Chapters Transcript Video Small Cell: Second Line ES-SCLC Um, so these are my disclosures. So I'm going to talk about second line small cell lung cancer option. I think I am highly privileged to present this. Um, if there's anything that should come from lung cancer, probably on Times Magazine at the end of the year, it's probably going to be one. Slide from here, I think there. um, I'm sure all of you in the room are aware. So, you know, relapse in small cell lung cancer is inevitable, as we know from the experimental arms and the control arms of extensive state lung cancer studies, uh, which is IM P 133 here, and then. The more recent, the Adriatic trial with even with limited small cell lung cancer that, you know, at, at 2 years or at 1 year, almost more than 50% of patients and in extensive stage, more than 80% of patients eventually relapse. Um, there has been limited progress for relapsed small. Lung cancer, and I'm sure, uh, Dr. Rakdashel and Marty Edelman and, and, uh, Dr. Langer probably know this better, that, you know, there was no big development in the, in, in the progress in extensive stage small cell lung cancer, especially in second line. Um, really, from 1996 when topotecan was approved, probably the only drug approved, topotecan, I guess we can say because of toxicities, uh, and then we had a couple of accelerated approvals in second line in immunotherapy that got backtracked because of lack of data. And then lrbinectadine still has an accelerated approval in second line, which now, you know, has, has a more stronger approval in first line, uh, until 2024 when we have the, the star kid on the block, which is Starlatumab. Uh, so this was based on the, the, the initial study, uh, the initial accelerated approval is based on thallaumab Delphi 301, which essentially was a dose optimization study. They were trying to look at whether 10 mg of thallatumab or, or 100 mg of thyatumab, which of, which of the one is, is a better drug in terms of side effects, toxicity, but also overall response and, and efficacy. So how the drug is usually given, um, and, and this is in general for most of the bi-specific T cell engagers, is that it's given in a step-up dosing fashion. To, to sort of reduce the, the incidence or, or monitor patients better for the cytokine release syndromes and, and some of the neurotoxicities that can happen in the early phases. So, um, it's given 1 mg IV dose on day one, and then 10 mg IV dose, a step-up dose on day 8, followed by 10 mg of IV dosing that's given on, on every 2 weeks. And then in the 100 mg, there was a little bit higher step up there. Um, so what was found in the study that, uh, essentially the efficacy or the overall response rates were largely similar for 10 mg and 100 mg, uh, but we do see that, you know, there were more toxicities with 100 mg, so 10 mg was thought as, as an optimal dose to move forward for phase three studies. Uh, we also learned about, um, um, by specific T cell engagers and toxicities. We knew this from the, from the world of leukemias, but these were first generational bites. These are probably what I would call a second generational bites, which, you know, don't need continuous infusions. They're albumin coated, so they can be given every 2. Two weeks, but we learned that, you know, the CRS, uh, which are the, the, the sort of the, the big problem child for, for Tarlata Maben and, and some of the upcoming bites, they do happen, but they do happen in the 1st 2 or maybe 3 cycles, and majority of them are grade 1 and grade 2. Uh, that is still a problem. Grade 2, CRS means that somebody needs to go on an oxygen, uh, either on an oxygen or needs, uh, either fluids and, and probably needs more monitoring. And these are in order of about 20, 25%. Uh, grade 3 toxicities are rare. The use of docillizumab is rare, at least reported in the study, but in a clinical practice, I think we are seeing more and more patients that, that probably need this support at least upfront. Um, uh, and so based on this, the, the FDA mandated that, you know, we, we, we need to observe these patients at least for the 1st 2 doses, for the 1st 24 hours. There was no clear guidance as to where you want to observe them. The term they used is appropriate healthcare setting, and what does that mean in this country, you know, nobody knows really. Uh, but then they also need to have a caregiver for, for 48 to 72 hours. So there are these two key determinant factors that, uh, you know, really came out of how the study was done and naturally, you know, the study had to be done the way it had to be done. Um So, yeah, so, essentially, you know, tatumab got accelerated approval. Um, and what I'm gonna talk about mainly is, is the, is the, is the study that, you know, led to a more firm approval and, and, and firm place in its second line setting, which is the Delph 5304 study, which was presented. Uh, in ASCO this year. So this took patients with, um, second line, um, extensive stage small cell lung cancer who had received at least one