded by the assumption that surgery was the obvious recommendation because I was young and healthy. The assumption that younger oncology patients necessarily warrant more radical treatment deserves reassessment. While younger patients have more years of life to lose from cancer, they also have more years to deal with the enduring medical, personal, and professional consequences of a life-changing surgery. It was not my youth that led me to choose surgery but my family situation: 10 years earlier, my youth likely would have led me to a watch-and-wait approach. The rising incidence of cancer among patients in their 20s and 30s highlights the need for a nuanced approach to this demographic.  Calculations on surgery versus a watch-and-wait approach in cases like mine, where there are no data showing that surgery improves outcomes, also require doctors and patients to account holistically for the severity of the surgery involved. Multiple surgeons discussed the immediate postsurgical risks and complications of a pancreaticoduodenectomy, but not the long-term challenges involved. When asked to compare the difficulty of my prior subtotal colectomy with that of a pancreatoduodenectomy, the surgeon who performed my procedure suggested they might be similar. The surgeon at the regional cancer center stated that the Whipple would be far more difficult. I mentally split the difference. The later assessment was right, and mine was not a particularly bad recovery compared with others I know. Having been through both procedures, I would repeat the subtotal colectomy for a theoretical oncologic benefit but would accept some calculated risk to avoid a Whipple. Most Whipple survivors do not have the privilege of asking whether their surgery was necessary. Many celebrate every anniversary of the procedure as one more year that they are alive against the odds. That I can question the need for my surgery speaks to the revolutionary transformation which immunotherapy has brought about for a small subset of patients with cancer. The long-term medical and personal consequences of surgery highlight the urgent stakes of fully understanding and harnessing the life-affirming potential of this technology. In the meantime, while the field accumulates more data, potentially thousands of patients and their physicians will face difficult decisions on surgery verses a watch and- wait approach in cases of GI tumors with particular biomarkers showing exceptional responses to ICI therapy.7,8 Under these circumstances, I hope that all patients can have effective and transparent conversations with their physicians that allow informed choices accounting for their risk tolerance, calculations of proportionality, and priorities.  Dr. Mikkael Sekeres: Hello, and welcome to JCO's Cancer Stories: The Art of Oncology, which features essays and personal reflections from authors exploring their experience in the oncology field. I'm your host, Dr. Mikkael Sekeres. I'm Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center at University of Miami. Today, we are so happy to be joined by Dr. Carl Forsberg, Assistant Professor of Strategy and History at the Air Force War College. In this episode, we will be discussing his Art of Oncology article, "A Whipple of Choice." At the time of this recording, our guest has no disclosures. Carl, it is such a thrill to welcome you to our podcast, and thank you for joining us. Dr. Carl Forsberg: Well, thank you, Mikkael, for having me. I'm looking forward to our conversation. Dr. Mikkael Sekeres: So am I. I wanted to start, Carl, with just a little bit of background about you. It's not often we have a historian from the Air Force College who's on this podcast. Can you tell us about yourself, where you're from, and walk us through your career? Dr. Carl Forsberg: Sure. I was born and raised in Minnesota in a suburb of Minneapolis-St. Paul and then went to undergraduate on the East Coast. I actually started my career working on the contemporary war in Afghanistan, first as an analyst at a DC think tank and then spent a year in Kabul, Afghanistan, on the staff of the four-star NATO US headquarters, where I worked on the vexing problems of Afghanistan's dysfunctional government and corruption. Needless to say, we didn't solve that problem. Dr. Mikkael Sekeres: Wow. Dr. Carl Forsberg: I returned from Afghanistan somewhat disillusioned with working in policy, so I moved into academia, did a PhD in history at the University of Texas at Austin, followed by postdoctoral fellowships at Harvard and Yale, and then started my current position here at the Air Force War College. The War Colleges are, I think, somewhat unusual, unique institutions. Essentially, we offer a 1-year master's degree in strategic studies for lieutenant colonels and colonels in the various US military services. Which is to say my students are generally in their 40s. They've had about 20 years of military experience. They're moving from the operational managerial levels of command to positions where they'll be making strategic decisions or be strategic advisors. So we teach military history, strategy, international relations, national security policy to facilitate that transition to a different level of thinking. It really is a wonderful, interesting, stimulating environment to be in and to teach in. So I've enjoyed this position here at the War College quite a lot. Dr. Mikkael Sekeres: Well, I have to tell you, as someone who's been steeped in academic medicine, it sounds absolutely fascinating and something that I wouldn't even know where to start approaching. We have postdoctoral fellowships, of course, in science as well. What do you do during a postdoctoral fellowship in history and strategy? Dr. Carl Forsberg: It's often, especially as a historian, it's an opportunity to take your dissertation and expand it into a book manuscript. So you have a lot of flexibility, which is great. And, of course, a collegial environment with others working in similar fields. There are probably some similarities to a postdoc in medicine in terms of having working groups and conferences and discussing works in progress. So it was a great experience for me. My second postdoc occurred during the pandemic, so it turned out to be an online postdoc, a somewhat disappointing experience, but nevertheless I got a lot out of the connections and relationships I formed during those two different fellowships. Dr. Mikkael Sekeres: Well, there are some people who used the pandemic as an excuse to really just plow into their writing and get immersed in it. I certainly wrote one book during the pandemic because I thought, “Why not? I'm home. It's something where I can use my brain and expand my knowledge base.” So I imagine it must have been somewhat similar for you as you're thinking about expanding your thesis and going down different research avenues. Dr. Carl Forsberg: I think I was less productive than I might have hoped. Part of it was we had a 2-year-old child at home, so my wife and I trying to, you know, both work remotely with a child without having childcare really for much of that year given the childcare options fell through. And it was perhaps less productive than I would have aspired for it to be. Dr. Mikkael Sekeres: It's terrifically challenging having young children at home during the pandemic and also trying to work remotely with them at home. I'm curious, you are a writer, it's part of your career, and I'm curious about your writing process. What triggers you to write a story like you did, and how does it differ from some of your academic writing? Dr. Carl Forsberg: Yeah. Well, as you say, there is a real difference between writing history as an academic and writing this particular piece. For me, for writing history, my day job, if you will, it's a somewhat slow, painstaking process. There's a considerable amount of reading and archival work that go into history. I'm certainly very tied to my sources and documents. So, you know, trying to get that precision, making sure you've captured a huge range of archival resources. The real narrative of events is a slow process. I also have a bad habit of writing twice as much as I have room for. So my process entailed a lot of extensive revisions and rewriting, both to kind of shorten, to make sure there is a compelling narrative, and get rid of the chaff. But also, I think that process of revision for me is where I often draw some of the bigger, more interesting conclusions in my work once I've kind of laid out that basis of the actual history. Certainly, writing this article, this medical humanities article, was a very different experience for me. I've never written something about myself for publication. And, of course, it was really driven by my own experiences of going through this cancer journey and recovering from Whipple surgery as well. The article was born during my recovery, about 4 months after my Whipple procedure. It was a difficult time. Obviously kind of in a bad place physically and, in my case, somewhat mentally, including the effects of bad anemia, which developed after the surgery. I found it wasn't really conducive to writing history, so I set that aside for a while. But I also found myself just fixating on this question of had I chosen a superfluous Whipple surgery. I think to some extent, humans can endure almost any suffering with a sense of purpose, but when there's a perceived pointlessness to the suffering, it makes it much harder. So for me, writing this article really was an exercise, almost a therapeutic one, in thinking through the decisions that led me to my surgery, addressing my own fixation on this question of had I made a mistake in choosing to have surgery and working through that process in a systematic way was very helpful for me. But it also, I think, gave me- I undertook this with some sense of perhaps my experience could be worthwhile and helpful for others who would find themselves in a situation like mine. So I did write it with an eye towards what would I like to have read? What would I like to have had as perspective from another patient as I grappled with the decision that I talk about in the article of getting a Whipple surgery. Dr. Mikkael Sekeres: So I wonder if I could back up a little bit. You talk about the difficulty of undergoing a Whipple procedure and of recovery afterwards, a process that took months. And this may come across as a really naive question, but as, you know, as an oncologist, my specialty is leukemia, so I'm not referring people for major surgeries, but I am referring them for major chemotherapy and sometimes to undergo a bone marrow transplant. Can you educate us what makes it so hard? Why was it so hard getting a Whipple procedure, and what was hard about the recovery? Dr. Carl Forsberg: Yeah, it was a long process. Initially, it was a 14-day stay in the hospital. I had a leaking pancreas, which my understanding is more common actually with young, healthy patients just because the pancreas is softer and more tender. So just, you know, vast amount of pancreatic fluid collecting in the abdominal cavity, which is never a pleasant experience. I had a surgical drain for 50-something days, spent 2 weeks in the hospital. Simply eating is a huge challenge after Whipple surgery. I had delayed gastric emptying for a while afterwards. You can only eat very small meals. Even small meals would give me considerable stomach pain. I ended up losing 40 lb of weight in 6 weeks after my surgery. Interestingly enough, I think I went into the surgery in about the best shape I had been in in the last decade. My surgeon told me one of the best predictors for outcomes is actual muscle mass and told me to work out for 2 hours every day leading up to my surgery, which was great because I could tell my wife, "Sorry, I'm going to be late for dinner tonight. I might die on the operating table." You can't really argue with that justification. So I went in in spectacular shape and then in 6 weeks kind of lost all of that muscle mass and all of the the strength I had built up, which just something discouraging about that. But just simply getting back to eating was an extraordinarily difficult process, kind of the process of trial and error, what worked with my system, what I could eat without getting bad stomach pains afterwards. I had an incident of C. diff, a C. diff infection just 5 weeks after the surgery, which was obviously challenging. Dr. Mikkael Sekeres: Yeah. Was it more the pain from the procedure, the time spent in the hospital, or psychologically was it harder? Dr. Carl Forsberg: In the beginning, it was certainly the physical elements of it, the difficulty eating, the weakness that comes with losing that much weight so quickly. I ended up also developing anemia starting about two or 3 months in, which I think also kind of has certain mental effects. My hemoglobin got down to eight, and we caught it somewhat belatedly. But I think after about three or 4 months, some of the challenges became more psychological. So I started to physically recover, questions about going forward, how much am I going to actually recover normal metabolism, normal gastrointestinal processes, a question of, you know, what impact would this have long-term. And then, as I mentioned as well, some of the psychological questions of, especially once I discovered I had a complete pathological response to the immunotherapy, what was the point to having this surgery? Dr. Mikkael Sekeres: And the way you explore this and revisit it in the essay is absolutely fascinating. I wanted to start at the- towards the earlier part of your essay, you write, "The surgeon's willingness to structure our conversation around the ambiguity of the case was immensely clarifying." It's fascinating. The ambiguity was clarifying to you. And the fact that you appreciated the fact that the surgeon was open to talking about this ambiguity. When do you think it's the right thing to acknowledge ambiguity in medicine, and when should we be more definitive? When do you just want someone to tell you, “Do this or do that?” Dr. Carl Forsberg: That's a great question, which I've thought about some. I think some of it is, I really appreciated the one- a couple of the oncologists who brought up the ambiguity, did it not at the beginning of the process but a few months in. You know, the first few months, you're so as a patient kind of wrapped up in trying to figure out what's going on. You want answers. And my initial instinct was, you know, I wanted surgery as fast as possible because you want to get the tumor out, obviously. And so I think bringing up the ambiguity at a certain point in the process was really helpful. I imagine that some of this has to do with the patient. I'm sure for oncologists and physicians, it's got to be a real challenge assessing what your patient wants, how much they want a clear answer versus how much they want ambiguity. I've never obviously been in the position of being a physician. As a professor, you get the interesting- you start to realize some students want you to give them answers and some students really want to discuss the ambiguities and the challenges of a case. And so I'm, I imagine it might be similar as a physician, kind of trying to read the patient. I guess in my case, the fact was that it was an extraordinarily ambiguous decision in which there wasn't data. So I think there is an element, if the data gives no clear answers, that I suppose there's sort of an ethical necessity of bringing that up with the patient. Though I know that some patients will be more receptive than others to delving into that ambiguity. Dr. Mikkael Sekeres: Well, you know, it's an opportunity for us to think holistically about our patients, and you as a patient to think holistically about your health and your family and how you make decisions. I believe that when we're in a gray zone in medicine where the data really don't help guide one decision versus the next, you then lean back towards other values that you have to help make that decision. You write beautifully about this. You say, "In the face of radical uncertainty, one must resort to basic values, and my priority is to survive for my children. A maimed, weakened father is without doubt better than no father at all." That's an incredibly deep sentiment. So, how do you think these types of decisions about treatment for cancer change over the course of our lives? You talk a lot about how you were a young father in this essay, and it was clear that that was, at least at some point, driving your decision. Dr. Carl Forsberg: Yeah, I certainly have spent a lot of time thinking about how I would have made this decision differently 10 years earlier. As I mentioned the article, it was interesting because most of my physicians, honestly, when they were discussing why surgery made sense pointed to my age. I don't think it was really my age. Actually, when I was 23, I went off to Afghanistan, took enormous risks. And to some extent, I think as a young single person in your 20s, you actually have generally a much higher risk tolerance. And I think in that same spirit, at a different, earlier, younger stage in my life, I would have probably actually been much more willing to accept that risk, which is kind of a point I try to make, is not necessarily your age that is really the deciding factor. And I think once again, if I were 70 or 60 and my children, you know, were off living their own lives, I think that also would have allowed me to take, um, greater risk and probably led me to go for a watch-and-wait approach instead. So there was a sense at which not the age, but the particular responsibilities one has in life, for me at least, figured very heavily into my medical calculus. Dr. Mikkael Sekeres: It's so interesting how you define a greater risk as watch and wait, whereas a surgeon or a medical oncologist who's making recommendations for you might have defined the greater risk to undergo major surgery. Dr. Carl Forsberg: And I thought about that some too, like why is it that I framed the watch and wait as a greater risk? Because there is a coherent case that actually the greater risk comes from surgery. I think when you're facing a life and death decision and the consequence, when you have cancer, of course, your mind goes immediately to the possibility of death, and that consequence seems so existential that I think it made watch and wait perhaps seem like the riskier course. But that might itself have been an assumption that needed more analysis. Dr. Mikkael Sekeres: Do you think that your doctor revealing that he also had young children at home helped you with this decision? Dr. Carl Forsberg: I think in some ways for a doctor it's important to kind of understand where your patient is in their own life. As a patient, it was interesting and always helpful for me to understand where my physicians were in their life, what was shaping their thinking about these questions. So I don't know if it in any way changed my decision-making, but it definitely was important for developing a relationship of trust as well with physicians that we could have that mutual exchange. I would consider one of my primary oncologists, almost something of a friend at this point. But I think it really was important to have that kind of two-way back and forth in understanding both where I was and where my physician was. Dr. Mikkael Sekeres: I like how you frame that in the sense of trust and hearing somebody who could make similar considerations to you given where he was in his family. One final question I wanted to ask you. You really elegantly at the end of this essay talk about revisiting the decision. I wonder, is it fair to revisit these types of decisions with hindsight, or do we lose sight of what loomed as being most important to us when we were making the decisions in real time? Dr. Carl Forsberg: That's a great question, one that is also, I think, inherent to my teaching. I teach military history for lieutenant colonels and colonels who very well may be required, God willing not, but may be required to make these sort of difficult decisions in the case of war. And we study with hindsight. But one thing I try to do as a professor is put them in the position of generals, presidents, who did not have the benefit of hindsight, trying to see the limits of their knowledge, use primary source documents, the actual memos, the records of meetings that were made as they grappled with uncertainty and the inherent fog of war. Because it is, of course, easy to judge these things in hindsight. So definitely, I kept reminding myself of that, that it's easy to second guess with hindsight. And so I think for me, part of this article was trying to go through, seeing where I was at the time, understanding that the decision I made, it made sense and with what I knew, it was probably the right decision, even if we can also with hindsight say, "Well, we've learned more, we have more data." A lot of historical leaders, it's easy to criticize them for decisions, but when you go put yourself in their position, see what the alternatives were, you start to realize these were really hard decisions, and I would have probably made the same disastrous mistake as they would have, you know. Let's just say the Vietnam War, we have our students work through with the original documents decisions of the Joint Chiefs in 1965. They very frequently come to the exact same conclusions as American policymakers made in 1965. It is a real risk making judgments purely on the basis of hindsight, and I think it is important to go back and really try to be authentic to what you knew at the time you made a decision. Dr. Mikkael Sekeres: What a great perspective on this from a historian. Carl Forsberg, I'd like to thank you, and all of us are grateful that you were willing to share your story with us in The Art of Oncology. Dr. Carl Forsberg: Well, thank you, and it's yeah, it's been a, it's a, I think in some ways a very interesting and fitting place to kind of end my cancer journey with the publication of this article, and it's definitely done a lot to help me work through this entire process of going through cancer. So, thank you. Dr. Mikkael Sekeres: Until next time, thank you for listening to JCO's Cancer Stories: The Art of Oncology. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all of ASCO's shows at asco.org/podcasts. Until next time, thank you so much. 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.   Show notes:Like, share and subscribe so you never miss an episode and leave a rating or review.  Guest Bio: Dr. Carl Forsberg is a Assistant Professor of Strategy and History at the Air Force War College.

Send us a textWelcome to The Oncology Journal Club Podcast Series 3Hosted by Professor Craig Underhill, Dr Kate Clarke & Professor Christopher Jackson | Proudly produced by The Oncology NetworkThe Oncology Journal Club team take a deep dive into three standout papers:Craig kicks us off with a timely perspective on the long-term toxicity of immune checkpoint inhibitors—are we ready to widen the lens? He highlights the need for more comprehensive research on survivorship issues including quality of life, financial impact and psychological outcomes.Kate brings us the exciting results from the INFINITY study on gastric and gastroesophageal cancers which shows impressive complete response rates in dMMR gastric cancers but at prohibitive costs — and poses a big question: are we ready to rethink treatment paradigms?And CJ unpacks the Common Sense Oncology principles for designing better phase 3 trials — Common Sense Oncology principles offer a patient-centred framework for designing and reporting clinical trials.Of course, we've also got our Quick Bites—those quirky, surprising papers that made us raise an eyebrow or two. From RNA vaccines in pancreatic cancer to updated ASCO guidelines for small cell lung cancer, it's a rapid-fire segment you won't want to miss.For links to the papers discussed and bios of our hosts, head to the show notes on oncologynetwork.com.au.Subscribe to The Oncology Newsletter for regular updates on the latest cancer research and join our community at oncologynetwork.com.au.The Oncology Podcast - An Australian Oncology Perspective

Dear Colleagues,Welcome to the OncoAlert Weekly Round up Covering the TOP News and Trials THIS WEEK in Oncology. This week:Prognostic implications of risk definitions from the monarchE and NATALEE trialhttps://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djaf031/8002826?login=false#google_vignetteEvaluating the impact of histological vs. nuclear grading on CPS + EG Score for HR + /HER2-early breast cancerhttps://link.springer.com/article/10.1007/s10549-025-07685-8?utm_content=buffer1d9c4&utm_medium=social&utm_source=twitter.com&utm_campaign=bufferFDA approves nivolumab with ipilimumab for unresectable or metastatic MSI-H or dMMR colorectal cancerhttps://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-msi-h-or-dmmr-colorectal-cancerCirculating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: 5-year outcomes of the randomized DYNAMIC trialhttps://www.nature.com/articles/s41591-025-03579-wAssessment of a Polygenic Risk Score in Screening for Prostate Cancer (BARCODE1) https://nejm.org/doi/full/10.1056/NEJMoa2407934Neoadjuvant Aumolertinib for unresectable stage III EGFR-mutant non-small cell lung cancerhttps://www.nature.com/articles/s41467-025-58435-9Circulating tumor DNA Clearance as a Predictive Biomarker of Pathologic Complete Response in Patients with Solid Tumors Treated with Neoadjuvant Immune-Checkpoint Inhibitors: a Systematic Review and Meta-Analysishttps://www.annalsofoncology.org/article/S0923-7534(25)00130-9/abstract

CME credits: 1.25 Valid until: 30-12-2025 Claim your CME credit at https://reachmd.com/programs/cme/applying-current-guidelines-in-the-first-line-treatment-of-msi-hdmmr-mcrca-case-discussion/29852/ The NCCN Clinical Practice Guidelines are crucial tool in the treatment of cancer and provide detailed recommendations for treatment selection. The guidelines are regularly updated as new therapies are approved or as drugs received expanded indications. Moreover, data are constantly evolving regarding the role of biomarkers and treatment choice. This activity has been designed to provide an overview of the NCCN guidelines for gastric, colorectal, and hepatocellular cancers and the optimal application of these recommendations to clinical practice.

CME credits: 1.25 Valid until: 30-12-2025 Claim your CME credit at https://reachmd.com/programs/cme/first-line-treatment-of-msi-hdmmr-mcrc-the-role-of-immunotherapy/29850/ The NCCN Clinical Practice Guidelines are crucial tool in the treatment of cancer and provide detailed recommendations for treatment selection. The guidelines are regularly updated as new therapies are approved or as drugs received expanded indications. Moreover, data are constantly evolving regarding the role of biomarkers and treatment choice. This activity has been designed to provide an overview of the NCCN guidelines for gastric, colorectal, and hepatocellular cancers and the optimal application of these recommendations to clinical practice.

