IMforte - Maintenance Lurbinectedin + Atezo FDA Approval for Extensive Small Cell Lung Cancer (SCLC)

Speaker 1 Hello and welcome everyone. We are the oncology brothers where the focus of our conversations is to bridge the gap wing community and academia in this rapidly evolving space of oncology. In this episode, we will be taking a deeper dive into the data from extensive stage small cell lung cancer, particularly focusing on IM Forte data and its clinical implications. I'm Rohit Ghosain and as always I'm here with my brother and Co host Rahul Ghosain. Speaker 2 Rohed I'm Forte data, which is the use of lurbinectodin and etisalizumab as maintenance treatment in frontline settings for extensive stage small cell lung cancer was initially presented at ASCO 2025. And right away, we saw overall survival benefit with us. But since then, we've also seen some updates of worldwide 2025. And just days ago, this is now also part of NCCN guidelines. So this indeed is now the new standard of care. To take a deeper dive in the data today we're joined by three thoracic medical oncologist doctors Isabel Persugal from Memorial Sloan Kettering, Doctor Tessiana Leo from Emory, and Doctor Steven Lou from Georgetown Lombardi Cancer Center. Speaker 1 Welcome, everyone. Let's dive right in. There's quite a bit to cover. Isabel, I'll start off with you here. If you could please outline the study design for IM Forte, especially the patient population that was included in the study and how Lurbinected in was incorporated as a maintenance therapy. Speaker 3 Absolutely. So just to give a little background, we have 3 approvals in the extensive stage small cell lung cancer space. We have carboplatin atopicide and atezalizumab, which is the EMPOWER 133 regimen. We have carboplatin atopicide followed by with durvalumab, which is the Caspian regimen. And we have the newly presented IM Forte phase three study looking at carboplatin atopicide and atezolizumab, followed by atezolizumab and lurbin and lurbinectedin maintenance. So let's go over the sort of the study schema first. So this was a large phase three study that was looking at patients with newly diagnosed extensive stage small cell lung cancer with no prior treatment. They went on to receive 4 cycles of induction therapy, which is carboplatin and atopicide and atezalizumab every three weeks for four cycles. And then if they had stable disease after those 4 cycles or even better response, they were then randomized to receive one of two therapies. One was a Tesla Lizumab every three weeks as maintenance and the other was a Tesla lizumab every three weeks as maintenance plus lurbinected in at 3.2 milligrams per meter squared every three weeks as well. And these maintenance cocktails were continued indefinitely until there was progression of disease or intolerability. Speaker 2 Isabel, thanks for walking us through. One thing that I do want to bring up here, within the study design, we also had primary prophylaxis with growth factors for all our patients in terms of the maintenance to help with neutropenia. Steven, this study got a lot of attention at ASCO and since its initial presentation, it was quickly adopted in our day-to-day practice because of that overall survival. Here, can you walk us through the data from ASCO and also touch on the recent update from World Lung 2025? Speaker 4 Yeah, happy to. So we know Libertarian is an active drug. It's been approved in the later line setting. It had activity and platinum refractory and in platinum sensitive disease. We've used it in the second line setting for many years. And so it's an active drug. So before the 1st patients enrolled, what do we expect from adding this drug in the maintenance setting from moving this up earlier? Well, compared to just standard immunotherapy alone and maintenance setting, we would expect some more responses. We would expect an improvement in progression free survival and we would expect an increase in toxicity with an active drug. But the big question is, would that translate to people living longer? And what we saw is that it did improve PFS, it did increase responses, it did add toxicity and fortunately that did translate to an improvement in overall survival. If we look at the PFS benefit, what's the degree of benefit here? Adding Lurbinactin into the maintenance setting improved progression free survival from 2.1 months with a TEZO alone to 5.4 months with Lurbinactin and then a TEZO that's APFS has ratio 0.54. It's pretty impressive improvement in PFS. Now if you first look at those numbers, you might say a TEZO alone, the PFS of 2.1 months seems low, seems like it underperformed. But the way this study was done, we're actually measuring from randomization at maintenance. So we're not including the 3.2 months of induction therapy. So if you take that 3.2 months of induction plus the 2.1 months with a TEZO alone, that's going to put us at 5.3. And that's really what we saw with the Power 133A TEZO PFS. The PFS was 5.2 months in that study. So remember, we're adding 3.2 months to the absolute numbers if we want to compare more apples to apples. I think the hazard ratio though at .54 is