platinum-based therapy with or without uh NTPDL1 inhibitors. Um, really good ECOG asymptomatic treated or untreated brain mets, uh, is treated but uh asymptomatic and untreated but asymptomatic were allowed, uh, and patients were randomized. Uh one is 21 totalatta about to standard of care chemotherapy. Uh, physician's choice, but most patients received actually topotecan. This was a global study, um, and that some patients received labinectadine and amirobicin. Um, really, the, the, the arms were predominantly balanced between the, the experimental group and the, and the standard of care group. Uh, and really, this is the slide. So, it's definitely, you know, survival benefit of about 4.5 months and hazard ratio of, of 0.6, a 40% benefit. And really, the cows separate early and, and remain sort of almost remain separated at 6 months and, and 12 months mark. So really, uh, really, uh, decreasing the chance of, or increasing the chance of survival for these patients on tatumab. Uh, the survival benefit was seen across different cohorts. So regardless of the patients that were platinum or, or chemotherapy or chemo immunotherapy, free interval being more than 90 days or less than 90 days, which we traditionally call them as, as platinum refractory patients, uh, or platinum resistance patients, we saw some benefit in, in those patients. Also, um, there was benefit seen in patients with liver metastasis. Without liver metastasis, although the data, you know, you can see is a little bit questionable there. Um, uh, this is the data on the PFS. Again, you know, I think OS OS was important, but we can also see that, uh, patients with, um, datumab, uh, had less, uh, less risk of having any progression, uh, on the therapy. Um, the other thing we saw was that, um, you know, thalatumab was associated with more frequent and more durable responses. So we saw with the, with the, with the phase one study that, you know, essentially you get a very quick response with thalatumab. Now this is a little bit different to what we see for immune checkpoint inhibitors, where we see that actually there is some time, there's some time. lag to response, but with bites, we are seeing that the response rates are usually very quick. And when the response happens, the response, uh, seem to stay durable, at least for, for many, many patients. So we get to know upfront within the first month, usually, whether somebody is going to be living on tlatumab for a long period of time. Um, tatumab does have CNS activity. Uh, so there's some small data coming from different groups, also from Delphi, uh, Delphi Group, but also independently from MD Anderson that it does have. Uh, secondary intracranial activity, so it can shrink tumors that are visible, not radiated. However, I would, I would warn caution because in my personal experience and also some of the data that has been published more recently, uh, we have seen that there is maybe some association between high degree of neurotoxicity. It's been labeled as ICAS, but it's probably something what we call as tumor associated inflammation. That may happen with untreated brain mets. Uh, and, and I've always had this discussion, I think, with a couple of patients with Doctor Weiss that, you know, I might want to get them radiated if we can get them before I start tarlatumab, because I've really seen some toxicities. Again, this could be anecdotal, but I've seen that some of other investigators also mentioned this, and that now there's some early data to support this. Uh, tarlatumab definitely improves symptoms, you know, it, it causes a rapid regression of, of tumors and, and, and essentially leads to improvement in symptoms for these patients, usually dyspnea, cough, chest pain. Um, uh, there's more updated data again from the, from the more, um, uh, randomized, the, the bigger randomized study about the incidence and severity of tatumab. So as expected, CRS is usually seen in the first few cycles. It's usually grade 1 or grade 2. I think the real world evidence, we're probably seeing more grade 2 side effects, uh, and, and that is important. But there is, there are also some cumulative toxicities, uh, although not as common as chemotherapy. But we do see leukopenia with, with datumab for, for really not, not specific, uh, good reasons. But we, we, we tend to give Neulasta. They seem to work in these patients, and so we, we keep them going with this drug. The other big side effect is taste. Loss of taste is a big, big problem with daratumab, um, but I always tell my patients that, you know, this is a good side effect to have other than, you know, having progressive disease and, and, and living, uh, you know, living shorter. So, um, So this is again, you know, about the incidents of ICANNS and dyscusia. Um, and it's not just Tarlataabs. So now, you know, based on the success of Tarlata maps, there have been other, um, numerous DLL 3 T cell engagers that have sort of started coming with some new data, which I'm not going to discuss right now for the