Dr. Shannon Westin and her guest, Dr. Brian  Slomovitz discuss the article “Pembrolizumab or Placebo Plus Adjuvant Chemotherapy With or Without Radiotherapy For Newly Diagnosed, High-Risk Endometrial Cancer: Results in Mismatch Repair-Deficient Tumors” recently published in the JCO and presented at the 2024 International Gynecologic Cancer Society. TRANSCRIPT The guest's disclosures can be found in the transcript.  Dr. Shannon Westin: Hello, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts and literature published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, gynecologic oncologist and JCO Social Media Editor by trade. I am thrilled because we are going to be talking about gynecologic cancer today. So, this is my jam. And specifically, we're going to be talking about a manuscript that's a simultaneous publication in the Journal of Clinical Oncology and presented at the Annual Meeting of the International Gynecologic Cancer Society on October 16, 2024. And this is “Pembrolizumab or Placebo, Plus Adjuvant Chemotherapy, With or Without Radiotherapy for Newly Diagnosed High Risk Endometrial Cancer: Results in Mismatch Repair Deficient Tumors.” This is affectionately the KEYNOTE-B21 trial, also known as the GOG-3053 trial and the ENGOT-en11 trial. And we are joined today by the primary author in this manuscript, Dr. Brian Slomovitz, who is the Director of Gynecologic Oncology at Mount Sinai Medical Center in Miami Beach, Florida, and the clinical trial advisor in uterine cancer for the Gynecologic Oncology Group foundation. Welcome, Brian. Dr. Brian Slomovitz: Hey, thanks, Shannon, so much. It's a pleasure to be here. And thanks for giving us the opportunity to discuss this trial. Dr. Shannon Westin: Yes, it's a great trial and I'm so excited to talk about it. And I think we'll start just because this is a broad group that listens to this podcast, they're not all GYN oncologists, experts like yourself, so can you just level set a little bit and speak a bit about the incidence and mortality of endometrial cancer overall and the recent trends in this disease? Dr. Brian Slomovitz: Yeah, sure. So, and it is nice to speak about gynecologic cancers, as we know, endometrial cancer was and still is the most common of all gynecologic cancers. The numbers are going up. Right now, there's about 65,000 to 70,000 cases each year in the US diagnosed with endometrial cancer. The numbers are going up. A lot of its obesity related, some other factors, but as the population gets less healthy, those are some of the risk factors for the disease. The thing that, however, is quite surprising is that we're seeing the deaths due to endometrial cancer going up as well, while for other diseases, we're making slow, steady steps to try to decrease the mortality we're actually seeing an increase in mortality. And the most discouraging point, Shannon, as you know is the number of deaths from endometrial cancer is going to outnumber the number of deaths from ovarian cancer if it hasn't done it already. I mean, now's the time. So, we really need to come up with better treatment strategies to everything to decrease the incidence of disease, to help with prevention, but for those poor women who are diagnosed, to come up with better treatment options so we don't have to keep this increasing trend in mortality. Dr. Shannon Westin: Absolutely. And I think some of that is related and we don't need to get on a soapbox here, but the amount of funding that goes towards research in endometrial cancer, and of course you, you have been leading the way and really trying to get a ton of trials in this space and getting our industry partners and our government partners to really support this. So really just commending you on how much you've worked on, on this area. And to that end, we've had a huge renaissance with immunotherapy and endometrial cancer, a lot of really big trials. Why don't you give the audience a rundown of where, so far, this seems to be best utilized for people with endometrial cancer? Dr. Brian Slomovitz: Thanks for that. And as you sort of alluded to, it's been a revolution, really, with immunotherapy. We started off at immunotherapy looking at microsatellite instability or the dMMR patients. What we found is similar to other disease sites in the second and third line setting that we saw good activity with the single agent checkpoints, pembrolizumab dostarlimab, that's based on the earlier KEYNOTE data and the GARNET trial. Really, a landmark study in the second line was Vicki Makker and her colleagues put pembrolizumab and lenvatinib combination for those patients with the cold tumors. Not the dMMRs or MSI Highs, but the proficient mismatch repair. And that study in a second line setting found that it was better than chemotherapy for an overall survival advantage. So right there, we know that it works in the second line setting in the dMMR population, and we got an indication in the PMR population saying that immunotherapy works in all women with endometrial cancer at some point, then we really had the groundbreaking trials. And Shannon, thank you. You are the leader on one of the four trials that happened, to DUO-E, AtTEnd, GY018 and RUBY trial, all very similar studies showing that the combination of immunotherapy with chemotherapy in the first line, metastatic or recurrent setting had a better outcome for patients than if given chemotherapy alone. That actually led to amazing things. We had three of those drugs have FDA approvals, pembrolizumab for all comers, dMMR and PMMR in the first line metastatic setting with chemotherapy; Dostarlimab, PMR, dMMR in the first line or metastatic with chemotherapy. And Shannon, in your study, I think we still have to learn a lot from your study. DUO-E, chemotherapy plus minus dostarlimab. And you also added a PARP inhib, and those patients with a PARP did better. So I'm really looking forward to your data, to the subgroup analysis to figure out which of those patients, depending on the biomarker, do better with PARP therapy. And right now, you have a dMMR FDA indication. But who knows? The future is really exciting to see- to be splitters, not lumpers. And I really want to see how that data pans out. And so that's how it came into the first and second line setting and that led us really to come up with the idea for this trial to put it into the adjuvant setting. Dr. Shannon Westin: Right. And so, I think this would be really important because we're so ingrained in this. We see this on the day to day. Can you kind of tease out a little bit what's different about those patients that would be treated in that advanced recurrent setting versus the patients that would be potentially treated in this B21 study? Dr. Brian Slomovitz: Yeah, so the first step, we demonstrated the efficacy in patients that really the treatment options were an unmet need. In the second line setting, we didn't have good treatment options. Those are the patients with measurable disease, with symptomatic disease giving immunotherapy. And not only did we see the efficacy, which was better, but we also were able to give it with limiting the side effects as seen with chemotherapy, which is nice. And then we know that the first line therapy, traditionally for endometrial cancer with carboplatin paclitaxel, response rates about 50%, progression free survival about a year, really something that we needed to improve upon. So, adding immunotherapy to the platinum backbone therapy really demonstrated an advantage. But now what we want to do is we want to see if we could prevent, in the high-risk patients, those without disease, what can we do to help prevent the disease from recurring and help patients live longer without really the need for really lifesaving types of treatments? We want to prevent it from recurring. Dr. Shannon Westin: Yeah, I think that's essential. We know that if we can sit on that prevention side and kind of invest all the time and effort that we need to upfront, that really does yield the longer survival. So why don't you just walk through the overall design of this trial, please? Dr. Brian Slomovitz: Yeah. So, this was an all-comers trial, meaning in individuals that had high risk endometrial cancer, high risk for recurrence, that included, in endometrial cancer, we have aggressive histologic subtypes, serous histologies, clear cell histologies, any stage, as long as there was some myometrial invasion. We also, for the first time, included patients looking at the molecular subclassifications. So, if there was a P53 mutation and they were stage 1 with myometrial invasion, they were included. And then in all comers, any patients with stage 3 or up to 4a disease, as long as the surgery was for a curative intent, and they had no residual disease after surgery, then they were allowed to enroll into this trial. One of the things is that this is the first time we've done an adjuvant trial this large. I think one of the reasons that helped us succeed in doing a trial like this is that we left radiation as investigator's choice, because a lot of times going into a trial like this, people feel strongly, we know our radiation oncology colleagues, rightfully so, feel that radiation could help prevent disease from coming back. And we also have the camp that says they don't need radiation. We took that question out of this study. We let investigators decide whether or not they're going to get radiation. It was for patients to get chemotherapy, who are going to normally get chemotherapy for their high-risk disease and randomize them to chemotherapy plus placebo or chemotherapy plus pembrolizumab, a PD-1 inhibitor, in order to see if we could prevent the disease from coming back. Dr. Shannon Westin: And the primary results of this study were just presented at ESMO and published in the Annals of Oncology. Can you give us just a quick overview of what that was, what they found? Dr. Brian Slomovitz: Yep. So, we enrolled 1100 patients. The primary objective of the study was to look at the ITT population, progression free survival and overall survival. And the overall study was negative. Okay, so the hazard ratio in the ITT population was 1.02, not demonstrating a benefit of adding pembrolizumab in this population. I would say disappointing, but at the same point, something that we could really learn a lot from and somewhere that we know that in the whole population, we need to come up with better strategies to help prevent recurrence of disease, better adjuvant treatment strategies. But there's also information that we learned from this trial and that we're reporting on that we're actually super excited about and we feel may be game changing. Dr. Shannon Westin: Yeah. So, let's go to that. This is the good news. Your manuscript in the JCO, thank goodness you published it here, was focused on that subset of mismatch repair deficient. So, tell us what you found. Dr. Brian Slomovitz: So, in this study, we found that the first stratification factor was dMMR versus pMMR. Now, in the pMMR group, those patients had further stratification factors, but dMMR by itself was a stratification factor. Amongst those patients that had dMMR tumors, we found the hazard ratio to be 0.31 benefiting those patients who received pembrolizumab in the adjuvant setting. Really something that when we look at the treatment studies, the GY018s, the RUBYs, the atTEnds, the DUO-Es, in a dMMR setting, we see a similar hazard ratio of 0.3, 0.4. But to get that hazard ratio, which was statistically significant, obviously, is something that we were quite pleased with and something that we felt was worthy of reporting further. I will say it was a pre-specified endpoint. We didn't allocate alpha to it. So, at the beginning, it was a pre-specified endpoint, but at the same time even though we didn't specify alpha towards that outcome, it still, we feel is clinically meaningful and can definitely add to affect the standard of care and the management of these patients. Dr. Shannon Westin: Yeah. I'm very intrigued to see what kind of people do with this. It makes sense, mechanistically, it makes sense if there was a population that was going to benefit, if not everybody does, this is the group that will. I mean, do you feel like there's enough data? What are you going to do? FDA approval aside, obviously, those kinds of things. But how do you feel about this? Is this something you're going to offer to your patients? Dr. Brian Slomovitz: The first answer is yes. I think it's something that I would like to offer my patients. As you know, we need one of two things: we either need an FDA approval or for a lot of our payers required to be in the NCCN listings. I don't serve on the committee. I have no influence on NCCN. I'm excited to see how they'll respond to not only the Annals article, but obviously in today's release of the JCO article, I hope that they'll look upon it favorably. It's a drug that we're used to giving. Pembrolizumab, we have a lot of experience with it. It's interesting. We didn't see any new safety signals, Shannon. Dr. Shannon Westin: Yeah, I was going to ask - that's great. Dr. Brian Slomovitz: There was nothing, nothing additional that we found in this trial. So, I feel that it can definitely improve the outcome of those patients, in my view, with high risk for recurrence, treating pembrolizumab in this setting. Dr. Shannon Westin: Yeah, I think it's important, of course, to look at the safety. What about quality of life? Any new findings there? Dr. Brian Slomovitz: Yeah, we did that quality of life as part of the phase 3 trial. No difference between the two arms. No difference between the two arms. When we looked at a couple of the other analyses, we found that the benefit is the same on stage 3, 4 tumors. We saw that the benefit was there as well. So, there were less patients in the stage 1, 2 group. But I think really, for all comers, for the patient population, I would definitely consider giving pembrolizumab, again, for those patients with a deficient mismatch repair. Dr. Shannon Westin: It's really exciting, and I think you mentioned some of the statistical limitations. Anything else that gives you pause about the study or things you wish you did better? I know we always like to armchair quarterback ourselves after we do these kinds of studies. Dr. Brian Slomovitz: Yeah, it's interesting. When we designed the study years ago, we used the best information we had at that time to come up with the study design, and we're happy with it, and we really don't think that we could have done it much better. I should say, this was a great partnership that we had here between the GOG, ENGOT and with sponsor Merck, Toon Van Gorp was the lead PI of the global trial. When he gave me the good opportunity to present it at the IGCS and to be the lead author on this, it was really a great partnership. And when we came up with a trial years ago, it was the best trial that we thought at that time. And based on the information now, I think it's really something that we're excited about these results, even though the overall trial was negative. Dr. Shannon Westin: Yeah, I agree with you. I think it's interesting, it's informative to think about, “Well, what would we do now or then if we knew what we knew now?” But still, you design the trial the best way you can. I think the results are super intriguing. I'm hopeful at the way they'll be reviewed. I agree I don't have any inside information about the NCCN committee, but I do hope that they'll consider the overarching data to support immunotherapy and mismatch repair deficiency and the findings of this study. And then I guess the last question I would just ask, as you're an expert here, what are you looking forward to seeing coming next in this space? What's the stuff you're intrigued about in endometrial cancer? Dr. Brian Slomovitz: I think, Shannon, you and I have talked about this for a while. I think we're getting really close to eliminating chemotherapy for some of the patients who suffer from this disease. So, I'm not sure if we'll do a follow up to this trial, but I think a logical type of follow up would be to see: what if we just took away chemotherapy altogether and we did pembro in the adjuvant setting, pembrolizumab versus chemotherapy? We don't have that trial in the adjuvant setting, but actually, we completed accrual of that trial in the recurrent setting and we're anxiously awaiting those results. That's KEYNOTE-C93, where in the dMMR population we studied pembrolizumab versus carboplatin paclitaxel. How those results may translate into this setting, I'm not sure. Right now, it's exciting what we have, but yeah. And I think future is bright for this. Just to highlight, in the two arms, there's 140 patients approximately in each arm; there were 25 recurrences in those patients who received placebo. Only eight recurrences in those that received pembrolizumab. Really, when we talk about numbers, it's really remarkable and it shows you the benefit it really had on the patients. Dr. Shannon Westin: Well, this was great. It flew by, as it always does when I'm having conversations with you. I just really want to thank you again for taking the time to share your knowledge with our listeners. Dr. Brian Slomovitz: Thanks, Shannon. Dr. Shannon Westin: And listeners. Thank you all for taking the time to hear about endometrial cancer. Again, this was “Pembrolizumab or Placebo, Plus Adjuvant Chemotherapy, With or Without Radiotherapy for Newly Diagnosed High Risk Endometrial Cancer Results in Mismatch Repair Deficient Tumors.” And this was the JCO After Hours. If you loved what you heard, please check out wherever you get your podcast to see what else we have to offer. Have an awesome day.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.        

In this episode, listen to Ana Oaknin, MD, PhD and Alexandra Leary, MD, PhD, share their clinical insights and takeaways on key updates and new data presented for ovarian, endometrial, and cervical cancer at the ESMO 2024 annual congress including:Phase III PRIMA/ENGOT-OV26/GOG-3012 Final OS Results: Niraparib as First-Line Maintenance in Advanced Ovarian CancerATHENA COMBO/GOG-3020/ENGOT-ov45: Rucaparib With or Without Nivolumab Maintenance in Newly Diagnosed Ovarian CancerPhase II PICCOLO Trial of Mirvetuximab Soravtansine in Recurrent Platinum-Sensitive Ovarian Cancer With High-FRα ExpressionPhase III KEYNOTE-B21/GOG-3053 Study of Adjuvant Chemotherapy With or Without Radiotherapy With or Without Pembrolizumab in Patients With Newly Diagnosed Endometrial Cancer or Carcinosarcoma After Curative Surgery With no Residual DiseasePhase III KEYNOTE-A18 Overall Survival Results: Pembrolizumab Plus Concurrent Chemoradiation in High-Risk Locally Advanced Cervical Cancer Program faculty:Ana Oaknin, MD, PhDHead of Gynaecologic Cancer ProgrammeDepartment of Medical OncologyVall d' Hebron University HospitalVall d'Hebron Institute of Oncology Barcelona, SpainAlexandra Leary, MD, PhDCo-Director, Department of Medical OncologyMedical Oncologist, GynecologyTeam Leader, Gynecologic Translational Research Lab, Institut Gustave RoussyParis, FranceResources:To download the slides associated with this podcast discussion, please visit the program page.

CancerNetwork® spoke with Ritu Salani, MD, about the expanded FDA approval of dostarlimab-gxly (Jemperli) in combination with carboplatin/paclitaxel for patients with primary advanced or recurrent endometrial cancer.1  Salani, a board-certified gynecologic oncologist and director of Gynecologic Oncology at the University of California, Los Angeles Health, discussed the clinical benefit the dostarlimab combination showed for patients with endometrial cancer, particularly those with mismatch repair-deficient (dMMR) tumors, in the phase 3 RUBY trial (NCT03981796). Data leading to the approval showed a statically significant progression-free survival (PFS) and overall survival (OS) benefit in patients with dMMR or microsatellite-instability high (MSI-H) endometrial cancer, as well as for those across the overall population. Noting the significant impact dostarlimab had on survival benefit without significant added toxicity, which investigators reported as early as March 2023, Salani said it was “wonderful” to have a relatively short turnaround time in making the combination therapy available for patients with primary advanced or recurrent endometrial cancer. Beyond the particular benefit among patients with dMMR tumors, she expressed the need to improve outcomes for patients with mismatch repair-proficient (pMMR) or microsatellite stable (MSS) tumors, who did not experience as much of a pronounced benefit from treatment with dostarlimab. Salani also addressed the role of immunotherapy in subsequent lines of treatment following frontline therapy. Being thoughtful about sequencing agents in this setting may be an optimal strategy to give patients the greatest survivability and quality of life. She also considered alternative treatment strategies for certain patients, such as those with pMMR tumors.  “The thing that is interesting is the study highlighted patients who had residual disease or measurable disease present when they were getting this therapy, and that seems to be where the most significant impact [is],” Salani said. “Seeing more data on the right selection of patients will be really important. There are other avenues of treatment for these patient populations, particularly the pMMR population, where you might see some other therapies that may have an equally profound impact as immunotherapy. Maybe that will lend itself to leading immunotherapy for second-line treatment, if needed.” Reference FDA expands endometrial cancer indication for dostarlimab-gxly with chemotherapy. News release. FDA. August 1, 2024. Accessed August 15, 2024. https://tinyurl.com/mtr6tpyp

Dr Westin discusses the FDA approval of durvalumab plus chemotherapy for patients with dMMR advanced or recurrent endometrial cancer.

La Dra. Julieta Gómez Avalos, oncóloga médica egresada del CMN "20 de Noviembre" del ISSSTE en la Ciudad de México y actualmente en entrenamiento en Oncología Gastrointestinal en el Hospital Clínico Universitario en Valencia, España, comparte los aspectos más destacados del Congreso de ESMO sobre tumores gastrointestinales realizado este año en Alemania del 26 al 29 de junio. TARZAN: evalúa la combinación de radioterapia, atezolizumab y bevacizumab en pacientes con cáncer de recto en etapas tempranas e intermedias, con el fin de evitar la cirugía radical y mejorar las tasas de preservación de órganos. El objetivo primario es evaluar la respuesta clínica completa a las 12 semanas mediante endoscopia y resonancia magnética, buscando una tasa superior al 25%. Los objetivos secundarios abarcan la respuesta patológica, la tasa de preservación de órganos, la seguridad del tratamiento y la supervivencia libre de recurrencia. NEST-1: estudio de un solo brazo que investiga el uso neoadyuvante de botensilimab, un inhibidor de CTLA-4 mejorado con Fc, junto con balstilimab, un inhibidor de PD-1, en pacientes con cáncer colorrectal resecable, tanto con microsatélite estables como con alta inestabilidad de microsatélites (MSI-H). El objetivo es evaluar la viabilidad, seguridad y eficacia de la combinación para un estudio más amplio. ECOG-ACRIN EA220: estudio fase II, de un solo brazo, que investiga el uso de nivolumab e ipilimumab, combinados con radioterapia de corto curso, seguidos de cirugía en pacientes con cáncer de recto localmente avanzado con MSI-H o dMMR (reparación deficiente por desajuste). El objetivo primario es evaluar la tasa de respuesta patológica completa después del tratamiento, con la posibilidad de incluir la respuesta clínica completa en un análisis combinado si la tasa de excisión mesorrectal total es menor de lo esperado. Abstract 7MO: el estudio analizó el ADN tumoral circulante y el ImmunoScore® en pacientes con cáncer de colon resecado en estadio III, utilizando datos post hoc de los estudios IDEA-France y HORG. El objetivo es evaluar el valor pronóstico de ambos elementos para mejorar la predicción y personalización de los tratamientos adyuvantes en estos pacientes. Fecha de grabación: 5 de julio de 2024               Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente.

Our 2024 ASCO epic trundles onto its next generation, advanced colorectal cancer. Over the last 10 years, treatment in this area has made incremental progress through the discovery of the clinically meaningful KRAS and BRAF mutation pathways and most recently with the potential for immunotherapy in the deficient mismatch repair (dMMR) and high microsatellite instability (MSI-H) subgroups. In this episode, Josh and Michael examine studies looking at KRAS G12C-mutated, HER2-positive and dMMR colorectal cancer, as well as a very exciting study examining the utility of transplantation in patients with liver-only colorectal metastases.Links to studies discussed in this episode (subscription may be required): CODEBREAK300: https://meetings.asco.org/2024-asco-annual-meeting/15829?presentation=234200%23234200 MOUNTAINEER: https://meetings.asco.org/2024-asco-annual-meeting/15829?presentation=231646%23231646 CHECKMATE 8HW: https://meetings.asco.org/2024-asco-annual-meeting/15828?presentation=231645%23231645TRANSMET: https://meetings.asco.org/2024-asco-annual-meeting/15828?presentation=231641%23231641For more episodes, resources and blog posts, visit www.inquisitiveonc.comPlease find us on Twitter @InquisitiveOnc!If you want us to look at a specific trial or subject, email us at inquisitiveonc@gmail.comOncology for the Inquisitive Mind is recorded with the support of education grants from Pfizer, Gilead Pharmaceuticals and Merck Pharmaceuticals. Our partners have no editorial rights or early previews, and they have access to the episode at the same time you do.Art courtesy of Taryn SilverMusic courtesy of AlisiaBeats: https://pixabay.com/users/alisiabeats-39461785/Disclaimer: This podcast is for educational purposes only. If you are unwell, seek medical advice. Hosted on Acast. See acast.com/privacy for more information.

Lots and lots of updates from the past weekend's ASCO annual meeting. 1. ADRIATIC (consolidation durvalumab in limited stage SCLC) 2. NADINA (neoadjuvant Nivo/Ipi in stage III melanoma) 3. *NICHE-2 (neoadjuvant Nivo/Ipi in dMMR colon cancer) 4. CheckMate 8HW (Nivo/Ipi in dMMR metastatic colon cancer) 5. TRANSMET (liver transplantation in colon cancer with liver mets) 6. Eposec (FLOT > CROSS in adenocarcinoma of the esophagus) 7. LAURA (forever osimertinib in stage III EGFR-mutated NSCLC post-chemoRT) 8. CROWN (5 year update of lorlatinib in ALK+ NSCLC) 9. Destiny Breast-06 (T-DXd vs. chemo in HER-2 low and "ultra" low MBC who haven't received chemo in metastatic setting) 10. ASC4FIRST (Asciminib first line in CML. Funny title, amirite?)

Featuring articles on neoadjuvant immunotherapy for dMMR colon cancer, TAVR in patients with a small aortic annulus, gene editing and retinal degeneration, and the genetic diagnosis of rare diseases; a review article on disorders of magnesium; a case report of a woman with metastatic breast cancer; and a Perspective on malicious midwives, fruitful vines, and bearded women.

Drs Nassar and Bou Farhat explain how tumor-only NGS could address the limitations of IHC testing for MMR mutation signatures across several tumor types.

