We have our keynote speaker for the afternoon session, Doctor Anne Chang, Associate Professor, Division of Thoracic Medical Oncology at Yale University School of Medicine, and Associate Cancer Center Director for Clinical Initiatives at the Yale Cancer Center. Dr Chang and I have known each other for a very long time to our collaboration um uh through the insignia study, the E cox swag uh phase three study that has now completed a crew and we're waiting for the results. And also because of my involvement with lung map which is ran through the swag. And I've always been appreciative of uh Ann's uh leadership and uh help in managing different uh issues that come up as part of a huge national uh lung cancer program. So we're happy to have her here. She's going to talk to us about immunotherapy and extensive stage small cell first line data. And an uh is one of the uh uh top experts uh with a lot of expertise in small cell and some innovations in this area. And I'm hoping that we can talk about it. Doctor Chang, please. Thanks so much for having me. Um talk about my favorite subject. Uh immunotherapy and extensive stage small cell. And I'm gonna go w work walk you through the first line data. Here are my disclosures. Um So we are gonna talk about the era of immunotherapy. I'm gonna talk about the positive phase three trial um results in this space and then um spend a little bit of time talking about how we can improve long term outcomes um by understanding more about small cell biology and heterogeneity. And I will talk about a new approach with the biomarker directed trial. So we're in the current era of immunotherapy. It started in 2018, really with the um approval of, of uh both a tizo and DVA in combination with chemo and I'm gonna talk about those trials. Uh And you'll hear later about Adriatic which is using immunotherapy in the limited stage setting. Um And since I'm a clinician, I always like to start with my patient case. Um This is my patient, uh 65 year old African American woman smoker. And she presented in COVID time with weight loss over several months, worsening, shortness of breath and exertion and abdominal discomfort. Um She had shoddy lymph nodes in her neck, in the axillary region. Uh And there you can see her pet scan shows a very hyper metabolic right, lower lobe mass and a satellite nodule. Um she had bulky adenopathy and her brain MRI was negative which was good. The biopsy showed small cell. Uh it was synapsis and positive. And she had a very high uh highly mi mitotic um reactive uh tumor with A K I 67 of 90%. So, how would you treat this patient? Uh What regimen would you use? Carbo, carbo to azo carbo erva, cysto toe erva. Um And actually the answer is that all of these are correct and they are all in the NCCN guidelines. Um, sometimes as you know, these patients are very sick and they'll present in the hospital with symptomatic um shortness of breath and sometimes you've got to get them going. And right now we usually uh use chemotherapy and we have not at least at Yale figured out how to get the um a tizo endura in house. Um but these all are options and so we'll go into the power 133. Um That was the first regimen to be approved by the FDA. Um And it utilized a tizo plus the platinum doublet followed by a tizo maintenance uh versus placebo. And this was for naive um uh patients who had not gotten any treatment, uh extensive stage PS zero or one, they had, they could have brain meds, but only if they had been treated and were asymptomatic. Uh and then the um primary end points, OS and PFS. So, here are the results of that trial which led to FDA approval, the median overall survival uh 12.3 months versus 10.3 months and a nice separation, the curve hazard ratio 0.76. Um And that led to approval. Um That's funny. So it doesn't change on my screen. All right, I'll just have to look at the, the bigger screen. All right. So, um so my patient got that exact regimen for cycles and did very well. Um had a bit of a rash, it was controlled with steroid cream and at the time of this picture was on cycle nine of maintenance, a tizo. So how long do you continue maintenance therapy in the trial? It was until a progression or loss of clinical benefit. Um And with that, of course, depends on the tolerability of the regimen. And so this is the safety uh adverse events uh of the of the trial, which was really pretty comparable between arms and pretty well tolerated. The maintenance of tizo treatment duration was 4.5 months and the total dose about seven doses. My patient actually went on to get 43 cycles of a tizo and then stopped it about a year ago because of COVID um and has been free of disease. So she really is an exceptional responder. And I think we're trying to understand if you know, some of those patients, let me know because we're really trying to understand why they do so well. Um In the Power 133 trial, those patients rolled over to an extension