telling. If we look at landmark, if we give maintenance to TEZO alone, so we finish induction and we do maintenance TEZO alone. At six months, 19% of patients were progression free. That's the small #19%. With lurbinectidin and a TEZO, that number goes from 19% to 41%. We over double the number of people that are progression free at six months. And I think it's important to give patients that period of time where their disease remains under control. So we have an improvement in PFS with a hazard ratio of .54. But what moves the needle here is survival. Does that translate to people living longer? And it did. We saw an improvement in overall survival from 10.6 months to 13.2. Again, 10.6 with a Tezo, add that 3.2 and that gets you, you know, closer to 13. That's much closer to what we saw than power 133. But you're going from 10.6 and maintenance to 13.2. That's a survival hazard ratio of .73. Now if the OS hazard ratio of .73 sounds familiar, it's because that's the same hazard ratio we saw with Caspian, the same hazard ratio we saw with Adriatic. This we know is a clinically meaningful improvement in survival. While the absolute numbers are lower because it's extensive stage small cell, the relative gain is the same in OS benefit with a hazard ratio of .73, an increase in the one year survival rate from 44% to 56%. So this is a gain. We see an improvement in response rate and again we kind of reset at the time of maintenance. So we do see more responses, but we also see an increase in toxicity. Now your point Raheed is very, very good one that we were giving primary prophylaxis with pegulated GCSF because of hematologic toxicity. And what we do see is we do see more heme toxicity. If we look at the tornado plot overall, we see lurbinected in side effects. We see more nausea, fatigue, we see anemia, we see neutropenia. Most of these are low grade toxicities. And the word tolerability, as is always tells us, is one that's really subjective and one that we should try to avoid as physicians. But one objective measure we can look at how often do people stop any part of treatment due to toxicity? How often do we stop therapy because of side effects? And that number was 6%. It's a pretty low number. So 6% of patients stopping treatment due to toxicity. The data were updated WCLC at Barcelona by doctor Martin Reck. And what they showed was that most of the adverse events, the adverse events we're seeing with the addition of lurbinectidin are grade 1-2. They typically occurred in the first nine weeks of therapy. And once we got pressed that first nine weeks, new adverse events were much less common. Those interruptions were seen with lurbinectidin, but these were mostly driven, as you'd expect by hematologic toxicities. And again, the rate of discontinuation of any drug was very low in both arms. So really toxicity a little front loaded, mostly hematologic, a lot of these are paper toxicities or lab abnormalities, not necessarily patients feeling this. The rate of discontinuation due to adverse and unfortunately was very low. So clearly an advance, an improvement in survival and something we really should consider for our patients to to improve their outcomes. Speaker 1 Well, thanks so much, Stephen for summarizing that. There's quite a bit to unpack here and these are again exciting time for our patients and also medical oncologist. Small cell lung cancer historically has been a heart disease to treat and we are now finally seeing as you stated, the overall survival here with a hazard ratio of .73 TCNA. Initially when IO was approved in small cell lung cancer, as Steven said that we had seen similar hazard ratio. What we are seeing that is in addition to lurbinectidine, this was a maintenance trial. So this oral survival benefit is in addition to what we've seen in the past. Can you please help us in the context for our patients and us as medical and colleges, what should this data mean to us? Speaker 5 Yeah. I think this is, you know, a trial that clearly is showing that there is clinically significant improvement in terms of the outcomes of progression free survival and overall survival. And I think this is as you stated a very difficult to treat disease. And while we had gains from immunotherapy and immunotherapy in combination with chemo and maintenance, you know that that benefit was modest but also meaningful and this builds upon that. So again, this is a study that is from randomization, we're calculating the overall survival. So we do have to take into account induction. And so this is a difference that's meaningful. It's definitely a gain we're seeing here 13.2 months, adding the induction, as Steven mentioned, at an additional 3.2 months. So certainly, I think for our patients who are fit and eligible for chemotherapy at maintenance, I think this is a strategy that offers improved outcomes, certainly having to balance side effects and quality of life and having that discussion with patients. But I think overall we're very accustomed to managing side effects from urbinected in. As previously stated, we've been using it in the second line and beyond. And so we've been accustomed to managing the side