Chapters Transcript Video Small Cell: Front Line ES-SCLC Uh, thank you, Doctor Burgay for inviting, uh, me. It's a, a great opportunity to be a part of, uh, Philly Lung. Hi everybody. I'm, uh, uh, uh, Valli Barkalov. Uh, I'm a junior attending at, uh, MD Anderson Cancer Center at Cooper, uh, and, uh, we'll have a pleasure to, uh, uh, talk about, uh, extensive stage small cell. I think uh if I were invited last year, for example, to make the same uh to discuss about the same topic, it probably will be just one slide and I was like, oh my God, 10 minutes, what I'm gonna talk about? uh uh but now I'm kind of worried about the time at the same time, so, um, so, uh, a little spoiler here what I will be talking about, uh, uh, you can see there's a carboplatin and toposide combination in the beginning. They had their sort of impact on the overall survival. You can look at the CaspianM P 33, uh, maybe transformative in small cell lung cancer, and then now I am 40, with some asterisks maybe next to it, and behind it it's a tarlatumab with the delta 303 coming up. So let's take a look and and those small planets there may be no treatment. So first we can talk about uh I think the trials that uh uh potentially transformed the small cell lung cancer, extensive stage. And demonstrated first improvement in overall survival by about 2, maybe 3 months. Uh, it's famous I Power 33 with it map maintenance and uh Drval map maintenance with the Caspian trial showed very similarly hazard ratios of 0.71, 0.73, 0.72. It was almost like a conspiracy theorist at this point, always the same hazard ratio in the first line, uh, extensive stage. Uh, so there are some other PD PD1 and PDL1 inhibitors, uh, approved outside of the US showing similar efficacy, uh, uh, uh, particularly in Asia, uh, with a similar hazard ratios, uh, um. This PD1 inhibitor serpulliab shows a little bit better overall survival, but there is some selection bias potentially that included patients with no brain metastasis. Surprisingly, pembrolizumab did not work in extensive stage small cell lung cancer. We know that TGS also did not show improvement in outcomes as well. So again, uh, we try to work on how can we predict outcomes and efficacy of immunotherapy, especially maintenance in patients with extensive stage small cell lung cancer. We now know based on the subgroup analysis of CASpian trials that PDL1 expression and tumor mutational burden does not provide any sort of clear predictive value in this case. There's very interesting work now is done in. This slide maybe will be a little bit better depicting this on transcriptomics trying to define new groups in small cell lung cancer, and then we now know more about this subtypes, small cancer, small cell lung cancer, subtype I, inflamed subtype respond very well to to immunotherapy maintenance. Unfortunately very A small percentage of Small cell lung cancers actually fall into this subtype. We learned some interesting results, maybe more idea generating at this point, the addition of a CTLA 4. It's a sort of invisible arm of Caspian trial where Durra was used in combination with the Tremi. There are some interesting signals in subgroup analysis showing that maybe additional CTLA 4 potentially beneficial. Um, and again, back to, uh, this point is, um, uh, let me see, I think later not working. Uh, so I think despite the fact that, uh, uh, subgroup I is only a small portion, uh, in a small cell lung cancer, I think the fact that subgroup A, uh, uh, this DLL3 expression, and you can see this on this table here. Uh, actually worked out pretty good for a small cell lung cancer, as we now know the TLL3, it's a very famous marker for small cell. So again, this is sort of established our timeline. Again, this is a standard of care for uh for almost a decade at this point. Uh, and, so again, my lecture probably done uh last year or maybe six months ago, but here you go in 2025, we have a couple new updates. Uh, uh, first line, uh, maintenance intensification. Uh, so this very interesting trial of IM Forte, when patients after completion of induction, uh, uh, uh, carboplatin and dopay and otezallizumab, uh, those patients who remain stable without evidence of progression. Uh, uh, was randomized into uh lubrinectidine and teallizumab, uh, maintenance versus Uh, uh, lizumab as a control arm, and then this trial showed a significant improvement in overall survival, and then I think it's a big breakthrough for small cell lung cancer. Whenever I, when I saw this trial, I first sort of thought this control arm underperformed. Uh, this is something is wrong here and again, uh, shortly I learned that uh uh uh survival was calculated from the time of randomization. Uh, not from the initiation of the systemic therapy. So additional 3 months, maybe 3.2 months should be added to 13.2 months and to 10.6 months here. Uh, so this is, uh, there are some debates. It is now FDA approved regimen as of October 2025, uh, and there are some question marks to questions to be reason. In this case, so first screening during this trial, uh, there were 660 patients sort of meet the criteria, were enrolled and started on the treatment. However, only 483 patients were randomized into the maintenance, so we lost about 2%, 27% of patients during this 1st 4 cycles. Um, I think we kind of touched on that point. Today that there are some patients that are being lost during the, for example, Pacific trial chemo rats, I think rate there was maybe 10, 12%, not 27, there's a quarter of the patients disappearing, and I think the question is this, are we selecting sort of patients who are more immunotherapy sensitive than subtype I maybe more falling into the maintenance group. So there is some selection bias possibly been introduced with this approach. I wonder if there was some further statistical analysis can be done if we randomly distribute