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Jacob Sands, MD: Hello. I'm Dr Jacob Sands, a thoracic medical oncologist at Dana-Farber Cancer Institute where I lead our small cell lung cancer program. Welcome to Medscape's InDiscussion series on lung cancer. Today I am particularly excited about a discussion focused on small cell lung cancer, and I have an exceptional guest today. I'd like to welcome Dr Lauren Byers, professor and physician scientist in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston where her research focuses on studying the biology and novel therapeutic approaches for small cell lung cancer. Dr Byers, welcome to InDiscussion.
Lauren Byers, MD: Thank you so much. It's really great to be with you, Jacob.
Sands: I'm excited to talk with you about small cell lung cancer. But before we get to that, what has your career path or your life path been that has led to this point in your career? What made you get into medicine, specifically medical oncology, and start focusing on small cell lung cancer?
Byers: I was really fortunate. When I was a medical student, I was accepted into a Howard Hughes fellowship program at the National Cancer Institute, and I got to spend a year there working in a lab that was using new technologies to see which genes were turned on in certain lymphomas. As part of that team, we figured out that even though lymphoma could look the same under the microscope between two patients' cancers, the patients could have very different genes that were turned on. That was a major driver of which patients were responding to the current treatments at that time. It really got me excited about the idea of personalized medicine and how a lot of these new technologies that look at the molecular aspects of cancer could potentially change how we take care of patients. That was a big driver for me. That was the year the first human genome was published, and the first targeted therapy was presented at the AACR annual meeting. There was a lot of excitement about where the field could go. And then when I came to MD Anderson as a medical oncology fellow, I had the opportunity to bring some of these interests into the lung cancer group where my mentor Dr John Heymach and many other colleagues and mentors there were starting to take a similar approach in lung cancer. They were trying to understand the different types of lung cancer and how to learn more about their biology to really drive what we were doing in the clinic.
Sands: I love that this started with an interest in personalized medicine because that has not been the way things have been for small cell lung cancer. And you're really leading the charge. Let's start with first-line therapy. In the last few years, we've seen immunotherapy become a part of first-line therapy. The standard of care, chemotherapy plus immunotherapy, namely atezolizumab or durvalumab with chemotherapy, both of which did not show tremendous differences in median progression-free and overall survival but did show statistical significance, and met their primary endpoints, particularly in overall survival. So, I'm asking a broad question. Can you speak a bit about the incorporation of immunotherapy and what makes it so special that it has been celebrated, despite not such a big difference in median progression-free and overall survival?
Byers: For decades, there had been no other new frontline treatments that had demonstrated benefit beyond what we had been doing for more than 30 years in terms of our standard chemotherapy, so this really was a step forward. I completely agree with you that going from a median overall survival from 10 months to 12 months is incremental, but it's a step forward. That was really exciting. There were new data recently presented from the KEYNOTE trial that added pembrolizumab to platinum-etoposide chemotherapy for the same extensive-stage patient population. And there were some recently updated data presented at the World Conference on Lung Cancer showing that patients in that trial who completed 2 years of immunotherapy and were responding and alive 2 years after starting the treatment have had really durable responses, even though the immunotherapy was stopped after the 2-year period. So again, this all points to the idea that there is a subgroup of patients who benefit from the addition of immunotherapy. But one of the really important questions is how do we identify who these patients are? And as importantly, how do we find more effective and more innovative ways to get more patients having durable responses to treatment?
Sands: I totally agree. What you are highlighting is that tail of the curve where this therapy didn't benefit a huge number of patients — which is why we don't see such a big change in the medians — but for those who benefitted, it's been a home run for some of them. I have a patient who was in that study of pembrolizumab first-line therapy. It was 2 years of pembrolizumab, and then it was stopped, and it had been years out. We unblinded her because she ended up having a small nodule that ended up being a new non–small cell lung cancer. We unblinded her, she was treated with pembrolizumab, and she is now years out without any evidence of disease progression at this time. It's these home runs we see. Let me ask you a tougher question because the drug hasn't been around for a decade yet. Do you think there are potentially some patients who are cured of their incurable small cell lung cancer? Are some of these really durable responses? Do you think any of these patients may not have progression again? What do you expect going forward?
