ES-SCLC later-line treatment strategies
Supported by Amgen
Jacob Sands, MD, and Eric Singhi, MD
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Hello, this is Dr. Jacob Sands, thoracic medical oncologist from Dana Farber, and I'm excited to welcome you to the Transforming Extensive-Stage Small-Cell Lung Cancer Care series. This episode, “Later-line management of extensive stage small-cell lung cancer: Applying evidence to practice,” and our guest today is Dr. Eric Singhi. Eric welcome to the program. Thanks Dr. Sands for having me. My name is Eric Singhi thoracic medical oncologist and Assistant Professor at UTMD Anderson Cancer Center. So, Eric let's kick it off right away because we have a brief amount of time and there is a ton to discuss now. So first of all extensive-stage small-cell lung cancer in the first-line setting, pretty established now platinum-etoposide I'd say carboplatin-etoposide and a PD-L1 inhibitor, but after that we have some new data in this space. How are you thinking about second-line small-cell lung cancer management? Yeah, Jacob, I think really the single most important shift that's happened in this space is tarlatamab. Tarlatamab is a bispecific T-cell engager, it's actually now the preferred category 1 second-line option for patients as of 2026 NCCN guidelines. We have that data now from ASCO not this year but actually last year, the phase 3 DeLLphi-304 trial showed us a clear overall survival advantage over chemotherapy for patients. We also saw an improvement in symptoms of dyspnea, of cough, as compared to chemotherapy. So that data has really solidified my practice for the majority of our patients in the second-line setting. Yeah, I mean to add to that, I think sometimes people don't fully appreciate how big this result is. All prior studies, we've never had a second-line trial where a drug beat another drug. So, this is the first time we see a superior trial with a therapeutic control arm. Tarlatamab won in progression-free survival, in overall survival, in symptom improvement, in toxicity profile. A pretty big win! And then we also saw in the brain metastases we see responses and the curves this year from ASCO in those with baseline brain mets and without baseline brain meds on the tarlatamab arm those curves entirely overlap. What about some other scenarios where in the first-line setting let's say someone's on maintenance PD-L1 inhibitor you have a solitary brain met, that's progression, what are you doing in that situation? Yeah. So Jacob, I see a lot of patients with non-small-cell lung cancer and we do see oligometastatic disease, oligoprogressive disease, and in those cases, I am talking to my multidisciplinary colleagues about the role of local therapy for patients particularly if they're tolerating their frontline therapy well, if they're on maintenance immunotherapy for example. So that is an option to be thinking about, but I'm watching these patients very closely. As you know, as you can appreciate, the histology of small-cell lung cancer is not non-small-cell lung cancer. And so, watching these patients very closely and making sure they're tolerating the therapy and moving very quickly if I have to change systemic therapy if that's warranted. Yeah, absolutely. You have to watch them closely. Some of my longest standing patients on first-line therapy though, are people that had brain met progression and so while they're on the PD-L1 inhibitor, getting SRS, focused radiation to those sites, while continuing the PD-L1 inhibitor, sometimes that can really prolong out. Of course, it's a little different if you have like a solitary adrenal metastasis but even then, sometimes treating that local site and continuing the PD-L1 inhibitor, I do think about differently than if you have multifocal progression.
How about outlier situations? Someone poor functional status, they have multiple sites of progression, poor functional status. It's from their cancer itself, not other comorbidities. Where's your line on treating these patients and what types of therapies are you considering in those cases? Yeah, I think this is a good point. You really have to understand the patient and disease characteristics at every line of therapy when you're making that decision. And so, you've hinted on performance status. We're also thinking about CNS involvement. We're thinking about the patient's marrow reserve. You name it, right? And so, I think all of that comes into play with decision-making. If their symptom burden is primarily driven by their disease progressing, I do not think that should limit you from really thinking about tarlatamab, if you're able to access it of course, and if you're able to do the step-up dosing, and the monitoring and everything that's required. I agree. Yeah. I mean, one of the things about tarlatamab that's different than the cytotoxics is that over a long duration of time, it doesn't wear people down like the cytotoxics. And so, someone that has a poor functional status, if I'm trying to give them chemotherapy, it can knock them down with each dose. Not terribly, I think most people do better with chemotherapy than they expect, but to be on something that has potential durability and, also, over time they can do rehab and can climb out of whatever is going on then I think that's a different kind of a paradigm. So, what are the key efficacy and safety considerations when evaluating currently available later-line therapies? How are you weighing that out? We've discussed tarlatamab, you can maybe discuss that further with tarlatamab and any considerations that you have around treating that patient, and then we'll move on to some of the other cytotoxics. Yeah, of course. I mean I think when we're thinking about clinically relevant endpoints just in general for relapse disease, I don't just care about the objective response rate. I also care about the durability of response and thinking does that translate to overall survival and of course symptom and quality of life. And so, you have to put all of that together, right?