study. It was a very few, number 18 but the results of that did show five year overall survival of 12%. So some of these patients can get out to five years. Obviously, we'd like to be able to extend that benefit to more of the patients. Um So we'll talk about that later. So here's another patient of mine 67 and I won't go through the details but presented almost exact same symptoms and picture. The difference is that he had brain Mets and you can see them here. Um And so what is the next step in treatment for this gentleman? Um These are the NCCN guidelines and I always like to bring this up if they're asymptomatic chemo works really well. So we can get going on the chemo. Um And some of these patients actually have resolution of their disease. You don't even have anything to radiate. Uh And but however, if they are symptomatic, um we would recommend that we would recommend treating with brain RT um before the systemic therapy. Ok. So the Caspian trial was very similar to power 133. Um but it did allow patients who had asymptomatic brain mats. And I think that is important because we have a lot of those patients who present, these patients were um uh randomized between three arms DVA plus EP, followed by DVA maintenance, DVA Trey plus EP, followed by DVA maintenance and then EP uh the control arm and in the control arm, they could have had chemo up until uh they could have had up to six cycles. The, the DVA Trey arm was not um positive. And so I'm not gonna talk about that. The results of the DVA Ep arm um are shown in the next slide, the overall survival and this is the three year update, the median overall survival almost identical to the previous trial for 12.9 months versus 10.5 and hazard ratio of 0.71. And I, I do show this to my patients sometimes because I think it's important for them to know that again, not for everybody. But there are, there is the, the hope of potentially doing really well. And with the addition of DVA, you can see a tripling of that three year overall survival from 6 to 18%. Again, we've got to be able to extend that benefit to other patients. Um This is the Astrom uh uh 0 to 5 trial and this was done in China. Uh It was a first line Cerulli. A, this is an anti PD one, the other ones were anti PDL one versus placebo in addition to combination chemotherapy. Uh And you can see that on the right side, the OS was uh quite good. The median overall survival was 15 months versus 10.9 months uh for the uh placebo arm uh a hazard ratio of 0.63. So looking pretty good. Um Why is the overall survival better maybe the population that was definitely in China or in Asia. Sorry. And, and there were a higher number of never smokers in that trial. So, um they are now um uh extending the trial and adding non Asian populations. Um This is Capstone one also done in China and this was uh another anti PDL one antibody. Um again showing a benefit of uh the meeting overall survival of 15 months compared to the placebo in combination with chemo. Um And then this trial, I would like to mention this is the er 701 trial again done in Asia. And this, it utilized an anti PDL one antibody in combination with an antiangiogenic TK I, that's in Latin um which hits VEG EPDGFFFGR and uh and chemotherapy and this showed a median overall survival of 19 months. So really good. So maybe there's an additional benefit. Um This was compared to at that time in China. The benefit, I mean, the, the standard of care was either chemo alone or chemo plus. Um and Latin. So this does not tell us whether it's better than our current uh front line doub uh triplet of, of carbo etop or platinum oppe plus uh immunotherapy. But I think it's, it's, it's uh provocative. OK. So all are correct in the future. We talked, maybe we will have an anti PD one antibody combination. Um Maybe we can uh add agents including antiangiogenic uh agents or by specifics and there, there are trials now ongoing with that. And um and the antibody drug conjugates look like a really effective way of providing chemo for small cell, not necessarily for non small cell, but at least for a small cell. And perhaps we can, we can uh add or replace some of those uh traditional chemo uh that we've used in the front line. OK. So how do we uh what are some approaches to improve the long term outcomes and extend that benefit to more patients? Uh Add more agents? I talked a little bit about that. I think we have to start to look at what we can learn from the lab and uh from the bench uh in terms of the heterogeneity of small cell and determinants of response and resistance and perhaps then leverage that knowledge to add targeted agents either up front or in the maintenance setting and um continue to improve our support of patients as they go through their journey. Um OK. So this is uh a slide from Carl Gay and, and Lauren Byers at MD Anderson and they took a retrospect, retrospective analysis of power 133. And they