European Lung Cancer Conference (ELCC) 2025 Highlights: KEYNOTE-799, LAURA, MARIPOSA, KRYSTAL-7

Intro Hello and welcome back to the Oncology Brothers Podcast. I'm Rahul Ghosain here with my brother and Co host Rohit Ghosain. While we're fresh off the European Lung Cancer Conference, ELCC 2025, and there's so much buzz around all the data that was presented here, out of hundreds of abstracts that were presented, we've handpicked a few that are practice informing or practice reinforcing the ones that we really need to know out in the community. To cover these key studies, we're joined by Doctor Joshua Sabari, A thoracic medical oncologist from NYU. Back with us. Josh, you were with us for ASCO 2024 and we're excited to have you back for ELCC 2025. Speaker 2 Yeah. Thanks for having me, Rahul. Always a pleasure, Rohit, always a pleasure. I love talking to the oncology brothers so looking forward to a great discussion. Speaker 3 Thanks, George. Welcome back. So we'll touch on four to five important studies. We'll start off our discussion with state's renown small cell lung cancer touching on Keynote 799 and then Laura update. And then we'll switch gears to metastatic space where we'll talk about Mary poster study and close off with the Crystal 7, which is certainly a rapidly evolving space with KRAS G12C. First up is Keynote 799 where we currently treat any patient whose unresectable non small cell lung cancer with conquering chemo rats followed by durvalumab based off of Pacific trial as long as they don't have any targeted mutation, particularly common ETFR and ALC. Keynote 799 Josh, with that background in mind, can you touch on Keynote 799 Study design and its findings, please? Speaker 2 Yeah. So, you know, really this is an interesting study. It's an older study. So here we're seeing the overall survival update. So this is looking at, you know, concurrent chemotherapy and radiation, plus PD1 inhibitor, pembrolizumab, and a lot of buzz, you know, back in 2021, is this safe? And we saw about a 8% grade 3 pneumonitis rate. But interesting, lo and behold, you know, we're seeing robust response rates. And the update in 799 here, you know, we saw median survivals. That impressed me. So I think this is a potential opportunity for patients. There is an ongoing phase three study in this population, but unfortunately they added elapirib in the consolidation setting. So you know very shaky on that data there. So phase two study, some toxicity, mostly pneumonitis and not uncommon if we're using APD 1 inhibitor in combination with concurrent chemo RT, but very impressed with the data presented here at ELCC. I think this is something that can become practice changing in the near future here. So median overall survival in cohort A which is SQUAM and non SQUAM 29 months, median and in cohort B which is patients receiving a more aggressive chemotherapy regimen with cisplatin 45.3 months. This is something that I think is practice changing overall survival for this population. We saw in cohort A 35.6 months and cohort B 56.7 months. So yes, I think this data is exciting. Am I using it in my practice on Monday? Probably not. I'm probably sticking with the Pacific regimen at the moment. Love to see though the randomized phase three data in the future. Speaker 1 Josh, thanks for touching on this. You brought this up early on. Our fear was, is it increasing toxicity when we're adding radiation. So right now, even with Pacific, there's data that the sooner you start immunotherapy, they're better outcomes. You're brought up, it's not ready for prime time, but are you pushing for immunotherapy right away based on this and Pacific, is this going to change how fast you're exposing immunotherapy to your patients? Speaker 2 Well, it's a great question. Historically in the Pacific regimen, we wanted to get immunotherapy with dirvalumab started within 14 days. We know on the study it was not feasible and it's not really feasible in my clinic either. So I have a cut of 42 days. That for me is can we rapidly get that scan after finishing concurrent chemo RT patients doing well doesn't have significant side effects from chemo RT, esophagitis, pneumonitis. I'd like to get them started within that 42 day window and it takes a lot of work and effort to coordinate with my radiation oncology colleagues as well as our nursing teams here. So this is not easy to get going, but there's a lot of data supporting starting quickly. Whether we combine though together. I'm still a bit on the fence and I'd love to see more data. Speaker 3 Well, we could certainly take all day talking about some of the nuances here. Shifting gears to EGFR disease for ASCO 2024 where we saw Laura, the use of ocmertinib in common ETFR mutation post chemo radiation therapy avoiding the use of dirvalumab. EGFR disease Ocmertinib as a result did get approved in September 2024. But interesting caveat has been ocmertinib use lifelong. Before we talk about Laura, the