With regards to tarlatamab, we first heard about that data with the DeLLphi-301 study, objective response rates were 40%, median duration of response just shy of 10 months, and then we heard updates with DeLLphi-304 phase 3, so overall survival was 13.6 months versus 8.3 months with chemotherapy, objective response rates around 35%. And that's really impressive to see, right? We haven't seen these numbers before in that space. Of course, you have to balance that excitement with the potential for toxicity. And so, the one to really talk about, and I want to unpack this with you, is cytokine release syndrome (CRS). Just over half of the patients did have some degree of CRS, predominantly grade 1 and grade two, thankfully, mostly during cycle one, but you do have to watch for it. A lot of us solid tumor oncologists are not used to this, right? And then ICANS makes people nervous as well too, thankfully it happened in a low degree of patients but still something to be paying attention to. Yeah, I agree. I mean these are big topics and really the most talked about topics when discussing tarlatamab. You know for CRS I would highlight that the majority of individuals end up with a grade one for which they take Tylenol, and they're fine. But at this point anyone who develops any grade two I just immediately give them dexamethasone and tocilizumab. I don't think there's any reason to withhold the tocilizumab. I like what you said about ICANS though because ICANS I find to actually be the more challenging one. You know CRS is just the first two doses and then it doesn't really happen again after you get past that that time frame. The ICANS is the one where I've recently come to appreciate more that older more frail individuals, in particular when they're in the hospital, if they have CRS now, they're in the hospital for two nights or three nights, and it seems like they have ICANS, I think in some cases it's really a hospital delirium, and so recognizing that when they're waxing and waning, having mental status issues, that it is delirium, that sometimes it's not necessarily the ICANS as the etiology, and sometimes getting patients out of the hospital can help, but I feel like that's a little tougher to manage.
How's your experience been with that? I agree. I mean, first just the recognition of it, right? And making sure that you appreciate it. Oftentimes, exactly what you said, cognitive changes, especially when a patient's in the hospital can be multifactorial and so it's really tough. But it makes me really nervous. So, it's definitely on my radar, you know, and our trainees know about it too, when they're also helping to cover. So, I think it's something to make sure that we're educating providers, patients and care partners about. Yeah. And then of course there's dysgeusia which is quite common and altered taste, but not a huge problem for the majority of patients. For some patients it is. All right. I know our second-line and beyond discussion has really been focused on tarlatamab, but overwhelmingly that comes from your first comment that there was a positive trial that showed tarlatamab to be superior in the second-line setting. Maybe as part of that, then, and maybe this further reinforces too though is, what patients would you not give tarlatamab, and instead offer one of the cytotoxics as second-line therapy. Yeah, I think one of the bigger questions up until recently was do you think about a drug like lurbinectedin, a cytotoxic chemotherapy. But now, Jacob, we have a second, unfortunately confirmatory trial, meaning we may no longer have access to lurbinectedin in the second-line setting, that's what it's looking like, right? The LAGOON study most recently came back negative and that was in addition to, and after, the ATLANTIS trial, and so I'm really struggling in terms of what second-line option because what we have left are cytotoxic agents. And if you're already worried about the performance status of the patient, how they're going to tolerate treatment, those aren't easy drugs with huge responses either. And so, I struggle to be honest, what are your thoughts? Yeah, I agree. I guess it comes down to access. You know, if someone has traveled on a flight and they don't have it locally available, for whatever reason, but I think at this point across the US, most people do have access. You're right. With the LAGOON trial, we saw in the press release that lurbinectedin underperformed against irinotecan. Irinotecan did have a surprising 10.7-month median overall survival. These are really extraordinary numbers, far more than what we expected. We saw similar with combination lurbinectedin plus irinotecan and underperformance from the lurbinectedin arm. I do still think lurbinectedin has a place in third-line and beyond after tarlatamab. I certainly hope it doesn't disappear.