effects of urbinected in. And importantly, I think here there weren't any sort of synergistic effects in terms of side effects when you added it to immunotherapy, there was an increased risk of immune mediated adverse events. So again, no signals there and and concerns, but certainly having the discussions about managing side effects and being proactive and certainly I think the growth factor is an important component of managing. Speaker 2 Ticiana, I echo what you said. Any survival here in this disease is meaningful. And we'll switch gears to talking about side effects. But before we do that, Steven, this data was adapted shortly after its ASCO presentation and now it's also part of NCCN guidelines. I think it's fair to say that most of our small cell lung cancer patients should receive this. So I think broadly, if we're using it, an important question would be who is perhaps not the right patient for this approach? Speaker 4 Good question. In the study to be eligible for that randomization, you had to have recovery of hematologic parameters. So you needed to sort of see that CBC come a little closer to normal. You had to have no progression importantly and still a good performance status. So I, I think we'll, we'll know them when we see them. Certainly if someone's progressing, we don't talk about maintenance therapy, we talk about second line treatment. It really would be a different strategy. But if patients still feel well and if the blood counts have recovered, it is something that we should consider. If patients are still prolonged cytopenias, neutropenia, that hemoglobin just not coming back up, maybe some with underlying MD's or some poor marrow reserve, this might not be the ideal strategy. If someone is just too frail after therapy, which does occur, this might not be the best strategy. We don't want to do any harm, but the patients are feeling well, which often they are. After we get that initial response, then I think it really should be considered and offered. Speaker 2 And again in second line, we have Luber Nectodine as a single agent and also terlatimab. So if the disease was to progress, we lean into those second line treatment options. Speaker 1 While talking about the side effects, this is a good segue to touch on that point and importantly, how to manage them. I know we talked about the prophylactic growth factors, which was part of the trial design when it comes to neutropenia, Isabel with leurbinectadin now combined with iOS, part of maintenance. What can we expect in terms of the side effects and how to manage them? Some clinical pearls around that please. Speaker 3 Sure. So yes, I think we've spoken about the neutropenia or just cytopenias in general that develop from induction chemotherapy. And our hope is that patients will recover some marrow marrow reserve from that. But we do see neutropenia, we do see cytopenias. We do see that includes anemia, thrombocytopenia and neutropenia. So all cell lines and I think it was about 73% of patients that continued the GCSF prophylaxis going into the maintenance setting upon randomization. And I do think that this is standard practice even in the second line setting. It is recommended to to if you're giving lurbinected in to offer GCSF support given its known baseline myelosuppressive effects. So I, I do think that this is not a surprise and I do think that this should be standard practice. The last thing we want is to have a patient get admitted for neutropenic fever or, or to have to dose reduce because of neutropenia, not because the patient is not able to tolerate it or, or having other side effects. So I think if we can, you know, get ahead of things that might be a good thing to do and just sort of be proactive rather than reactive. So I do agree with that. And while there were grade 3 and grade 4 toxicities, I don't think there was anything that was unexpected. When looking at the tornado plot, as Stephen had said earlier, I think we saw fatigue, we saw nausea and we saw cytopenias as the main as the main side effects. There are are other more rare side effects that can happen. I think there's rhabdomyolysis which is reported and I actually have had a case of that that I inherited, which is unfortunately devastating, but but can happen, but manageable. And if you keep your eyes open for it, I think that's something that you need to be aware of. But these are, these are manageable and we can be proactive about these things. And, and I do think that with the right support and with the right knowledge going into it, you can support your patients. And I do think that this is the right regimen to go ahead with for the right patient. Speaker 1 It's important to keep all these side effects in mind. But thankfully, as you stated, Isabel, that discontinuation due to toxicity in on Forte with lupinexidin was rather low TCN. Any additional thoughts with regards to managing these side effects, especially when you get started the patient on 3.2 milligram per meter square, DU dose reduced to 2.6 milligram per meter square. Or rather, give them a break and let the counts recover and then initiate at the same dose. Speaker 5 It definitely