ESMO 2023 Lung Cancer - Chapter 2 Highlights – PAPILLON, MARIPOSA, MARIPOSA-2, LIBRETTO-431

Welcome to ESMO 2023 Lung Cancer Highlights Hello everyone I am Rahul Ghosain. And I'm Rohit Ghosain and we are oncology brothers post ESMO 2023. We've seen multiple practice changing studies in bladder cancer, GI cancer and of course lung cancer. Specifically in lung cancer, we saw a lot of data in patients with actionable mutations and one drug that should be on your radar is amevantimab to cover all things amevantimab. And look at the data for paplan study in EGFR, Exxon 20 mutation in first line, then Mariposa and Mariposa 2 for activating EGFR mutations. We're joined by Doctor Alex Spira in this discussion. We're also going to cover some clinical pearls on managing toxicity from Imivantamab and then close off with Libretto 431 data for Rep fusion positive non small cell lung cancer. We have a lot to cover here, so let's get started. Alex. Thank you so much for joining us. Speaker 3 Thanks for having me guys. Speaker 2 Welcome, Alex. PAPILLON Study: Amivantamab Plus Chemo in NSCLC To get started, let's take a look at our first study, the pavilion, a phase three study looking at the combination of Amy Vantumab with chemo versus our current standard of care chemo for EGF 4X120 insertion mutation. Amy, Vantumab is already approved in second line for this particular patient population and we also have mobile certinib here, but that is being pulled off the market because of the weak data that we have. Coming back to papillon study, what did the study exactly show? Speaker 3 Yeah. So the the idea about Papillon is trying to move, as you said, moving Hemivantamab in the first line setting. It was felt not to be good enough to beat chemo on its own, which is why the study is comparing it with chemo rather than in lieu of chemo. Obviously, that's still a good question. But I mean these are curves that are as, as good as it gets, right? I mean and the bottom line, if you look at PFS. 12 year landmark, 48 versus 13 percent, 18 month, 31 versus 3% progression free survival or hazard ratio of .39. You know that's as good as it gets. So clearly significantly better when you get amavantamab in the frontline setting. And of course none of us are too surprised by this, right? I think we were surprised more about how good it was improved based upon the data. So this is practice changing and it was a current New England Journal presentation. Speaker 1 Thanks for bringing that up. I think it is so important to consider our best treatment options upfront. And again something to reiterate, the treatment response with this combination was also a whole lot better. So yes, the PFS has improved, but also the response rate was better with the combination, Alex, in your clinic based on PAPLAN study, a patient with EGFR exon 20, are you going to be prescribing amyvantamab with chemo upfront moving forward? Speaker 3 Yeah. So I think outside of a clinical study and there are actually are some other good clinical studies ongoing as we speak. But to me this is a no brainer right now everybody should be getting this in the front line setting for lots of reasons. One is it's better and two, if you really drill down to some of the data and by the way this data was not, it was good, but remember there was crossover as well. So this is accounting for the fact that many people got ad me a progression. So in theory, the data is even better. It's of note that in all these studies, there's a real percentage of the population. I don't know if they reported in Papillon, they didn't. It was looked at in both Mariposa and Florida too. About the 3rd to 40% of patients never get to second line therapy. So you're going to be giving people targeted therapy here and a significant number of those never would have gotten a chance to get it. So yes, the answer is yes, completely. MARIPOSA Study: Amivantamab & Lazertinib for EGFR NSCLC So we're moving along from one practice changing to another practice changing study. All right. Now let's assume that we are doing a good job with NGS testing and instead of Exxon 20, we see one of the common activating EGFR mutations, Mariposa. Another phase three study compares the parent standard of care, OC Mertnib with laserdinib, oral combination of amivantimab and laserdinib. The primary endpoint here is PFS and secondary endpoint is OS. What did the study show Alex? Speaker 3 Yeah. So this is thanks for bringing those up. So I can see it. This is a very straightforward study and I have slightly different conclusions when you get to what does this mean for practice changing. But bottom line is and we're now we're just looking at AMI Las versus OC. The Las versus OC was related to document that OC that I'm sorry that Las is going to be just as good as OC which we believe it was and it was shown here. But what you can see is #1 patients responding clearly improved, duration of response clearly improved. 