most important thing is testing for NGS in early stage non small cell lung cancer. Exposing to dirvalumab or any immunotherapy is a wrong decision. Josh, could you please walk us through the Laura study and its findings here? Speaker 2 Yeah. So lower study as you mentioned practice changing, this is something I'm using you know, months ago and we're still using my practice currently. So these are patients with unresectable stage 3 non small cell lung cancer harboring and activating EGFR mutation, Exxon 19, Dell or LA5NR as you mentioned you have to test. If you don't test your patients, if you're not getting broad panel NGS upfront, you're going to miss these patients and give them immunotherapy by accident to the detriment of your patients. So when you test and identify an EGFR mutation patient, post concurrent chemo, RT and unresectable patients, these patients were randomized 2 to one to receive ossimertinib at 80 milligrams versus placebo. And the data was quite astounding, right. We remember at ASCO a significant improvement in median progression free survival. The overall survival was immature and there was a lot of controversy there, especially given the lifelong ossimertinib. Here at ELCC, we saw an update on the overall survival. Still immature, but improvement 58.8 months for patients receiving ossimertinib versus 54 months for a placebo. This really solidifies my practice. Speaker 1 Again, osimertinib wrote you brought up got approved in September. Josh, you're touching on this is now the standard of care for stage 3 unreceptable non small cell lung cancer with EGFR mutations. Josh, in the same setting, what's your practice for uncommon EGFR mutations or compounded mutations? Practice for uncommon EGFR mutations I don't know if you recall just a few months ago I reached out to you about this exact scenario. In my clinic, a patient has gone through concurrent chemo radiation. What next? Speaker 2 Yeah. These are difficult questions because we don't have prospective data in the setting, but e.g, Fr, L861, Qi would give them this regimen with consolidation. Ossimertinib we can extrapolate from the metastatic setting and we have a lot of experience, but the, you know, other uncommon or pack mutations, you know, G719 or S768. I want to see more data before we utilize ossemertinib. The label in the metastatic setting is afatinib and we all know afatinib is a tough drug, really tough to give in the adjuvant or consolidation setting and gosh, lifelong that would be really difficult for patients. Rahul, I know you reached out to me and we discussed, but I don't have a great answer for you in 2025 without prospective data in this setting. Speaker 3 And with regards to the indefinite ETFR therapy, any role of CTDNAI know that these patients are as we've talked about back at ASPIR 2024 conversation where you said that stage 3 is almost like stage 4, but have you utilized CTDNA here? Speaker 2 I mean, you can use CT DNA to help guide clearance, but patients with EGFR mutations that have unresectable disease, I put them in the stage 4 category. I don't think we're curing disease with adjuvant or consolidation ossemertinib. I continue therapy indefinitely even in my stage 3A patients. If you remember the ADORA data, three years, when we stop therapy, we start to see those curves coming together. And gosh, we've all had patients who have recurrence after stopping the ossemertinib. So you know, it's definitely discussion with patients. I agree with you in a row. I do use CT DNA as well as pet CT sometimes to better understand is there any viable disease, but I worry about stopping the therapy in these high risk patients. Stage 1B, stage two different discussion certainly, but stage 3B and 3C unresectable. I think we got to continue lifelong therapy here. Speaker 1 And another caveat to add here is CNS recurrence along with that PET CTCTDNAA lot of us are doing that MRI in these patients. So you got to keep that CNS recurrence in mind. Speaker 2 Yeah, critical point. I get scans every six months. It's so important for our patients. Speaker 1 All right, sticking with the theme of EGFR mutated disease, let's talk about metastatic non small cell lung cancer with EGFR mutation. Metastatic non-small cell lung cancer with EGFR mutation We now have three options, osimertinib alone chemo with OC based on Flora two study and the update that we're about to talk about amivantamab with losartanib. Yes, we'll get into the details of particular side effect management, but it is amazing to see that this subset patient population is living in living longer and longer. And of course, the spoiler here is at three years, median overall survival with amivantamab is 60 percent, 60%. That's huge. But this is also, of course, coming at a cost with more side effects. Josh, let's start off with Mariposa and then talk about how to better manage some of the side effects with the cocoon study. Big question here is in your clinic