Video series: Transforming SCLC care
Transcript: ES-SCLC first-line and maintenance treatment
Supported by Amgen
Jacob Sands, MD, and Solange Peters, MD, PhD
All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
Hello, and welcome to the final episode, episode three, in the accredited video series on extensive-stage small-cell lung cancer hosted on Medthority within the Lung Cancer Nexus, also available on YouTube. I am Dr. Jacob Sands, thoracic medical oncologist at Dana-Farber and very excited for the discussion today with a phenomenal guest, Dr. Solange Peters. Dr. Peters, can you introduce yourself to the audience? –Thanks so much, Jacob. You're too kind. My name is Solange Peters. I am the Director of Oncology at the Lausanne University Hospital in Switzerland. –Now, in this episode, we're going to be talking about applying first-line and maintenance treatment strategies in extensive-stage small-cell lung cancer. So, Solange, let's jump into the first question here. In patients with newly diagnosed extensive-stage small-cell lung cancer, how do you approach decision-making in the first-line setting? So, we're starting at like just treatment initiation. –Yeah. So, the first thing which is important also in the trials conducts that we have to do and to adapt to when we want also to make an innovation happen is the emergency. Most of the time these patients are highly symptomatic and they come at the time and at a stage where starting the treatment might not wait 2 weeks. So, very often what you need to start is to start the chemo. And since already almost 10 years, it's not only the chemo, but we like to start at the same time a checkpoint inhibitor, which in our countries is an anti–PD-L1. By the way, anti–PD-L1 do the same, but usually for us it's atezolizumab or durvalumab. So, as soon as you can, I would say, and even not waiting for enrollment in a clinical trial, most of the time you need to start with platinum, etoposide, and an anti–PD-L1. I would say platinum is also interesting because I remember these old days where we're discussing cisplatin or carboplatin. I think at the era of immunotherapy, start with carboplatin. It's fine. Your patient doesn't need to have nausea and ototoxicity. That's fine with carboplatin. –Yeah, completely agree. I give carboplatin to essentially everybody, not cisplatin as you're pointing out. Also, just say that, you know, I give carboplatin, etoposide, a great PD-L1 inhibitor, I do a scan after two cycles, which I think is very informative, and for most patients, that scan looks wonderful. And then I do a scan again after four cycles. So, you kind of get that how much of a response did you get at first and then after completing what kind of change do you note there, oftentimes looks fairly similar from the after two to after four cycles. I know sometimes we find when I talk with community oncologists in the US in particular, some have mentioned difficulty getting scans approved in that setting, the Q2 weeks. Are you noticing that as well or is this, in Europe, pretty standard, Q2 weeks, cycles? –I love to scan also after two cycles because it gives you also a glimpse into what you are doing, how much you want to continue. And you're right, after four cycles usually it's the same but not always. Half responders after two cycles, where you can already see a start of progression, a chemo resistance already at four cycles. So there are still 20–25% of these patients who don't really do wonderfully under the chemo. It's probably good to anticipate then somehow. The other thing is the brain. I like to have an assessment. We are in Switzerland, so we do lots of exams, but I really like to know initially if they are brain mets or not, just because the surveillance will not be the same because there is room now we know for stereotactic radiation in the brain even in small-cell. I would even say there's no room for whole brain most of the time nowadays. So it's really something you need to pay a specific attention to. So, I think the CT scan after two is fine. I think an imaging of the brain, ideally MRI, is useful at baseline, but I know it's not always accessible, right? But I think it's important to have this assessment. It can also be at cycle one or during cycle one because they will not disappear, the brain mets, at least not in 5 days, right? –Yeah, I agree. I think an MRI brain at baseline is extremely important if it can be done prior to treatment preferred, but I don't hold treatment, especially if someone's symptomatic, they just need to start immediately and then we monitor. And then MRI brain is Q3 month monitoring at least. If it's positive, then I'll do that MRI brain much earlier as well to just verify that we're seeing a response with platinum-based therapy and PD-L1 inhibitor. –Yeah. What is interesting is we probably don't irradiate these brain mets if they are asymptomatic. I wouldn't even say partially symptomatic, right? The only reason to irradiate would be a threatening lesion in a bad location in the brain where really you fear that any progression might be dangerous, right? But we like to see the effect of what we give also acting in the brain, right? To the same extent as systemically, usually. –Yeah. So, the next question we have is around interpreting clinical evidence underpinning first-line recommendations in extensive-stage small-cell lung cancer. You've already highlighted carboplatin–etoposide with a PD-L1 inhibitor being the standard, and maybe in this setting we could go through what about the trials has made that the standard of care, and what are you assessing in trials going forward in the first-line setting? Of course, it's always, you know, a risk–benefit