Chapters Transcript Video Metastatic Disease: Front Line Studies Update And thank you so much, Hass. I'm, I'm Bla Homos, but thanks to Lubason. I'm, I'm known as the poop guy, um, uh, in, in Philadelphia, uh, probably forever. Um, it's a very, very cold room but very warm hearts. It's so nice to see so many old colleagues and friends, you know, here in Philadelphia and very specifically I have to say congratulations, you know, Has, you know, bringing this together, multiple institutions, the city of brotherly love, exac exac exactly, yeah, so an amazing job. Um, now I was given the, the, the, the task of talking about frontline studies updates and, um, you know, kind of, uh, a little bit of a boring topic I have to say, uh, uh, I was driving down, you know, yesterday. I missed all the trick or treating, so I decided that maybe we'll do some trick or treating, uh, you know, right here today, uh. So you know, you, you might not believe, but we actually be talking about Count Dracula, basics of, you know, Halloween decorations, some scary, scary stuff, had to pick the best treats. I'm sure Haas is very good at that, um, and what happens when you actually have too much candy, the worst, worst Halloween and some Philly trick or treaters at, at the very end. Um, I was, I was ashamed that I'm bringing 45 slides, but, uh, I saw that Corey brought 95. So I actually do not feel, and I don't, I don't feel that bad, but let's let's get going. So I'm actually from Eastern Europe. My wife is actually from Transylvania, from, from, from Count Dracula's county, and that's Count Dracula's castle, the Bran Castle. Now I live, you know, with somebody from, from Transylvania, so imagine my my day to day life, um. Um, so, you know, frontline studies, uh, you know, just, just today it popped up that I think it was exactly 20 years ago, uh, that Doctor Allison made the original, uh, discovery leading to two Nobel Prizes, but also just a complete transformation for our field between him and Professor Hanzhou, two very well deserved Nobel Prizes, discovering the two key checkpoints that are. Now, uh, so many effective treatment strategies for us and just, just diving in, of course, chenote 24, truly a milestone trial comparing for biomarker positive TPS score high positive patients, single agent immunotherapy fairly well tolerated versus our best chemotherapy, and it's not just that the study was very positive but transformational. I think it's just one of those pivotal trials of medical oncology. It transformed our mindset about how to take care of patients with metastatic lung cancer, uh, that we, we can have loftier goals, you know, some of these patients, we can not just enjoy seeing a remission, you know, going into remission, but those remissions last, last for a long time, and then in fact, it seems like maybe some of those patients are actually getting cured. That is what's quickly followed by keynote 42 now looking at. The larger patient population, 1% plus positive study as well, but setting some boundaries that the biomarker is really important. As soon as we go out of the 50 50% plus boundary, suddenly immunotherapy is OK. It's, it's, it's not great, um. Of course it's nice to see consistency and then there's multiple trials with other single agent checkpoint inhibitors achieving the same, but we needed to do better for patients outside of the TPS score high positive range. But for those patients, now we have 5+ years of, you know, survival, and what we see is not just that 30% of the patients are allowed. And well, but many of them are alive and well, off of therapy now for 34 years. Actually, I've I've had patients in clinic, now 5 years out of any treatment for metastatic lung cancer, do we stop doing CAT scans on them? It's like, I don't I don't, I don't know what to do at this point, um, but it's a great visit with them every single time, that's for sure. So expanding horizons, you know, we didn't really realize, but it turned out that combining chemotherapy and immunotherapy is now counter counterintuitive but synergistic, and of course Cory Langer, you know, some of those early studies ultimately culminating in keynote 189 and 407, the two trials that are established now the most typical standard of care. For many of our patients with metastatic lung cancer, non-squamous squamous cell lung cancer alike, again significant benefits over chemotherapy alone, and for some patients, long term benefits. Now again, 5 years plus, we can see maybe not 30% as for TPS score high positive, but 20% of the patients are alive and well at 5 years, doubling the number of patients who can survive. Uh, you know, without progression of their lung cancer. Same thing for squamous cell lung cancer trial that I was very lucky to be a part of at the time. And here the same thing, 5 year outcomes now prove those long term benefits. The benefits are more enriched, of course, as you go into the higher TPS score range, somewhat questionable for patients with TPS score less than 1%. And here I