Lung Cancer ASCO 2026 Highlights: LIBRETTO-432, CROWN Update, CHRYSALIS-2, HARMONi-6

Hello and welcome back to the oncology brothers podcast. I'm Rahul Gossane here with my brother and co-host Rohit Gossane. At the time of recording of this podcast, we just literally got back from Asco, 2026, where we saw thousands of studies being presented. Today we're focusing on lung cancer, and here Rohit and I have picked a few that we believe are practice changing or practice reinforcing in our community practice. To walk us through this data, we're excited to welcome back Dr. Isabel Prishagal from Memorial Sloan, Ketring, Isabel, thanks for joining us. You just got back from Asco, and you were in clinic earlier this morning already, probably thinking through the data, applying some of these studies this past weekend. Thanks for joining us. - Thanks so much for having me, both of you. - Isabel, welcome. Have you used libretto today and your clinic already? - So actually had a patient that I saw and followed up that was on study, so yes. - Oh, exciting times of day. - But haven't had that opportunity yet. We are looking forward from community standpoint to start utilizing these therapies. While focusing on Asco, 2026, we'll be touching on four key studies. Two of them from Plenary, the libretto 432 in ret positive disease, and Harmonie 6 in Squamous Cell lung cancer. And the other two studies will be crown trial update in out positive disease and chrasalus for atypical EGFR mutation. Let's start off with our first study here. Isabel, can you touch on the study design of libretto 432 and it's finding please? - So libretto 432 was a study in the adjuvant setting. So these were patients that had resectable disease. So stage two to stage three A, harboring a ret fusion. They underwent upfront resection. Some underwent adjuvant chemotherapy. And after that, they were then randomized to receive cell per catnip, 160 milligrams twice a day, versus a placebo twice a day. And then they were followed for up to three years. And I think this is really important because we have lots of other studies in the adjuvant setting where we're moving targeted therapy in there. We're looking at Adora and the EGFR space, Alina with patients that harbor alkyfusions. And now we have this libretto data with patients that harbor ret fusions. And I think before we dive into some of these findings, it's really important to just emphasize that all patients regardless of stage should undergo next generation sequencing testing. So we need full DNA based testing and RNA based testing to not miss these fusions like ret and alky. Some of the findings that you can see here, just very clearly you see a nice separation of the curves. And what we're seeing here is that for patients with resected stage two and stage three disease, 92% of the patients were cancer-free at two years, versus about 60% of the patients that were on placebo. With a hazard ratio of 0.172, which is astounding. You are reducing the risk of death by over 80% by offering this for your patients. That is convincing enough for me, even though this was event-free survival. And obviously we want to know the overall survival data when you've already potentially cured someone with surgery and adjuvant chemo. But this is definitely enough to be practice changing for me at this time. Obviously I know toxicity. And I think that that is something that we can't lose sight of because we're committing these patients to target a therapy for years. And it's not a free lunch, right? We're worried about transaminitis here. We're seeing some of the dry mouth. We're seeing some of the billy-roobin increase. We're seeing some of the hyper-recemia constipation. It's not super easy to tolerate. There is wiggle room for dose adjustment. But I think for the right patient that's motivated and data-driven, I definitely think it's worth a discussion and offering. Rahul, do you recall this has a ratio of 0.17 from multiple myeloma refractory tectera? That's a stounding idea. Absolutely. We continue to see more and more active drugs come to us in our clinic. But a few things here is about like a dooro trial with adjuvant osomrtonib. Here's salt per cattonib is for three years. A lectinib is for two years in alenotrial. Here for libretto 432 chemotherapy was allowed. I have two questions. Let's start off with the first one. Do we really need chemotherapy for all? For EGFR disease with osomrtonib, do skip it for our stage one. B patients, is that going to be your practice here for rep positive disease? I think it's a really tough question. And if you were to ask 100 oncologists, you'd probably get different answers. Some people are of the mindset that targeted therapy does not cure on its own. In which case, those are the believers in giving the four cycles of adjuvant chemotherapy for those patients that had resected, maybe even stage one V to stage three A disease. But then if you have someone that's maybe older, maybe a little more frail, multiple medical comorbidities, earlier stage, some folks may say we could get away with out giving the adjuvant chemotherapy. I think it's all about talking to your patient about the potential risks and potential benefit and what that's gonna look like and make sure that whatever you offer them is in line with their goals and their wishes for their treatment course. I tend to stick to the book and offer adjuvant chemotherapy if I think someone's fit enough for it and then offer them the targeted therapy. But it's really a risk for a benefit discussion and it's not a one-size-fits-all. - And again, because with adjuvant chemotherapy, we have that overall survival. So we have