25 versus 16 months and the primary endpoint PFS one year, landmark 73 versus 65, two year landmark 48 versus 34%. So clearly doing better with AMI Las right now. We kind of expected this because we knew, we know Amavantamab in the second line setting and we'll look at that a little bit again with Mariposa too. But there's been very good data from Chrysalis that showed that Amavantamab is a very good luck. Good drug in the second line setting and by giving it in the front line setting, you're improving outcomes really across the board. Has your ratio not quite as good as Papillon at .7? Speaker 1 Alex, this data is of course exciting, but as a community oncologist, I also have to get comfortable with supportive care. Clinical Pearls: Managing Amivantamab Combination Toxicity Can we dive into the side effects of this combination for a second? We saw higher venous thromboembolisms with Amivantamab and lezertinib. Do we need to start prophylactic apexaban or rivaroxaban upfront now? Speaker 3 So you're now going to have three options of the frontline setting. You're going to have OC by itself. We know about flora two which was chemo OC versus chemo and now you have amylase and there are some subtle differences in this you it is going to be recommended that you give patients prophylactic anticoagulation. Unclear if that's going to be a black box warning or mandatory, it'll probably just be a very strong recommendation. There was clearly increased toxicity. With DVTS and PES, nothing major, they were all manageable. When you're given the combination, the etiology is unclear. Some hypothesize that it works so well that you were killing tumor so much with the combination that you're having a DIC LE effect like effect. Some hypothesize that's an inflammatory spec. With the combination, of course we don't know the answer, but this does require, in my mind, prophylactic anticoagulation, prophylactic doses, not therapeutic doses. History of prior DVT or PE should not make you not think about this. But of course, putting patients on a blood thinner is a risk, as is everything every time we do it. Speaker 2 And thanks for covering that Alex. And as you stated and just to dwell on that, but now we have the option of OC mertnib or lasertinib balloon versus chemo with OC mertnib or ameventumab with lasertinib in your clinic. When you are going to prescribe an event or single agent, OC Martnib, what do you think will that scenario look like and when would you even consider this? Speaker 3 So I guess when am I gonna dose escalate is what you're saying, right. And that's a really tough question and if you look at the discussions. And I went, I'm a co-author in Mariposa, I'm the steering committee. I was very enthusiastic about it. But when you get to talk to everybody at these meetings, which is the fun part, it was a lot more muted. I mean while you haven't proven in outcomes here, it comes with real toxicity. And he does have you have to give people DDT prophylaxis you. Of course, worried about the amivantamab toxicity, which is skin rash, Paronychia infusion related reactions, the IR Rs will likely go away because there's a lot of thought and the development of a subcutaneous form not available yet. Hopefully it demonstrates that it does will free up chair time, make lives easier for patients, less IR Rs as well. But you're still talking about increasing toxicity And let's face it, guys, it's very nice to give somebody a pill and have them come in and say you're on a pill, you're doing great and it does work. Really well. So we need more analysis. There will be some patients that have higher burden of disease that you want to drive more tumor down in. There was the beginning of an OS benefit in Mariposa. We didn't quite see that in Florida too. And if you ask 100 oncologists right now that are thoracic oncologists. About 2/3 say they don't think they're going to see an overall survival benefit in Florida too. We do think we're going to see one in Mariposa because it was almost there. The P value was .11. So we'll probably get there with the next data cut, which would be great, but there's a lot to go into it. You know they're going to be looking at things as do you do worse if you have L858R? Because we do know those patients don't do as well as Exxon 19 is a Co mutation such as P53 or RB1 going to vote for worse, None of us know that answer, right. So we're all going to struggle right now as to what's a better drug to give in the frontline setting. You know we, I like to say you can just have the discussion with your patients, but you know you guys are oncologists, you know what the answer is going to be, what do you think I should do doc? And I also will tell you that if you tell them one thing, somebody else will tell them the other thing. I think just because. We've all had that. I'll go for the second or third opinion and let's face it patients and and I think a big take home message is if you look at