Doctors James Ferriss, Linda Duska, and Jayanthi Lea discuss the promise and the challenges of targeting the immune system with immune checkpoint inhibitors, or ICIs, in cervical and endometrial cancers. They also examine emerging data that support the use of ICIs in recurrent cervical cancer, the potential for curing some patients with advanced endometrial cancer, and molecular factors that make cervical cancer a good target for immunotherapy. TRANSCRIPT Dr. James Stuart Ferriss: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. James Stuart Ferriss, your guest host of the ASCO Daily News Podcast today. I'm an associate professor of gynecology and obstetrics and the Gynecologic Oncology Fellowship Program Director at Johns Hopkins Medicine. In today's episode, we'll be discussing the use of immunotherapy in cervical and endometrial cancers to advance the treatment of these malignancies. I'm delighted to be joined by two acclaimed experts in this space, Dr. Linda Duska and Dr. Jaya Lea.   Dr. Duska is a professor of obstetrics and gynecology and serves as the associate dean for clinical research at the University of Virginia School of Medicine. Dr. Lea is a professor of obstetrics and gynecology and chief of gynecologic oncology at the University of Texas Southwestern Medical Center.  Our full disclosures are available in the transcript of this episode, and disclosures related to all episodes of the podcast are available at asco.org/DNpod. Drs. Duska and Dr. Lea, it's great to have you on the podcast today.  Dr. Linda Duska: Thanks, Dr. Ferriss.  Dr. Jayanthi Lea: Thanks, Dr. Ferriss.  Dr. James Stuart Ferriss: So, let's get started. In recent years, we've had a revolution in the treatment of advanced endometrial and cervical cancers with improved outcomes for patients treated with immunotherapy. And when we say immunotherapy, we're specifically talking about immune checkpoint inhibitors today. A few of these agents have actually been approved in the United States for the management of these diseases. In our discussion, I'd like to review the promise and challenges of targeting the immune system in patients with advanced endometrial and cervical cancers, as well as review the most recent evidence we have in these spaces.  Let's start with cervix. We've had a lot of improvements in outcomes here, Dr. Lea, and with cervical cancer, we've seen improved overall survival with the incorporation of immunotherapy along with chemotherapy and anti-angiogenic therapy for advanced and recurrent disease. Can you remind us why cervical cancer is a good target for immunotherapy?  Dr. Jayanthi Lea: Yes, Dr. Ferriss. Immunotherapy for cervical cancer is supported by several molecular factors. And I think first and foremost, it's so important to remember that the majority of cervical cancers are HPV-positive. And HPV-positive cancers can induce a high level of inflammation, but this high level of inflammation actually contributes to evasion of immune surveillance. What it also does is that it's responsible for the induction of PD-L1. And we've seen several studies that have shown that cervical cancers express PD-L1 anywhere from 50 to 90 percent of cases. Other pertinent factors to consider are that cervical cancer can be considered a tumor with a high tumor mutational burden. So, the number of somatic mutations that we see in the DNA can be considered as a proxy for neoantigens. And so the higher the level of neoantigens, the more immunogenic the tumor. And then lastly, about 1 in 10 cervical cancers present with microsatellite instability, which is an already established key biomarker for the response team in care.  Dr. James Stuart Ferriss: So, thinking about targeting PD-L1, what clinical evidence do we have that supports the use of immune checkpoint inhibitors in recurrent cervical cancer?  Dr. Jayanthi Lea: We now have several studies that have shown a benefit for immune checkpoint inhibitors. For example, KEYNOTE-158 was a phase 2 basket [trial] that investigated the antitumor activity of pembrolizumab, which is a PD-1 inhibitor, in multiple cancer types. And specifically for patients with previously treated advanced cervical cancer, we were able to see an overall response rate of about 15% in those patients who had PD-L1 positive. And similarly, the EMPOWER CERVICAL-1 study, which was a phase 3 randomized trial that investigated the efficacy of cemiplimab, which is another PD-1 inhibitor, versus investigator's choice of single agent chemotherapy, showed a significant difference in median overall survival and progression-free survival in the cemiplimab group. There are several other studies that have investigated the efficacy of PD-1 or PD-L1 inhibitors in cervical cancer. One specific PD-1 inhibitor is nivolumab. In CHECKMATE-358, nivolumab was associated with an overall response rate of 26% in women who had recurrent/metastatic cervical cancer.  Dr. James Stuart Ferriss: Dr. Duska, do you have any thoughts?  Dr. Linda Duska: I'm really interested in PD-L1 as a biomarker because in the KEYNOTE-A18 study, which we're going to get to, 95% of patients were PD-L1 positive by CPS, which is the scoring system that we use in cervix cancer. And some of the studies that you already mentioned, including BEATcc, which we're also going to talk about, reported results where PD-L1 wasn't even considered. And so it begs the question, since PD-L1 is actually – again, depending on when in the course of disease you look at it, but more recent studies suggest 95% of cervical cancers express PD-L1, and – agnostic is the word I was looking for – it seems at least in BEATcc and similar trials that PD-L1 is agnostic, but I wonder if PD-L1 is really a good biomarker for response to checkpoint inhibitor therapy and I wonder what your thoughts are.  Dr. Jayanthi Lea: I think that's an excellent question. To your point, that's correct that we saw in KETYNOTE-A18 that more than 90% of the patients had PD-L1 positivity and the result is sort of generalizable to all comers. That's still a matter of debate as to how we see PD-L1 as a biomarker to incorporate checkpoint inhibitors in the treatment of patients.  Dr. James Stuart Ferriss: So, let's talk about the use of immune checkpoint inhibitors in the frontline setting. Until recently, we haven't seen much improvement in overall survival since the introduction of anti-angiogenic therapy to the chemotherapy backbone, and that was in GOG 240. Let's talk about the changes that have recently occurred in this space.  Dr. Jayanthi Lea: So, we've had some very exciting data specifically from initially KEYNOTE-826 and its primary metastatic or first line salvage settings. So, KEYNOTE-826, which was a phase 3 randomized, controlled trial was very practice-changing for us because it showed that incorporation of pembrolizumab to the first-line treatment of patients with metastatic or recurrent cervical cancer, really changed the landscape for treatment in this group of patients. So, keep in mind that prior to the study, the standard of care was carboplatin, or cisplatin with paclitaxel plus or minus bevacizumab, which yielded a median overall survival range in anywhere from 13 to 17 months depending on whether you use bevacizumab or not. And then adding pembrolizumab to that regimen, increase the median overall survival to 24 months, which is very promising.  Dr. James Stuart Ferriss: If I remember correctly, KEYNOTE-826 allowed investigators choice, use of bevacizumab, and initially we were unsure about which regimen was best. Has there been additional data since?  Dr. Jayanthi Lea: There has been additional data since. And another study that was done in the same vein was the BEATcc trial, which also looked at the different checkpoint inhibitors, atezolizumab in combination now with bevacizumab and platinum-based chemotherapy. And the control arm for this study was the GOG 240 regimen, which included bevacizumab. And this study showed both a progression-free and overall survival difference. The median overall survival in this study was 32 months with the incorporation of the checkpoint inhibitor to the bevacizumab and platinum-based chemotherapy. So, the way that I look at it is that the BEATcc trial basically confirmed the findings of KEYNOTE-826 and highlights that it is important for us to incorporate checkpoint inhibition with immunotherapy along with bevacizumab when we're treating patients with a recurrence.  Dr. James Stuart Ferriss: Also, folks with primary advanced treatment for cervical cancer, this would be a great regimen, is that right?  Dr. Jayanthi Lea: Absolutely. Primary advance, we would want to use the same regimen for that.  Dr. James Stuart Ferriss: Okay. What about locally advanced in primary treatment? What advances have we seen?  Dr. Jayanthi Lea: So we've had some major changes in that field as well, especially with the recent KEYNOTE-A18 data where pembrolizumab was administered in combination with external beam radiation and concurrent chemotherapy. And this study showed that there was significant and clinically meaningful improvement in progression-free survival compared to chemoradiation alone. Specifically, the progression-free survival at 24 months using pembrolizumab with chemoradiation was 68%, and 57% when in the placebo group. The hazard ratio for disease progression was 0.7 and no new safety signals were observed, which is fantastic, especially given the 0.7 hazard ratio that received PFS.  Dr. James Stuart Ferriss: Yeah, absolutely. These patients with locally advanced cervical cancer often are quite symptomatic, and the prospect of adding chemo, radiation, and now immunotherapy on top of that is really encouraging to see that it was such a well-tolerated regimen. I believe that there were patient-reported outcomes recently reported at SGO.  Dr. Jayanthi Lea: Absolutely. So, the safety profile of pembrolizumab and chemoradiation was consistent with the known profile of the individual treatment components. And no new safety signals emerged in the pembrolizumab chemoradiation arm. So, you're right. It was very well tolerated.  Dr. James Stuart Ferriss: What would you say are the takeaways for folks who are seeing these patients in the community? These locally advanced cervical cancer patients that are now adding immunotherapy in a space that we have not used routinely in the past in terms of combining it with chemo radiation in gynecologic cancer. What are some things they should be looking out for?  Dr. Jayanthi Lea: Well, I think that with the hazard ratio of 0.7 and the patient-reported outcomes showing no new signal, I think we can say that there is a positive benefit-to-risk profile of adding pembrolizumab in combination with chemoradiation, and that we should feel comfortable using this regimen. Now, of course, we have individualized patient care, and be able to know when to use bevacizumab, when to use immunotherapy. So, taking the whole patient into consideration becomes important. But for those individuals who are able to receive these drugs who don't have concrete issues to not receive these drugs [then I'd say we could] incorporate them since the safety profile is set.  Dr. Linda Duska: I would add to that, Dr. Ferriss, that right now we only have FDA approval in the U.S. for stage 3-4A disease, and that's 2014 staging. Mind you, we are now in 2018, so we should be very careful in and follow the correct FIGO staging. But the FDA only gave approval for stage 3-4A disease, even though the study included patients with earlier stage disease and positive nodes.  Dr. James Stuart Ferriss: That's a great point, thank you.  So, Dr. Duska, thinking about endometrial cancer and advanced endometrial cancer, we have seen a similar revolution in the care of patients over the past few years, with major shifts in our approach. Can you remind us how we got here?  Dr. Linda Duska: Yes, I would say in the ‘90s and before, and maybe even in the early 2000s, we used a lot of radiation for endometrial cancer as adjuvant therapy following surgery. The general consensus and what we were all taught was that this was a chemotherapy-resistant disease. And then we learned from a variety of GOG at the time, Gynecologic Oncology Group trials, that this disease is actually chemosensitive. And we went through a series of chemotherapy drugs, ranging from adriamycin cisplatin to taxel adriamycin cisplatin, and finally to taxel and carboplatin, demonstrating that this disease is actually quite chemosensitive.  With this realization came the idea that maybe it would be important to combine chemotherapy and radiation particularly in high-risk endometrial cancer cases, so those with positive nodes or patients with high-risk histology such as clear cell or serous cancers. So two very important trials were done, one of them was PORTEC-3 and the other was GOG-258, which looked at combining chemo and radiation together to see if we could do better than one or the other alone. And they were very different trials, and they looked at different populations of patients and they looked at different things. For example, PORTEC-3 randomized patients to receive chemotherapy and radiation versus radiation alone, while 258 looked at chemotherapy and radiation versus chemotherapy alone. Without going into a great amount of detail, I think what we learned from both of those studies, and I think surprised many of us, that the arms that included chemotherapy, those patients did better.  In fact, the results of GOG-258 can be interpreted – and this is somewhat controversial – but can be interpreted that many of these high-risk patients don't need radiation at all, or perhaps need tumor-directed radiation. For example, chemotherapy followed by tumor-directed radiation either to the vaginal cuff, because the vaginal cuff is at risk for recurrence, or perhaps to an area of concern, maybe the cervix if there were cervical involvement or if there is a particular concern for local recurrence in a particular patient. So, I think the pendulum has swung from almost always using radiation alone to, in more modern day, using chemotherapy and using radiation much more sparingly, and then comes immunotherapy.  Dr. James Stuart Ferriss: So, update us on the results of NRG-GY018 and RUBY?  Dr. Linda Duska: So, we've already talked about the KEYNOTE basket trials, which really contributed a lot to our understanding of the importance of MMR deficiency and microsatellite unstable disease. The KEYNOTE-158 study and the GARNET study showed us how important it was for women with MMRd and MSI endometrial cancer to receive checkpoint inhibition, and actually with remarkable response rates to women who had already been pretreated. But we also learned from the GARNET trial, which included MMRp patients, that the response rates in MMRp were not that great. And that led to KEYNOTE-775, which looked to combine pembrolizumab with a VEGF inhibitor, lenvantinib, to see if we could make the cold tumor hot. And indeed, we could. And not only could we improve the response rate in patients with MMRp tumors, but we could also improve the response rate in patients with MMRd tumors. They did better with the combination than they did with pembro alone.  That led to the idea of combining checkpoint inhibitors with chemo upfront. The idea there was we were going to take paclitaxel and carboplatin, which were our backbone for advanced or recurrent endometrial cancer, and add immunotherapy to that. And to your point, GY018 and RUBY trials did just that. And they allowed MMRd and MMRp patients and combined paclitaxel and carboplatin, either with dostarlimab in the case of RUBY, or pembrolizumab in the case of GY018. These studies, both of which were reported and published in the New England Journal of Medicine last year, showed remarkable findings in the upfront setting and potentially in the curable setting. And the OS data for RUBY were presented at SGO this year and were remarkable for MMRd patients. In the whole population, in the whole group in RUBY, there was a 16.4-month improvement in overall survival with the addition of dostarlimab which is just huge.  When you look at the MMRd group, I think Dr. Powell described the overall survival improvement as unprecedented. I believe that was the word that he used. Also, he called it very robust, with a hazard ratio of 0.32 for the group that got dostarlimab, and a median OS that was not reached. So really remarkable. In addition, in the MMRp group, there was a seven-month improvement in OS that was significant. So that's really amazing in the RUBY trial. It's also of note that the RUBY trial allowed carcinosarcomas, whereas the GY018 study did not. So, I think it's fair to say that these results apply to carcinosarcomas.  It's also really important to note that many of the patients in the immunotherapy group who received placebo, 41% of them got IO in a later treatment line, and these OS data still stand. So that's really interesting and hypothesis-generating. For GY018, we don't have mature OS data yet, so we can't talk about OS. But we saw a similar improvement in PFS in both arms, in the d and the pMMR, with an OS trend in both arms that was also reported at SGO. GY018 was a little bit different though, because they unblinded at the time of the PFS reporting last year, and so those patients were unblinded a lot earlier than the RUBY patients were. So, to interpret the data in that vein, the OS data is not mature, but we anticipate looking at the PFS curves and the preliminary OS curves, that the OS data will also be statistically significantly improved in core pembrolizumab in GY018.  What's also really interesting, and we haven't talked about molecular subtypes, is that when we look at the molecular subtypes in RUBY, and I'm sure we're going to see data on the molecular subtypes in GY018 coming up, different molecular subtypes of endometrial cancer respond differently to IO. And so, there's going to be lots of really interesting data coming our way soon that we're really excited to see, and that will help us triage patients appropriately into treatment regimens.  Dr. James Stuart Ferriss: Dr. Lea, did you have a thought?  Dr. Jayanthi Lea: Yeah, I just wanted to comment that looking at the dMMR survival curve in the file that was presented recently, one thing that really strikes me is the importance of adding the IO at the time of initial treatment. The separation of the curves persists. And, like you just mentioned, Dr. Duska, I mean, some of those patients who received placebo then later on went to get an IO treatment, but at the same time, we still see a vast separation of those curves. So, I think it's really important to note that immunotherapy should be used upfront, especially in dMMR.  Dr. Linda Duska: Yeah, I completely agree with that. And I think that might be– I mean, this is just a hypothesis, but I think that that might be why we saw a difference with the addition of immunotherapy in the MMRp group, because it's possible that the chemotherapy created an immune environment that made the checkpoint inhibitor work more successfully than it would have otherwise. So, a really good point. You definitely need to include dostarlimab or pembrolizumab with the chemotherapy and then as maintenance therapy after.  Dr. James Stuart Ferriss: So, you mentioned, we're increasingly thinking about endometrial cancer in smaller and smaller buckets of patients with very prescribed molecular profiles. We don't yet have enough information to specifically tailor treatment. How are you approaching that today in patients that you see in clinic?  Dr. Linda Duska: Well, the MMR, and I'm interested in what you both are doing also, it's easy with the MMRd and MSI high patients. Those patients all should receive a checkpoint inhibitor, no question. The patients that are p53 mut, I test them for HER2, because we do have data to suggest that atezolizumab or TDX-d might be useful in those individuals, HER2 positive. And then the remaining patients, also called the NSMPs. That's a difficult group. I'm interested to know how you all manage them. I think that's the group where more clinical research is really needed to determine what the best treatment regimen for them is. But I'm interested in both of your thoughts on that.  Dr. James Stuart Ferriss: Dr. Lea?  Dr. Jayanthi Lea: I would have to say that I do exactly like you do, Dr. Duska.  Dr. James Stuart Ferriss: And I would say our approach is very similar. And we have a robust discussion always about the use of immunotherapy with chemotherapy and in patients who are proficient MMR. But I think that most of us believe that the PFS data is certainly compelling. And now the OS data from RUBY, very compelling in both groups. And so, we are routinely recommending the use of immunotherapy along with chemotherapy in these advanced patients.  Dr. Linda Duska: I've heard the argument made that GY018 required measurable disease, and so does not necessarily apply to patients without measurable disease. I'm not sure that I agree with that. I think there were clinical trial reasons why that was a requirement rather than biologic reasons. In addition, as we already discussed, RUBY included carcinosarcomas and GY018 did not. I don't think there's a reason to only use dostarlimab for carcinosarcomas, but that said, I don't know that pembrolizumab has an indication for carcinosarcomas. The devil's in the details, don't get too lost in the weeds. I think the take-home message here is that it's really important to use IO, particularly for the MMRd patients with endometrial cancer, upfront. And based on the OS that we saw in both RUBY and preliminarily in GY018, we may be curing some people with this regimen, and I think we should focus on that. The overall survival for advanced endometrial cancer is not great, and if we can improve that and potentially cure some people, that's a huge advance for our patients.  Dr. James Stuart Ferriss: Do you envision a day that we might even ask the question, “Do we need to do surgery?”  Dr. Linda Duska: So, the rectal data would support that assertion. I'm not sure that endometrial cancer and rectal cancer are the same thing. And I think that taking out a postmenopausal woman's uterus is a lot less morbid than potentially radiating or taking out somebody's rectum. I think a different question would be, is there a day when we would stop doing no dissection? We could definitely debate that, but I don't see that happening. Do you see that happening anytime soon? A stopping of hysterectomy for endometrial cancer? Dr. Jayanthi Lea: I don't see that happening anytime soon. And I think, as you said, taking out the uterus, tubes, and ovaries, it does provide us with some information about whether you're even dealing with a secondary primary. But also, it's from a quality-of-life standpoint. If a woman has a large uterus, that's uncomfortable. Postmenopausal bleeding, avoiding bleeding during the course of treatment, so many reasons why I wouldn't be in too much of a hurry to want to not do surgery for these patients. Dr. James Stuart Ferriss: So, we'll put a plug in for our fellow gynecologic oncologists that we still have a role to play in the incorporation of treatment regimens for patients with advanced uterine cancer. So it's not just medicine, there's still a role for surgery.  Dr. Linda Duska: I think that's very fair, yeah. Dr. James Stuart Ferriss: Okay. I think that's all the time we have for today.  I want to thank our listeners for their time, and you'll find the links to all the studies we've discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you.  Dr. Linda Duska: Thank you. Dr. Jayanthi Lea: 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.    Find out more about today's speakers: Dr. James Stuart Ferriss Dr. Linda Duska @LDuska Dr. Jayanthi Lea   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures: Dr. James Stuart Ferriss: Honoraria: National Board of Medical Examiners Dr. Linda Duska: Consulting or Advisory Role: Regeneron, Inovio Pharmaceuticals, Merck, Ellipses Pharma Researching Funding (Inst): GlaxoSmithKline, Millenium, Bristol-Myers Squibb, Aeterna Zentaris, Novartis, Abbvie, Tesaro, Cerulean Pharma, Aduro Biotech, Advaxis, Syndax, Pfizer, Merck, Genentech/Roche, Cerulean Pharma, Ludwig Institute for Cancer Research, Leap Therapeutics Patents, Royalties, Other Intellectual Property: UpToDate, Editor, British Journal of Ob/Gyn Dr. Jayanthi Lea: Consulting or Advisory Role: Roche

During the 2024 Society of Surgical Oncology Annual Meeting (SSO), CancerNetwork® spoke with a variety of surgical oncology experts regarding the topline data they presented. Each conversation also expanded upon how these results can be implemented into the clinical space and the next research steps.  First, Adrienne Bruce Shannon, MD, a complex general surgical oncology fellow at Moffitt Cancer Center, discussed findings from her presentation highlighting responses to neoadjuvant immune checkpoint inhibitors among select patients with mismatch repair deficient (dMMR) gastroesophageal cancer.1  Looking ahead, Shannon described her aim to optimize treatment strategies for this patient population, which may include assessing whether single-agent treatment can be efficacious while avoiding toxicity associated with combination regimens.  Next, Sean Dineen, MD, an associate member in the Gastrointestinal Department, section leader for Peritoneal Disease, and the program director for the Complex General Surgical Oncology Fellowship at Moffitt Cancer Center, spoke about his session, which was aimed at determining appropriate conditions for using cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) for those with colorectal cancer (CRC) and peritoneal metastases.2  Dineen highlighted that there is “good evidence” in support of HIPEC as a “valid treatment option” and emphasized the need to encourage medical oncologists to refer patients for consideration of surgery. Additionally, he spoke about other advancements he hopes to see in this patient population, including the development of markers of various disease volumes that can help identify potential recurrence in those who receive surgery.  Finally, Muhammad Talha Waheed, MD, a research fellow in the Department of Surgical Oncology at City of Hope National Medical Center in Duarte, California, detailed findings from a retrospective analysis indicating disparate treatment access and cancer-related mortality based on racial-economic segregation.3  Specifically, data showed that those who lived in Black and poor majority areas were less likely to receive care that was in accordance with various treatment guidelines while having worse overall survival outcomes. Regarding the next steps, Waheed described his intentions of sharing his findings with policymakers who may create legislature intended to mitigate the disparities observed in the analysis. References 1.        Shannon AB, Mehta RJ, Mok SR, et al. Pathologic response to neoadjuvant immunotherapy in DNA mismatch repair protein-deficient gastroesophageal cancers. Presented at the Society of Surgical Oncology 2024 Annual Meeting; March 20-23, 2024; Atlanta, GA. Abstract 94. 2.        Dineen S. Optimal tumor burden for CRS/HIPEC in colorectal cancer. Presented at the Society of Surgical Oncology 2024 Annual Meeting; March 20-23, 2024; Atlanta, GA. 3.        Waheed MT, Sullivan KM, Haye S, et al. Impact of racialized residential segregation on guideline concordant cancer care and survival. Presented at the Society of Surgical Oncology (SSO) 2024 Annual Meeting; March 20 – 23, 2024; Atlanta, GA; abstract E126.

The Oncology Journal Club - Delivering Oncology News DifferentlyThe Oncology Podcast, part of The Oncology Network, is proud to present Episode 3 in the second series of The Oncology Journal Club Podcast.Dr Kate Clarke explores a clinical conundrum with the latest insights on neo-adjuvant immunotherapy for DMMR, MSI-high GI cancers, discussed with the clarity and depth you've come to expect from our team. For Professor Craig Underhill's main paper segment, Dr. Ashray Gunjur drops by to discuss the microbiome's predictive power in immunotherapy responses, Professor Christopher Jackson delves into the OPRA study's latest findings on chemo-radiotherapy sequencing for rectal cancer, bringing to light the pivotal role of patient-centred discussions.In Quick Bites, the discussion hits home with the three S's—sitting, shitting, and sex—and their profound impact on post-cancer quality of life. Highlighting the importance of comprehensive support systems in these often-overlooked areas, we also dissect the worrying trend of early-onset colorectal cancer and its broader implications. With a review of a study about the duration of immunotherapy in non-small cell lung cancer, this episode promises to fuel ongoing debates on treatment duration and patient outcomes, highlighting our commitment to keeping you at the forefront of oncology discourse.The conversation takes a crucial turn as we tackle the uncomfortable yet necessary topic of presenting unfunded treatment options in oncology, exposing the delicate balance healthcare professionals must maintain in an era marked by scarce resources and rising demands.For papers, bios and other links visit the Show Notes on our website.For the latest oncology news visit www.oncologynews.com.au.We invite healthcare professionals to join The Oncology Network for free - you'll also receive our free weekly publication The Oncology Newsletter.The Oncology Podcast - An Australian Oncology Perspective

El Dr. Jorge Gallardo, oncólogo médico, Coordinador de Oncología Médica en la Clínica INDISA en Providencia, Santiago de Chile junto con la Dra. Marytere Herrera Martínez, oncóloga médica adscrita a la Unidad de Tumores Gastrointestinales del Instituto Nacional de Cancerología, en la Ciudad de México, México nos hablan sobre los estudios más relevantes presentados durante el Simposio de Cánceres Gastrointestinales 2024 :   Tubo digestivo KEYNOTE 590: resultado a 5 años del estudio fase III, aleatorizado, doble ciego, que evaluó el uso de pembrolizumab en combinación con quimioterapia (QT) con cisplatino y 5-fluorouracilo vs. placebo + QT como tratamiento de primera línea en pacientes con cáncer esofágico avanzado metastásico. MATTERHORN: estudio fase III, aleatorizado, doble ciego que evaluó el tratamiento de durvalumab o placebo neoadyuvante-adyuvante y QT FLOT (fluorouracilo + leucovorina + oxaliplatino + docetaxel) seguido de durvalumab o placebo adyuvante en pacientes con cáncer resecable de la unión gástrica y gastroesofágica. KEYNOTE 585: estudio fase III, aleatorizado, doble ciego, el cual comparó pembrolizumab perioperatorio más QT vs. placebo perioperatorio más QT en pacientes con cáncer en la unión gástrica o gastroesofágica localmente avanzada. Cabe destacar que se realizó una cohorte en donde se evaluó pembrolizumab + FLOT y los resultados mostraron un aumento en las respuestas patológicas completas con pembrolizumab perioperatorio más FLOT vs. FLOT solo. Tumores neuroendocrinos NETTER-2: estudio fase III, multicéntrico, aleatorizado y abierto que evaluó la eficacia y seguridad de Lu-177 dotatate en combinación con octreótido en pacientes con tumores neuroendocrinos gastroenteropancreáticos (TNE-GEP) con altas tasas de proliferación (G2 y G3). Se observaron mejoras significativas en la supervivencia libre de progresión con la combinación vs. octreótido en dosis elevadas. Carcinoma hepatocelular EMERALD-1: estudio fase III, global, aleatorizado, doble ciego, controlado con placebo que evaluó el uso de durvalumab + quimioembolización transarterial (TACE, por sus siglas en inglés) concurrente, seguido de durvalumab con o sin bevacizumab hasta la progresión, en comparación con TACE solo en pacientes con carcinoma hepatocelular (CHC) irresecable elegibles para embolización. Cáncer colorrectal CheckMate-8HW: estudio fase III, abierto, en el cual se observó una mejora en el objetivo primario de supervivencia libre de progresión (SLP) con la combinación de nivolumab + ipilimumab vs. la QT elegida por el investigador (mFOLFOX-6 o FOLFIRI con o sin bevacizumab/cetuximab) en el tratamiento de 1L para los pacientes con cáncer colorrectal metastásico (CCRm) con inestabilidad de microsatélites alta (MSI-H, por sus siglas en inglés) o deficiencia en la reparación de emparejamiento (dMMR, por sus siglas en inglés). BESPOKE: estudio de cohorte observacional, prospectivo y multicéntrico en el cual se inscribió un total de 2000 pacientes en etapa I-IV y se realizó un seguimiento de los mismos durante un máximo de 2 años con análisis seriados de ctDNA programados con las visitas de atención estándar. Fecha de grabación: 24 de enero de 2024.               Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente.