to keep that in mind. Another thing that you alluded to, maybe we're not curing the disease. And we see this in unresectable disease after concurrent chemo-radiation for that EGFR positive disease. When we're using Osomaritinib, it's for lifelong. Are we going to extrapolate this data with sulper-catinib in those settings? If so, for how long? Would you extrapolate this for your unresectable disease? For your given concurrent chemo-radiation and there is that ret positive disease? - You mean outside of a clinical trial? - Absolutely. This is all outside clinical trial in clinical practice and community settings. What should I do? - I think if you can get it approved, I think it's worth a discussion. I would bring the case to tumor board. I might talk to someone that focuses primarily on fusions and what their take is. I do a liturist to just make sure there wasn't some small study somewhere that looked at this and it had some crazy safety signal. - Absolutely. - I think what's happening here is that we're seeing targeted therapy in the stage force space, creeping into the early stage space one driver at a time. And I'm excited about this. And if you guys have me back next year, maybe we'll be talking about it. - Again, I think it'll be patient shared decision-making though telling them that there is no data existing, but again, there is a targeted mutation. Just like what we do for a lectinib right now for unresectable disease itself. - Yes. - And is it available with regards to toxicity? What we see is trans-eminentis, diurea, dry mouth. If you don't mind touching on some of the important clinical toxicity and clinical pearls around that. - Yeah, so in my practice, the most that I'm seeing really is the trans-eminentis. And whenever I see that, I always want to make sure they're not unstattained. They're not taking Tylenol for post-op pain or something that I'm unaware of. No supplements, herbs, nothing they bought on the internet that could potentially be interacting here. And once you've really eliminated all of that, you wanna make sure you're not missing an autoimmune hepatitis or anything along those lines. So there's a lot that I check into before I blame it on the salper. But if it does end up being salper-catnib as the culprit, I think you always wanna make sure what grade toxicity is this. - And these. - If it's grade one versus grade three, grade three requires a hard stop, right? And then you wanna just recheck again, and if it resumes down to a grade one, you can consider resuming at a dose reduction. But obviously if it's much greater, if it's grade four, you know, no rechallenge at all. And then grade two, I tend to also hold for grade two and repeat labs and then cautiously resume. Sometimes we need to add steroids in here if there's some kind of drug-induced hepatitis, in which case we do weight-based prednisone, 1 milligram per kilogram, and I involve our hepatology team right away. I think their expertise is unmatched. So you always wanna partner and have it be more of a multidisciplinary approach. In regards to the diarrhea, the dry mouth, the cough, haven't really seen all that much of that. Maybe diarrhea here, there, it's really the transaminitis. And other than that, we do watch the EKGs very, very closely. You wanna make sure, 'cause there can be EKG changes. So anytime someone has starting on a new drug that might potentially change the QTC, like a new mood agent or another anti-nauget tablet, you always wanna check an EKG and be very aggressive about that. And also if anyone has any chest discomfort or anything along those lines, we don't wanna miss a cardiac event here. - Indeed, this is one drug that does prolong that QTC. All right, onto our next study, that is Crown Tri-Hole, looking at L'Orlatinib in front line, metastatic non-small salon cancer with out positive disease. We've seen an update about two years ago, and now we are seeing a seven year update here at Ask A 2026. Isabel, what are we learning from this update and side effects to keep in mind? - Sure, this was the seven year follow up in regards to progression-free survival. And what we can see here based off of these curves is that there's 55% of the patients that are still progression-free, meaning their cancer has not grown at seven years, which is amazing. And in addition to that, we have maintained excellent CNS control, 'cause we worry about brain tasks to see these patients. And there were no new CNS events after two and a half years, which is demonstrating outstanding CNS control in my book. - I think the reason why we need to talk more and more about these side effects is because of these interventions, these patients are living longer. So even those grade one, grade two side effects, start to accumulate. So now, if you can touch on these side effects, that'd be great. So similar to the other alktrugs, you worry about GI toxicity, you're about transeminitis, you worry about edema, maybe not so much. But some of the more unique side effects with lorlantinib are hyperlipidemia, especially if you're already on a statin, or you're already have baseline elevated cholesterol and you're not on a statin. So I always check a lipid panel and pretty aggressive about that and I repeat it pretty frequently actually for my patients until about a year when I kind of back off to make sure that we're not missing any early toxicity. So in addition to that, there's also some mood changes. If you have somebody that's already with underlying anxiety and depression, it can exacerbate this. I've seen it unfortunately twice in my clinic in someone that was of the older population that ended up being somewhat altered and