have to say I was very lucky, you know, to have, you know, Haa's leadership on this paper pooling, you know, patients from, from keynote 21, 189, and 407 and actually highlighting that there's a benefit, although definitely more modest than patients with, um, higher TPS scores. Now this is, you know, uh, uh, Haas's favorite study, a medical oncologist's least favorite study, checkmate 227, because it's been debated so much. But at the same time, a study comparing Nvo EP versus double chemotherapy with a third arm that that we'll not talk about too much today actually reached both of its primary endpoint, both in terms of PFS prolongation for TMB selective patients and OS prolongation for PD. One selected patients. It's a positive trial, is it more positive than chemo IO alone for certain patients remains a question to be asked. But again, we can see the 5 year plus updates now and very nice to see that especially for the TPS score low patients, you know, we're reaching again close to 20% of the patients are alive and well at 5 years, and maybe that's the pool of patients where the combination immunotherapy provides some additional evidence. And this is really hot off the press. I, I realized that Haas just published a paper this week. Uh, this is now the 6 year update on Checkmate 227. And you know, if you look at that blue wave in the middle of the survival curve, those are the patients who are alive and well without significant adverse events, and you can see that on the naval EP arm, that's a beautiful, you know, large wave as opposed to just a trickle in patients, uh, having received chemotherapy. Now, you know, we, we can look at the doublet chemo double IO studies, and that's, you know, like the Halloween, maybe just a little too much decoration dependent on, uh, you know, who, who you ask. Um, this is a kitchen 6 check midnight in LA, 2 rounds of chemotherapy, combination IO alongside positive trial versus chemotherapy alone, but is it more impressive than some of the chemo IO studies? A Little bit, little bit hard to say. And the other one is Poseidon, now looking at the AstraZeneca quadruple. Again, positive, no questions asked, but is it, is it better than, you know, what we can achieve the QUI alone, you know, something that we still do not know up until today. It's always nice to follow NCCN guidelines, but if you look at the guidelines for IOUs, I mean, this is exactly like the New Jersey Turnpike, just congested, just congested, and there's no, no real way to, uh, you know, go, go fast here, um, and I can, I, I can attest, you know, from last night, um. So how to pick the right treat for each and every patient, you know, what is, what is the right choice. But the ESCO guidelines, which I'm lucky to be part of, is a little bit maybe more clear as to where's the strong evidence and where's the evidence that's a little bit weaker, and TPS score high positive, single agent IO is the strongest evidence, chemo IO for 1 to 49, and you can just see that in reality the evidence is weak for everything for TPS score 0, and that's just the reality that we'll need to do better for that patient population. Now IU versus chemo IU for TPS score high positive, but we've learned from the FDA actually that age makes a difference. You know, the older you are, maybe chemo IU is the less likely to be beneficial, and never smoker status really stands out from every single trial. If you're never, if you're a never smoker patient, please do not give them immunotherapy alone. That will not be the right strategy. So we learned two little, you know, tricks, tricks, uh, as to how to help our patients just from the FDA. Of course we learn more actually again from Habsburg guy right here from the Insigna study, which completed accrual and we look forward to seeing the results and hopefully the ECAG I can group with the AIE study will actually achieve something on elderly patients as well. You're holding your head. I'm not sure what that means, Haas. Um, so going on CTL4, well, we don't know if it adds value, but we do know that it, it has toxicity, no question, and I was lucky enough to work with the Merck team looking at the match adjusted indirect comparison, looking at pool data, you know, from checkmate versus chemo trials. You can see the gray curves, they completely overlap. Those are the control arms. The two trials showing that we had consistency in terms of matching the patient population well enough, and no combination immunotherapy did not add value for TPS score positive patients. And we've learned that now from keynote 598 from a large randomized trial and from Japan, the study actually had to be stopped due to excessive toxicity, uh, you know, with CTLA4 inhibition. Do we have biomarkers to guide choices beyond PDR1? There's a long list, of course, that we can think about, but PDR1 remains the most validated biomarker, and the higher we go with TPS1, the more confidence we can have in the in in in the results. More than 90%, you can see the response rate is up to