who's getting OC with flora to versus let's say OC alone? Are you just keeping OC for that failed patient or someone who's saying I just want oral agents? How are you dissecting all the options here? Speaker 2 Yeah. What an amazing space and really a testament for our patients and groups developing new therapies here. Three years ago, we had one regimen available for patients, single agent ossiemertinib. Now we have 3 that are FDA approved and hopefully many more coming, but all of these at a cost to the patient. As you mentioned, the Mariposa trial builds upon the successes of ossiemertinib. It's a randomized phase three study of amivantamab and lizertinib. Amivantamab and EGFR met by specific Lizertinib, a third generation EGFR PKI and we're studying that versus Aussie Mert of the control arm. And we've seen the data many times, PFS positive, right, 23 months versus about 16.7 months. But here at ELCC 2025 we saw the updated overall survival analysis and as you mentioned at three years we have not reached median not reached is a great thing for patients, right? So on average if you do the sort of analysis, you know it's about a 12 month potential benefit in overall survival for this patient population. But I think you hit it on the head roll. We're adding toxicity and who are the patients that will benefit? So there are significant cutaneous toxicities, dermatologic toxicities, acneiform rash, pustular eruptions on the scalp, there's an increased rate of VTE, venous thromboembolism, and clearly there's the issue with the infusion related reaction. So I'm discussing all three regiments, Ossiemerton, Ossiemo and the Mariposa. Amy Vanceben Lazertin. Am I fit young patients with high risk disease, EGFR L858R, cold mutations with P53 as well as CNS metastasis? I am opting for amivantumab and lasertinib in this patient population. Speaker 3 So how do you pick between again, where we stand with Flora 2 OC with chemo as well as Amy Labs? Because both of them have done well and even in high risk settings, whether that's visceral Mets or TP53 commutations itself. Speaker 2 Yeah, it's a great question. I think Flora too is definitely an advancement for patients, but it's adding conventional chemotherapy, carboplatin, pemetrexed to Ossie. Merton chemotherapy has been a standard of care in our second line setting. I really would need to see the updated overall survival, which is not yet mature. We hope to see that in the near future. For us now seeing the Mariposa data of a significant improvement in overall survival versus Ossie alone, I think that's what I'm reaching for right now. Do we have head to head comparisons of Mariposa Amylaz versus FLORA 2? No, but that could be a great study to do. I think in the cooperative group setting, we don't have that data yet. So really it's a discussion with patients, explaining the toxicities and going forward with what we feel is the best regimen for the patient. Speaker 3 Right. My practice has been OC alone, but after this compelling overall survival, you cannot ignore the advantages 1 can see with amylase. It is important to stress that patients are living longer and better. We're longer aspect, yes, we see from these curve, but better does come with some of the important supportive regimens that we have to rely on. Supportive regimens for OC Thinking about the regimen, so the skip IRR, right, We know that we can prevent infusion related reactions by using dexamethasone 8 milligrams two days before, a day before for a day of. We hope that the subcutaneous form will be approved in the future. As you mentioned for VTE Rohit, it's important to use prophylactic anticoagulation. We just saw the updated data on the COCOON study, very impressive, very rapid enrollment and I think a real world study for patients to see how can we get a regimen like this to be better tolerated. And we saw that prophylactic regimens using antibiotics, topical ceramide containing creams reduce the risk of Eugenia's toxicity is 3 or 4 fold compared to a reactionary type regimen. I've been doing this in my practice for the past three or four years. I could have told you that the cocoon study would be positive because because I see it in my clinic day-to-day. Speaker 1 And again, three years ago from us just recommending osmertinib to our patients, this is now an hour conversation with our patients explaining all these options because again these patients are living longer, but they have unique side effects, be it exon 20 mutation or a fund, these common EGFR mutations out in the community, we will get exposed to ambivantamab. So through skipper or cocoon data, we have to make sure we're getting better at just managing the side effects skin toxicities. We've touched on VTE, the prophylaxis of anticoagulation for first four months. All this is going to be very critical. All right, let's shift gears to KRS G12C disease, which ends up being one of the most common mutations in non small cell lung