then someone in the younger population that just needed a little bit more emotional support during the initial onset of treatment within the first couple of weeks. So my recommendation is to partner very closely with their psychiatrist and follow these patients every two weeks for the first six weeks and then maybe even more frequently after that if you need to if you're making any adjustments. But really close touch points and over communicating to their caregivers as well. If you notice a mood change, you notice the patient is altered. Something's off. Please call us. It may be the lorlantinib. Also, what I've seen is dose reduction really helps here. So something to keep in mind. Definitely. Before I close off the topic of out positive disease, as a ball, we saw some very good data around lorin trial, which is a rather a small phase two study looking at lorlantinib in neoadjuvant for out positive disease. This is still early, but given a mason results, any patient today that you would consider that in your clinic, especially for that borderline resectable disease that could potentially go for curative surgery after a front lorlantinib. So I am very tempted, especially given the data from neoadora that looked at neoadjuvant OC versus OC plus chemo versus placebo. And it was astounding how well all of the OC containing arms had much higher major path response and much higher nodal downstaging. So obviously, I think the data from lorin is not quite mature yet and is not nearly as robust as neoadora at this time. But I think if they're outside of a study, I think it's something that I would once again present to our group and share that this is a data free space. But if I had that opportunity, I might, you know, for a fit patient, it might be something that I would discuss. But then there's a question of like, well, then what would we do after like with the elina data there, which I think is always that push pull even with neoadora and adora. So I think the jury is not out yet. Given that we're in this data free zone, if we're talking about lorin trial, if we are using lorin latinab upfront in neoadjuvant settings, we should continue with electinab or lorin latinab in those adjuvant settings, because you don't want to further go because the strong data and the approval is actually in those adjuvant settings based off elino trial. Okay, now on to chrysalis to study looking at amylaz and metastatic atypical eGFR mutated and non-small cell lung cancer. Amylaz is already approved for common sensitizing eGFR mutation. For these atypical mutations, historically, we were using a fattenab. And we also saw data from unicron trial for ulcer mrettenab. And here now we're looking at amylaz is about what can we learn here and importantly, what is your preferred treatment for these atypical mutations? So I have to tell you, I was thrilled with this. It had been one of the most exciting things that was presented at asco to me because I have a large patient population with atypical eGFR alterations. And it is always a battle and a fight with the insurance companies about getting the treatments that I want for these patients and that they so, so deserve. So the chrysalis trial, as you can see here's a little bit complicated. There's, you know, multiple cohorts. We're going to focus on cohortsy, which is the atypical eGFR. So when we say atypical, we mean patients with L861Q, not like the classical eGFR alterations like X-N-19 and X-N-21 L858R. I think this is a new option for these patients. Maybe the new standard of care, I would definitely consider this front line with a median overall survival 41 months. I think 55% if my memory serves me right, we're alive at three years. I think we're dealing with a fattenab, which is very toxic, very challenging. It may not be as good as this. I don't really know. We know I'm doing cross trial comparisons here. It's difficult to say. But I think that this for me will become the new standard of care for these patients. And then to be the first to lean into that is because of the overall survival roads here, we are finally seeing an overall survival, which is amazing. Right. And we know a fattenab is not the easiest treatment regimen to tolerate with regards to diarrhea. Most of the patients would incur that. And when you talk about amylaz, sure, again, this one is chemo-free regimen. However, there are side effects associated with this as well. And as a result, we have to educate our patients about the rash, ret risk, and staying compliant with the supportive regimen is extremely important here. Actually, sorry, before we run away from that, this whole idea of chemo-free, I want to bring that up. Again, we say that it's chemo-free, but this is not side effect free. Right. Right. But before we move on to harmonies 6, this is chemo-free regimen, but amy-ranthamemla-zert has its own fear of side effects. Yeah, I have to say I don't love that term, although it's somehow been adopted. I tell my patients, even if you're on a pill, it still has its own toxicity. And I want you to kind of imagine it's a chemo pill that you're taking every day. Because the patients are like, why am I still living toxicity? Why is this happening? What's going on here? If they kind of wrap their mind around the fact that they're in a way, not really taking chemo, but taking a little bit of chemo every day, it's kind of easier way to conceptualize that they're getting treated for their cancer every day. We're getting better and managing these side effects via with cocoon regimen or just being proactive, but again, educating our patients on what to expect is so important here. Indy, all right, moving along into