In this episode, Brian Slomovitz, MD, MS, FACOG, and Keiichi Fujiwara, MD, PhD, share their thoughts and opinions on seminal data presented at the 2023 IGCS annual meeting for endometrial, ovarian, and cervical cancers, including:Phase III NRG GY018 trial of carboplatin and paclitaxel with or without pembrolizumab followed by pembrolizumab or placebo maintenance for 2 years in patients with measurable stage III/IVA, stage IVB, or recurrent endometrial cancer. Phase III ENGOT-EN6/GOG-3031/RUBY trial of carboplatin and paclitaxel with or without dostarlimab followed by dostarlimab or placebo maintenance for 3 years in patients with primary advanced or recurrent endometrial cancer. Results from the double-blind, randomized, placebo-controlled phase III AtTEnd trial of atezolizumab plus carboplatin/paclitaxel in advanced or recurrent endometrial cancer.Randomized, multicenter, double-blind, placebo-controlled phase III DUO-E study of carboplatin and paclitaxel vs durvalumab plus carboplatin and paclitaxel followed by durvalumab maintenance with or without olaparib as frontline treatment of newly diagnosed, advanced, endometrial cancer.An international, randomized, multicenter phase III trial evaluating short-course chemotherapy followed by chemoradiation vs chemoradiation alone in patients with newly diagnosed stage IB1N+, IB2, II, IIIB, IVA squamous, adeno, adenosquamous cervical cancer (INTERLACE).Randomized, double-blind, placebo-controlled phase III KEYNOTE-A18 trial of pembrolizumab plus concurrent chemoradiotherapy vs placebo plus chemoradiation in patients with high-risk locally advanced cervical cancer.Phase III ICON8B study comparing carboplatin, paclitaxel, and bevacizumab every 3 weeks vs dose-dense weekly paclitaxel plus bevacizumab every 3 weeks in newly diagnosed high-risk epithelial ovarian cancer, either stage III (with residual disease or requiring new adjuvant chemotherapy) or stage IV.Presenters:Brian Slomovitz, MD, MS, FACOGDirectorGynecologic OncologyMount Sinai Medical CenterProfessorObsterics and GynecologyFlorida International UniversityMember, Board of DirectorsGOG FoundationUterine Cancer LeadGOG PartnersMiami, Florida Keiichi Fujiwara, MD, PhDProfessor of Gynecologic OncologySaitama Medical University International Medical CenterHidaka, JapanProfessor of OBGYNInternational University of Health and WelfareNarita, JapanThis educational activity is supported by educational grants from AstraZeneca, Genmab, GlaxoSmithKline, Merck Sharp & Dohme Corp, Novocure, and Seagen. Link to full program, including a downloadable highlights slideset and ClinicalThought commentaries:https://bit.ly/424E3Uq

In this episode, Isabelle Ray-Coquard, MD, PhD, and Ana Oaknin, MD, PhD, provide expert insights on new clinical trial data presented at the 2023 ESMO annual congress for endometrial, ovarian, and cervical cancers, including:Results from the double-blind, randomized, placebo-controlled phase III AtTEnd trial of atezolizumab plus carboplatin/paclitaxel in advanced or recurrent endometrial cancerRandomized, multicenter, double-blind, placebo-controlled phase III DUO-E study of durvalumab plus carboplatin and paclitaxel followed by durvalumab maintenance with or without olaparib as frontline treatment of newly diagnosed, advanced, endometrial cancerFirst results from a phase II biomarker-directed platform study with assigned treatments for patients with measurable persistent or recurrent platinum-resistant epithelial ovarian cancer based on tumor-specific molecular alterations (ENGOT-GYN/GOG-3051/BOUQUET)Randomized, double-blind, placebo-controlled phase III KEYNOTE-A18 trial of pembrolizumab plus concurrent chemoradiotherapy in patients with high-risk locally advanced cervical cancerAn international, randomized, multicenter phase III trial evaluating short-course chemotherapy followed by chemoradiation vs chemoradiation alone in patients with newly diagnosed stage IB1N+, IB2, II, IIIB, IVA squamous, adeno, adenosquamous cervical cancer (INTERLACE)Primary results from the global, randomized phase III BEATcc trial of atezolizumab plus platinum-based chemotherapy + bevacizumab as frontline treatment in patients with persistent, recurrent, or metastatic cervical cancerInterim analysis results from the global, randomized, open-label phase III innovaTV 301 study of tisotumab vedotin vs investigator's choice of chemotherapy in second-line or third-line recurrent/metastatic cervical cancerPresenters:Ana Oaknin, MD, PhDHead of Gynaecologic Cancer ProgrammeDepartment of Medical OncologyVall d' Hebron University HospitalVall d'Hebron Institute of OncologyBarcelona, SpainIsabelle Ray-Coquard, MD, PhDPresident of the Gineco GroupCentre Leon BérardLaboratories RESHAPE Université Claude Bernard Lyon EstLyon, FranceThis educational activity is supported by educational grants from AstraZeneca, Genmab, GlaxoSmithKline, Merck Sharp & Dohme Corp, Novocure, and Seagen. Link to full program, including a downloadable highlights slideset and ClinicalThought commentaries:https://bit.ly/424E3Uq

In this "Podcast Takeover," Dr. Lidia Schapira guest hosts to discuss with Dr. Shannon Westin her own JCO paper, which reports on the DUO-E Trial. Dr. Ramez Eskander also joins in this lively discussion. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor of the JCO and Gynecologic Oncologist by trade. And actually, I'm super excited today because we are going to have a podcast takeover because we are discussing my own work, which was simultaneously presented at the European Society of Medical Oncology 2023 Congress and published in the Journal of Clinical Oncology on October 21st, 2023. And this was the DUO-E trial, “Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer.” Because we're discussing this work and we wanted you to have an unbiased podcast discussion, Dr. Lidia Schapira, who is a Professor of Medical Oncology at Stanford University and an Associate Editor of JCO and the Art of Oncology podcast host, is going to take over this podcast and really just pepper me with questions about this exciting work.  Welcome, Dr. Schapira.  Dr. Lidia Schapira: Thank you so much. It's such a pleasure to be with you. Dr. Shannon Westin: And before I turn over the reins, I also want to introduce one of my colleagues, who's going to be providing quite a bit of insight on this topic, Dr. Ramez Eskander, who is Professor of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Diego. And you will know he's the principal investigator of the GY-018 study, which established pembrolizumab and chemotherapy as the new standard of care in endometrial cancer. Welcome, Ramez.  Dr. Ramez Eskander: Thank you. Thank you, Dr. Westin. It's a pleasure to be here. And congratulations again to you and your study team for this exceptional work.  Dr. Shannon Westin: Thank you. And congratulations to you.  Dr. Schapira, thank you for being here and please do take it away. Dr. Lidia Schapira: So let's start by having you tell us a little bit about the standard of care for women with endometrial cancer and advanced endometrial cancer prior to this study. Ramez, I'm going to direct this question to you first. Dr. Ramez Eskander: For many years, actually since about 2012, carboplatin and paclitaxel, which ironically is a chemotherapy backbone really across all of our gynecologic tumors, emerged as the preferred doublet chemotherapy regimen for the management of advanced-stage metastatic or recurrent endometrial cancer. It evolved through a series of different clinical trials, in fact taking us from whole abdominal radiation, systemic chemotherapy, comparing single agents to doublets and then triplet regimen of TAP to carboplatin and paclitaxel, which ultimately, then, following the presentation of GOG Protocol 209 and its publication, as the chemotherapy backbone, being carboplatin and paclitaxel. And it's been that way for many, many years. Dr. Lidia Schapira: And how effective is the regimen? Dr. Ramez Eskander: The response rates to carboplatin and paclitaxel are actually quite reasonable in the patients who have advanced-stage disease, particularly if they haven't had prior systemic chemotherapy. Response rates in the 50% to 60% range. The issue is that the responses tend to be limited and disease recurrence is an expectation in these patients who have advanced-stage disease. And so that really highlighted the importance of trying to continue to advance therapeutic opportunities in these patients to improve long-term outcomes.  Dr. Lidia Schapira: As we think about improved long-term outcomes, we're thinking about a better treatment and also a kinder treatment, perhaps one that is also less toxic. Can you talk a little bit about the population of women with endometrial cancer? Are these older women? Do they have comorbidities?  Dr. Ramez Eskander: What we're seeing is, interestingly, there has been an evolution a bit in this space. Historically, we used to think about endometrial cancer as—the phrases we used to use are type I and type II. These type I tumors, we would say, are estrogen-driven malignancies; they tend to be seen in overweight or obese patients. And we would identify them in a theoretically younger patient population. And then we had these type II, or what we termed estrogen-independent malignancies, that we would see in an older patient population. Of course, with obesity came metabolic syndrome and other cardiovascular comorbidities, etc. But really, that narrative has evolved dramatically, and that's really something that will be highlighted in, I think, our discussion of these studies today, where the nomenclature that we used to historically use has evolved because of our understanding of the molecular characterization of this disease. So we've really gone away from that, and now we understand that we're seeing all of these different heterogeneous endometrial cancer types amongst patients of different ages, different comorbidities, different races and ethnicities. And so it's created a more complex picture for us. But certainly, there are comorbidities that these patients face, and that's important as we look to identify treatments strategies that are both effective and tolerable. Dr. Lidia Schapira: My final question before we jump into this very exciting study is about the Cancer Genome Atlas work. Can you tell us how that's changed the thinking and the design of the studies? Dr. Ramez Eskander: It was a seminal publication, really, back in 2012/2013 looking at an assessment of endometrial cancers to try and determine whether or not all of these "endometrial cancers" that we used to enroll on a single study are similar or divergent. And it's important because the study I referenced that really established the standard of care, GOG Protocol 209, as carboplatin and paclitaxel, there was no real consideration of molecular characterization at all. We enrolled all patients onto this study without thinking about these variables, of course, because it was designed, conducted, and completed before the TCGA data emerged. But what we learned from the TCGA is there appeared to be four distinct molecular subgroups. There were the POLE-mutated patient population. There was the mismatch repair deficient or MSI-high endometrial cancer population. There was the copy number-high or what we say are the p53-mutated. And then the last cohort was called the NSMP (no specific molecular profile). But now, that's even evolved; some people term it TP53 wild type. That's a bit of even a heterogeneous cohort amongst itself. So we're going to take these subsets, independent of POLE and an MSI-high, and we're going to look at TP53 or copy number-high, and that will probably be divvied out further, and the NSMP, and that will probably be subdivided. But really, it gave us these four components, which has then evolved. Many of you may have heard of the ProMisE algorithm or ProMisE Plus, which looked to take the data from TCGA so that we can start to really look at it in clinical practice. So it's really revolutionized how we think about these patients, how we think about the disease, and how we design trials.    Dr. Shannon Westin: And I just want to add to that because I think that it's so important, what Ramez said about the way we were developing trials, the way we were designing trials. We knew that these classifiers—we were learning these classifiers are prognostic. Now what we're really trying to hone in on is how predictive they are. And certainly, one of the major classifiers that we're going to talking about today is mismatch repair status, and that is most definitely predictive of response to therapies. But we're still learning about the other classifiers and how we might adjust the way we treat people, even deescalating care for certain patients. That is still being proven in clinical trials, although we suspect that it's going to be borne out as other clinical trials report. Dr. Lidia Schapira: It's a perfect segue to this current trial. Tell us a little bit about the objectives and the design of DUO-E. Dr. Shannon Westin: As Ramez said, the standard of care was chemotherapy. And so we wanted to see if there was a way to improve outcomes for these women with advanced and recurrent endometrial cancer in a really clinically relevant, meaningful fashion for patients. And so we knew that this TCGA classifier, the mismatch repair, was so important, and we thought that the addition of immunotherapy to chemotherapy would most certainly work in that population but could even work in the entire population because, generally, endometrial cancer seems to be a little bit more responsive to immunotherapy and to activation of the immune system than, say, some of our other gynecologic malignancies. And so we set out to see what the addition of durvalumab, which is a PDL-1 inhibitor, would add to chemotherapy. And this was two chemo as well as followed by durvalumab maintenance.  But even further, we had some really kind of exciting science data from our lab that said that if we combined a PARP inhibitor with immunotherapy that we could accentuate on the response to therapy and we could get more benefit. And there's kind of a lot behind that, but essentially, what we thought was that the damage that's caused by the PARP inhibitors would create an activation of different immuno-pathways, like STING pathway and activating cytokine release, and that we would get this synergistic activity. So one of the other objectives was to see if the addition of the olaparib, the PARP inhibitor, to durvalumab in that maintenance setting could even further improve benefit. So we had a dual primary endpoint looking at progression-free survival, so the amount of time people live without their cancer coming back. And that endpoint was first, the durvalumab-alone arm to control, and then the second portion of that was the durvalumab/olaparib arm back to control. Dr. Lidia Schapira: So before you tell us about the results, tell us a little bit about the study itself. I mean, I was very impressed that you did it in so many different locations. Tell us about that effort.  Dr. Shannon Westin: This was a huge collaborative effort both with the GOG Foundation, the Gynecologic Oncology Group Foundation, as well as ENGOT, which is our European colleagues that do amazing clinical trials. But in addition to that, we really worked very closely with our industry partner to really make sure we spanned the globe. And so we had groups from all over the world that participated and really were exceptional. The care that was taken and the hard work that went into this type of study across the world really can't be overstated. We were very lucky to have a wonderful infrastructure group. We met weekly for a long time, just keeping an eye on the data and making sure that everything was as positive as possible and, of course, that we were watching the outcomes of the patients very closely and making sure that there was no evidence of harm or issue. And so it really did take a village, truly, to run this study and to ensure that at the end of it, we got really great data that we can trust. Dr. Lidia Schapira: So tell us the results. Dr. Shannon Westin: So DUO-E was positive for both of its primary endpoints, which was very thrilling. So for the first analysis, which is the durva-alone arm to control, we saw a reduction in the risk of progression of 29%, so a hazard ratio of 0.71. And then the addition of olaparib seemed to further enhance this benefit, so a 45% reduction in the risk of progression for a hazard ratio of 0.55. But what's really exciting is our follow-up time was pretty long; it was about 17 months, so we were able to look at a couple of different analyses, including an 18-month landmark analysis where we saw approximately 50% of the patients were still alive progression free at 18 months, as compared to only 21% of patients being alive progression free in the control arm. So there was a doubling in that progression-free survival time point at 18 months, which is thrilling. Dr. Lidia Schapira: So Ramez, as an expert in the field, what was your reaction when you read or heard these results?  Dr. Ramez Eskander: It's exciting, honestly. So we have gone a long time without seeing really significant successes in the endometrial cancer space, a testament to the fact that we hadn't yet developed our understanding of how we could move this needle forward. But Dr. Westin and the DUO-E team conducted an exceptional clinical trial, as you mentioned, international study, rational and important hypothesis to adjudicate. And what we saw here was both now we had other studies—the RUBY trial, the GY018 trial, the  AtTEnd—and now here DUO-E, which added this hypothesis of PARP maintenance in addition to checkpoint to try to augment response and consistent, really provocative data, exciting, in line with what we've seen and hopefully will continue to drive the science in this space, most importantly. Dr. Lidia Schapira: So let me ask you a follow-up question to that. What kind of scientific questions are in the air now as a result of this trial and what the trial found? Dr. Ramez Eskander: Oh, goodness. Shannon and I could both take this, I'm sure. But I think in the dMMR population, we recognize that there's a ton of data that is supportive of the fact that these tumors are immune responsive, particularly in dMMR endometrial cancer, whether it's an epigenetic promoter hypermethylation, or a mismatch repair gene mutation. I think the data has emerged that immunotherapy is here to stay for these patients in the newly diagnosed advanced stage, even chemo naïve, who need adjuvant therapy.   The pMMR population, this is where we're seeing more and more questions emerge because we realize that that may be a cohort of different cancers. And I'll let Shannon speak to this briefly, but even the incorporation of the PARP inhibitor, in addition to the checkpoint, there's a biologic rationale for combining those two together to augment response. And to see the benefit in that trial—arm three and arm two, we can look at descriptively and look at the differences, but who are those patients? Where is the PARP and the checkpoint most effective? How do we expand that to a larger population of patients potentially? These are questions that emerged because, as Dr. Weston will allude to, I know we also talk about HRR mutations, which are captured, but we even have a lot to understand about that in endometrial cancer, where we've had more research in the ovarian cancer space. Dr. Shannon Westin: Being mindful of time, because I have, like, 1,000 hypotheses that have been generated by this study, which, I think, shows it's a great study, right? Because you get some answers, and as our colleague Brad Monk says, “The only definitive study is the negative studies.” This most certainly was not that. But just kind of expanding on what Ramez said, the interesting thing about DUO-E is that really the biggest benefit for the combination of the durvalumab and olaparib was in that mismatch repair proficient group. And I personally thought that we were going to see accentuation of the impact in the mismatch repair deficient group based on the science, but that just wasn't borne out by the data. It doesn't seem that the combination has that much to add in that mismatch repair deficient group. And when we tease out the mismatch repair proficient group, I think that's where a lot of interesting information is going to come because, to Ramez's point, we're going to tease out: Is it driven by the P53-mutant population? Is it driven by the population that has homologous recombination deficiency? How do we even measure homologous recombination deficiency in endometrial cancer? So I'm super excited about what we found and how that may help us to make those decisions for the patient in front of us.  The other thing I think needs to be made mention of—and this was something we saw in DUO-E as well as AtTEnd—we had a large population of patients that were recruited in Asia, 30%. Interestingly, when we look at the forest plot, that group doesn't seem to benefit as much from the addition of the olaparib. So we really need to tease out what's different about that population because what Nicoletta Colombo presented around AtTEnd, it looked like they didn't benefit from the atezolizumab either in that study. So there's clearly something different about that population, and we have a really big opportunity to look at that since we had such a large proportion of patients that were enrolled there. So that's another, I think, really intriguing question. Dr. Lidia Schapira: So how does this fit in the context of endometrial cancer treatment, and what are we going to do with patients in the clinic? I'd love to hear both of your perspectives, starting with you, Ramez. Dr. Ramez Eskander: It's an evolving answer, to say the least. What we can say definitively is that we have a United States FDA approval for the regimen of dostarlimab plus carboplatin and paclitaxel in the mismatch repair deficient, advanced-stage/recurrent or metastatic patient cohort. And again, that's because the magnitude of benefit that we saw in the RUBY trial, which looked at that, was actually analogous to what we saw in 018, AtTEnd, and DUO-E, again, consistently highlighting the benefit of the IO and the dMMR. We have yet to see how this is going to evolve the landscape in the larger patient population, which is the pMMR patient population. And it may be that based on the data that we have, we will see immunotherapy plus carboplatin and paclitaxel as the new standard of care in the pMMR cohort, or it may not. That's yet to be defined. And I think Dr. Westin will add to this, but I think that's also going to depend on the perception of how we view the cohort. Is it one group of patients? Are we going to have to think about subsets within the pMMR population? That is an active conversation. Dr. Shannon Westin: I would just add, having treated patients on this combo regimen with the durvalumab and olaparib, I have multiple patients that still remain on study, and this—we're looking at three and four years out. I just never saw anything like that before with standard chemotherapy, so there's definitely something here. So I want to know who those patients are, who benefits really the best from the combination, and who could we just give the immunotherapy to and get that same benefit. So we obviously always want people to live as long as possible. That's the bottom line. But we don't want to overtreat. And so I think balancing that is really important. Dr. Ramez Eskander: The point that was made earlier: We have yet, aside from MMR response to checkpoint, within the pMMR population, we understand that there may be subsets, but we have yet to prospectively validate that these molecular cohorts within the pMMR population are truly defining response to a particular therapeutic strategy. So we have to be cautious not to limit the treatment opportunities for these patients without having the data that we need to do so because, as Dr. Westin mentioned, for us—whether it was the Gy018 trial, the RUBY, the DUO-E trial—what we saw is there are pMMR patients who have a dramatic response even though they are “biomarker negative.” They're pMMR, they're TMB low, they're not POLE mutated, but yet they still derive a dramatic benefit. And so that goes back to the hypothesis about why we're even combining checkpoint with chemotherapy in which, for example, in lung cancer, there's been established success and approval. So I think we're all eager to see these strategies emerge as treatment opportunities for the pMMR patients as we work to still develop additional effective opportunities. Dr. Lidia Schapira: So, based on all of this and sort of the new twists on the scientific hypotheses that are now generated, what are the next steps? Dr. Shannon Westin: Well, I think we have to see if these drugs are available for patients. So looking at things like compendium listing and regulatory approvals obviously is going to be very important. But from the things that I can control, we are looking at the different molecular subtypes and understanding the different mutation status and trying to tease out who may be driving the biggest benefits so that we can help advise and make sure that we're doing the right thing for the patients. Dr. Lidia Schapira: And wearing my supportive care hat, I have to ask you, Shannon, about the tolerability. We often find that the quality of life and studies come out after, sometimes months or years after, the original trials are published. So let me take this opportunity to ask you now: How did women tolerate these drugs? Dr. Shannon Westin: The bottom line, Lidia, is, as expected, when you add additional drugs, you see additional side-effects. I think the good thing is that we're very comfortable with immunotherapy and we're very comfortable with PARP inhibition in gynecology because we have had access to these agents and so we know how to manage the toxicities. And so, from a standpoint of incidence, there was a higher incidence of grade three and higher adverse events in the group that had durvalumab/olaparib. But this was primarily driven by anemia, which is as expected and is usually pretty time-limited at the start of olaparib. From a long-term standpoint, there was a slightly higher proportion of patients that discontinued therapy, but it actually wasn't as much as I was worried about. So we saw a 19% discontinuation rate in the group that was just the control arm, and that went up to 24% in the dual arm, so definitely higher, but not that much higher. And when we moved to maintenance, which is really where—that's where the arm becomes unique, it was much lower at about 12%. And so that's exciting to me, that patients were able to stay on a drug and were able to tolerate it.  And then, to your other point, we do have a very nice patient-reported outcomes plan, and that is actually being analyzed as we speak with the hope of presenting it at the next major meeting, our Society of GYN Oncology meeting in March. So not right away, but I think in a pretty timely fashion, we'll have those data. Dr. Lidia Schapira: Congratulations, Shannon, on leading and presenting this wonderful study. So it's been a real pleasure to chat with the two of you. Dr. Ramez Eskander: Thank you. Dr. Shannon Westin: Thanks so much, Lidia. I really appreciate it. Thanks, Ramez, for being here.  And I will just say thank you to all of our listeners. We really hope you enjoyed this episode of JCO After Hours, where we discussed the DUO-E trial, which is a phase III trial evaluating durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer. And again, please do enjoy this publication that was online at the Journal of Clinical Oncology on October 21st, 2023. And do check out our other podcast offerings wherever you get your podcasts. Have a wonderful day. 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.      