You know it has the approval from first-line maintenance, outside the scope of our discussion today, but in the third-line and beyond, if it hasn't been used in first-line maintenance, I think it's still an important drug and offers an option for patients. What about the cytotoxics now? So looking past tarlatamab, third-line and beyond, what are the different therapies you're using and I think it's really important to highlight this because I often have patients that come see me because their local oncologist told them there's nothing else that's available and they still have a few different lines given their functional status and such. Yeah. So, we started talking about this. We have irinotecan, we have topotecan, for example, as well we have temozolomide as well that we can consider. So those are some options that I have reached for patients. Of course, you should be talking to patients, as well, about best supportive care and using that concurrently, and in parallel, with that. But I do think having supportive care and also, talking about access to these cytotoxic agents is reasonable if the patient's wanting to do it and their performance status is reasonable too. Yeah, I think all of those are important to remember. Just to add, paclitaxel of course as well which I often give weekly dosing three weeks on, one week off or six weeks on two weeks off also. So, we now have tarlatamab which we've discussed quite a bit. There's an array of other cytotoxics now that we've outlined. What do you see as the main gaps and challenges now? It's kind of the classic, alright where do we need to do better and where should the research be focused? I know there are an array of drugs we can discuss in a moment but first what do you see as the gaps? Yeah, I mean I think the first one I'll talk about, and we've hinted about this already, is just the access and logistics. And so, I'm going to go back to tarlatamab again one more time because I think that is a gap. So, not everyone has access to this drug and the logistics right now are quite difficult for everyone to overcome, the CRS monitoring, the cost, administration complexity. So, I think that's one big barrier and gap that needs to be addressed quickly especially if we are now saying that that is the preferred second-line option. Outside of that, if we take a big step back, I mean, I think subgroups that still need help, brain metastasis, we're starting to see updates, meaningful updates about what these drugs are doing for patients with brain metastases. And so, I think continuing to invest in that, continuing to invest in leptomeningeal disease are important unmet needs in specific subgroup populations. I also wonder more about these poor performance status (PS) populations, platinum refractory populations as well, too.
How else can we make an impact for them? Those are some of the main ones that I'm thinking about. I'm curious, Jacob, what are you thinking about? Yeah. Well, right now, I'd say in first-line therapy with the PD-L1 inhibitors, there's the potential for years of disease control. So, there is reason to be very optimistic when starting treatment. Even if it's just a subset of patients, there's the realistic possibility of this. Second-line, tarlatamab, again, there's a realistic possibility of long-term disease control. In the third-line is where things really start falling apart a bit because this is where when we get to the cytotoxics, realistically, if there's response to treatment, the drugs tend to work for months not years, and of course we string them together and try to add more meaningful amounts of time but this is where I think the biggest need exists. And we do have an array of drugs coming in which I know I held off in the discussion so I'll just, there are various antibody–drug conjugates that are showing really impressive response rates even after prior topoisomerase inhibitors. So, these are drugs with topoisomerase inhibitor payloads working really well after prior topoisomerase inhibitors. So, I do think that the antibody drug conjugates are delivering these payloads in a way that's really meaningful. But with the last bit of time, let's get into then how are you sequencing? So, after first-line, I'll just say for everyone out there, I'll outline first-line carboplatin-etopiside plus a PD-L1 inhibitor. I tend to get scans after two cycles and then after four cycles. I don't continue platinum-etopiside beyond those four cycles and then do the maintenance PD-L1 inhibitor. Let's say a case; there is now multifocal clear systemic progression. We've discussed second-line tarlatamab, after tarlatamab what's your order then, what's your thinking process and how are you treating patients? I am actively scanning my protocol is for clinical trial enrolment that's really important, right, so we don't have an antibody–drug conjugate (ADC) approved yet for patients but I think the way to get it for patients beyond tarlatamab, and beyond progression in the frontline setting, is to reach for a clinical trial so big, big plug for that, and discussing that with your clinical trial team because it's showing so much promise already and so, that's what I'm thinking about. Outside of a clinical trial, we've already discussed some of the other cytotoxics to be considering, but I'm really hopeful for a clinical trial and access to an ADC for my patient. I love that answer because right now, I'd say more than ever before, clinical trials options are important for patients just in sorting out what is the best treatment for them. This is not about what is going to help in the future in future populations, but for individuals with small-cell lung cancer.