balance and efficacy and toxicity. So, first of all, what are you seeing as far as outcomes with the PD-L1 inhibitors that has made that the clear first-line standard of care? And then we can get into some of the what we're looking at with trials. –Yeah. So, well, a modest benefit, but still when these trials emerged, right, it was the first time we could change something in small-cell not having superimposed survival curves. So, basically to make a long story short, from 10 months to 12 months median overall survival. So you get 2 months, but significantly impacting the hazard ratio, meaning a continuous benefit over time with a hazard ratio of 0.7-something in both trials. So, what I mean by that is you have a significant and meaningful benefit, but still to be improved with new technologies we will discuss later on. The other thing which is important is the emergence for the first time of a tail of the curve, meaning that in both trials, despite both of them having a long-term follow-up, which can be debated, it was not the main aim of the trial but now we want to know. But let's say 10–15% of these patients might be long-term controlled, which is unbelievable in small-cell lung cancer until immunotherapy. So, there's also this hope for a minority of them to have a long-term benefit from the introduction of anti–PD-L1 in CASPIAN and IMpower133. –Yeah, I think that's the most important point for me. You know, we saw the trial with durvalumab as well as atezolizumab get approved based upon a 2.7- and 2-month improvement in median overall survival, but to me it's the tail of the PFS curve. It's the patients that are getting years of ongoing disease control, and these drugs are absolute magic when they work. Unfortunately, they don't work for the majority, which is why there continues to be such a need in the space, but that kind of durable disease control is amazing. Now, as far as what we're looking at... –And you know, the main thing about that is we would like to be able to predict who are these patients, right? –Yeah. –And we tried and we tried and we failed. –Yeah. –So, we looked at PD-L1, we looked at TMB, and we also looked at some subtyping, and we don't have the time to discuss, but it also failed because small-cell is heterogeneous, plastic, very, very, I would say, changing over time, heterogeneous across lesions and even within the same lesion. So what I mean by that, we tried to predict and we failed. So, unfortunately, you give this checkpoint to all in order to have 10–15% having a long-term benefit. –Great point. Great point. And then as far as trials going forward, how are you weighing out, you know, this is so nuanced that it's hard to discuss in a broad way, but the different outcomes within new first-line trials, what are you essentially analyzing in those and anticipating? –In new trials starting frontline? –Yeah, as trials are released in the first line, what's the data that you're looking for to guide your practice? –Absolutely. So, well, we need to move if we want to change this frontline strategy, we need to move into promises of long-term benefit. So, because replacing platinum–etoposide, it's a wonderful chemo regimen, right? So, you will not be more powerful in the chemo part of it, and you know the response is fantastic, so you cannot really improve the chemo part of it. So, whatever you do has to really lead to this plateau, to lead to something which will be long-lasting, that's what we expect. And this is measured by overall survival, and even by long-term overall survival. Of course, we all hope the median will be better, but the tail of the curve will be the most meaningful, I would say, endpoint for all of us. And it means certainly moving what we will discuss some immune mechanism, like T-cell engagers, earlier in the course of the treatment; but maybe also ADCs, if you believe that the combination with the checkpoint give rise to some kind of immune reaction, which can give rise to memory T cells. So, all what we do should build on looking at the curve 2 years down the road and not immediately because here platinum–etoposide is fine. You don't even need a checkpoint. –So, now if we're saying, okay, trials happen and are positive, how does this then get incorporated into routine clinical practice? What's the process of that? How meaningful are guidelines, for example? –Well, I guess in small-cell, if we can find a treatment which dramatically changes the prognosis of this patient, it will immediately adopt it in guidelines. And this is probably true in Europe and in the US. So, we have seen with the new data, there's always a criticism about accessibility, but still we're moving quite fast, I must say. And at least we are moving quite fast in having this argument from guidelines to the practice that we need to have access. So, I think we have this, I would say, this feeling of an urgent need to be able to implement. And I think the community will do its best to have it happening, right? In the US, you have this FDA early approval, but in Europe we can also handle some negotiations and we'll discuss it later on, but the tarlatamab, for example, is a very good example of negotiating and trying to get access in each countries we are living in, and it works pretty well. –Yeah, and then just to highlight subpopulations for trials, I'd say in small-cell lung cancer, asymptomatic untreated brain mets are very common. So, this is something that is really meaningful to be included into clinical trials. And then, you know, one of the aspects of this was around what patients are saying and experiencing and what we're seeing in data. You know, sometimes there's a little bit of a difference there. And I guess