like 80%. Um, so again, you know, within the 50% plus range, there's more, more, more room for nuancing for the clinician. Some scary, scary stuff, you know, for Halloween night, and that's STK 11 coupons marker 4 for you right there. When we see them in the molecular reports, we know these are patients with very aggressive disease, you know, very concerning in terms of overall prognosis, and this this story is emerging. Are we able to deal with these bad guys? Well, this is where the Poseidon trial highlighted that maybe, just maybe, that's where the combination, the added. CTLEF4 has value. This now needs to be borne out. The Triton study is completing accrual, but it's too small of a study to really be able to settle this question, to be honest. Very important to know what does not work, and immunotherapy does not work for EGFR mutated patients. We know that now from two randomized studies, keynote 17789 and checkmate, I forget the number, maybe 522. And I just, I just made that. Um, so very important to know, and, and this is again just the clinician now has, has, has, has some art in terms of your, your, your, your practice. You can look at tumor related factors, patient related factors to decide, do we go from anti-PDF1 monotherapy all the way to doublet chemotherapy to see CTL for PDI1 that that's maybe just for the TPS score zeros, maybe for the STK-11 ones today. Adverse events, what happens when you have just too much candy. You know, a lot of immune adverse events, maybe you can be split in two. you know, we heard from Doctor Edelman as to what can happen on immunotherapy. A lot of toxicities, but we're learning more and more about, you know, both the, both the time frame as well as how to manage them. But there's a lot of unique patient populations, patients with baseline comorbid autoimmune illness, organ transplants, etc. We need friends. We need friends, not just amongst oncologists, but in other specialists. As well, to be able to deal with the large array of immune adverse events that our patients can experience. Now how long to continue immunotherapy remain remains an unanswered question, but actually Lova's Sun and Sharo Agarwal provided the nicest piece of data here to say that maybe 2 years is actually sufficient. There didn't seem to be a benefit of continued immunotherapy beyond. Can we do less than 2 years? Well, hopefully the EcoGne group will be able to run a trial to address it. We're struggling with the right design. A lot of emerging biomarkers, you know, interesting aspects in proteomics, CTDNA dynamics. So a lot of elements, you know, here to see, but nothing, nothing fully validated yet. And of course what's next, you know, digits, but it doesn't look like we're entering the digital age yet, uh, you know, based on a lot, a lot of negative studies, LG 3 still has some legs, and of course there's a lot of interest in terms of KRAS trope 2, agents that are moving into the front line. The die specifics, I would imab, you know, a lot of hope now with this, you know, cooperative interaction between the VF PD1 access and a lot of positive trials as to PFS. But what we, what we have not seen is an US benefit and in fact at the Worldlo meeting, a PO of 0.06, that's, that's what it will cost some $26 billion I think on that day or something of that nature, the scariest Halloween, uh, you know, for, for, for the researcher. So lastly, lastly, our Philly trick or treaters. I have to say that 90% of my slides were Philly oncologists, you know, Lova, you know, Haas, you know, uh, uh, Corey, etc. You guys, you guys are pretty good at, uh, at providing treats to, uh, the larger oncology field, and, and these are our Philly trick or treaters, uh, uh, right here, and I have to say that, you know, Marty Haas and Charlie look pretty happy trick or treating, but Corey, I think Corey. Corey would just rather just write a poem, right. It's just a waste of time. So a bunch of key takeaways. Single agent I excellent choice for patients with TPS score high 50% plus. Chemo is the most widely used regimen. Otherwise, CTRA for maybe, maybe for some patients, but a lot more to learn. But what we learned is the huge impact of immunotherapy now, and this is a beautiful example from the French experience. Decade by decade, tiny bits. Benefit, but suddenly in the last 10 years, that's going from the blue to the red line, huge advances with the introduction of targeted immunotherapies, and on the right hand side you can see, you know, those two specific areas highlighted, and we put trucks into the survival curves, but for today, you know, you get, you get, you get a large, large pumpkin, uh, to show that the er the curves separate and they're not banana shaped. They're not, so Corey, don't worry. Uh, so with that, happy Halloween and again just such a pleasure to be here. Created by Related Presenters Balazs Halmos, MD, MS Professor, Department of Oncology (Medical Oncology). Associate Director, Clinical Science, Montefiore Einstein Comprehensive Cancer Center