depends on the degree of decrease of the counts that we're seeing and sort of the clinical implications. You know, when you think about neutropenia, you know that's important. But really what is most important is, is there clinical significance? Was there febrile neutropenia And on the trial the rates of febrile neutropenia was very low and the rates of infections, grade 3-4 infection was also low. So I think that is sort of the most important piece of that. But certainly in the trial there was sort of the median treatment duration with the combination was actually double that of a tessomonotherapy. So a ES that developed during treatment can be managed with dose hold and dose modification. I think it depends on how the patient is doing for you know, low counts despite GCSF that would require a dose hold and then certainly require a dose reduction. And I think, you know when you look at the trial data, we did see that there was higher rates of dose interruptions or modifications. It was 38% with Lurbi plus atezo compared to 13.8% with atezo monotherapy. Again, same thing for the fatigue. I think for the fatigue, if patients are developing cumulative fatigue, especially higher grade level of fatigue impacting you know their day, day-to-day life, dose hold and dose reductions that can be very effective to managing that. Speaker 2 And this is where Art of Oncology comes in. I know there's some comfort of managing these side effects because again, we've been using lobenactatin as second life treatment option. Now we're just moving it in earlier lines as maintenance. OK. So now I'm feeling a little more comfortable in managing these side effects. And for that patient that is in my clinic, I am repeating CAT scans and brain MRI regularly while they're on this treatment. But then as as we're talking about brain MRI, this brings us back to where we started the patient selection. Steven, when it comes to small cell lung cancer, CNS involvement is something we always worry about. I am Forte excluded patients with CNS Mets in a patient with de Novo brain Mets who has undergone whole brain radiation upfront and is now starting systemic treatment, is this still a fair approach? And do we have any hint of Lurbinectidine having CNS activity? Speaker 4 Yeah, I think it's a pretty critical question. We don't have a lot of activity or a lot of evidence of activity for CNS meds, for lurbinactin. And this is not what I would consider a very CNS active drug. And so those patients were excluded from the study. They were also included, excluded from EMPOWER 133. And I think it's really just to try to keep that patient population very homogeneous to isolate the question, have as few variables as possible. This is a setting where if patients had brain metastases, I would still feel comfortable with the maintenance lurbinactin approach, but I would really, you know, pursue treatment of the brain metastases with radiation therapy. And so if the patient had had those brain metastases radiated, I would feel very comfortable with this approach if they met all the other relative criteria. If someone had small asymptomatic brain meds that were not radiated, we started with therapy, we had a modest response, and then we were considering maintenance libinectidin before we considered that maintenance approach. I would radiate those, I would treat them. And if you look at the in Forte study, patients were allowed to have path were prophylactic cranial radiation, not many did, but you could have it and they allowed for 9 weeks from the end of induction to the start of maintenance. And that's sort of the time frame with which I would pursue radiation therapy if someone did have brain meds. So I would treat them, but those patients, if anything, I think are at higher risk for relapse and potentially more likely to get benefit from a more aggressive maintenance strategy. Speaker 2 In those settings, are you still doing MRI every three months or are you doing it sooner? Speaker 4 I I still am doing it every three months, yes. Speaker 1 CNS enrollment in this particular disease is indeed a challenging topic. TCN. Another practical implication that we are tied in, especially in community and even in academics is that the use of durvalumab because patients are on carboplatin, the toposide and durvalumab now the maintenance option with a tisalizumab and lurbinectidin. When it comes time for maintenance, are you switching them to a tizilizumab lurbinectidin? Speaker 5 Good question. I think that's a really tricky one because the way that the regimen was studied and showing the benefits was with this combination. So I think if I had in mind that this patient would be eligible for maintenance with lurbinectidin, I would certainly choose the induction strategy with a tizilizumab upfront and would try to avoid the switch. But I think in certain situations would I do the switch? I probably would, but I think that, you know, I would rather start with a Tezo upfront in the induction strategy. Speaker 2 And Rohit, the reason why you're bringing that up is dirvalumab being every four weeks, whereas a TEZO is every three weeks and LURBI is every three