related to that, I would highlight specifically alopecia. I think alopecia often gets underdiscussed. It's not causing people uncomfortable symptoms, but it's not just a matter of vanity either. I think alopecia is the one where people wake up and look in the mirror and are struck with, again, like, oh, I have cancer and I'm getting treated. It also is something where they cannot not tell people about their diagnosis. It's going to come out. And for people to have the ability to control that, I think is meaningful too. And so, I've started really trying to be very forthcoming in any discussion about toxicity when alopecia is a part of that because I think for patients that matters more than the way we often end up discussing it. –Absolutely. We have been seeing it when we introduced ADCs, right? We always forget a bit about the alopecia and then you predict, you know, the mucositis and so on, and the patients come back telling I have alopecia and we forgot to speak about it, right? So, it's very important because this is visible. This is a kind of a signal for the surrounding that you are sick. So, I think it's something extremely important. But, and remember, this strange study showing that patients who you promise a treatment with long-term benefit tend to underreport the side effects because the main fear the patients have is that you will stop the treatment if they tell some toxicities. So, remember that what the patient tell you might even be way less than what he really experiences on a daily basis. So, you really need to push the narrative to happen, right? Because otherwise it might look too favorable like we see in clinical trials. It's always too favorable in clinical trials. Patients just don't want to stop because you have promised a long-term survival. –Well, and that's part of the, you know, continuing to talk with the nurses in the infusion room too. Sometimes, patients are much more direct with them about the challenges they're facing, while in the, you know, during the office visit, they just push through, like no, just keep going, keep going and then they go back to the infusion room and actually tell the nurse about more of the problems sometimes. But there's a lot that came out of ESMO. One of the things, of course, DeLLphi-305, tarlatamab plus durvalumab in the maintenance setting. So, related to that is, we'll get into that data specifically, but in the maintenance setting, what are you looking for? And then we'll talk about some of the data from ESMO. –Yeah. So, the maintenance strategy in general, well, we do maintenance, we did maintenance 1 year ago or 2 years ago because atezolizumab or durvalumab continued until progression. But very often the time on those drugs was very short, right? After the four cycles, atezolizumab or durvalumab, you could count the weeks, right? Not really the months. But it's already a maintenance. What we have been introducing in the maintenance setting of small-cell is a switch maintenance, meaning that you add a treatment which is a new treatment in the course of a control of the disease when you have finished platinum–etoposide. So, the first thing we did was, and I participated in this trial. It's not an easy one, but we added lurbinectedin in for the trial, which was a switch chemo. We did it a lot in the past in non–small-cell lung cancer. We are not convinced anymore, but we were doing it. So, you early switch the chemo in order to prevent the rapid emergence of progression and chemoresistant clones, right? So, lurbinectedin is also a chemo of a different kind, of a different class. So, probably not crossing with the resistance to platinum–etoposide, but also with its toxicities, right? You need G-CSF, you will have an hematotoxicity, you will have the fatigue. So, you will have the chemo hurdles. What do you want to measure? You want to measure a benefit in survival because, not to give holidays, to continue something which adds additional new toxicities on a previous treatment deserves and needs to demonstrate a worth benefit. And here in IMforte, it was 3 additional months. So, remember you had 2 months with the checkpoints, 3 months IMforte. So, I think, it's already an improvement, but still toxic, right? And not really a new mechanism of action, if you allow me to say, because it's still chemo after chemo. So, that was not, you will tell about the most inventive thing of the DeLLphi-305, but I think IMforte was the first, and it will still be applied for a certain number of months in many countries, but already an improvement to avoid this very early progression at the end of platinum–etoposide. But, maybe you want to tell us a bit more about the DeLLphi-305, which was really more exciting by nature. –Well, I enrolled to the IMforte trial too. But I think, you know, to highlight some of what you're saying, I agree with, is like that we're doing this research hoping that we're going to improve more people's disease for years, not just some months, and preferably without toxicities. So, at ESMO, I was very excited to present DeLLphi-305, which was after completing initial treatment induction therapy with platinum–etoposide and durvalumab to then get maintenance tarlatamab plus durvalumab or durvalumab alone, which has been a standard of care as we've discussed. The trial did allow for asymptomatic untreated brain mets. It was very exciting to be able to present that it improved median overall survival to 21.1 months from 12.7, with the caveat that the median follow-up is still only about 16 months so this could evolve further. For median progression-free survival, we saw 7.4 months versus 1.9 and, you know, if we look at the 1-year time point for PFS in the durvalumab