Byers: We've seen a signal of that in non–small cell lung cancer and certainly in other cancers. And I do think this is going to be the case for a small number of patients with small cell lung cancer. Especially the recent data from these patients, like the one you were describing who received pembrolizumab — several of these patients have been off immunotherapy for a couple of years now and still have complete control of their cancer. I think this points to the fact that there may be some potential cures — and I am always cautious about using that term. But hopefully this is the case, and hopefully we can find ways to get more patients who are having durable remissions and eventually eradicating the cancer.
Sands: Yes. And to be clear, I am not at all saying that's what's been demonstrated, but that if we have people who in the next 10 years don't end up with progression, would we then consider this a cure? And the fact that this is even considered a possibility is just overwhelmingly exciting. Let's go into second-line therapy. We've now seen fairly recent approval of lurbinectedin as a second-line therapy. This was based on a 105-patient single-arm basket trial that led to FDA approval. Of course, there are other ongoing studies with lurbinectedin. Can you give an overview of your impression of the data and if it has factored into your clinical practice?
Byers: It's definitely nice having a new option in the relapsed small cell lung cancer setting. We need as many different opportunities as we can for our patients. For some patients, lurbinectedin can be somewhat easier to tolerate in terms of the side effect profile, and it had an encouraging signal of activity in the trials that have been done. But for many of my patients, it still can be similar to chemotherapy in a lot of ways — in terms of the effect on the blood counts, thrombocytopenia, and especially with fatigue. So as with many drugs, it seems to be different between patients, where for some patients it's a great option for them, and for other patients, we need to keep looking for drugs that have a better side effect profile.
Sands: I think that's fair. It is a cytotoxic drug, and so certainly the cytopenias were reported. Neutropenia was actually quite high — around 46%, I think, in patients with grade 3/4 small cell lung cancer. But the study did not allow for prophylactic G-CSF (granulocyte colony-stimulating factor). You mentioned thrombocytopenia, which of course the prophylactic G-CSF would not help with, but is that something you are using when treating patients with lurbinectedin or platinum-based therapy, for that matter? What are you using as far as prophylaxis or monitoring? What are your thoughts on this?
Byers: I don't routinely use prophylactic G-CSF in everyone, so it's more patient specific. Especially if, for example, in newly diagnosed patients, they've had postobstructive pneumonias or other things that make them higher risk, I'm definitely more proactive about using G-CSF. And for patients with lurbinectedin, some of it is looking at how recently they have received other cytotoxic therapy. And have they had challenges maintaining their counts, or infections, or other things that point to them being a higher-risk patient?
Sands: Since we've kind of forayed into this prophylaxis discussion, and it started with your mention of thrombocytopenia, is trilaciclib something you utilize? It was approved for platinum-based therapy and topotecan in particular. What are your thoughts on the trilaciclib data, and have these data factored into your clinical management of patients in your clinic?
Byers: It's a new approach that's approved to prevent some of the cytopenias. We now have it on our formulary. We're not necessarily using it across the board, but for patients who seem like they would be high risk because of their clinical histories. We would use it especially in patients who are frailer, have recent infections or who are at potentially high risk for developing infection. These are patients for whom we are using a preventive approach as opposed to growth factors and boosting the blood cell count after they've been affected. I think trilaciclib can be a useful tool for that.
Sands: I agree. I don't tend to use it for everybody either. I have used it, and so far, it's worked quite well, particularly in patients who have had issues with prolonged thrombocytopenia or in whom I'm concerned about anemia. Generally, if I'm just concerned about neutropenia in particular, I tend to use G-CSF or Neulasta (pegfilgrastim) more in treating or preventing prolonged low blood cell counts. But now to transition to some of the other treatments. Topotecan has been a long-standing second-line therapy. I find that people tend to use a lot of topotecan or no topotecan. Some individuals, myself included, tend to use irinotecan rather than topotecan. Aside from lurbinectedin, what do you think as far as second-line therapy — are you a topotecan user? Do you prefer irinotecan? What are your thoughts?