Meet Dr. Ulka Vaishampayan* – an oncologist and leading expert in treating people with kidney cancer, including renal cell carcinoma (RCC) which is the most common type of kidney cancer in adults. She understands all too well how scary and overwhelming hearing the words “you have cancer” can be for anyone – especially when facing an advanced diagnosis in RCC. In these cases, Dr. Vaishampayan believes that information is power and people can feel better prepared to move forward if they have a support system and strong patient-doctor communication.  On today's episode of the Cancer Horizons podcast, Dr. Vaishampayan shares information that's important to understand about RCC and navigating a diagnosis, key questions patients and caregivers should ask their doctor, and insights into a potential dual immunotherapy treatment option for certain patients. When it comes to making a treatment plan, Dr. Vaishampayan believes in involving her patients closely in the process. “In my practice I tend to explain what options are available to someone, including the pros and cons of each, and I sometimes make a recommendation about a treatment approach if I feel that's appropriate in their case,” she explains. “I would still explain the reasons for my choice. My intention is that either way it's a discussion, as it should be a joint or shared decision-making process.” Terry Broussard**, a man who was diagnosed with advanced RCC, also shares advice from his experience. In Terry's case, his doctor recommended the dual immunotherapy treatment combination Opdivo® (nivolumab) plus Yervoy® (ipilimumab), which is approved by the U.S. Food and Drug Administration for certain newly diagnosed adults whose kidney cancer has spread (advanced renal cell carcinoma) and have not already had treatment for advanced RCC. It is the first and only combination of two immunotherapies of its kind approved to treat advanced kidney cancer, or RCC. To learn more, listen to the podcast, visit www.Opdivo.com and see below for Important Safety Information. *Dr. Vaishampayan is a paid consultant of Bristol Myers Squibb. Dr. Vaishampayan's statements/opinions are those solely of Dr. Vaishampayan and are not necessarily those of Bristol Myers Squibb. Individual results/experiences may vary. **Terry is an actual patient who has been compensated by Bristol Myers Squibb. Terry's results may not be typical. Medication may not work for everyone. Indication OPDIVO® (nivolumab) is a prescription medicine used in combination with YERVOY® (ipilimumab) to treat adults with kidney cancer in certain people when your cancer has spread (advanced renal cell carcinoma) and you have not already had treatment for your advanced RCC. It is not known if OPDIVO is safe and effective in children younger than 12 years of age with melanoma or MSI-H or dMMR metastatic colorectal cancer. It is not known if OPDIVO is safe and effective in children for the treatment of any other cancers. OPDIVO (10 mg/mL) and YERVOY (5 mg/mL) are injections for intravenous (IV) use. Important Safety Information for OPDIVO® (nivolumab) + YERVOY® (ipilimumab) What is the most important information I should know about OPDIVO + YERVOY? OPDIVO and YERVOY are medicines that may treat certain cancers by working with your immune system. OPDIVO and YERVOY can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. These problems may happen anytime during treatment or even after your treatment has ended. You may have more than one of these problems at the same time. Some of these problems may happen more often when OPDIVO is used in combination with another therapy. Call or see your healthcare provider right away if you develop any new or worse signs or symptoms, including: Lung problems: new or worsening cough; shortness of breath; chest pain Intestinal problems: diarrhea (loose stools) or more frequent bowel movements than usual; stools that are black, tarry, sticky, or have blood or mucus; severe stomach-area (abdominal) pain or tenderness Liver problems: yellowing of your skin or the whites of your eyes; severe nausea or vomiting; pain on the right side of your stomach area (abdomen); dark urine (tea colored); bleeding or bruising more easily than normal Hormone gland problems: headaches that will not go away or unusual headaches; eye sensitivity to light; eye problems; rapid heart beat; increased sweating; extreme tiredness; weight gain or weight loss; feeling more hungry or thirsty than usual; urinating more often than usual; hair loss; feeling cold; constipation; your voice gets deeper; dizziness or fainting; changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness Kidney problems: decrease in your amount of urine; blood in your urine; swelling in your ankles; loss of appetite Skin problems: rash; itching; skin blistering or peeling; painful sores or ulcers in the mouth or nose, throat, or genital area Eye problems: blurry vision, double vision, or other vision problems; eye pain or redness. Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with OPDIVO and YERVOY. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include: Chest pain; irregular heartbeat; shortness of breath; swelling of ankles Confusion; sleepiness; memory problems; changes in mood or behavior; stiff neck; balance problems; tingling or numbness of the arms or legs Double vision; blurry vision; sensitivity to light; eye pain; changes in eye sight Persistent or severe muscle pain or weakness; muscle cramps Low red blood cells; bruising Getting medical help right away may help keep these problems from becoming more serious. Your healthcare team will check you for these problems during treatment and may treat you with corticosteroid or hormone replacement medicines. Your healthcare team may also need to delay or completely stop your treatment if you have severe side effects. Possible side effects of OPDIVO + YERVOY OPDIVO and OPDIVO + YERVOY can cause serious side effects, including: See “What is the most important information I should know about OPDIVO + YERVOY?” Severe infusion reactions. Tell your healthcare team right away if you get these symptoms during an infusion of OPDIVO or YERVOY: chills or shaking; itching or rash; flushing; shortness of breath or wheezing; dizziness; feel like passing out; fever; back or neck pain Complications, including graft-versus-host disease (GVHD), of bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be severe and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with OPDIVO or YERVOY. Your healthcare provider will monitor you for these complications. The most common side effects of OPDIVO, when used in combination with YERVOY, include: feeling tired; diarrhea; rash; itching; nausea; pain in muscles, bones, and joints; fever; cough; decreased appetite; vomiting; stomach-area (abdominal) pain; shortness of breath; upper respiratory tract infection; headache; low thyroid hormone levels (hypothyroidism); constipation; decreased weight; and dizziness. These are not all the possible side effects. For more information, ask your healthcare provider or pharmacist. You are encouraged to report side effects of prescription drugs to the FDA. Call 1-800-FDA-1088. Before receiving OPDIVO or YERVOY, tell your healthcare provider about all of your medical conditions, including if you: have immune system problems such as Crohn's disease, ulcerative colitis, or lupus have received an organ transplant have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic) have received radiation treatment to your chest area in the past and have received other medicines that are like OPDIVO have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome are pregnant or plan to become pregnant. OPDIVO and YERVOY can harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if OPDIVO or YERVOY passes into your breast milk. Do not breastfeed during treatment with OPDIVO or YERVOY and for 5 months after the last dose of OPDIVO or YERVOY. Females who are able to become pregnant: Your healthcare provider should do a pregnancy test before you start receiving OPDIVO or YERVOY. You should use an effective method of birth control during your treatment and for 5 months after the last dose of OPDIVO or YERVOY. Talk to your healthcare provider about birth control methods that you can use during this time. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with OPDIVO or YERVOY. You or your healthcare provider should contact Bristol-Myers Squibb at 1- 844-593-7869 as soon as you become aware of a pregnancy. Tell your healthcare provider about all the medicines you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements. Please see U.S. Full Prescribing Information and Medication Guide for OPDIVO and YERVOY.

Dr Naumann discusses the role of frontline maintenance therapy for patients with endometrial cancer; which patients are likely to benefit from the RUBY and NRG-GY018 trial regimens; and ongoing research that may elucidate optimal treatments for patients with recurrent, dMMR disease.

Gynaecological malignancies are a diverse group of terrible malignancies. From ovarian to endometrial to cervical, these cancers are notorious not just for their mortality burden, but the significant morbidity that they can inflict. To explore how to combat these challenging clinical entities, Michael and Josh interview Dr Vish Boolell, a clinical oncologist who brings his vast practical and trial experience to bear in exploring how to best treat patients and manage the myriad challenges gynaecological cancer can present. Today's episode is a must-listen for anyone who has been confronted by a malignant bowel obstruction, or wondered about the significance of dMMR in endometrial cancer, or who simply want some practical tips about how to best help their gynae onc patients. For more episodes, resources and blog posts, visit www.inquisitiveonc.comFind us on Twitter @InquisitiveOnc!If you want us to look at a specific trial or subject, email us at inquisitiveonc@gmail.comArt courtesy of Taryn SilverMusic courtesy of Music Unlimited: https://pixabay.com/users/music_unlimited-27600023/Disclaimer: This podcast is for educational purposes only. If you are unwell, seek medical advice. Hosted on Acast. See acast.com/privacy for more information.

In this rebroadcasted episode of the IJGC podcast, Editor-in-Chief Dr. Pedro Ramirez is joined by Dr. Mansoor Raza Mirza to discuss the RUBY Trial. Dr. Mirza is a highly qualified medical oncologist with expertise in Medical and Radiation Oncology, holding multiple degrees and licenses in these fields. He currently serves as the Chief Oncologist at the Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Denmark, and holds the position of Medical Director of the Nordic Society of Gynaecologic Oncology-Clinical Trial Unit (NSGO-CTU). Dr. Mirza is actively involved in numerous medical societies, clinical research, and international trial collaborations, and has contributed significantly to the development of clinical protocols and guidelines for the management of various cancers.   Highlights: The phase 3 RUBY trial evaluated the combination of dostarlimab, a PD-1 inhibitor, with carboplatin and paclitaxel versus placebo, carboplatin, and paclitaxel in patients with primary advanced or recurrent endometrial cancer. Interim analysis of the trial showed improved progression-free survival (PFS) in the population with mismatch repair–deficient (dMMR) endometrial cancer. The 2-year PFS rate in the dMMR population was 61.4%, with a hazard ratio (HR) of 0.28. Some patients treated with the dostarlimab combination showed no disease progression after 12 months of follow-up, suggesting potential cure. The dostarlimab combination also demonstrated a trend toward overall survival (OS) improvement in both the dMMR and mismatch repair–proficient (pMMR) subgroups. However, the OS data are still immature, and further follow-up is needed to determine the efficacy of the treatment.  

Dr Mirza discusses the FDA approval of dostarlimab plus chemotherapy in patients with dMMR/MSI-H primary advanced or recurrent endometrial cancer; key efficacy and safety findings from the RUBY trial, and ongoing research investigating the role of frontline immune checkpoint inhibitors in patients with endometrial cancer.

In this episode, Kathleen Moore, MD, MS, and Nicoletta Colombo, MD, PhD, provide expert insights on key updates and new clinical trial data presented at the 2023 ASCO Annual Meeting for cervical, endometrial, and ovarian cancers, including:ENGOT-EN6-NSGO/GOG-3031/RUBY: phase III study of dostarlimab plus chemotherapy followed by dostarlimab maintenance in primary advanced or recurrent endometrial cancer outcomes by BICRCCTG CX.5-SHAPE: phase III trial of radical hysterectomy and pelvic node dissection compared with simple hysterectomy and pelvic node dissection in low-risk, early-stage cervical cancer Final OS results from KEYNOTE-826: phase III study of CT with or without pembrolizumab as first-line treatment for patients with persistent, recurrent, or metastatic cervical cancerDUO-O: a randomized, placebo-controlled phase III study of durvalumab plus carboplatin, paclitaxel, and bevacizumab and then maintenance bevacizumab, durvalumab, and olaparib in patients with newly diagnosed advanced ovarian cancer and no BRCA1/2 gene alteration MIRASOL: an initial report from a phase III study of mirvetuximab soravtansine vs investigator's choice of CT in platinum-resistant ovarian cancer with high expression of FRαPatient-reported outcomes from the phase III ENGOT-EN6/RUBY trial of dostarlimab plus standard-of-care CT in primary advanced or recurrent endometrial cancerPresenters:Kathleen Moore, MD, MSAssociate Director, Clinical ResearchDepartment of Gynecologic OncologyStephenson Cancer Center, University of OklahomaOklahoma City, OklahomaNicoletta Colombo, MD, PhDAssociate Professor of Obstetrics and GynecologyEuropean Institute of OncologyUniversity of Milan-BicoccaMilan, ItalyContent supported by educational grants from AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme Corp., Novocure Inc., and Seagen Inc.Link to full program, including a downloadable highlights slideset and ClinicalThought commentaries: bit.ly/43Q5CBI

Podcast Description: In this episode of the IJGC podcast, Editor-in-Chief Dr. Pedro Ramirez is joined by Dr. Mansoor Raza Mirza to discuss the RUBY Trial. Dr. Mirza is a highly qualified medical oncologist with expertise in Medical and Radiation Oncology, holding multiple degrees and licenses in these fields. He currently serves as the Chief Oncologist at the Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Denmark, and holds the position of Medical Director of the Nordic Society of Gynaecologic Oncology-Clinical Trial Unit (NSGO-CTU). Dr. Mirza is actively involved in numerous medical societies, clinical research, and international trial collaborations, and has contributed significantly to the development of clinical protocols and guidelines for the management of various cancers.   Highlights: The phase 3 RUBY trial evaluated the combination of dostarlimab, a PD-1 inhibitor, with carboplatin and paclitaxel versus placebo, carboplatin, and paclitaxel in patients with primary advanced or recurrent endometrial cancer. Interim analysis of the trial showed improved progression-free survival (PFS) in the population with mismatch repair–deficient (dMMR) endometrial cancer. The 2-year PFS rate in the dMMR population was 61.4%, with a hazard ratio (HR) of 0.28. Some patients treated with the dostarlimab combination showed no disease progression after 12 months of follow-up, suggesting potential cure. The dostarlimab combination also demonstrated a trend toward overall survival (OS) improvement in both the dMMR and mismatch repair–proficient (pMMR) subgroups. However, the OS data are still immature, and further follow-up is needed to determine the efficacy of the treatment.

In this episode of the IJGC podcast, Editor-in-Chief Dr. Pedro Ramirez is joined by Dr. Ramez N. Eskander to discuss NRG-018 pembrolizumab and chemotherapy in uterine cancer. Dr. Eskander is a gynecologic oncologist who specializes in the comprehensive management of female reproductive system cancers, including ovarian, uterine, cervical, vulvar and vaginal cancer. His expertise includes diagnostic and therapeutic procedures, including minimally invasive (robotic) surgery, chemotherapy and novel drugs. Highlights: NRG-GY018 showed that the addition of pembrolizumab to chemotherapy, followed by maintenance pembrolizumab, resulted in a 70% lower risk of disease progression or death in patients in the dMMR cohort and a 46% lower risk in the pMMR cohort than in the placebo group. These data suggest that the incorporation of immunotherapy into the first-line treatment of advanced or recurrent endometrial cancer improves oncologic outcomes, regardless of MMR status or histologic findings. Previous monotherapy drugs against PD-1 and PD-L1 in recurrent or metastatic pMMR endometrial cancer resulted in only modest improvement.

It is always nice to be able to say the phrase: "This cancer has an excellent prognosis." That is the case with endometrial cancer, which for the majority of sufferers, can be cured and carries an excellent survival. However, there are cases that unfortunately present late, and for these patients, the outlook is significantly more grim.Some oncologists have little experience treating advanced endometrial cancer; for those listeners, this episode is specifically for you! In our 40th episode, Josh will discuss the foundations of endometrial cancer treatment, a topic that is vital but very boring, much like Josh himself. Michael will discuss the new frontier of immunotherapy in dMMR endometrial cancer, something that is transformative and very exciting but also unfortunately irrelevant to the majority of patients, much like Michael.Links to studies discussed in this episode (subscription may be required):GOG0209: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676887/RUBY: https://www.nejm.org/doi/full/10.1056/NEJMoa2216334For more episodes, resources and blog posts, visit www.inquisitiveonc.comFind us on Twitter @InquisitiveOnc!If you want us to look at a specific trial or subject, email us at inquisitiveonc@gmail.comArt courtesy of Taryn SilverMusic courtesy of Music Unlimited: https://pixabay.com/users/music_unlimited-27600023/Disclaimer: This podcast is for educational purposes only. If you are unwell, seek medical advice. Hosted on Acast. See acast.com/privacy for more information.

In this episode of the IJGC podcast, Editor-in-Chief Dr. Pedro Ramirez is joined by Dr. Ramez N. Eskander to discuss NRG-018 pembrolizumab and chemotherapy in uterine cancer. Dr. Eskander is a gynecologic oncologist who specializes in the comprehensive management of female reproductive system cancers, including ovarian, uterine, cervical, vulvar and vaginal cancer. His expertise includes diagnostic and therapeutic procedures, including minimally invasive (robotic) surgery, chemotherapy and novel drugs. Highlights: • NRG-GY018 showed that the addition of pembrolizumab to chemotherapy, followed by maintenance pembrolizumab, resulted in a 70% lower risk of disease progression or death in patients in the dMMR cohort and a 46% lower risk in the pMMR cohort than in the placebo group. • These data suggest that the incorporation of immunotherapy into the first-line treatment of advanced or recurrent endometrial cancer improves oncologic outcomes, regardless of MMR status or histologic findings. • Previous monotherapy drugs against PD-1 and PD-L1 in recurrent or metastatic pMMR endometrial cancer resulted in only modest improvement.

Dr Gilbert discusses the FDA approval of dostarlimab in patients with endometrial cancer, key efficacy data from the GARNET trial, and how this agent bolsters the endometrial cancer treatment paradigm.

The latest QuadCast episode discusses the status of Pluvicto, breast conservation therapy for patients with multifocal breast cancer, the reason that whole brain radiation has neurocognitive impact, impressive results of immunotherapy for dMMR endometrial cancer, the timing of prostate SBRT, and newly approved Narcan nasal spray. Be sure to tune in! QuadShot Website