lack of time. But there are many new models of DLL-3 T cell engagers that have, that have come and, and are showing some really good response in various other high grade neuroendocrine carcinomas, you know, either extrapulmonary or pulmonary, and so forth. So, you know, one big challenge that we identified initially. When alaumab had an accelerated approval was, you know, the, the need for caregiver, the need for monitoring, um, and, and how are we going to manage these patients in medical oncology setups that are not used to these drugs. Our hematologists have been used to these drugs. So, um, we, we reached out for some help and, you know, thanks to Ride Heart Breathe Easy, we have a, we have a funding mechanism to, to achieve 222 objectives. The first objective is we want to learn a little bit more about mechanisms of resistance. So we know that they have about. 40 to 50% ORRs, uh, which is, uh but then patients do eventually progress after a year, a couple of years, which means there's some secondary mechanism of resistance that happens. But there are about 50%, 60% patients that do not respond to tarlatumab and are, are probably have primary resistance, and it would be nice to know what's going on with them. So we have some biospecimen collection study that's going on. If you have any patients with small cell and would like to refer, then we, we, we, we would start enrolling probably next month or so. Uh, and then the other big is the barrier, the, the socioeconomic barriers that we have to face when, when we have to give Tarlatamab. I, I work at two different sites, you know, the Cotman Avenue Campus and the Temple University Hospital, very different population. Uh, but then the, the, there are logistical challenges of delivering tarlaumab. I would like to say that we now have capabilities at both these places to give tarlatumab. Uh, but then we are, we are trying to support our patients by providing them hotel stays, especially if they come from far off. We, we have also come up with these novel ideas of giving them monitoring kits as long as they have a caregiver. The caregiver problem is something that I have not solved. So if you have ideas regarding that, come to me and we can, we can tackle that together. Um, so the other drugs is, uh, uh, again, ADCs in small cell lung cancer. There's some really exciting data about, uh, antibody drug conjugates, especially targeting a protein known as B7H3. Uh, and then there is this other target antigen, which is 6. The, the beauty about small cell is that it, it comes from a really rare cell, uh, which is a pulmonary neuroendocrine cell. So a lot of the antigens that are expressed on the cells are not expressed, uh, in, in, in, in other normal tissues. And so it's, it's, it's a nice model to study and, and it differentiates a lot. So it expresses a lot of oncofetal. Antigens. Um, so a lot of ADC. So this is just an example of, of a second line data for a B7H3 ADC IDXT. Uh, again, uh, similar to TDXT, aristoan payload, uh, showing an ORR of about 54, 55%. Uh, but the big thing is, you know, the median duration of response is about 4 to 5 months. So it's, it works like chemotherapy, it behaves like chemotherapy, and acts like chemotherapy, but it is showing responses in post-chemo IO treated small cell lung cancer patients, and it's showing response more than what we traditionally saw with labinectidine and Topotecan again, the side effects, as I discussed previously with drotocan is pneumonitis. So these are a barrage of ADCs that have been there in pre-treated small cell. You can see. The response rates in second line, about 50 to 60%. Um, the median PFS and OSS, this is a single, single arm study, so I won't, I won't take much from that. Mainly hematological toxicities, pneumonitis, roughly 5 to 10%, which is a concern. But the one point which is not there is the duration of response. It's, it's almost 4 to 5 months. You, you won't get, I, I don't think it's hard to get a duration of response more than 89 months that we saw with the initial Delphi. Uh, the, the bites that we saw, which is a more sort of associated and immune mechanism of a long-term response. So really the key takeaway is thatthatumab is the new current standard of care for patients with relapsed second-line small cell lung cancer, and I I would really call it the light of the end of the tunnel for my patients with small cell lung cancer. Toxicity monitoring is important for the first two cycles with tatumab. Uh, there are real logistical challenges delivering tatumab, and, and we're trying to take them one at a time. And I think as institutionalized, we, we get more familiar, we're going to get better. And there are multiple other DLL 3 T cell engagers and ADCs that are being tested in relapsed and frontline setting and are expected to change the treatment landscape of small cell in the coming years. Thank you. Created by Related Presenters Parth A. Desai, MBBS, MD Assistant Professor, Department of Hematology/Oncology,Fox Chase Cancer Center