the patients who fail, who were not included into maintenance phase and include them in additional analysis and see if results will be the same. So crossover was not allowed in the control arm. I was very surprised and I still scratched my head. I wonder if I were to be, to have a patient who was on a control arm and if the patient were to progress on Atizo, I wonder what would be my next option. Uh, I would really like to give lubinectidine, which was only FDA approved option in second line settings. I mean, uh, Topotecan has a nickname of Topoticent for a reason. Uh, uh, uh, and then, uh, I guess, uh, uh, we're introducing the new toxicities here, um, uh, early on. I, I think what I would like to know that whether lubinectidine, uh, uh, uh, is beneficial now or later. Should I introduce it early on, or should I introduce it a little bit later upon progression? But instead we kind of learned this trial was of lubinectadine now versus never, um, so I think it's a little bit, a couple, I, I, I found like I have too many questions about this trial, but still very intriguing. What is important is that we are still dealing with very aggressive disease and introduction of a more aggressive chemotherapy early on is very important. Uh, frequently patients with small cell upon progression, they become ineligible, uh, uh, for chemotherapy. So I think it's still a very good point here, very good idea to introduce lubinectidine early on despite this, uh, uh, limitations. And again, if we maybe add these limitations, maybe the impact of IM Forte kind of going a little bit smaller than it really is, if we had a fair comparison arm, but I think people will never know. So this is where we are right now. I let myself, uh, add the 3 more months there. I said, OK, we went from Caspian. I am 40 from 12 to 16 months now, uh, and let's see where we're heading. Uh, not to steal your thunder, Doctor, uh, you know, we will talk about second line options, uh, but the Tarlata ma Visadelphi, 303, uh, recently was, uh. Results were quite striking, just unbelievable results for small cell. It's phase 1 B trial. Yes, they included some patients, maybe about 20% of patients who were limited stage at the time of diagnosis, but still. What they did is that they used the maintenance thalatumab and PDL1 inhibitor and it was sort of free to use either Atizo or Dorba at that point. Uh, and then, uh, people are talking about this is my conversation with one of our colleagues. He said, What do you think about Delphi 303? I said, Oh my God, it's mind blowing. I can't sleep at night. Uh, uh, many lawyers 25 months. Uh, I so wanna give it before FDA approval. Uh, uh, so I don't know, it's a very intriguing trial, and, and we folks are talking about it. And again. 25.3 months of overall median overall survival again was after patients completed uh er it was after randomization. It's at the time from the beginning of the maintenance. So it's actually, again you're gonna add 3.2 months to 25.8 to 25.3 months uh and then it's it's still quite intriguing results. I think there are some um Concerns for toxicity as SRS, a little bit lower rates of SRS in in in in in the first line settings, um, but I think we will talk about it in more detail when we move to second line options. And what was always sort of a question mark to me why PFS is so small with terlaumab, why there is such a big gap between PFS and OS even in Delta 304, you know, teratumab studies. I just started digging around and in the protocol, it was allowed to treat patients with stelatima beyond progression as long as there is a clinical benefit. It's almost a quote unquote, and then you can see here red line, actually it's a progression of disease. And you see progression of disease, one of those lines clearly going down. So if patients having a progression, maybe oligo progression, they received the radiation and the teratumab was continued beyond progression. So one of the lines you can see goes up, progression and then goes down again. So it's something we have to learn if patients on terlatumab progresses. Maybe we should not. Uh, call it the, uh, call it the day sort of and stop tlaam up. Um, so that's where we are right now. I think, uh, first line, uh, uh, settings, we're heading, uh, uh, towards. Uh, uh, Beyond 2 years potentially, we're looking forward, of course this is very early data, phase 1B, as early as you can get, uh, uh, uh, but we're looking forward to phase 2 and phase 3 data, uh, upfront intensified maintenance with extensive stage small cell lung cancer. I think I'm gonna end the er remarks er er this lecture er with a, a story from my fellowship when I was learning about breast cancer. I was reading a book and says OK er. HER2 positive, um, very aggressive disease, more aggressive than triple negative, and I look at the outcomes and survival. I said, huh, it's interesting, but HER2 positive, they live longer. How does it work? Uh, so I go to my attendants, I keep asking, sorry, this is such a stupid question. What's going on here? I know HER2 positive, it's more aggressive. What they say, it's one of our leading books, and I said, but they live like significantly longer than triple negative. And my thing is something that I had no idea about, she said that yes, HER2 is indeed very aggressive, but after the introduction of HER2 therapies in 2002, this drug kind of changed almost a Biology and the trajectory of this disease. So I wonder if thlatumab DLL-3 is introducing sort of a HER2 effect to lung cancer. Maybe at some point we will be talking about and confusing our fellows like this in the future. Hopefully small cell will double the survival here. Thank you so much. Created by Related Presenters Veli Bakalov, MD Assistant Professor of Medicine, Cooper Medical School of Rowan University. Hematologist/Oncologist, Cooper University Health Care.