Dr. Mohamed Salem, Dr. Myriam Chalabi, and Dr. Andrea Cercek discuss pivotal neoadjuvant immunotherapy clinical trials for patients with MSI-H/dMMR colorectal cancer, focusing on the development of active therapies in the neoadjuvant setting—where patients are treated without surgery, radiation, or chemotherapy—and the importance of patient selection in finding the right target and treatment to improve outcomes. TRANSCRIPT Dr. Mohamed Salem: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host today, Dr. Mohamed Salem. I'm a GI oncologist at the Levine Cancer Institute at Atrium Health. Today, we will be discussing very promising advancements in the neoadjuvant immunotherapy for patients with MSI-H/dMMR colorectal cancer. And I'm very delighted to welcome two world-renowned oncologists whose research has tremendously helped shape the treatment landscape of colorectal cancer. Dr. Myriam Chalabi is a GI medical oncologist at the Netherlands Cancer Institute, and Dr. Andrea Cercek is a medical oncologist at Memorial Sloan Kettering in the United States.  Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/DNpod.  Dr. Chalabi and Dr. Cercek, welcome to the ASCO Daily News Podcast. Dr. Myriam Chalabi: Thank you for having me. Dr. Andrea Cercek: Thank you very much for having me. Dr. Mohamed Salem: It's a pleasure to have two world-renowned stars like you. Thank you for taking the time.  So, before we start going deep into the topic, obviously, now we are seeing emerging data in CRC using immunotherapy as the neoadjuvant approach, which actually can reduce or even eliminate some of the other treatment modalities and potentially save patients from toxicities. Both of you led what I think are landmark studies in this field. I wanted to give you the chance to tell our audience about your studies and why you think they're important. Dr. Cercek? Dr. Andrea Cercek: Sure. Thank you so much. So, our study was a neoadjuvant study in early-stage, locally advanced rectal cancer with tumors that were mismatch repair-deficient or MSI-H. And rectal cancer normally is treated with chemotherapy, chemoradiation, and surgery. And the goal of the trial was to utilize PD-1 blockade alone in this subpopulation and evaluate the response.  Patients received six months of dostarlimab, which is a PD-1 blocking agent, and then were evaluated for response. If there was no residual disease, they were able to avoid radiation and surgery. And what we've seen thus far in the presentation at GI ASCO in 2022 was that all patients who received six months of dostarlimab had a clinical complete response, so no residual tumor, and were able to avoid chemotherapy, radiation, and surgery and are on observation. And the study is ongoing and actively accruing patients. Dr. Mohamed Salem: All of us were very excited seeing that presentation at ASCO. And when we came back to the clinic everyone was talking about it, including patients, obviously. Thank you for this, Dr. Cercek. Dr. Chalabi, you also led a similar study that was actually presented in ESMO in 2022. Can you please give us, like, a brief description of that trial? Dr. Myriam Chalabi: Yeah, sure. So, this is the NICHE trial, and actually the NICHE trial has been ongoing for quite some time now. We recently presented a larger NICHE-2 study, but basically– so what we started out by doing in NICHE is giving patients what we considered back then a window of opportunity study. We treated patients with MMR-deficient tumors, which I'll be focusing on for now, with two cycles of nivolumab and one single cycle of low-dose ipilimumab. And patients all undergo surgery within six weeks of registration within the study. And back in 2020, we published the first data of NICHE-1 showing 100% pathologic responses with 60% pathologic complete responses and decided that this should definitely be a treatment that we need to explore in a larger group of patients. And that's where NICHE-2 was born, which we presented at ESMO last year, where we treated over 100 patients with this neoadjuvant approach of two cycles nivolumab, one single cycle ipilimumab, showing 99% pathologic responses, including 95% major pathologic responses and 67% pathologic complete responses. And this was all within five and a half weeks of the first treatment with immunotherapy, so a very short treatment duration with dual checkpoint blockade. Dr. Mohamed Salem: Amazing results, too. And I know you had a standing ovation when you presented the outcome of the study. And again, congratulations to you, your investigator, and also all the patients participated. Dr. Myriam Chalabi: Thank you so much.  Dr. Mohamed Salem: I guess the first question that comes to my mind - we have two trials, obviously, now we're moving from one size fits all to precision therapy, like getting actually the right treatment for the right patient. But in the NICHE study, it was a checkpoint inhibitor, and the rectal study was a single agent. I want to start with you, Dr. Chalabi. In your opinion, when should we use single agent or double blockade immunotherapy? Dr. Myriam Chalabi: That is a great question. I'm going to start off by saying that I don't know the exact answer. I don't think we know that answer. And Dr. Cercek is going to share also her thoughts on this because we're seeing, of course, fantastic responses with monotherapy as well in Dr. Cercek's study. And we've also seen that in a study by Dr. Overman with monotherapy. So that may suffice in some patients, although what we're seeing is that you need to treat patients longer, probably to achieve that response, at least clinically. And I think that is the difference with dual checkpoint blockade, that we're giving in NICHE where we're seeing these very deep responses in just under six weeks' time.  So, I think it may be more of a question of how long we want to treat patients for to achieve the endpoint that we're aiming for. And, of course, there may be, at some point, patients that need dual checkpoint blockade, but so far, we're seeing great responses in both of our studies. So I think we need more patients, more data to see whether we're going to see non-responders. And hopefully, the studies that are ongoing in the metastatic disease setting will give us at least a little bit of insight into what the differences are in response to mono and dual checkpoint blockade and whether we can tell which patients might benefit more from the combination. But I think there's still a lot of work to be done in that field. Dr. Mohamed Salem: I totally agree. Dr. Cercek, same question to you. What do you think?  Dr. Andrea Cercek: Dr. Chalabi answered beautifully and very comprehensively. I agree completely with what she said. It's hard to argue with the responses that we're seeing with PD-1 blockade alone. But then again, dual checkpoint inhibitors in the NICHE study with just one month of therapy had phenomenal responses as well. So I think it's a question of duration of therapy and, really importantly, what we're trying to achieve. If our goal is organ preservation, then perhaps longer duration is better. The question then becomes, can we do, should we do longer duration with dual checkpoint inhibitors versus single agent? So I think, as she concluded, I couldn't agree more that we just need more information, we need more work to do, basically to answer this question for our patients. Dr. Mohamed Salem: More to come and more studies, which is fascinating.  So, Dr. Chalabi, you created actually a new term on Twitter called ‘Chalabi Plot'. It was amazing to see such a response. But we're curious, among those patients who achieved complete response so far, did you see any relapse? Dr. Myriam Chalabi: Short answer, no.  we're waiting, of course on the disease-free survival data, the three-year DFS data for NICHE-2, and we hope to have that by the end of this year, beginning of next year. But as of now, we showed that data, and so far, we haven't seen any recurrences in, actually, any of the patients treated in NICHE-2. Dr. Mohamed Salem: Fantastic. Dr. Cercek. So I think your slide -- I remember clearly from the ASCO presentation -- was all complete response, every single patient.  Same question, did you see any relapse so far? Dr. Andrea Cercek: So far, no, we have not. Dr. Mohamed Salem: Amazing. So, Dr. Cercek, as you know, and obviously, this is metastatic disease, but in KEYNOTE-177, as you know, about 30% of patients with MSI-high tumors did not respond to checkpoint inhibitors. So that makes some of us feel nervous about using checkpoint inhibitors alone in colorectal cancer, even with MSI-high status. I was curious if you can comment on this and if there is a way we can perhaps sort out who actually is likely to respond and who is likely not going to respond. Dr. Andrea Cercek: I think that's a really important question and an excellent point. And we believe that the difference lies in the fact that in KEYNOTE-177, the patients had metastatic disease, whereas in our neoadjuvant studies that we're discussing, they have early-stage disease. And whether that has to do with the tumor differences, young tumors versus older tumors once they become metastatic, or the microenvironment, remains to be determined. But certainly, there is this pattern of incredible responses with checkpoint inhibitors in early-stage dMMR tumors. And in KEYNOTE-177, as you mentioned, about 30% of patients progressed. And I think we don't know why that is. We are seeing this, about a third of progressors repeatedly in the metastatic setting with checkpoint inhibitors. And so perhaps there is a population. But whether this is driven by genomics or something else, we don't know. Dr. Mohamed Salem: Great. So, along the same lines, especially rectal cancer, obviously, because surgical resection is a key component in the treatment paradigm, do you feel patients who achieve pathological complete response should still go under surgical resection or should go under the ‘watch and wait' approach? Dr. Andrea Cercek: In general, I'm a fan of organ preservation. I think in rectal cancer, the reasons are obvious. It's a challenging surgery. It's very toxic to the patients. It changes their lives forever. In survivorship, 30% of them require a permanent colostomy because of the location of the tumor. So there, the field of rectal cancer, in general, is moving towards non-operative management, even in the MSI-proficient patients, by trying to optimize therapy to increase clinical complete responses and therefore omit surgery. So that's the difference with rectal cancer. In colon cancer, it's a different discussion. I think for many patients, surgery is very straightforward. It's a hemicolectomy. It doesn't alter lifestyle in survivorship, so it's not as morbid as it is in rectal cancer. Of course, I think if a patient is older with MSI-deficient tumor perhaps can undergo surgery, then clinical complete responses become critical because then we can monitor them after just checkpoint blockade, and they don't need surgery.  The challenge there, and I would love to hear Dr. Chalabi's comments on this, too, is just that imaging is challenging. We have a hard time in colon cancer determining whether someone has a clinical complete response or not. It seems to be very different than in rectal cancer, where with endoscopy and with the rectal MRI, we really can't tell whether the tumor is still present or not. This remains a challenge in colon cancer. Dr. Mohamed Salem: Dr. Chalabi, I would like to hear your thoughts and also how you practice in Europe. I don't know if it's the same like here in US or different. Dr. Myriam Chalabi: I completely agree with Dr. Cercek. Well, if we look at the rectal cancer patients, I think this is fantastic. That even though this is a small population achieving this high clinical complete response rate, not having to operate or even give any chemotherapy or radiation therapy to these patients, it is extremely important both in the short term but also in terms of long-term complications and morbidity. When it comes to the colon cancer responses that we're seeing in NICHE, those are all pathologic responses, of course. And we have been evaluating also preoperatively using scans to see whether we can assess these complete responses based on imaging. That doesn't seem to be the case. We do see responses in all patients, so we see these are all very large bulky tumors that we're treating in NICHE-2. And we do see responses in almost all of these patients, but it's not close to complete responses, definitely not in all of the complete responders that we're seeing. So that makes it difficult.  And the question is, what if we would be waiting or treating longer because these bulky tumors need more time to disappear or to be cleared before you're going to see it on the imaging? So that is a question that I don't have an answer to just yet. We may be getting some more data on that with the currently ongoing trials. And as Dr. Cercek pointed out, the endoscopies when you have a right-sided colon tumor are different than doing just a sigmoidoscopy for a rectal tumor. So, we actually do have one patient who hasn't undergone surgery, and that is actually a patient with an MMR-proficient tumor within the NICHE trial who had a complete response. And that patient has a sigmoidal tumor, and he actually had toxicities which prevented him from undergoing timely surgery and now has a complete response after two years, both endoscopically and on imaging. So, he hasn't undergone surgery, and that is a great example of how we may be doing this in the future. It's an interesting case within the trial to follow and see how we can do it in the future. Dr. Mohamed Salem: That's fascinating news. So, was it MMR-proficient? Dr. Myriam Chalabi: Yes, this is an MMR-proficient tumor.  Dr. Mohamed Salem Wow. Any particular biomarkers that you think he or she had to predict that? Dr. Myriam Chalabi: We have treated more patients with MMR-proficient tumors. We have 31 patients, and we have seen actually responses in 9 out of 31 patients in the MMR-proficient tumors with the same combination of two doses of nivolumab and one of ipilimumab. We previously published on half of the cohort approximately on what the possible predictive biomarkers of response could be, and that was a costimulation for CD8 and PD-1. So PD-1 positive CD8 T cells. And we're currently doing the same work for the rest of the cohort. So hopefully, we'll be able to show that soon and see whether this still stands for the completed MMR-proficient cohort. But definitely also very exciting data for the MMR-proficient. Dr. Mohamed Salem: So, this is actually a very good segue to my next question because I know all of us are looking for this. Like, obviously, we're seeing a fascinating response in those patients with MSI-high tumors, but majority of colorectal cancer, as you know, they actually have MSS-proficient tumors. Any thoughts about how we can overcome the primary resistance for this tumor to checkpoint inhibitors? So let me start with you, Dr. Cercek.  Dr. Andrea Cercek: I'm very much looking forward to Dr. Chalabi's data on this because, honestly, we have not seen such amazing responses to immunotherapy in MSS tumors. The initial studies were complete flatline, no responses at all. And here, she just described a patient that had a complete response to just a month of checkpoint inhibitors. So that's phenomenal, and hopefully, we'll learn from the responders.  We believe that there is a subpopulation of MSS colorectal cancer that is more immune sensitive, immune hot, whichever term you like to use. And it's just a matter of appropriately identifying those patients. And personally, I think the answer lies in the neoadjuvant setting in early tumors where they're treatment-naive, not exposed to chemo, not exposed to radiation, younger, have their innate microenvironment. And so, I think it's likely a combination of the above. But obviously, the ultimate goal is to find out who those patients are and then potentially treat them just like this with immunotherapy. And that would be another nice chunk of the pie where we could utilize immunotherapy for our patients. Dr. Mohamed Salem: Very true. Dr. Chalabi, especially with your experience and just showing there is a chance for those people to respond, what are your thoughts about how we can overcome this primary resistance? Dr. Myriam Chalabi: It's great to be here with Dr. Cercek because, obviously, we have very similar interests but it's also good to see that we think the same way because I completely agree with what she just said in terms of neoadjuvant. I think that was one of the most important things that we did here, giving this neoadjuvant treatment in non-metastatic tumors. It's probably a very important driver in the responses that we're seeing. So, we've been seeing data now a bit more in the metastatic disease setting where MSS tumors seem to be responding to new generations of checkpoint blockade. And the question is how those would do in the neoadjuvant setting that would be even different than what we're seeing now. But there's definitely some proof of MSS tumors that can respond to immunotherapy. The question on how to overcome the primary resistance, I think that question is for us: Who are the patients with primary resistant tumors and why are they primarily resistant? And then we can think about how to change that and how to change them into the tumors that are responding. I think these types of data will be key to understand more and know; hopefully, even you said, in the metastatic disease setting, to make these tumors more pliable in response to immunotherapy. Dr. Mohamed Salem: I agree. So, both of you are leading us toward how to choose the right patient with the right target for the right treatment. That's an amazing journey you're taking all of us on.  So, Dr. Cercek, I have to admit that with your data, it created some problems for us in the clinic because all patients the following day came in asking for immunotherapy. We had a hard time trying to explain that maybe this is not the right treatment for them or, like, not the right platform. But I wanted to ask you, if we'll have a patient tomorrow in the clinic with localized rectal cancer and happen to have an MSI-high tumor, what would be your recommendation in terms of how to approach that patient? Dr. Andrea Cercek: I think, ideally, you would discuss clinical trials with the patient. We have opened the study now to not just rectal cancer but colon cancer and, in fact, all solid tumors that are mismatch repair-deficient. So I think at this time, the patients really should be treated on a clinical trial. As we learn more, in particular, until we are more comfortable assessing for a clinical complete response and follow-up. I think the surveillance piece will be critically important. In rectal cancer, it's well established, but it's not in the other tumor types. So my recommendation would be to enroll the patient on a trial. Dr. Mohamed Salem: Just to add to that too, obviously, as you know, there is now the cooperative group trial that's looking at that option and we obviously encourage all centers to participate and open that study to have this option for our patients. Dr. Chalabi, so what do you guys do in Europe for these patients? Dr. Myriam Chalabi: In Europe, it's a very different situation. I would have answered this question differently by saying, well, we don't have that option of treating patients outside of clinical trials. So basically, we have to make sure that we have clinical trials for these patients. And that's something that we've had for colon cancer patients. That is still the case. And we're getting rectal cancer trials also for patients with MMR deficient tumors and have those also for MMR proficient tumors. For us and I agree completely that we should be treating patients within clinical trials, we don't have another option. But still, even if we did, I think it's important to create data within clinical trials to be able to ultimately also show why this should be standard of care and how we can make it standard of care. Because if you're not accumulating that data, then it's going to become very difficult if accrual is lacking. Now, we treat patients either with standard-of-care treatments, but usually, we try to find something within clinical trials.  Dr. Mohamed Salem: I totally agree. And as we always say, the standard of care should be a clinical trial participation. So, I must say, both of you, Dr. Cercek and Dr. Chalabi, you made 2022 a very exciting year for us in GI cancers. You really changed the way we look at how to treat these patients and give them a huge chance of, I would say, actually cure and obviously organ preservation. So, I'm very curious to know what you are both are working on now and what we should expect in 2023 and 2024.  Dr. Andrea Cercek: So, for me, the study is ongoing, as I mentioned, and we've expanded to all mismatch repair-deficient solid tumors with the same approach of six months of dostarlimab and then the option of nonoperative management. And I think that it'll be important for us to learn in terms of responses on the luminal versus some of the other tumor types, like, for example, pancreas cancer, where we don't see these robust responses in the metastatic setting, that will be important to do. We're doing some correlative analysis, as Dr. Chalabi described as well in our patients.  And then, I'm interested in optimizing neoadjuvant approaches to minimize therapy in rectal cancer specifically. So, we have a study now for HER-2 amplified RAS wild-type patients with locally advanced rectal cancer with a similar approach of utilizing HER-2 targeted therapy first and then in combination with chemotherapy. In our case, it's a combination of trastuzumab and tucatinib and then chemotherapy with CAPOX and assessing for response and potential omission of radiation and surgery depending on responders. So, I'm very excited that study is open and actively accruing, and hopefully, we can get similar responses that we did in the MSI population with PD-1 blockade. Dr. Mohamed Salem: Is that only available at MSK? Dr. Andrea Cercek: It is at this time. However, we will likely be expanding, so if there's any interest, let me know. Dr. Mohamed Salem: Great. I'm sure many centers will be. Great. What about you, Dr. Chalabi? Any sneak peek in the future? Dr. Myriam Chalabi: So many sneak peeks, where to begin? I think it's very exciting to be working in this space at this time, and we're very lucky to be in it. So, for NICHE, we're actually accruing now in new cohorts for both MMR-deficient and MMR-proficient tumors. For the patients with MMR-deficient tumors, we're actually testing a new combination of nivolumab plus relatlimab, so anti-LAG-3 plus anti-PD1. And we're testing the same co-formulation in patients with pMMR tumors. In addition to another cohort for the pMMR tumors with nivolumab, all within this window of opportunity, as we did previously in NICHE, and to see if we're going to see more responses if these are going to be different tumors than the ones responding to nivolumab and ipilimumab. And for the MMR deficient tumors, we're treating longer with this combination now. So, we're operating after eight weeks instead of six weeks. We're giving two cycles, four weekly cycles, to see whether we can even improve the PCR rates, even though this is, of course, a different combination treatment. So, very exciting times for NICHE, and we'll have the readout for the DFS at the end of this year, so that's also very exciting. And then, well, it's similar to Dr. Cercek. So again, we're on the same page when it comes to these neoadjuvant treatments. We have actually an ongoing trial for neoadjuvant treatment of patients with MMR proficient rectal cancers, and that is using a combination of radiation therapy followed by a combination of atezolizumab or anti-PDL1 with Bevacizumab with the aim of organ sparing approach in these patients. And we actually presented stage 1 of this trial as a poster at ASCO GI, showing that we achieved 56% complete or near complete responses clinically at 12 weeks. And after at least a year of follow-up for all patients, we have 50% organ preservation. So those are very exciting data as well. Also, in the MMR proficient tumors, I'm very excited to hear about the HER-2-positive tumors and Dr. Cercek's study. So there's definitely a lot going on that we hope to share as soon as the data are available. Dr. Mohamed Salem: We'll be looking forward to your next presentation and seeing that. So again, most of your work showed us that we really have to choose the right patient with the right target for the right treatment to achieve the best possible outcome. So we're getting short on time here. But before we conclude, ASCO Daily News Podcast has a huge audience of oncologists, I wanted to give you the chance to share anything you'd like to share with our audience today before we finish. Dr. Cercek? Dr. Andrea Cercek: I believe this is an incredibly exciting time in colorectal cancer. I think it's finally our turn, which feels really nice, and obviously, we have a lot more work that needs to be done. But my personal belief is to keep trying to chip away at the pie and identify responders and keep working to have better-targeted drugs and better treatment options that will improve responses and improve outcomes for our patients. But I certainly believe that we are well on our way there, and it's very exciting. Dr. Mohamed Salem: I totally agree. Dr. Chalabi, any thoughts? Dr. Myriam Chalabi: I think after 2022 and the data that we've been showing, I think it's important to– and I think by now, maybe it's not even necessary anymore to say it– but I think it's important to really look at the tumors and look at these MMR proteins or MSI, and to make sure that you're treating the patient in the right way, and to consider that. Before, it wasn't as important in the neoadjuvant setting or these localized tumors, but now it's becoming essential.  And I think if you would have looked five years ago and you would say, yeah, these MSI tumors are important to find, it's a very small proportion of patients, in rectal cancer even lower than in colon cancer. But still, it has such a huge impact on what you're doing in these patients and your chances of cure. So I think that would be my most important giveaway to test for MMR deficiency before deciding on a treatment for your patients. And we're working on trials with neoadjuvant immunotherapy. Also in other tumor types, Dr. Cercek is also doing the same. I think those will be very important also outside of the GI field to see whether this approach works for a much larger patient population, despite the low incidence.  Dr. Andrea Cercek: Dr. Chalabi just made a critical point that that is most important is to remember that we do have biomarkers in colorectal cancer that, in the neoadjuvant setting and in the metastatic setting, especially MSI, that we need to test for. And then, just to add from a clinical perspective, in rectal cancer, the large majority of patients that have mismatch-repair deficient or MSI tumors actually have Lynch syndrome. So really, if you identify a patient that's mismatch-repair deficient or MSI-high anywhere, but especially in the rectum, they absolutely should get germline testing. Dr. Mohamed Salem: I echo that and second that. And Dr. Cercek, thank you, and I know you did a lot of work in colorectal cancer in the younger adult population, too, so I think you've had a huge impact on that area too. I would like to thank both of you again for being here today, but more for the great work you and your teams are doing to advance the field. It's really a very exciting time in GI cancers now, and thank you so much for your work and for sharing your insights with us today on the ASCO Daily News Podcast. Dr. Myriam Chalabi: Thank you so much for having me. It's been great. Dr. Andrea Cercek: Thank you for having me. Dr. Mohamed Salem: Of course, and thanks to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:     Dr. Mohamed Salem @SalemGIOncDoc   Dr. Myriam Chalabi @MyriamChalabi   Dr. Andrea Cercek @AndreaCercek   Learn about other key advances in GI Oncology: SWOG 1815, PARADIGM, and Other Advances at GI23   Follow ASCO on social media:      @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Mohamed Salem: Consulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol-Myers Squibb, Exelixis, QED Therapeutics, Novartis, Pfizer, Daiichi Sankyo/Astra Zeneca Speakers' Bureau: Genentech/Roche, Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck Dr. Myriam Chalabi: Consulting or Advisory Role: MSD, Bristol-Myers Squibb/Celegne, Numab Research Funding (Institution): Bristol-Myers Squibb, Roche/Genentech, MSD Travel, Accommodations, Expenses: Roche/Genentech, Bristol-Myers Squibb Dr. Andrea Cercek: Consulting or Advisory Role: Bayer, GSK, Incyte, Merck, Janssen, Seattle Genetics, G1 Therapeutics Research Funding (Institution): Seattle Genetics, GSK, Rgenix          

Listen to a soundcast of the February 9, 2023, FDA approval of Jemperli (dostarlimab-gxly) for mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer that has progressed on or following a prior platinum-containing regimen.

Neste Vídeo-MOC, os Drs. Fabio Kater e Antonio C. Buzaid debatem sobre o uso de pembrolizumabe no tratamento de tumores com MSI-H e a incorporação da estratégia na prática clínica. Confira também o Vídeo-MOC completo. mocbrasil.com/blog/videos-moc/vol14num02/

Featuring an interview with Dr Manish Shah, including the following topics: Role of targeted and immunotherapy regimens for upper GI cancers (0:00) Future of CAR T-cell therapy for patients with gastric cancer (11:26) Case: A man in his mid 60s with HER2-positive gastroesophageal adenocarcinoma (15:59) Case: A woman in her mid 70s with newly diagnosed HER2-negative, pMMR gastric cancer (29:57) Case: A man in his mid 50s with dMMR, HER2-negative gastric cancer (37:32) CME information and select publications

Após a publicação do Estudo com dostarlimabe para tratamento de câncer de reto - confira o ep.105 do nosso podcast - o NICHE-2 avaliou o uso de imunoterapia em paciente com câncer de cólon avançado com ausência das proteínas de gene de reparo de dna.Apesar de ser um estudo fase II, os doutores Ranyell Spencer (H9J), Allan Pereira (HSL) e Renata D'Alpino (Oncoclínicas), discutem o abstract publicado e apresentado na ESMO 2022.Estudo importante, que certamente irá mudar a conduta nesses pacientes!Sejam bem vindos a mais um episódio do Clinical Papers Podcast!

CME credits: 0.50 Valid until: 30-11-2023 Claim your CME credit at https://reachmd.com/programs/cme/establishing-the-role-of-immunotherapy-in-microsatellite-instability-high-msi-h-or-mismatch-repair-deficient-dmmr-endometrial-cancer/14459/ Are you testing for MSI-H/dMMR in your patients with advanced endometrial cancer? Listen in as Drs. Robert Coleman, Susana Campos, and Ana Oaknin break down the progress being made in biomarker testing and immunotherapy treatment for these patients.

CME credits: 0.50 Valid until: 04-11-2023 Claim your CME credit at https://reachmd.com/programs/cme/advances-in-the-care-of-patients-with-msi-hdmmr-or-her2-colorectal-cancers/14480/ In this chapterized panel discussion, Drs. Aparna Parikh, Dustin Deming, and Scott Kopetz take us through NCCN recommended guidelines and best practices for identifying biomarkers. Armed with this knowledge, you'll be able to select systemic therapies more accurately for your patients with MSI-high disease, as well as patients with HER2-amplified CRC.

Dr. Myriam Chalabi, a GI oncologist at the Netherlands Cancer Institute, joins the show after making waves at the latest ESMO Congress for her NICHE-2 study – an assessment of neoadjuvant immune checkpoint inhibition in locally advanced dMMR colon cancer. She shares the initial inspiration to give neoadjuvant immunotherapy for dMMR tumors, the surprisingly positive early results that led to expanding the study, her feelings and expectations leading up to her talk at ESMO, and her reaction to the Twitter phenomenon with the “Chalabi Plot” – how the medical community was in awe of her rare and exceptional waterfall plot. This episode is a good reminder of the value in executing a well-designed clinical trial and the benefits that patients stand to gain from good science. Check out Chadi's website for all Healthcare Unfiltered episodes and other content. www.chadinabhan.com/ Watch all Healthcare Unfiltered episodes on Youtube. www.youtube.com/channel/UCjiJPTpIJdIiukcq0UaMFsA

El Dr. Sebastián Mondaca, oncólogo médico de la Pontificia Universidad Católica en Santiago, Chile, junto con el Dr. Ángel López, oncólogo médico adscrito a OPCION Oncología en Monterrey, NL, México, nos comentan algunos de los estudios más destacados sobre el tratamiento de tumores gastrointestinales presentados durante el Congreso Anual de ESMO 2022 en París, Francia. Cáncer colorrectal NICHE-2: Estudio fase II, multicéntrico y no aleatorizado, que evaluó nivolumab + ipilimumab neoadyuvante, en donde a corto plazo demostró respuestas patológicas significativas en casi todos los pacientes con cáncer de colon con deficiencia en la reparación de errores de emparejamiento (dMMR, por sus siglas en inglés) no metastásicos. SAMCO-PRODIGE 54: Estudio fase II, aleatorizado, que evaluó avelumab vs. quimioterapia estándar de 2L en pacientes con cáncer colorrectal metastásico (CCRm) con inestabilidad de microsatélites. KRYSTAL-1: Estudio fase I/II, multicohorte, que evaluó la seguridad y eficacia de adagrasib con o sin cetuximab en pacientes con CCRm que alberga una mutación KRAS G12C. CodeBreak-101: Estudio fase Ib, que evaluó la seguridad y eficacia para la cohorte de expansión completa de sotorasib en combinación con panitumumab en CCR refractario mutado KRAS G12C. MOUNTAINEER: Estudio fase II, aleatorizado y multicéntrico, que evaluó tucatinib + trastuzumab o tucatinib solo en pacientes con CCRm o no resecable HER2+ después de terapias estándar de atención previas. FRESCO-2: Estudio fase III, multirregional y global, que evaluó la eficacia y seguridad de fruquintinib en pacientes con CCRm refractario. Cáncer gástrico DESTINY-Gastric02: Estudio fase II, de un solo brazo, que evaluó trastuzumab deruxtecan en pacientes occidentales con cáncer de la unión gástrica/gastroesofágica HER2+ que progresó durante o después del régimen con trastuzumab. Fecha de grabación: 21 de septiembre de 2022 Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente.

In deze podcast bespreekt internist-oncoloog Koos van der Hoeven met internist-oncoloog Myriam Chalabi, werkzaam in het Antoni van Leeuwenhoek te Amsterdam de NICHE-2-studie; neoadjuvante immunotherapie bij dMMR-coloncarcinoom. Chalabi presenteerde de studie tijdens een Presidential Symposium op het ESMO Congress 2022. Aan bod komen onder andere waarom de studie is uitgevoerd, hoe en de belangrijkste resultaten.