weeks. So from the get go, I think that you and I have chatted about this as well in my practice. From the get go, you're having that discussion saying your whole treatment paradigm is chemo, immunotherapy, induction and then you're switching to that maintenance phase with Lurbi immunotherapy. Speaker 1 Well, before we close, we can go around in this virtual circle to gather our key take home messages. Here. Isabel, I'll start off with you here, any take home messages and then I'll move on to TC, Anna and Steven. Speaker 3 Yes, I think that as I had mentioned when we started, we have three options for patients with extensive stage small cell lung cancer. All of them are great options, but I think with this data, it's exciting to me. We always worry about relapse in that maintenance phase and if we have something that could prolong someone's progression free survival and overall survival statistically. I think this is definitely a regimen to consider for the right patient using shared and informed decision making always. Speaker 1 Indeed, it is the new standard of care and patient shared decision making is always the key. Steven, your take on messages, Sir. Speaker 4 You know, one thing that I hear concern about with the maintenance approach is, is, you know, why not just save this to second line? And I think the big thing here is that there's a huge amount of attrition in small cell lung cancer. And if we look at the number of people that get any second line therapy, it's a little bit less than half. And so the point of this maintenance strategy is to give a treatment before progression to try to prevent progression, be proactive and give our patients more time that if we wait until progression, that 50 to 6% of patients will not get any second line therapy. Despite tarlatumab Lurban acted in being available, they won't get any therapy because the act of progression itself can be one that makes people too sick to get any therapy or can be fatal. And so it really is being proactive, moving right into the next treatment and trying to prevent progression, trying to delay those events. Speaker 2 Right. We've seen this as a generalist as well, right over and over, not just in small cell lung cancer. This is a similar trend that we see across tumor types where it be a breast cancer, colon cancer, even for a non small cell lung cancer that often the patients are not exposed to that second and third line active treatments. Speaker 1 Indeed, TCNA, your take home message here. Speaker 5 Yeah, I think I agree with Steven as well as Isabel. This has been an important game for patients with small cell lung cancer. Now already included in the NCCN guidelines is a standard of care for first line maintenance. And I think the only thing I'll add is, you know, having the patient voice and making sure that we review this option with patients upfront before even starting induction so that they know what to expect for the course of their induction treatment as well as be prepared for maintenance. You know, where we're talking about introducing lurbinectidin, first line maintenance in combination with immunotherapy and explaining that to them in ways that they can understand and make their choices. I think for, you know, for the majority of patients, this is a treatment that, you know, we are going to be discussing and I think patients are going to be interested in it. Obviously, there's some patients that may not be eligible, but, but I do think it'll be a small percentage of our patients as long as we optimize their care and work in a multidisciplinary fashion to get them there. Speaker 2 Absolutely, that shared and informed decision is so important. And you know, as medical oncologist, we acknowledge that small cell lung cancer is indeed a devastating disease, but these are exciting times as we are seeing improved overall survival and our patients are living longer because of these interventions. Steven Isabel Ticiana, thank you so much for taking the time to go through the data in hand for small cell lung cancer with us today. For our listeners, let's us go over a quick recap from today's discussion. Speaker 1 In today's discussion with doctors Isabel Pershagal, TC, Anna Leo and Steven Lou, we had a chance to take a deeper dive in treating extensive stage small cell lung cancer, particularly focusing on M Forte given its overall survival benefit. We have seen more than doubling of PFS and close to three months of overall survival benefit here with hazard ratio of 0.73 with lurbinectedin maintenance with etisalizumab. Speaker 2 Rohit, one thing that kept coming up was the importance of overall survival here because small cell lung cancer still remains an aggressive disease. Besides this, we also touched on the importance of prophylactic use of growth factors to help with neutropenia. Getting comfortable in managing side effects that come along with our interventions so that our patients can stay on these treatments for longer safely is equally important. Thanks for joining us. Make sure to check out our other discussions around recent approvals, treatment algorithms, and challenging cases. We are the oncology brothers.