the data and this is true from both for Mariposa and Floor, 240% of patients never get the second line therapy. That's a huge number of patients. And here you have a controlled setting of a clinical study, right. What happens in the real world. They were actually also able to look at some of what's called the PFS two analysis. And said many patients just went on to single agent CKI once they progressed on one of these two which I find a little strange as well. So in me I think it's going to involve looking at the patient thinking about how aggressive they want to be, how young they are, do they want to put up with everything. It's because while we can say those other analysis will be great, you know as well as I, it's going to be another 24 months before we get those analysis. So to me it's really drilling down to the patient desires and how I want to treat patients right now. You know, I didn't mention much about Florida. Two, you know, you know, it's nice to offer patients a non chemo option. If you ask me, there's not a lot of different toxicity between Flora two and Mariposa. You know, carbopem is a pretty well tolerated regimen for the most part. There's obviously something very nice about a chemo free regimen which is what Mariposa offers. So I basically dodged your question. Speaker 1 No, I think this is important because at the end of the day, having these conversations and understanding the granular data and maybe just picking the right patient is so important. So thank you for covering that. MARIPOSA-2: Amivantamab Post-Osimertinib Progression Moving on, I think a bigger unmet need is also what to do next. Appreciating a small cell lung cancer clone or looking for resistant mutation at the time is very important, but again that is a small portion of our patients. Meripostat 2 looks at this unmet need comparing Amivantamab, liszertinib combination with chemo versus Amivantamabit, chemo or chemo alone. The primary endpoint again here is PFS and OS is our secondary endpoint. Alex, your thoughts here. Speaker 3 So you know the standard of care is chemotherapy, 1,000,000 clinical trials ongoing. So the idea here is, can you improve on chemotherapy? And it looks like you can, right So. AMI chemo versus chemo clearly improvements here. The question is whether or not you had Lazertina or not. The Lazertina versus AMI chemo, you know, those lines don't look significantly different, right there. There's a lot of overlap as well and you know you're probably not going to go into a lot of these, but some of the other slides did not show, did not even look as good as this one. So to me, it's looking at the blue line versus the. Tan line right now or the red line versus the tan line and clearly we we learn it's not a surprise based upon Chrysalis that AMI does improve outcomes with chemo versus chemo alone and once approved is a new standard of care in that scenario. The hazard ratios are great here as well. You know whether or not you know Lazerna needs to be done probably does not need to be done. We consider LAZ the same as OC, so you know right now. In my mind, we give up a lot of people osmertonib with chemotherapy just because it's totally in the absence of data and it's one of those things we're not supposed to be doing. But I don't know what it's like by you guys, but everybody I know says just just give it. Well, just give. It comes with toxicity cost and it also comes with a financial cost. That it's easy to say forget about, but you can't. So to me AMI clearly is a standard of care right now with chemo, the addition of lazertinib, neither here nor there. And then it's going to come down to there will be some people that say give OC Frontline, give chemo AMI second line and you hit everybody. And that's not unable to do right now. Although you are missing some of those people that never get the second line. But it's not an unreasonable combination here that we can do right now. And as you can see the response rates were not reasonably different. I mean basically the same AMBI in the on the on the left side, Amy Chemo versus Amy last chemo. Oh, thank. Speaker 2 You for sharing that it is important that we do look at this data and dive in especially with the CNS benefit, which is commendable whether you combine that with Las, Las urtinib or not. Just looking at this data, particularly from Amy Vantimab, because we'll be utilizing this drug a lot in our clinics. Practical Management of Amivantamab Infusion Reactions As we've talked about the rash, some of the toxicity now, would you suggest to dose reduce if we see any of these toxicities or how would you recommend managing some of these side effects? Speaker 3 So the management of AMI is is you know, dose reduction doesn't do a heck of a lot. It's usually dose delays. There's a lot of skin creams, lotions, topical steroids, you know, I usually start with. For lack of a better term and hate to use brand name, Selsun Blue actually works