In this episode, Jubilee Brown, MD, and Elisabeth Diver, MD, provide expert insights on new data presented at ASCO 2022 for ovarian, endometrial, and cervical cancers regarding:Subgroup analyses from KEYNOTE-826 evaluating pembrolizumab in combination with chemotherapy with or without bevacizumab in persistent, recurrent, or metastatic cervical cancerPreliminary subgroup analyses from phase III ENGOT-EN5/GOG-3055 SIENDO trial of selinexor vs placebo maintenance in recurrent endometrial cancerUpdated analyses from phase I GARNET trial of dostarlimab in dMMR/MSI-H and pMMR/MSS advanced/recurrent endometrial cancer (cohorts A1 and A2)EndoBARR trial of atezolizumab, bevacizumab, and rucaparib in previously treated recurrent and progressive endometrial cancerPhase III ATHENA-MONO trial of first-line rucaparib vs placebo maintenance after platinum-based chemotherapy in patients with advanced ovarian cancerPresenters:Jubilee Brown, MDProfessor and Division DirectorGynecologic OncologyLevine Cancer Institute, Atrium HealthCharlotte, North CarolinaElisabeth Diver, MDClinical Assistant ProfessorDivision of Gynecologic OncologyDepartment of Obstetrics and GynecologyStanford UniversityStanford Cancer InstituteStanford University Hospital and ClinicsStanford, CaliforniaContent supported by educational grants from AstraZeneca, GlaxoSmithKline, Karyopharm Therapeutics, and Merck Sharp & Dohme Corp.Link to full program, including a downloadable highlights slideset, and ClinicalThought commentaries:https://bit.ly/3ufB8Js

On this week's episode, Agustin discusses the recent data release of Jemperli and how it may be a viable solution for dMMR solid tumor patients. He also provides updates on Amylyx Pharmaceuticals and their recent approval in Canada, Leap Therapeutics and their prostate cancer readout, and Infinity Pharmaceuticals and their risky jam-packed future. If you are a fan of this show make sure to like, comment, subscribe and follow me on Twitter @biotech_bros. If you have any questions regarding the product offerings feel free to explore my website biotechbros.com

In the longest episode of "Dose of Joy" to date (The podcast will be off the week of March 27th.), your Host Joy shares SO Much Life-Saving Colon Cancer Information for all to hear!  From risk factors for colon cancer to tests to help detect colon cancer to signs & symptoms to watch for ... along with typical treatments by stage of colon cancer ... this under an hour show is jam-packed with essential information.  For example, cancer.net currently states, "All colorectal cancers should be tested for problems in mismatch repair proteins, called a mismatch repair defect (dMMR). There are 2 reasons for this testing."  Discover the reasons in the show.  This helpful show includes laughs for you too as you'll hear a story featured in the book Joy authored "Cancer with Joy."  Be listening for the semicolon part of the story!  Finally, get the number for a free call line from FightColorectalCancer.org.     Support the show (https://www.patreon.com/doseofjoy?fan_landing=true)

In this episode,  Nicole Concin, MD, PhD, highlights key data for endometrial and ovarian cancers presented at the ESGO 2021 annual meeting, including:Pooled data from 7 phase III clinical trials evaluating surgical outcomes as prognostic factors for patients with high-grade serous, low-grade serous, mucinous, and clear cell ovarian cancerUpdate from the phase I GARNET study in patients with advanced/recurrent mismatch repair deficient/microsatellite instability‒high or proficient/stable endometrial cancerResults from the TOTEM trial evaluating the impact of minimalist vs intensive follow-up on health-related quality of life and cost for patients with endometrial cancerPresenters:Nicole Concin, MD, PhDProfessorDepartment of Gynaecology and ObstetricsMedical University InnsbruckInnsbruck, AustriaConsultant in Gynaecological OncologyDepartment of Gynaecology and Gynaecologocial OncologyKEM Evang. Kliniken Essen-MitteEssen, GermanyContent supported by an educational grant from GlaxoSmithKline.Link to full program, including a downloadable highlights slideset and ClinicalThought commentaries:https://bit.ly/30PjPnl

In this episode, Prof. Isabelle Ray-Coquard, MD, PhD, and Bernard Doger de Spéville, MD, PhD, provide expert insights on key new data from ESMO 2021 presented for endometrial and ovarian cancers including:Data from the phase III OReO/ENGOT Ov-38 trial of olaparib rechallenge in patients with recurrent ovarian cancer previously treated with a PARP inhibitor  A subgroup analysis of KEYNOTE-775, comparing lenvatinib vs pembrolizumab vs TPC, with outcomes by tumor histology and prior lines of therapyA preplanned analysis from phase III NRG-GY004 of outcomes by HRD status for olaparib with or without cediranib vs platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancerQuality-adjusted time without symptom or toxicity from the phase III PRIMA trial of maintenance niraparib vs placebo in newly diagnosed advanced ovarian cancerPresenters:Prof. Isabelle Ray-Coquard, MD, PhDProfessor of Department of Medical OncologyClinical Science Institute of the Léon Bérard CenterLyon, FranceBernard Doger de Spéville, MD, PhDMedical OncologistSTART-Madrid, Early Phase Clinical Trials UnitHospital Fundación Jiménez DíazMadrid, SpainContent supported by an educational grant from GlaxoSmithKline.Link to full program, including a downloadable highlights slideset and ClinicalThought commentaries:https://bit.ly/3dAttwi 

In this episode, Domenica Lorusso, MD, PhD, and Alexandra Leary, MD, PhD, provide expert insights on practice changing data from IGCS 2021 presented for endometrial, ovarian, and cervical cancers regarding:A subgroup analysis from phase III KEYNOTE-775 evaluating lenvatinib plus pembrolizumab efficacy in patients with advanced endometrial cancer and dMMR statusA subgroup analysis from the phase I GARNET trial─cohorts A1 and A2─in patients with advanced endometrial cancer who had received either 1 or ≥2 prior lines of therapyData from the TOTEM trial reporting survival outcomes for patients undergoing intensive vs minimalist follow-up in following treatment for endometrial cancerAn exploratory analysis from the phase III ARIEL3 trial evaluating characteristics of patients with ovarian cancer with exceptional benefit from rucaparibA post hoc analysis from the phase III NORA trial assessing efficacy of starting PARP inhibitor maintenance following either ≤4 vs >4 cycles of platinum-based chemotherapyHighly anticipated results from the phase III EMPOWER-CERVICAL 1 trial of cemiplimab vs investigator's choice chemotherapy in women with cervical cancerPresenters:Domenica Lorusso, MD, PhDAssociate ProfessorGynecologic Oncology DepartmentClinical Research UnitFondazione Policlinico Gemelli IRCCSRome, ItalyAlexandra Leary, MD, PhDMedical Oncologist and Team Leader  Gynecology Translational Research LabDepartment of MedicineGustave Roussy Cancer CenterParis, FranceContent supported by an educational grant from GlaxoSmithKline.Link to full program, including a downloadable highlights slideset and ClinicalThought commentaries:https://bit.ly/3dAttwi

This week, we'll be reviewing two recent FDA approvals in the oncology space, for patients with mismatch repair–deficient, or dMMR, recurrent or advanced solid tumors, and for adult patients with cancers associated with von Hippel-Lindau (VHL) disease.Coverage of stories discussed this week on ascopost.com:FDA Grants Accelerated Approval to Dostarlimab-gxly for dMMR Advanced Solid TumorsFDA Approves Belzutifan for Cancers Associated With von Hippel-Lindau DiseaseTo listen to more podcasts from ASCO, visit asco.org/podcasts.

In this episode, Linda R. Duska, MD, MPH; Robert L. Coleman, MD, FACOG, FACS; and Leslie Randall, MD, MAS, answer questions from an audience of healthcare professionals on topics related to the management of patients with endometrial and ovarian cancer including:  Adding bevacizumab to chemotherapy in frontline endometrial cancerLenvatinib and pembrolizumab in MSI-H/dMMR endometrial cancerPARP inhibitor maintenance in ovarian cancerBevacizumab with or without PARP inhibitors in ovarian cancerPresenters:Linda R. Duska, MD, MPHLawrence W. Penniston MD Family Professor in Women's Oncology ResearchDivision of Gynecologic OncologyDepartment of Obstetrics and GynecologyUniversity of Virginia School of MedicineCharlottesville, VirginiaRobert L. Coleman, MD, FACOG, FACSGynecologic Oncologist and Chief Scientific OfficerUS Oncology, US Oncology ResearchThe Woodlands, TexasLeslie Randall, MD, MAS  Diane Harris Wright Professor and DirectorDivision of Gynecologic OncologyDepartment of Obstetrics and GynecologyMassey Cancer CenterVirginia Commonwealth UniversityRichmond, VirginiaLink to full program, including downloadable slidesets, expert commentaries, and on-demand webcast:https://bit.ly/3e6pZCM 

In this episode, David Scott Miller, MD, FACOG, FACS, and Melissa M. Hardesty, MD, MPH, provide expert perspectives on new data from ASCO 2021 presented for endometrial, ovarian, and cervical cancers regarding:Results from a pilot study of pembrolizumab monotherapy in patients with Lynch-like vs sporadic MLH1-methylated endometrial cancerUpdated analyses from the phase I GARNET trial, including data for patients with dMMR solid tumors (endometrial cancer and nonendometrial cancer cohorts)Final analyses from a study of mirvetuximab soravtansine plus bevacizumab in platinum-agnostic recurrent ovarian cancerResults from the randomized phase III BOOST trial evaluating optimal treatment duration of bevacizumab in combination with carboplatin and paclitaxel in ovarian cancerHighly anticipated results from the phase III OUTBACK trial of CRT ± adjuvant CT in women with locally advanced cervical cancerA post hoc, pooled analysis, from phase I and phase II data of bintrafusp alfa, a first-in-class bifunctional fusion protein comprising a TGF-βRII (TGF-β trap) fused to a human monoclonal antibody targeting PD-L1Results from a prospective multicenter phase II trial evaluating anlotinib plus sutimlimab in recurrent/advanced cervical cancersPresenters:David Scott Miller, MD, FACOG, FACSAmy and Vernon E. Faulconer Distinguished Chair in Medical ScienceDirector and Dallas Foundation Chair in Gynecologic OncologyProfessor of Obstetrics & GynecologyUniversity of Texas Southwestern Medical CenterMedical Director of Gynecologic OncologyChair, Cancer CommitteeParkland Health & Hospital SystemDallas, Texas  Melissa M. Hardesty, MD, MPHAffiliate Associate ProfessorOB/GYN/GYN OncologyUniversity of Alaska AnchorageGynecologic Oncologist and Managing PartnerAlaska Women's Cancer CareAnchorage, AlaskaContent supported by an educational grant from GlaxoSmithKline.Link to full program, including a downloadable highlights slideset, and ClinicalThought commentaries:https://bit.ly/3dAttwi

CME credits: 0.25 Valid until: 06-05-2022 Claim your CME credit at https://reachmd.com/programs/cme/keeping-pace-womens-cancer-targeting-advanced-endometrial-cancer/12479/ Therapeutic options are changing for many patients with advanced endometrial cancer. Join us as Dr. Richard Penson and Dr. Nicoletta Colombo discuss new immunotherapeutic approaches and the importance of a patient’s tumor genomic profile when determining which interventional strategy, they receive. Also hear from Ms. Christine Ghione, a patient advocate, who provides a firsthand perspective of shared decision-making and how the process may be improved. Since the production of this activity, the FDA has approved the use of dostarlimab for the treatment of patients with recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing chemotherapy and whose cancers have a specific genetic feature known as dMMR, as determined by an FDA-approved test. Visit the FDA statement dated 22 April 2021 to learn more.

Host: Richard T. Penson, MD, MRCP Guest: Nicoletta Colombo, MD Guest: Christine Ghione Therapeutic options are changing for many patients with advanced endometrial cancer. Join us as Dr. Richard Penson and Dr. Nicoletta Colombo discuss new immunotherapeutic approaches and the importance of a patient’s tumor genomic profile when determining which interventional strategy, they receive. Also hear from Ms. Christine Ghione, a patient advocate, who provides a firsthand perspective of shared decision-making and how the process may be improved. Since the production of this activity, the FDA has approved the use of dostarlimab for the treatment of patients with recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing chemotherapy and whose cancers have a specific genetic feature known as dMMR, as determined by an FDA-approved test. Visit the FDA statement dated 22 April 2021 to learn more.

CME credits: 0.25 Valid until: 06-05-2022 Claim your CME credit at https://reachmd.com/programs/cme/keeping-pace-womens-cancer-targeting-advanced-endometrial-cancer/12479/ Therapeutic options are changing for many patients with advanced endometrial cancer. Join us as Dr. Richard Penson and Dr. Nicoletta Colombo discuss new immunotherapeutic approaches and the importance of a patient's tumor genomic profile when determining which interventional strategy, they receive. Also hear from Ms. Christine Ghione, a patient advocate, who provides a firsthand perspective of shared decision-making and how the process may be improved. Since the production of this activity, the FDA has approved the use of dostarlimab for the treatment of patients with recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing chemotherapy and whose cancers have a specific genetic feature known as dMMR, as determined by an FDA-approved test. Visit the FDA statement dated 22 April 2021 to learn more.

CME credits: 0.75 Valid until: 28-04-2022 Claim your CME credit at https://reachmd.com/programs/cme/pulse-points-prostate-cancer-embracing-advances-parpi-combinations/12472/ During recent years, advances in the understanding of the underlying genetic events and biology in prostate cancer development, including the DDR and MMR pathway alterations, have yielded new avenues for clinical exploration. Prostate cancers with deleterious aberrations in DNA damage repair (DDR) genes, including homologous recombination repair, such as mutations in BRCA1/2 and ATM, are associated with response to poly (adenosine diphosphate–ribose) polymerase (PARP) inhibition. PARP inhibitors are now gaining FDA approvals for the treatment of patients with mCRPC, and ongoing clinical trials are evaluating these PARP inhibitors as monotherapy or in combination with other treatments such as androgen pathway inhibitors. The National Comprehensive Cancer Network (NCCN®) is now recommending germline testing and molecular biomarker analysis, including tumor testing for HRR mutations, and to consider tumor testing for MSI or dMMR for metastatic disease. PARP inhibitors for the treatment of mCRPC in patients harboring germline and somatic BRCA/ATM mutations, and in combination with androgen pathway inhibition, are poised to propel the management of mCRPC toward a more personalized approach. In this activity, expert faculty will review, discuss, and provide their expert insights on recent and emerging practice-changing advancements with PARP inhibitors for the treatment of mCRPC, with a ...

CME credits: 0.75 Valid until: 28-04-2022 Claim your CME credit at https://reachmd.com/programs/cme/pulse-points-prostate-cancer-embracing-advances-parpi-combinations/12472/ During recent years, advances in the understanding of the underlying genetic events and biology in prostate cancer development, including the DDR and MMR pathway alterations, have yielded new avenues for clinical exploration. Prostate cancers with deleterious aberrations in DNA damage repair (DDR) genes, including homologous recombination repair, such as mutations in BRCA1/2 and ATM, are associated with response to poly (adenosine diphosphate–ribose) polymerase (PARP) inhibition. PARP inhibitors are now gaining FDA approvals for the treatment of patients with mCRPC, and ongoing clinical trials are evaluating these PARP inhibitors as monotherapy or in combination with other treatments such as androgen pathway inhibitors. The National Comprehensive Cancer Network (NCCN®) is now recommending germline testing and molecular biomarker analysis, including tumor testing for HRR mutations, and to consider tumor testing for MSI or dMMR for metastatic disease. PARP inhibitors for the treatment of mCRPC in patients harboring germline and somatic BRCA/ATM mutations, and in combination with androgen pathway inhibition, are poised to propel the management of mCRPC toward a more personalized approach. In this activity, expert faculty will review, discuss, and provide their expert insights on recent and emerging practice-changing advancements with PARP inhibitors for the treatment of mCRPC, with a ...

In this episode, Jubilee Brown, MD, and Ursula Matulonis, MD, provide expert perspectives on new data from SGO 2021 presented for endometrial and ovarian cancer including:Results from KEYNOTE-775, a phase III trial of lenvatinib plus pembrolizumab in advanced endometrial cancerResults from the confirmatory phase III ARIEL4 evaluating rucaparib vs chemotherapy in BRCA-mutated relapsed ovarian cancer5-year follow-up from SOLO-1 trial of olaparib vs placebo in BRCA-mutated, newly diagnosed ovarian cancerLong-term follow-up results from the phase III ENGOT-OV16/NOVA trial of niraparib in patients with recurrent ovarian cancerOPAL: a phase II study evaluating dostarlimab, bevacizumab, and niraparib in platinum-resistant ovarian cancerPresenters:Jubilee Brown, MDProfessor and Director of Gynecologic OncologyLevine Cancer InstituteAtrium HealthCharlotte, North CarolinaUrsula Matulonis, MDChief, Division of Gynecologic OncologyBrock Wilson Family ChairDana-Farber Cancer InstituteProfessor of MedicineHarvard Medical SchoolBoston, MassachusettsContent supported by an educational grant from GlaxoSmithKline.Link to full program, including a downloadable highlights slideset, and ClinicalThought commentaries:https://bit.ly/3dAttwi 

CME credits: 0.25 Valid until: 23-12-2021 Claim your CME credit at https://reachmd.com/programs/cme/keeping-pace-gi-cancer-advances-immunotherapy-msi-hdmmr-metastatic-colorectal-cancer/12082/ Recent immunotherapy approvals have changed the treatment paradigm for first and subsequent lines of treatment for patients with microsatellite-high or mismatch repair deficient metastatic colorectal cancer. Join us as we deep dive into recent and newly emergent data to better understand how to bring these advances into the clinic.

Host: Edward Chu, MD Guest: Michael J. Overman, MD Recent immunotherapy approvals have changed the treatment paradigm for first and subsequent lines of treatment for patients with microsatellite-high or mismatch repair deficient metastatic colorectal cancer. Join us as we deep dive into recent and newly emergent data to better understand how to bring these advances into the clinic.

Host: Edward Chu, MD Guest: Michael J. Overman, MD Recent immunotherapy approvals have changed the treatment paradigm for first and subsequent lines of treatment for patients with microsatellite-high or mismatch repair deficient metastatic colorectal cancer. Join us as we deep dive into recent and newly emergent data to better understand how to bring these advances into the clinic.

In this episode, an expert medical oncology panel led by John L. Marshall, MD, with Jamie E. Chaft, MD, and Scot Niglio, MD, provides a brief overview on the revolutionary changes brought by immuno-oncology to the management of gastrointestinal, thoracic, and genitourinary cancers. Then, the panel answers clinician questions on important topics such as:Selecting immuno-oncology vs targeted therapy in MSI-high cancers with co-occurring alterations (eg, BRCA, HER2, BRAF, NTRK)Switching to a new immuno-oncology strategy at progression on first-line immune checkpoint inhibitionNeoadjuvant treatment with immune checkpoint inhibitorsFinancial considerations when selecting chemotherapy vs immuno-oncologyPresenters:John L. Marshall, MDChief, Division of Hematology/OncologyDepartment of MedicineGeorgetown University HospitalWashington, DCJamie E. Chaft, MDAssociate Attending PhysicianThoracic Oncology ServiceMemorial Sloan Kettering Cancer CenterNew York, New YorkScot Niglio, MDMedical OncologistBethesda, MarylandContent based on an online CME program supported by an educational grant from Merck Sharp & Dohme Corp.Link to full program:https://bit.ly/31vQtqb

FDA ended June with 5 new approvals. *selinexor for r/r DLBCL *pembrolizumab for cutaneous squamous cell carcinoma *pembrolizumab for MSI-h/dMMR met. colorectal cancer *avelumab maintenance for met. bladder cancer *SC trastuzumab/pertuzumab/hyaluronidase

Entrectinib and larotrectinib have been approved to treat tumors with fusions in the neurotrophic tropomyosin receptor kinase (NTRK) gene – irrespective of the tumor’s site of origin. These drugs are the second and third agents, overall, to have a tissue-agnostic indication approved by the FDA. The first was pembrolizumab, an immunotherapy agent, indicated for tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017. Have we finally reached the point where tumor biology has become a more important consideration than site of origin?

Consensus or Controversy? Clinical Investigators Provide Perspectives on the Current and Future Management of Prostate Cancer — Part 1: Our one-on-one interview with Dr Antonarakis featuring emerging research and cases from his practice. Initial evaluation of prognostic indicators in hormone-sensitive prostate cancer (HSPC) versus castration-resistant prostate cancer (CRPC) (0:00) Effect of prostate-specific antigen (PSA) doubling time on time to metastasis and overall survival in nonmetastatic CRPC; improvement in metastasis-free survival with androgen receptor antagonist therapy (4:16) Perspective on the use of intermittent androgen deprivation therapy (ADT) for patients with nonmetastatic HSPC and rising PSA levels (12:35) Structural and mechanistic similarities and differences between available (apalutamide, enzalutamide) and investigational (darolutamide) androgen receptor antagonists (19:39) Initial results of the Phase III ARAMIS trial: Metastasis-free survival improvement and tolerability of darolutamide versus placebo for nonmetastatic CRPC (22:41) ARASENS: An ongoing Phase III trial evaluating darolutamide versus placebo in combination with standard ADT and docetaxel for patients with metastatic HSPC (25:38) Perspective on the new drug application and potential FDA approval of darolutamide for nonmetastatic CRPC (27:02) Spectrum and frequency of systemic and CNS-related side effects associated with apalutamide, enzalutamide and darolutamide (28:29) Updated analysis of progression-free survival with first subsequent therapy (PFS2) in the SPARTAN study of apalutamide for high-risk nonmetastatic CRPC (31:50) ARCHES: Design, efficacy and tolerability results from a Phase III trial of ADT with enzalutamide or placebo for metastatic HSPC (36:22) Selection and sequencing of therapy for patients with metastatic prostate cancer (42:01) Correlation between the presence of androgen receptor splice variant 7 (AR-V7) and outcomes with secondary hormonal therapy and chemotherapy in metastatic CRPC (45:58) Prevalence and detection of AR-V7 in patients with metastatic CRPC (50:48) Overview of BRCA1/2 and other DNA repair gene mutations that may confer sensitivity to PARP inhibition (54:32) Efficacy and FDA breakthrough therapy designations for olaparib and rucaparib for metastatic CRPC (58:49) GALAHAD: Preliminary results of a Phase II trial of niraparib for patients with metastatic CRPC and biallelic DNA repair gene defects (1:1:10) Response to PARP inhibitor therapy in patients with metastatic CRPC with BRCA1/2 versus ATM mutations (1:4:06) Activity of platinum-based chemotherapy in patients with metastatic CRPC and germline BRCA mutations (1:7:29) Clinical experience with PARP inhibitor-associated side effects in men with metastatic CRPC (1:12:35) Perspective on the negative results of the Phase III ERA 223 trial evaluating radium-223 dichloride in combination with abiraterone acetate for patients with chemotherapy-naïve metastatic CRPC and bone metastases (1:14:56) Appropriate use of radium-223 for the treatment of symptomatic metastatic CRPC (1:19:54) Biologic rationale for and ongoing investigation of lutetium-177-prostate-specific membrane antigen (PSMA)-617 for progressive PSMA-positive metastatic CRPC (1:23:03) KEYNOTE-199: Updated analysis of a Phase II trial of pembrolizumab monotherapy for patients with metastatic CRPC previously treated with docetaxel (1:27:39) Initial results of the Phase II CheckMate 650 trial of nivolumab with ipilimumab for metastatic CRPC (1:30:11) Prevalence of microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) molecular phenotype and response to immune checkpoint blockade in patients with prostate cancer (1:35:02) Emerging data with olaparib in combination with anti-PD-1/PD-L1 checkpoint blockade for metastatic CRPC (1:37:38) Select publications  

Go online to PeerView.com/FJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Cancer immunotherapies are demonstrating remarkable clinical activity in an increasing number of solid tumors and hematologic malignancies. Reliable biomarkers are needed to guide clinical decisions regarding treatment selection and identification of patients who are most likely to benefit. Testing for programmed death-ligand 1 (PD-L1) expression and the presence of DNA mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) should presently be routinely done in oncology and pathology practice in alignment with the latest recommendations and indications. Assessment of tumor mutational burden (TMB) is also showing great promise as a new and distinct predictor of benefit from cancer immunotherapies. Other novel biomarkers are undergoing investigations as well. How can pathologists ensure that immuno-oncology biomarker testing is carried out according to best practices, and collaborate with oncologists and other members of the cancer care team in interpreting the results to guide therapeutic decisions for patients with cancer? In this activity, based on a recent CME/MOC/CC-certified symposium held during the 2019 Annual Meeting of the United States and Canadian Academy of Pathology (USCAP) held in National Harbor, Maryland, a panel of experts discuss the latest clinical advances with cancer immunotherapies and the research underway to further refine biomarker testing and maximize the use of checkpoint inhibitors and combinations across a broad spectrum of malignancies. Upon completion of this activity, participants should be better able to: Characterize the efficacy/safety profiles and clinical roles of the current and emerging immunotherapies and combinations across the spectrum of solid and liquid cancers, Describe evidence supporting the use of PD-L1, MMR/MSI, TMB, and other promising biomarkers as predictors of benefit from cancer immunotherapies, Discuss practical aspects of immunotherapy biomarker testing and interpretation, including benefits/limitations of different testing methodologies, assays, cut-points, and other nuances, Assess the potential role of novel strategies and technologies being evaluated as part of cancer immunotherapy biomarker development for predictive and other purposes, Implement best practices for cancer immunotherapy biomarker testing in community and academic settings based on the latest evidence and recommendations, Establish effective strategies for interdisciplinary collaboration among pathologists, oncologists, and other key professionals regarding biomarker testing and interpretation to guide decisions about the use of cancer immunotherapies and combinations in patients with cancer.