our last study here, which is harmonies 6, focusing on metastatic squamous cell disease, another plenary discussion, looking at Iwanesimab with chemotherapy, as well. What are we learning from harmonies 6 year? So I think one key takeaway is what is Iwanesimab? And this is dual headed drug, right? So one head is Vajaf and one head it has as an immunotherapy head on it. And I think that it's, you know, we're seeing Iwanesimab in combination with chemo and combination with antibody drug conjugates, you know, it's really, we're not sure where it lives, but I'm excited about this drug and I think, you know, especially in this very challenging to treat squamous cell population, any signal that we get and any option that we get is exciting for me. Obviously, this was a unique patient population. It was a China study, but that doesn't mean that we can't consider extrapolating some of that data and looking into this drug for our potential patients with the median overall survival of around 27.8 months versus 23 months in the Carbo-Taxal Tessilismab arm. I think that you're clearly seeing a benefit there. You're seeing a nice separation of the curves. I think when looking at the tornado plot, when talking about adverse related events, I think they were fairly comparable between both arms, whether it's chemo, Carbo-Taxal with Iwanesimab versus Carbo-Taxal with Tessilismab, just an immune single agent immunotherapy with chemotherapy. I would say you're seeing the toxicity you would expect with a Vegeph inhibitor. You're seeing the proteinuria. You're seeing the hypertension and some of that, but I would have expected maybe bleeding events or something along those lines and I'm happy to see that we didn't see any of those. And I would say this data is intriguing to me. Can I jump here just to reiterate a few things. Ivo is indeed this bi-specific targeting Vegeph and PD1 together. It's about you also touched when we're using our Vegeph inhibitors for a screamous cell historically. We've been worried about risk of bleeding. Here in Inclusion criteria, we had to be mindful of who's included. But to me, this is indeed intriguing that the bleeding risk was roughly 3% in Iwanesimab arm. This is not zero, but thankfully, this is still very low. Another thing to keep in mind, this is China-only study. This ongoing global trial, but I do think that a global trial ends up being positive. This is going to be a new drug that becomes available to us and I'm personally excited about it because there's not much we've seen in screamous cell lung cancer. Such an unmet need. I know we've covered a lot here in a short time, but any final thoughts from Asco 2020-26 for lung cancer? I think the take home message for me was, do your molecular testing regardless of stage and regardless of histology. There was a beautiful paper that came out that talked about finding driver alterations in patients with screamous cell carcinoma. So please, please, please, don't cherry pick who gets next-gen testing. Every patient that walks in the door that sees you if they haven't had next-generation sequencing testing, non-small cell lung cancer, regardless of stage and histology, they should. Your missing treatment options, your missing better outcomes for your patient potentially. So that's my take home. GS or biomarker, testing here is essential to be at screamous or adenol, regardless of their background to back exposure or anything. This is now the standard of care. On our end for completion sake, I do want to at least mention there was an update from Delphi 304 for a turtle actimab in second-line small cell lung cancer showing very good CNS activity and there's certain survival benefit with Tarlat Mab here, discontinues to reaffirm that Tarlat Mab is the standard of care option in this settings. I know there's a lot of data coming at us, but I'm hoping that these bite-sized discussions keep our community colleagues afloat. Isabel, thank you so much for taking the time to walk us through these important studies from ASCO 2020-26 for our listeners. Let's go over a quick recap. - Today, we have covered four studies that we picked out in the space of non-smalls along cancer from ASCO 2020-26, with Dr. Isabel Prishigal. The first one was libretto-432, where we now have event-free survival data with sulpercatnib in ret-positive disease. This is very likely going to get approved, and we will look out for overall survival here. Then we also touched on crown trial update with Lourlatnib. That's a seven years progression-free survival, which is sitting at 55% versus 3% with croissant-nib. With Lourlatnib, we have to be mindful about the side effect profile. As a good portion of patients do see these. Rahul, what do you want to add here? - Well, we also touched briefly on the role of Lourlatnib and neo-aggiven settings. This is a small study, but that signal upfront is very impressive. Then we touched on chrysalis-2, where we saw updated data from amylaz and atypical eGF-form mutations. This is exciting to see overall survival benefit in these settings. Then two clothes we touched on harmony trial, another plenary discussion, where we saw Ivo-ness-Mab with chemotherapy improved overall survival in metastatic scrimous cell cancer. But this is China-only study. We're looking forward to global study before adopting this in our practice. And then we also touched on Delphi 304 update, where Tarlatnib continues to be our standard of care in second-line settings for small cell lung cancer. Thanks for tuning in. Make sure to check out our other discussions including our conference highlights, treatment algorithms, and FDA approvals. We are the oncology brothers.