well on the scalp peroxide washes or other washes, chlorhexagine washes on the hand oral doxycycline. It's not going to be mandatory that you give these patients, so it's not going to be in the label, but probably you know we were actually talking and you know is it going to be recommended that you give patients a starter kit of those over the counter medicines as well as DOXY as well to take it to 1st onset. So there's a lot that has to be done, you know? But dose reductions don't do a heck of a lot for this. So it's probably going to be more just symptomatic management as it comes up, which is tough, right? I mean, but honestly it's not going to be much different than zatuximab. We're all pretty much used to give them zatuximab. And you know, I'm, you know, in this day of Uber specialization, a lot of thoracic oncologists may not remember how to give zatuximab, but that's probably how you manage it. Speaker 1 And again, one thing that we've briefly touched on before are the infusion related reactions. They happen usually during first time and then we never tend to see them again. That's been my experience, that's been the experience and most of the clinical trials. So another thing to keep in mind that after a patient has had a reaction upfront, we tend not to see this again. Speaker 3 Yeah. And it's interesting because if you talk to the people that are giving it that are all thoracic oncologists, you know, we're all community based doctors. So we're used to seeing things like daratumumab infused in the clinic and they're like Oh my God, Oh my God, how are community oncologists going to do this? Well, we've been giving Darah. For a long time. And it's the exact same thing. It's the exact same basis of the antibody. And it literally is, if you get it the first time, you don't get it the second time. What you learn over time is you just need a whiff that first day. You know, it's the first daily dose is put into two doses and if they get that whiff, they almost never react the second day. So it's not. Speaker 1 It's really easy to do if you remember that as you guys said very eloquently, it's not like Taxol, if you get the first day, don't give it the second time, it goes away very nicely, absolutely. LIBRETTO-431: Selpercatinib for RET Fusion NSCLC OK. So for the last little bit let me change your focus to Rep fusion positive non small cell lung cancer. Lung cancer truly has been the poster child for precision medicine and yet another phase three practice changing study Libretta 431 where we look at sulpercatineb versus chemo IO approach in frontline settings. At the time of progression on chemo IO again the crossover was allowed. Alex, what did the study show? Speaker 3 I mean to me this, you know? To me, there's no surprise here. I mean, this is almost stating the obvious. You have a phenomenal drug that works in red fusions and you're basically asking, is it targeted therapy that works really well, going to be better than chemo IO? And we all would have guessed the answer is yes, and this confirms that the answer is yes. What patients would not want to go on an oral drug that has very limited toxicity versus you know Keno 189 which is triplet therapy. So it works. There's no surprise here. I imagine most of these patients were done XUS because most of us, a standard of care were given us anyhow in the United States. But again, it confirms that a targeted therapy by TFs by response rates is better than chemo IO here. Speaker 2 Right. Key Takeaways from ESMO 2023 Lung Cancer Studies As you stated, no surprises here. This is yet another data which sets a new standard of care treatment amongst our Red Fusion patient population. Alex, thank you so much for going over these practice changing data from ESMO 2023 with us today for our listeners, stay tuned for our summary. Speaker 3 Thanks for having me. It was a great ESMO. We were kidding around. Speaker 1 It was ESMO Lung indeed. Indeed. We keep hearing this. Speaker 2 In this segment, we have covered 4 important studies. In lung cancer from ESMO 2023 with Doctor Alex Spira Amivantamab with chemotherapy in metastatic EGFR exon 20 insertion mutation. In non small cell lung cancer patient population should be in fact a new standard of cure. Speaker 1 The same agent Amivantamab, but in combination with lezertinib also showed improvement in progression free survival in first line settings for activating EGFR mutation, you have to be mindful about increased risk of Vtes and infusion reactions. We also now have data on Amivantamab in second line in the same patient population and the CNS responses here are very impressive. Speaker 2 With Doctor Spira, we also covered the data supporting the use of cell per catnip in frontline setting for red fusion positive small small cell lung cancer patient population. Thank you for joining us. Make sure to check out our highlights on breast, GI and Gu cancer from ESMO 2023. We are the oncology brothers.