Go online to PeerView.com/FJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Cancer immunotherapies are demonstrating remarkable clinical activity in an increasing number of solid tumors and hematologic malignancies. Reliable biomarkers are needed to guide clinical decisions regarding treatment selection and identification of patients who are most likely to benefit. Testing for programmed death-ligand 1 (PD-L1) expression and the presence of DNA mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) should presently be routinely done in oncology and pathology practice in alignment with the latest recommendations and indications. Assessment of tumor mutational burden (TMB) is also showing great promise as a new and distinct predictor of benefit from cancer immunotherapies. Other novel biomarkers are undergoing investigations as well. How can pathologists ensure that immuno-oncology biomarker testing is carried out according to best practices, and collaborate with oncologists and other members of the cancer care team in interpreting the results to guide therapeutic decisions for patients with cancer? In this activity, based on a recent CME/MOC/CC-certified symposium held during the 2019 Annual Meeting of the United States and Canadian Academy of Pathology (USCAP) held in National Harbor, Maryland, a panel of experts discuss the latest clinical advances with cancer immunotherapies and the research underway to further refine biomarker testing and maximize the use of checkpoint inhibitors and combinations across a broad spectrum of malignancies. Upon completion of this activity, participants should be better able to: Characterize the efficacy/safety profiles and clinical roles of the current and emerging immunotherapies and combinations across the spectrum of solid and liquid cancers, Describe evidence supporting the use of PD-L1, MMR/MSI, TMB, and other promising biomarkers as predictors of benefit from cancer immunotherapies, Discuss practical aspects of immunotherapy biomarker testing and interpretation, including benefits/limitations of different testing methodologies, assays, cut-points, and other nuances, Assess the potential role of novel strategies and technologies being evaluated as part of cancer immunotherapy biomarker development for predictive and other purposes, Implement best practices for cancer immunotherapy biomarker testing in community and academic settings based on the latest evidence and recommendations, Establish effective strategies for interdisciplinary collaboration among pathologists, oncologists, and other key professionals regarding biomarker testing and interpretation to guide decisions about the use of cancer immunotherapies and combinations in patients with cancer.

Go online to PeerView.com/FJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Cancer immunotherapies are demonstrating remarkable clinical activity in an increasing number of solid tumors and hematologic malignancies. Reliable biomarkers are needed to guide clinical decisions regarding treatment selection and identification of patients who are most likely to benefit. Testing for programmed death-ligand 1 (PD-L1) expression and the presence of DNA mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) should presently be routinely done in oncology and pathology practice in alignment with the latest recommendations and indications. Assessment of tumor mutational burden (TMB) is also showing great promise as a new and distinct predictor of benefit from cancer immunotherapies. Other novel biomarkers are undergoing investigations as well. How can pathologists ensure that immuno-oncology biomarker testing is carried out according to best practices, and collaborate with oncologists and other members of the cancer care team in interpreting the results to guide therapeutic decisions for patients with cancer? In this activity, based on a recent CME/MOC/CC-certified symposium held during the 2019 Annual Meeting of the United States and Canadian Academy of Pathology (USCAP) held in National Harbor, Maryland, a panel of experts discuss the latest clinical advances with cancer immunotherapies and the research underway to further refine biomarker testing and maximize the use of checkpoint inhibitors and combinations across a broad spectrum of malignancies. Upon completion of this activity, participants should be better able to: Characterize the efficacy/safety profiles and clinical roles of the current and emerging immunotherapies and combinations across the spectrum of solid and liquid cancers, Describe evidence supporting the use of PD-L1, MMR/MSI, TMB, and other promising biomarkers as predictors of benefit from cancer immunotherapies, Discuss practical aspects of immunotherapy biomarker testing and interpretation, including benefits/limitations of different testing methodologies, assays, cut-points, and other nuances, Assess the potential role of novel strategies and technologies being evaluated as part of cancer immunotherapy biomarker development for predictive and other purposes, Implement best practices for cancer immunotherapy biomarker testing in community and academic settings based on the latest evidence and recommendations, Establish effective strategies for interdisciplinary collaboration among pathologists, oncologists, and other key professionals regarding biomarker testing and interpretation to guide decisions about the use of cancer immunotherapies and combinations in patients with cancer.

Go online to PeerView.com/FJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Cancer immunotherapies are demonstrating remarkable clinical activity in an increasing number of solid tumors and hematologic malignancies. Reliable biomarkers are needed to guide clinical decisions regarding treatment selection and identification of patients who are most likely to benefit. Testing for programmed death-ligand 1 (PD-L1) expression and the presence of DNA mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) should presently be routinely done in oncology and pathology practice in alignment with the latest recommendations and indications. Assessment of tumor mutational burden (TMB) is also showing great promise as a new and distinct predictor of benefit from cancer immunotherapies. Other novel biomarkers are undergoing investigations as well. How can pathologists ensure that immuno-oncology biomarker testing is carried out according to best practices, and collaborate with oncologists and other members of the cancer care team in interpreting the results to guide therapeutic decisions for patients with cancer? In this activity, based on a recent CME/MOC/CC-certified symposium held during the 2019 Annual Meeting of the United States and Canadian Academy of Pathology (USCAP) held in National Harbor, Maryland, a panel of experts discuss the latest clinical advances with cancer immunotherapies and the research underway to further refine biomarker testing and maximize the use of checkpoint inhibitors and combinations across a broad spectrum of malignancies. Upon completion of this activity, participants should be better able to: Characterize the efficacy/safety profiles and clinical roles of the current and emerging immunotherapies and combinations across the spectrum of solid and liquid cancers, Describe evidence supporting the use of PD-L1, MMR/MSI, TMB, and other promising biomarkers as predictors of benefit from cancer immunotherapies, Discuss practical aspects of immunotherapy biomarker testing and interpretation, including benefits/limitations of different testing methodologies, assays, cut-points, and other nuances, Assess the potential role of novel strategies and technologies being evaluated as part of cancer immunotherapy biomarker development for predictive and other purposes, Implement best practices for cancer immunotherapy biomarker testing in community and academic settings based on the latest evidence and recommendations, Establish effective strategies for interdisciplinary collaboration among pathologists, oncologists, and other key professionals regarding biomarker testing and interpretation to guide decisions about the use of cancer immunotherapies and combinations in patients with cancer.

Go online to PeerView.com/FJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Cancer immunotherapies are demonstrating remarkable clinical activity in an increasing number of solid tumors and hematologic malignancies. Reliable biomarkers are needed to guide clinical decisions regarding treatment selection and identification of patients who are most likely to benefit. Testing for programmed death-ligand 1 (PD-L1) expression and the presence of DNA mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) should presently be routinely done in oncology and pathology practice in alignment with the latest recommendations and indications. Assessment of tumor mutational burden (TMB) is also showing great promise as a new and distinct predictor of benefit from cancer immunotherapies. Other novel biomarkers are undergoing investigations as well. How can pathologists ensure that immuno-oncology biomarker testing is carried out according to best practices, and collaborate with oncologists and other members of the cancer care team in interpreting the results to guide therapeutic decisions for patients with cancer? In this activity, based on a recent CME/MOC/CC-certified symposium held during the 2019 Annual Meeting of the United States and Canadian Academy of Pathology (USCAP) held in National Harbor, Maryland, a panel of experts discuss the latest clinical advances with cancer immunotherapies and the research underway to further refine biomarker testing and maximize the use of checkpoint inhibitors and combinations across a broad spectrum of malignancies. Upon completion of this activity, participants should be better able to: Characterize the efficacy/safety profiles and clinical roles of the current and emerging immunotherapies and combinations across the spectrum of solid and liquid cancers, Describe evidence supporting the use of PD-L1, MMR/MSI, TMB, and other promising biomarkers as predictors of benefit from cancer immunotherapies, Discuss practical aspects of immunotherapy biomarker testing and interpretation, including benefits/limitations of different testing methodologies, assays, cut-points, and other nuances, Assess the potential role of novel strategies and technologies being evaluated as part of cancer immunotherapy biomarker development for predictive and other purposes, Implement best practices for cancer immunotherapy biomarker testing in community and academic settings based on the latest evidence and recommendations, Establish effective strategies for interdisciplinary collaboration among pathologists, oncologists, and other key professionals regarding biomarker testing and interpretation to guide decisions about the use of cancer immunotherapies and combinations in patients with cancer.

Go online to PeerView.com/FJP860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Cancer immunotherapies are demonstrating remarkable clinical activity in an increasing number of solid tumors and hematologic malignancies. Reliable biomarkers are needed to guide clinical decisions regarding treatment selection and identification of patients who are most likely to benefit. Testing for programmed death-ligand 1 (PD-L1) expression and the presence of DNA mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) should presently be routinely done in oncology and pathology practice in alignment with the latest recommendations and indications. Assessment of tumor mutational burden (TMB) is also showing great promise as a new and distinct predictor of benefit from cancer immunotherapies. Other novel biomarkers are undergoing investigations as well. How can pathologists ensure that immuno-oncology biomarker testing is carried out according to best practices, and collaborate with oncologists and other members of the cancer care team in interpreting the results to guide therapeutic decisions for patients with cancer? In this activity, based on a recent CME/MOC/CC-certified symposium held during the 2019 Annual Meeting of the United States and Canadian Academy of Pathology (USCAP) held in National Harbor, Maryland, a panel of experts discuss the latest clinical advances with cancer immunotherapies and the research underway to further refine biomarker testing and maximize the use of checkpoint inhibitors and combinations across a broad spectrum of malignancies. Upon completion of this activity, participants should be better able to: Characterize the efficacy/safety profiles and clinical roles of the current and emerging immunotherapies and combinations across the spectrum of solid and liquid cancers, Describe evidence supporting the use of PD-L1, MMR/MSI, TMB, and other promising biomarkers as predictors of benefit from cancer immunotherapies, Discuss practical aspects of immunotherapy biomarker testing and interpretation, including benefits/limitations of different testing methodologies, assays, cut-points, and other nuances, Assess the potential role of novel strategies and technologies being evaluated as part of cancer immunotherapy biomarker development for predictive and other purposes, Implement best practices for cancer immunotherapy biomarker testing in community and academic settings based on the latest evidence and recommendations, Establish effective strategies for interdisciplinary collaboration among pathologists, oncologists, and other key professionals regarding biomarker testing and interpretation to guide decisions about the use of cancer immunotherapies and combinations in patients with cancer.

These tests can evaluate your tumor for different biomarkers, including MSI-H or dMMR. Some biomarkers are used to help select patients that may benefit from certain treatments. Talk to your doctor to see if a laboratory test for the MSI-H or dMMR biomarker is right for you. A tissue sample (biopsy) of your tumor is taken, and your doctor orders the test.Your doctor typically gets the results in 10 to 14 days.You talk with your doctor to discuss treatment options based on your results.   

Neoadjuvant ipilimumab plus nivolumab veroorzaakt belangrijke pathologische responsen in 100% van de patiënten met een mismatch-repairdeficiënte colontumor en staat chirurgie niet in de weg. In deze podcast bespreekt drs. Myriam Chalabi (Antoni van Leeuwenhoek, Amsterdam) de opzet van de studie en de resultaten. Vervolgonderzoek naar neoadjuvante immunotherapie bij dMMR coloncarcinoom is nodig en heeft de potentie om de huidige standaard te wijzigen.

Neoadjuvant ipilimumab plus nivolumab veroorzaakt belangrijke pathologische responsen in 100% van de patiënten met een mismatch-repairdeficiënte colontumor en staat chirurgie niet in de weg. In deze podcast bespreekt drs. Myriam Chalabi (Antoni van Leeuwenhoek, Amsterdam) de opzet van de studie en de resultaten. Vervolgonderzoek naar neoadjuvante immunotherapie bij dMMR coloncarcinoom is nodig en heeft de potentie om de huidige standaard te wijzigen.

080 | Pursuing cures and advancing innovation   Welcome to another episode of Biotechnology Focus radio! I am your host – Michelle Currie – here to give you the rundown on what’s been happening on Canada’s biotech scene. It has been a busy last couple of weeks as the new genomics cloud platform was launched, a researcher from Roche Canada shares her input on future of innovation in cancer care, and the fight against cancer innovation trust invests almost half a mil in Ontario research technologies.   +++++  The world is opening up to the idea of genome sequencing. What was once a far-fetched idea is now beginning to materialize – and we are only at the tip of the iceberg. Information technology like Facebook, Google, Wikipedia and Uber are all prime examples of impactful software platforms that connect people with data that have set the stage for the next act.  When you look at where DNA sequencing began back in the 1970’s with the “Sanger sequencing method” as a process of determining the order of bases in the length of DNA, we’ve come a long way. But still, researchers are at the forefront of this revolution of gathering our personalized genetic information and using it to power the next generation of safer and more effective “precision” medicines.  This is where Marc Fiume and his team from DNAstack, a Toronto-based cloud genomics company, have their role to play. Started in 2014, the company began work with some exciting researchers from around Canada whose hot topics included autism and cancer research. But constantly they were told that the researchers just didn’t have enough samples to make sense of all the data they were collecting and that they really needed a platform that would connect them with other researchers globally who found themselves in the same position. Inspired by the concept of Facebook, they decided to build their own platform where genetic research could transpire among researchers worldwide.  He refers to the lack of data access as “potentially keeping life-saving information in a basement server room” and is one of his biggest frustrations when it comes to genomic research. Unveiling the sequence of a genome is challenging, time-consuming and expensive. Perhaps that is the reason why such a platform can no longer be just a notion, but become a mandatory tool so we can further our knowledge unified, instead of trying to connect the dots apart.  Genome sequencing is a lot like “decoding” of a foreign script or ciphering out a code of each individual’s personal genome. It is a long string of letters that forms a sort of molecular blueprint that is unique for each of us. These “strings” of letters are about six billion long, and currently, researchers are only grasping about a very small per cent of what those letters represent. This is why the need for sharing information should be a necessity.  In an attempt to break this societal self-inflicted mold, Marc worked with Dr. Stephen Scherer from The Centre of Applied Genomics on the “Personal Genome Project Canada” to facilitate the publication of health and genome records online for free. The intention being that whether you are sick or healthy, it is incredibly useful personally and for the research community to have your genome sequenced. Perhaps you have a predisposition to a potentially harmful genetic disease that you were not aware of before and could catch it before it starts, or if you are a carrier, or if you simply want to learn more about your ancestry. All of this is possible with genome sequencing. While some may not be ready to have theirs published online, it could still be made available to you in the privacy of your own home.  Marc and Ryan Cook, the other co-founder of DNAstack, have both tried to decrease the unease attached to publicly airing one’s genome sequence by publishing their own. “It’s about empowering and making key decisions about their healthcare in a way that’s not scary and also to break down barriers about data sharing,” comments Marc.  There are now 56 genome researchers that are bearing it all for the world to see, and encouragingly are following up on some of the data that they have found.  DNAstack recently launched their Canadian Genomics Cloud platform that is designed to better connect data, researchers and systems across the country to accelerate genomic discoveries and the implementation of precision medicine. It was invented by Canadian leaders with decades of experience in genomics, sequencing, cloud computing, software, security, and policy to democratize access to best-in-class infrastructure while respecting the unique national and provincial requirements for data privacy and security. Their aim is to service the needs of Canadian genome scientists from research institutions, clinical laboratories, pharmaceutical companies, hospitals, and industry.  The hope is to demonstrate that Canada now does have the capacity to do a precision medicine initiative at scale. Canada is really ready for this.” – says Marc.   +++++  For most of us, the start of a new year is a natural time to reflect on our progress as individuals. We take stock of the lives we’ve lived, the advances we’ve made, the impact we’ve had on those around us and the steps we need to take in the year ahead to achieve our goals.   For the Pharmaceutical and Biotechnology industry, the start of the new year is much the same. Standing at the doorstep of 2018, many of us who have spent our lives trying to advance healthcare around the globe believe that we are at a point in our careers, where science is progressing at a rapid rate.  In fact, some of us would venture that science is progressing at a rate that is outpacing our ability – as healthcare providers, as governments, as payers and as hospital institutions – to integrate these cutting-edge advances into clinical practice. While this reality poses significant challenges, it’s exciting to be on the threshold of so many unprecedented discoveries and novel treatment approaches for some of the world’s most devastating diseases.  The field of biotechnology is rich with discoveries that will have a dramatic impact on Canadians in 2018 and beyond. However, there are three key developments in the area of oncology in which we can expect to see some of the most transformative and immediate changes. These include:  the expanded role of diagnostics to optimize treatment choice;  the adoption of histology-agnostic treatment approaches; and  the next phase of true precision medicine     Expanded Role of Diagnostics  In recent years, the use of diagnostic tests within the Canadian cancer care setting has become an increasingly important practice, particularly for guiding treatment decisions and optimizing the patient’s chances for positive outcomes. In fact, it’s estimated that nearly 70 per cent of all treatment decisions today involve a pathology and/or laboratory investigation.  While the role of predictive biomarker testing has already been well established for some time in certain tumour types (such as HER2 in breast cancer or EGFR and ALK in lung cancer) we are witnessing the emergence of two trends that could further enhance patients’ care and their experience with our healthcare system. These include the ability to simultaneously look beyond a single biomarker through genomic profiling, and the viability of liquid/blood-based biomarker testing.  In 2018 we can expect to see a continued shift among healthcare providers to rely more on comprehensive genomic profiling to map each patient’s unique genomic profile to identify alterations across hundreds of genes known to be relevant in the development and progression of cancer. This broad approach optimizes the use of the available tumour tissue and provides physicians with the most comprehensive information to help guide their treatment selection. There is particular value in this approach for patients who have exhausted all standard treatment options or for those with rare forms of cancer with limited known effective treatment options.  Canadian institutions, like the British Columbia Cancer Agency, University Health Network in Toronto and The Jewish General Hospital in Montreal among many others, have already begun to demonstrate international leadership in this area with their in-house testing platforms and world-class genomic research programs.  We are also seeing the emergence of third-party molecular information providers, such as Foundation Medicine Inc., an organization that has partnered with Roche to offer genomic tests to provide physicians with information about a tumour’s unique genomic profile based on an interrogation of over 300 genes. These external services provide options for institutions that may not have the internal capabilities to offer such testing services and for patients who are looking for more comprehensive diagnostic information. All of these efforts are striving to rapidly expand treatment options by matching patients with approved targeted therapies, immunotherapies, and clinical trials based on their tumour’s molecular profile.  The second emerging trend in the space of predictive biomarkers is blood-based testing, which offers physicians a less-invasive testing mechanism for cases, in which there is insufficient tissue available for analysis. This may also prove to be a better option when a traditional tissue biopsy is not feasible due to tumour location, when a patient is in poor health, or when a physician and/or patient simply prefer a non-surgical option. In addition to supporting initial treatment choice, blood-based testing may also offer physicians the potential for continued monitoring in the future, resulting in earlier detection of disease progression and an assessment of resistance mutations to inform subsequent lines of therapy.     A Change in Mindset  Further to the evolution of diagnostic technologies, the increasing prevalence of targeted medicines is fundamentally challenging the way cancer research is conducted.  We are no longer seeing only large randomized Phase III studies measuring overall survival for drug development, but more novel trial designs, including basket and umbrella studies, as well as smaller Phase II designs to measure the safety and efficacy of a drug.  These new study approaches are aimed to accelerate scientific advancement and are addressing the challenges that exist when the prevalence of a particular molecular alteration is so limited that traditional trials seeking a large bolus of patients simply aren’t feasible.  In a basket trial, the impact of a single treatment across a spectrum of tumour types harbouring a particular alteration can be investigated. In contrast, umbrella trials inverse the approach, where multiple treatments are studied in patients with a common tumour type but who are stratified by molecular subtype.  Close to home, the Canadian Profiling and Targeted Agent Utilization (CAPTUR) trial sponsored by the Canadian Clinical Trials Group in partnership with several pharmaceutical companies and academic institutions across the country is a combined basket/umbrella study enrolling patients of all cancer types who are stratified into different arms of the study to receive treatments based on the genomic profile of their tumours.  Studies like CAPTUR will fundamentally shift how physicians view cancer, forcing them to look less at the type of cancer (e.g., breast, lung, colorectal) and focus on the molecular structure of the tumour.  This histology-agnostic approach is one that is also gaining traction with regulatory authorities around the globe. In fact, the U.S. Food and Drug Administration (FDA) recently approved a PD-1 inhibitor to treat patients with any cancer type, provided their tumours were unresectable or metastatic and classified as microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR).  This approval represented a significant departure from the traditional evidence requirements expected from a regulatory body and opens the door for further discussions and opportunities in other countries.  The final development, which seems like a natural extension of our evolving mindset around the use of diagnostics and targeted medicines in oncology is our view regarding how medicines can be engineered to offer truly individualized treatments to patients.  Though personalized medicines and immunotherapies are no longer considered ‘new’ in the rapidly evolving clinical landscape, the emergence of two types of truly bespoke cancer therapies marry these concepts to create what many consider a bold step in our quest to cure cancer.  Recently, two chimeric antigen receptor (CAR) T-cell therapies were approved in the United States, ushering in the next wave of personalized cancer care. These therapies involve the genetic engineering and reinfusion of a patient’s own T-cells to fight their unique cancers.  While approved in specific hematologic cancers today, researchers are also exploring these therapies in many solid tumours and the hope remains that they will offer a whole new way to think of treatment in cancer.  Still in its infancy, the second area of significant research is personalized cancer vaccines developed and manufactured for an individual patient based on the molecular profile of their tumours. Where off-the-shelf cancer vaccines have failed in the past, there is hope that these custom, uniquely tailored vaccines, in combination with checkpoint inhibitor therapies will succeed in transforming cancer care.  Close  In closing, while it’s easy to become discouraged by the often necessary hurdles required to integrate transformative products into current clinical practice, there has never been a more exciting time for those of who have built a career in the biotechnology industry; and there has never been a more exciting time for those of who have waited for a cure to cancer – a disease that has ravaged many of our families and has taken many of our friends and loved ones.  The reality is that science will continue to outpace clinical practice. But the promise of these discoveries can be realized if we – as stakeholders within the healthcare system – are willing and open-minded to collaborate on solutions, especially as we look at the impact personalized medicines can have in therapeutic areas beyond oncology, offering meaningful solutions to an infinitely greater number of patients, enabling them to live longer, healthier lives.  +++++  The fight against cancer innovation trust announces four new recipients of funding through its prospects oncology investment competition. Those recipients are Dalriada Therapeutics Inc., 16-Bit Inc., a cancer biomarker study at the Ontario Institute for Cancer Research (OICR), and a virus-based therapeutic under development at the Ottawa Hospital and the University of Ottawa.  FACIT’s investments are imperative in bridging the capital gap often experienced by early-stage Ontario companies, helping corporations establish jobs and build roots in the province. The wide-ranging scope of the innovations, which span therapeutics, machine learning and biomarker development, reflect the rich talent pool within the Ontario oncology research community.  Dalriada is a Canadian start-up founded with a mission to develop small molecule-based therapeutic technologies to battle diseases for which current treatment strategies are suboptimal or non-existent. With broad expertise in drug discovery, their efforts are currently centred on the preclinical development of a novel class (DT1) of small molecule inhibitors in cancers of the blood and brain as well as the development of a natural product for topical treatment of psoriasis and other inflammatory skin disorders.  16-Bit, a start-up founded by two medical doctors from the University of Toronto’s Diagnostic Radiology Program, is developing a machine learning algorithm to automate triaging of screening mammograms for breast cancer detection. Their focus is to utilize modern developments in machine intelligence to improve the accuracy, reliability, and speed of medical image interpretation while decreasing cost and barriers to healthcare.  Diagnostics Development Program at OICR leader Dr. John Bartlett has developed a diagnostic gene test to predict which breast cancer patients can benefit from anthracycline chemotherapy and which patients can avoid the associated toxicity because the drug may not be effective against their cancer.  The Ottawa Hospital and the University of Ottawa have developed a tumour-destroying virus based on the Vaccinia virus which adds a micro-RNA payload to enhance cell killing against pancreatic cancer. This targeted therapy is expected to be more precise and less toxic than conventional therapies for this difficult-to-treat tumour.  The Prospects Oncology Fund delivers on FACIT and OICR’s shared vision of advancing breakthrough innovations to the benefit of patients and Ontario’s knowledge economy.  Translating early-stage innovations and positioning them to raise additional funding supports Ontario’s competitive position as a destination for biotechnology.  Congratulations to all the strong applicants and in particular these outstanding awardees in their quest to make a difference for patients living with cancer.  +++++  Well, that wraps up another episode of Biotechnology Focus radio. I hope you enjoyed it. If you have a story idea or would like to be on the show, please email me at press@promotivemedia.ca. To see the articles in full check out the website biotechnologyfocus.ca and laboratoryfocus.ca so you don’t miss a beat! Have a momentous week. From my desk to yours – this is Michelle Currie.