There are more promising drugs in development right now, available in clinical trials, than the culmination of everything up to this point. And so, I think right now it's so important for patients to be evaluated for what clinical trials they are eligible for and is there something that is potentially the best option for them in the moment. I'll highlight a couple other things that post tarlatamab especially if there's any CNS concern, brain metastases that need to be treated, something that previously got irradiated and is now progressing so can't get radiation again. Topotecan and irinotecan both have good CNS penetration; I tend to use irinotecan rather than topotecan just because of the toxicity profile. Lurbinectedin I do think is still an important drug, it does not have CNS efficacy though, but that would be a line I'd consider next after tarlatamab if there's no CNS concerns, very convenient Q3 week dosing after those two lines of therapy then weekly paclitaxel as I described, and then temozolomide, another one with good CNS penetration, and not great response rates, but another consideration. OK, Eric, so we've now discussed the standards, I've mentioned the antibody drug conjugates, of course, that's not the only thing, but what are your thoughts on recent and emerging data in later-line therapy? Let's start with the antibody–drug conjugates and then you can add on to that anything else. So much going on to discuss. Yeah, that sounds good. I think that's the most promise here right now. There's a lot of promising early data already emerging for ADCs. They're targeting DLL3, B7-H3, TROP2, you name it. And they're moving through the clinical pipelines actively. And so, one of my colleagues, Dr. Lauren Byers did present some data at the ASCO annual meeting about ABBV-706. It targets SEZ6 and, really impressive objective response rates, right, Jacob? It was almost in excess of 80% which is amazing for patients with small-cell lung cancer and so I'm excited about that agent. What other agents are you excited about? Yeah, you're right. I mean really impressive. ABBV-706 in the second-line setting I think had a response rate around 60%. We've also seen that from ifinatamab deruxtecan, a B7-H3 antibody drug conjugate, both of these now being looked at in the first-line space instead of platinum-etoposide, to replace platinum-etoposide, you know we're not discussing first-line so much in this conversation but I think when you have something that has response rates that high second-line post-platinum-etoposide, you think what are those response rates going to be like in untreated patients?
I think there's real viability here, so these are unprecedented response rates in second-line and beyond with these antibody drug conjugates. We've seen the Zai labs, the ZL-1310, a DLL3 ADC. We see intracranial responses across all of these antibody–drug conjugates. Impressive. There's CAR-T treatment that has shown enough of a signal to be excited about it, but still needs further validation and more study. Radioligand therapies, it's still pretty early. We'll see. So, a lot of different kinds of classes of drugs that I think ultimately may find their way into the first-line setting. You know, the one other thing to mention, and this is more relative to first-line probably, although it is being studied, is dual checkpoint inhibitors. So, we have these dual checkpoint inhibitors, some of them with VEGF, that have also shown impressive response rates. So, an array of drugs and, again goes back to the statement you made earlier, Eric, around the value and importance of clinical trials as treatment options for patients, and all the more reason that patients really should be seen for what trials are available in their regions as potential treatment options for them, as best options. A lot to discuss and we kind of had to breeze through this a little bit, but first of all thank you Dr. Eric Singhi for joining me today. Thanks for having me, Jacob, really appreciate it. And thank you everyone for tuning in.
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