cancer right now. KRS G12C In second line, we have adagrasib and soterosib that's available as single agent. My preference here is adagrasib. I think the data is better. But as always, we talked about can we expose KRS inhibitors earlier and that takes me to Crystal 7. Josh, your thoughts here on this study and is it ready for prime time? Speaker 2 Yeah, So intimately involved in the development of both Adagrasive and sotiracid in the later line. And I was honestly depressed to see as we move to phase three studies, response rates lower, PFS lower and some of the OS data really makes you worry about these agents in the frontline setting. I agree with you. Adagrasive is my go to in patients who have progression on standard chemotherapy and immunotherapy. Adagrasive has better CNS penetration, better pharmacokinetic data and the data in the GI space appears to be largely better here. The question is, can we move it into the frontline setting? And I think you hit it on the head, Rahul, is this ready for prime time? I was impressed by this data as Crystal 7 is looking at patients in the frontline with G12C mutation getting concurrent K res G12C inhibitor at aggressive and standard of care therapy. These are the PDL 1 high patients who are already benefiting tremendously from immunotherapy. So here we saw at ELCC response rates phenomenal in that 6070% range. But what was impressive was the median progression free survival 27.7 months for those patients receiving adagrasib. And if you compare that to the historical control in Keno 189 who were PDL, one greater than 50 was about 11-12 months. This looks to me to be a dramatic improvement. Again, at what cost? We know that transaminitis, so immune mediated transaminitis elevations in the ASD and ALT can be be dramatic and need to be monitored very closely. Median overall survival for this study was not yet reached and here we're only presenting subsets from Cohort 1A and cohort 2. There is a larger phase three study underway right now. So really looking forward to that data and I hope that can change practice for our patients in the frontline setting. Speaker 3 So this data is very impressive, but at this point, George, if someone was to come down to your clinic with KR SG12C and P high PDL one, are you going to add KR SG12C in a better year? Speaker 2 Yeah, I would not yet. I think that if you have a high PDL one patient, I would still give a PD one or PDL 1 inhibitor in the frontline setting. But if you have access to the trials with Adagrasic, with olmiracid, right, the LY 9A2 deviracid or the Merck compound MK1084, I think those are great options for patients. And those are all randomized phase three studies. But I agree with you Rohit. I'm still using single agent PD1 inhibitor in this patient population until I have prospective randomized phase. Speaker 3 Certainly important and one can never undermine the aspect of clinical trials. So whenever possible, please definitely consider your patients to be enrolled in those. Josh, over the last few minutes, we've covered a lot here. Key Takeaways from ELCC 2025 Thanks for touching on some of the key highlights from the European Lung Cancer Congress 2025 for our listeners. Let us go on a quick recap though. Hundreds of abstracts were presented at ELCC 2025. In our discussion today with Doctor Joshua Sabari from NYU, we had a chance to focus on four key studies, 2IN unresectable stage 3 space from non small cell lung cancer and then 2IN metastatic space. Big take away is NGS. Even an early stage for non small cell lung cancer is critical. Update from lower study continues to reaffirm that OC mertnib in stage 3 EGFR disease after concurrent chemo rats is in fact the standard of care. Data from concurrent chemo rats and immunotherapy altogether in Keynote 799 with pembrolizumab is exciting but less likely to change the standard of care until we see longer term randomized data here. For now, the standard of care certainly is Pacific trial in unresectable stage 3 disease. Rahul, your takeaways from metastatic space? Speaker 1 Yeah. Again, mutated EGFR was a hot topic here as well, Roy. We had a chance to touch on the improved overall survival from Mariposa study, which is amivantamab and lizertinib in first line. And of course we were doing cross trial comparisons between Mariposa and Flora 2, which is also maritinib with chemotherapy. Also importantly, how to manage side effects that come along with these approved agents. We touched on cocoon part of skip IRR is very important. Yes, these patients are living longer. Let's make sure they can live better with these new agents. And then we closed off with Crystal 7 as we look forward to moving these K Ras G12C inhibitors in frontline, but we still need mature and bigger data to change your practice today. Thanks for joining us. Make sure to check out our other conference highlights, treatment algorithms and top ship discussions. We are the oncology brothers.