arm, we see 10% of patients with ongoing progression-free survival at 1 year. This is the magic of these checkpoint inhibitors for that subset of patients, but 38% in the combination tarlatamab–durvalumab arm. So, very exciting. And then from a toxicity standpoint, we saw a truly manageable toxicity. I think I have a little bit of a pet peeve in that anytime someone's at the podium and talks about a toxicity profile, they say manageable, and so, I, you know, I hate using that. But this really does not add any toxicities beyond what we've seen before; no synergistic toxicities with durvalumab. And, as far as patients that discontinued drug, essentially the same between the two arms. In the durva arm, there were 10 that discontinued for treatment-related adverse events. In the combination, there were 9 that discontinued tarla and 9 that discontinued durva. So, certainly not more. There were no deaths for treatment-related adverse events in the combination. So, we saw cytokine release syndrome, which we do with tarlatamab, but this was broadly manageable too. It was 7.4% that had grade 2 and only a single patient with grade 3. Only three patients, 1.1%, with ICANS. And so, overall, I'd say compared to what we've seen in prior tarlatamab trials, this even compares quite favorably. So, I know you've said wonderful data, but what's your impression, and does this move the needle on standard of care? –Well, absolutely. One may be moving a little earlier. Your T-cell engager might be better. I think the most important thing when you see this patient benefiting so much from a T-cell engagement, right? In a disease which need that, right? Because we know that the presentation machinery of the neoantigen is completely deficient in this tumor. So, you need to have this engagement of T cells. The only thing we really need to discuss is to make sure that the benefit is given to the large majority of patients. So, it's a new mechanism of action and we'd like to see a maximum of patients being treated. So, I'm not so sure that giving it with cycle two, for example, maybe not cycle one for a timing issue. I'm not sure it will really improve the magnitude of benefit because of the chemo, because of the steroids, but anyway, it will expose a bit more of patients, a bit higher number of patients. So, it would even be sufficient to make the argument valid, right? Because at every step in small-cell, you have an attrition, right? From every cycle of chemo, some patients have to give up or will not continue. So, I think this magnitude of benefit has to be given to the majority of patients if possible. The other thing is about toxicity. I agree with you, it's manageable, or no, it's manageable after having learned how to manage it, right? But I mean we know how to deal with this toxicity because first we had done CAR T cells and TILs and now we do T cell engagers, so we are used to that. But, you know, if you want this drug to be distributed on a 1- to 2-hour outpatient clinic in the middle of nowhere in Switzerland, you need to make a little bit of education. It's manageable as long as you have been taught what to do and what to tell your patient about the symptoms which might come. Because if you don't, it might really turn very badly for exceptional but for some patients, right? The other thing is, so manageable when manageable after teaching. The statistics, I agree with you it's very immature because you have this censoring at the follow-up is shown, but when you start to simulate the end of the curve it doesn't look to be going worse, rather probably slightly better in term of hazard ratio. So, a good statistician, I always ask my statistician to simulate, he was pretty positive and we had the poster, maybe you want to tell about it. We had the poster of the DeLLphi-303, which was the phase 1b, and here we have a number, which again is fantastic. Remind me, it was 30? –So, it was first presented at World Lung last year and just for everyone to hear, so it's the combination of tarlatamab with PD-L1 inhibitor in the maintenance setting. So, same setting but essentially single-arm phase 1b. Last year at World Lung, reported a median overall survival of 25.3 months and now with longer follow-up, it's 37.9 months. So, more than a year, a longer median OS, and that's with median follow up of 30.8 months, so it's still not necessarily the final median OS, and that can evolve further. So, we'll see what happens, but I think that was another one I had on my list to mention at ESMO. And then just to throw one more in there, we did have the randomized trial of serplulimab or atezolizumab. This was in a US population. It was essentially to take what had been a previous randomized trial and to get enough patients for FDA consideration, I believe. And so there were about 100 patients in both arms. And I'd say what we see is actually a kind of impressive trend in those curves as well that looks to be favoring serplulimab. There was no statistical plan for that. So, this was not something where we're looking at hazard ratios and all of this. But overall, certainly trending favorable, I think, to try and demonstrate that this is certainly not worse than atezo. But, I'd say, it's actually kind of a reassuring trend to see on that as well. So, we'll see what comes from that in the future as well. But, unfortunately, we have used up all the time. Solange, I feel like we could talk about this for another hour, and I'm so appreciative of you joining me. Thank you, Solange, for the discussion. –Thanks to you. –And thank you everyone for joining us as well in this discussion about small-cell lung cancer on Medthority.
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