Byers: It's so interesting because we all use essentially the same approach in the front-line setting. And then I feel like almost everybody uses a different approach in the second-line setting. Even within our group of thoracic medical oncologists, if you ask each person, they probably give you a slightly different answer. I do not use topotecan much at all. It's pretty rare that I use it. I'm always looking for potential clinical trial options, as I'm sure you are also. I tend to use a lot of temozolomide as a single agent. That's something that we had a lot of experience with from some of the early trials we ran that looked at temozolomide in combination with PARP inhibitors. But what I found is that some patients have had really remarkable benefit, including a really prolonged benefit in some patients, and it tends to be very well tolerated. It's an oral agent. So it's something I use quite a bit, probably more than other people do.
Sands: I find temozolomide to be particularly good in patients who have central nervous system (CNS) disease, especially if they've previously had radiation. With temozolomide, obviously you get very good CNS penetration. That's where I will preferentially utilize it. We've seen two different dosages of this drug. There was the standard 75 mg/m2 per day on days 1-21 of a 28-day cycle. And then there's the 200 mg/m2 on days one through five. That was more recent, and obviously not as big of a number, although I believe the authors from that study suggested this could now be a new way of dosing temozolomide. Do you have a preference on the dosing? What are your thoughts about the dosing?
Byers: I usually use the 200 mg/m2 on days one through five. We usually give patients antiemetics to take on the days they're taking the temozolomide because it seems to be generally well tolerated, except for some nausea, which is well managed this way. For patients in whom I'm more concerned about their blood counts, I'll sometimes start at 150 mg/m2. That's the regimen we've used. And I agree completely with you. Especially for patients who have had previous whole-brain radiation and have a relapse in the CNS, it's something that can be quite a great tool because it gets really good CNS activity as well as outside of the CNS.
Sands: You mentioned PARP inhibitors. Of course there have been the combinations, as you mentioned, of temozolomide plus a PARP inhibitor. Is that something you've continued to utilize, or was that just in trials?
Byers: I have used it just in the clinical trials, although I know some people have used it in standard practice as one tool they go to. It's been exciting to see the data that have come out from Dr Goldman and colleagues in terms of their recent trial, which showed a pretty high response rate in patients with relapsed small cell lung cancer — so around 40% with the combination of temozolomide and talazoparib. This is now the third trial or so in the relapsed setting to demonstrate a fairly high response rate to combination with a PARP inhibitor. It's something that we, as a field, need to think about, whether we should be leveraging this combination more. But there are biomarkers that may help us identify who is potentially going to get the most benefit from PARP inhibitor–based combinations. Ultimately, we need drugs that engage the immune response more effectively. I think it'll continue to evolve.
Sands: I have a patient who was in Dr Farago's olaparib temozolomide study for years, with impressive years of ongoing control. That combination has really been compelling, and we saw good response rates. That being said, PARP inhibitors have been a tough one. There's this hint of efficacy, although not really demonstrated enough for PARP inhibitors to become part of the established approved standard of care. Now we've seen data with Schlafen 11 as well. Of course, you've done a lot of this work, but what are your thoughts around PARP inhibitors and Schlafen 11? Maybe that even transitions us toward some of the subtyping, as well?
Byers: We have a clinical trial that was the first to use Schlafen 11, which is a biomarker, but it's a gene that basically causes cells that have DNA damage to die. So it predicts, in preclinical studies and in retrospective studies of clinical trials, the patients who seem to get relatively greater benefit from PARP inhibitors and potentially other drugs that work by damaging DNA, such as cisplatin or carboplatin chemotherapy. I'm really excited about this trial we've been running through the SWOG cooperative group because it's the first one to select patients for PARP inhibition as part of their maintenance treatment following frontline chemoimmunotherapy based on being Schlafen 11–positive. This study is getting close to completing accrual. Hopefully in the coming year, we'll have some data on how that group of patients did and whether the biomarker-selected approach may be helpful for enriching it. That being said, we're also really excited about the new small cell lung cancer subtypes we've been doing a lot of work around. Just like with non–small cell lung cancer, we're going to keep seeing the biomarkers and different subgroups of small cell lung cancer continue to grow and evolve as we learn more about how to move this forward.
Sands: The subtyping, I think, is some of the more exciting potential foundation upon which the future of small cell lung cancer is potentially going to be built. Now, I realize there's Charlie Rudin's proposed subtypes, and that, of course, your and Dr Gay's proposed subtypes, both of which are very similar and set a similar foundation upon which to look at small cell lung cancer. Before I dive into some of the questions around that, can you outline what the subtypes of small cell lung cancer are?