said, OK, let's let's look at the transcriptome profile of these patients and uh cluster them. And what they found is that there are four subtypes and they're characterized by uh for the most part for the up regulation of transcriptional a activators. So, subtype A has um high expression of A SCL one transcriptional activator, uh subtype N uh lots of expression of neuro D one. Those are the two neuroendocrine subtypes. And then there's a subtype P that has upregulation of pou two F three. And then another category which they term subtype I for inflammatory. They did not have upregulation of those other three, but they did have up regulation of checkpoints um as well as other immune um factors such as interferon gamma and sting. And what they found is looking at the results of the Ower 133 that subtype I actually enjoyed the best benefit with immediate overall survival of 18 months uh in the arm that received immunotherapy and that benefit went away uh in the placebo arm. So some of the this is really exciting because it indicates that there is a way to mark or a biomarker for these patients who can really benefit from immunotherapy. And so of course, the next question is, is there some sort of marker that can show us uh benefit in the other subtypes where we can leverage um therapeutic agents there? And, and this is again a slide from Carl Gay. Um And for, and if you look in the middle, for the neuro endocrine subtypes, there are preclinical models that show that you, they are very sensitive to par inhibition if they are slain 11 positive. Um And in slain 11 negative models, the loss of a tr is a synthetic lethal and then finally, on the left side, there's um preclinical small t small cell subtype P models are very sensitive to inhibitors independent of the Schlaf 11 status. So, and then if you look at the eye subtype, um you have high expression of NK cells and in particular HLAE um that NKG two A ligand is very high, highly expressed in, in, in the subtype I. So putting this all together. Um I'm really excited to say that this trial swag uh 24 09, the prism trial will be activated in early 2025. And this is going to be a really breakthrough trial. I think for the field, we're gonna have about 900 patients and get their tissue during their induction phase. So when they're, you know, getting their chemotherapy, uh we'll look at their tissue and then look at what type subtype they have and what their slain 11 status is. And based on that, um they'll be randomized in the, in, in the maintenance setting to either um IO alone or IO plus that targeted agent. And for the neuroendocrine subtypes that are slain 11 positive or the P subtype, that'll be a part inhibitor for the neuroendocrine subtypes that are slain 11 negative. It'll be an A TR inhibitor. And for subtype I, we're gonna activate those NK cells uh plus IO plus versus IO alone. So this is a super exciting trial and we hope that you guys will open it I actually talked to doctor decide and that will be the plan. Um, but I think regardless of the results of that, of the agents, we're gonna learn so much just by having that tissue uh for these patients. Ok. Finally, um I'll just say this is a, an article that my, my fellow did with me for the Asco education book. And we actually, besides just doing updates on small cell talk to several patients and ask them what they would have liked. Their conversa what, what information they would have needed or what they would like to say to doctors and, and health care provide writers. And they said, basically, please talk to us about our prognosis and our expectations. We're so scared to do that because we don't wanna tell people that they're gonna do poorly or we don't wanna tell them that they're gonna do well in case they do poorly and vice versa. But they just said, please talk to us. It's, it's really gonna help alleviate our anxiety and it's gonna help us go through this. Um So the key takeaways here, immunotherapy is here to stay for extensive stage, small salon cancer, stay tuned for front line combinations with additional agents. Um Understanding biology is gonna lead to more effective and targeted treatments. And I have a picture of all those cookies because it's not just black and white, it's not just limited stage versus extensive stage. We have a lot of different subtypes that we should try to understand and then leverage that understanding to target um and part of that will be through getting biopsies uh and, and changing our clinical trials to fit the patients. So for example, the, the swag trial that I talked about patients can have their 1st 1st cycle of chemo uh off trial. And then, and then come in with, with um the chemo IO um consider um the S 24 09 for your portfolio and then always talk to your patients about their expectations and their prognosis. Um And that should be an ongoing conversation. Thank you.
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