Byers: Absolutely. This goes back to early work by leaders in the field, Dr John Minna and Dr Adi Gazdar, who recognized that there were these different small cell lung cancers. They look different under the microscope and seem to have some different behaviors biologically. As research in small cell lung cancer has continued and progressed, there was a signal that there were certain subtypes of small cell lung cancer, many of which could be defined based on transcription factor genes that were turned on. So for example, three of the major ones that had been identified were small cell lung cancers that expressed high levels of genes called ASCL1, NEUROD1, or POU2F3. But there were still other small cell lung cancers that didn't really fall into these three transcription factor gene groups. So we had taken an unbiased computational approach to try to ask how many major groups there are across some big groups of small cell lung cancer patients. That really led us to a new fourth group that, instead of being defined by a specific transcription factor gene, was characterized by having really high expression of immune checkpoint genes and other signatures or markers of inflammation. We called that the inflamed subgroup. The current framework now is around these three transcription factor gene subtypes. And then, there is this fourth inflamed subgroup that has come out more recently.
Sands: Essentially, the premise is that different treatments may be more effective for patients with different small cell cancer subtypes. So much like non–small cell lung cancer, we subtype small cell lung cancer into adenocarcinoma and squamous cell carcinoma, as well as others, and this has treatment implications for us. What you've proposed is that for small cell lung cancer, by doing these subtypings, we may actually be better able to specify which treatment is going to be more effective for an individual. Can you speak a little bit to that point? Do we see shifting in some of these subtypes to where it helps with treatment decisions or reevaluation at a later point? Can you address all of these things?
Byers: I'll do my best. I will say the big headline from the subtypes is when we went back and had a chance to look at how patients did in the two randomized phase 3 trials we were talking about earlier — the IMpower133 trial and the CASPIAN trial where immune checkpoint blockade was added. What we found was that patients who were in the inflamed subtype group were the patients who seemed to get relatively more benefit from the addition of immunotherapy. So in the case, for example, of patients who are in the IMpower133 trial with the addition of atezolizumab, the patients who were in the inflamed group and who received immunotherapy, their survival doubled, median survival doubled for those patients who with the addition of the immunotherapy. And again, we saw very similar results with the CASPIAN trial, with enhanced benefit from immunotherapy in patients with the inflamed subtype. Right now, we are in a place where we've been able to identify this group that seems to be getting more durable responses that are making up the tail of the curve. What we need to do next is figure out how can we find ways to enhance immune response for patients who have the other molecular subtypes, as well. That's really the direction we're going. There are two big picture ways in terms of how to do this. The first is that we're already developing tests and biomarkers that can be done on patients' tumors, similar to what we do with non–small cell lung cancer patients when we need to look for mutations or PD-L1. But for patients with small cell lung cancer, the blood-based assays are going to be a real opportunity where we can do biomarker testing ultimately from the blood, and from circulating tumor DNA and other approaches that will let us be able to look not just at the time of their diagnosis — but to your point, Jacob — longitudinally at progression. How has their cancer potentially changed to escape the prior treatment? And how can we use the information about what's going on at that moment with the cancer to then decide what's going to be their best next treatment option?
Sands: These are such important points. Immunotherapy has led to such a huge success but unfortunately for just a fraction of the individuals who have small cell lung cancer, and it is so much fun to have somebody in clinic who is now at the point of what I like to call high-five visits. They've been treated for years. They come in and their scans look great. It's so much fun to see people getting back to their lives in a lot of ways. But the majority of individuals with small cell lung cancer have disease progression, and we really need better treatment options. Dr Byers, you are leading the way and setting the foundation for this evaluation. With that, I want to thank our listeners for tuning in. Dr Byers, thank you so much for joining me. This is Dr Jacob Sands for InDiscussion.
Primary Analysis From the Phase 2 Study of Continuous Talazoparib (TALA) Plus Intermittent Low-Dose Temozolomide (TMZ) in Patients With Relapsed or Refractory Extensive-Stage Small Cell Lung Cancer (ES-SCLC)
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Cite this: Small Cell Lung Cancer: What Are the First-line and Second-line Treatment Options? - Medscape - Nov 15, 2022.