Treating BRAF V600E Mutated Non-Small Cell Lung Cancer (NSCLC) with Dr. Gregory Riely

[MUSIC] We are at the oncology brothers. >> Hello, and welcome back to the oncology brothers' podcast. I'm Robert Gersain alongside my brother in Coho's Rahul Gersain. We are both practicing community medical oncologist, and our goal with these discussions is to keep you, our fellow community oncologist up to date in this ever-changing field of oncology. Today, we are taking a deeper dive into the space of B-Raff V6 into the E-driven non-small cell lung cancer. For this discussion, we are thrilled to have Dr. Greg Riley, a thoracic medical oncologist from Memorial Sloan Kettering Cancer Center. Greg, welcome. >> Thrilled to be here. Thanks for having me. >> Greg, thank you so much for joining us. It's exciting to see a few options in this particular subgroup of non-small cell lung cancer, but we still continue to debate a few things here. Big one ends up being, how do we sequence our available options? Who's the right patient for immunotherapy or chemotherapy? And of course, who should get those B-Raff Mekkenabitters? Before we get into the sequencing, can we start broad? How prevalent is B-Raff V6 100 E in non-small cell lung cancer? And how is this disease behaving compared to other subsets? Because when it comes to colon cancer, this particular mutation often carried a poor prognosis. So recently, we got N-corraffinab in front line settings, and that ended up doubling the overall survival. So coming back to non-small cell lung cancer, how common is B-Raff V6 100 E and what should we expect in terms of patient characteristics? Yeah, so I think when we think about all of these oncogenic drivers in patients with non-small cell lung cancer, we feel like we get it. These are never smokers. It's all very, very simple and straightforward. I think B-Raff and of course K-Raff 2 is very different. B-Raff Mutant Non-small Cell Lunk Cancer. So I think there's a couple of parts with this. First, B-Raff Mutations are broader than just the V6 100 E. So when you look at that report coming back from your NGS provider, you got to pay attention to which B-Raff mutation it shows. Because if you look broadly, there are about 5% or 6% of patients have B-Raff alternations. But when we dig down to just the B-Raff V6 100 E, which is where we have the therapeutic opportunities today, those patients, this is right around 1.5% to 2% of patients with non-small cell lung cancer. Putting in that same category as things like Ross-1 rearrangements, EGFRX on 20 insertions, retrearrangements, not the most common thing you're going to see, but important to know about. The other mutations in B-Raff that we see are sometimes referred to as class 2 and class 3. These mutations, you might run into them like G466, G4669, D594. These are the ones, frankly, we see them as almost as much as the V6 100 E. But they're not targetable with our current drugs for the most part. It is an ongoing area of drug development, those are there are trials that are involving those patients. And hopefully we can have this podcast in three or four years and have drugs available for those mutations. Indeed, those exciting times how fast this field continues to change just in this treatment algorithm. We have seen the addition of her two target at therapy recently as well. So yes, I'm pretty hopeful for that. So Greg, with regards to some of the patient and disease characteristics that you talked about, we're talking about B-Raff and you brought up K-RAS as well. These are one of those mutations where we can actually use chemotherapy or immunotherapy unlike EGFOR or ALC positive disease, where immunotherapy is certainly not an option. With regards to the treatment options that are available for B-Raff combination, there are two of these combinations that are targeted therapies, and graphinib, binomethneb, or de-baraffinib, trimitneb. Outside of that, immunotherapy, whether that's single agent or dual checkpoint inhibitor or chemotherapy with immunotherapy. Focusing on targeted therapy option that is for B-Raff-Mek inhibitors, though we don't have head to head trial comparison amongst the two, but can you touch on some of these two trials that led to the approval of end graphinib, binomethneb, the ferrous study, though it is phase two, but if you could just go over the data and we'll let to the approval here. Yeah, absolutely. So I think the key thing is that patients with B-Raff-Mek and lung cancer, they're somewhat uncommon. And so as a consequence, we don't have the randomized data that we'd love to see. Now, some of that may be a question of, you know, the will of the sponsors, you know, 'cause we do have randomized data for a ret and we have randomized data in a variety of things, but nonetheless for B-Raff, we don't have randomized data. And so when we look at the targeted therapy options, both the graphinib, trimitneb, and graphinib, binomethneb, these build off of a prior experience where they people looked at just single agent B-Raffinibs. And of course that was the same sort of thing people didn't know. And they saw response rates in the 30-ish percent range, which told us it was a targetable entity, but told us it was not that great. So then we add in the Mech inhibitors, so the graphinib, trimitneb, or an graphinib, binomethneb, those combinations, yield significantly higher response rates and significantly longer progression-free survivals. If we look at the original data with a D-Raffinib, trimitneb, these publications came out in the early 2020s. The response rate in treatment naive patients was 68%, and the response rate in patients who previously had therapy was 64%. So that really shows us that these drugs have activity, and it's a reassuring finding to tell us that we're gonna be able to have real. More recently, we've seen the data from the pharaoh study, which looked at end graphinib and binomethneb. So again, this is the same upfront patient population. Although these data are several years later, this is not looking at resistance, which is an important area. This is looking again at that sort of same group of patients who would get the graphinib, trimitneb, patients are getting a graphinib, binomethneb. And from an efficacy perspective, we see frankly pretty similar response rates. We see a response rate in treatment naive patients of about 75%, and for patients who have been previously treated, we see a response rate of 46%. In terms of efficacy, what we are seeing in this more recent data is longer progression-free survival, as longer duration of response as longer overall survival. I think there may be some confounding effects related to better testing, and that sort of thing that gives us a healthier patient population or something like that. But the takeaway from this is that this new combination, a graphinib, binomethneb, has data that support a bit longer overall survival is in progression-free survival. - Roy, you brought this up that Ferros is a face-to-study, but again, overall response rate here and that updated overall survival here is over four years. This is mind-boggling. Thankfully, we have these options for our patients. But another thing to keep in mind here ends up being tolerability. With the graphinib, binomethneb, we're seeing less pyrexia, but more GI symptoms. And again, on our end, we'll get a chance to take a deeper dive on the side effects in our talk-check episode, Greg, what about the data in hand for the graphinib and tremic combination? Do we have any updated long-term outcomes here? - We don't have new data to tell us that these patients do particularly well. And I think as we think further about first line options, we'll talk a little bit about some retrospective data. But if you look at the prospective data, we don't have much beyond the original clinical trial data. But I do think that toxicity data is something really to focus a little bit on. And I'm glad you guys are having a separate episode on that. You're right, the main difference is the pyrexia part. There's a much lower rate of treatment-related pyrexia. There are some other events of pyrexia that maybe weren't captured in the treatment-related, but there were still much fewer episodes of pyrexia in patients who received a graphinib and binomethneb compared to de-braphinib, tremetneb. And of course, if you've used de-braphinib, that's the annoying side effect to manage with patients. And so that's a plus when you're using an graphinib and binomethneb. - Right, at least from community standpoint, we are lucky to have utilized these therapies out in melanoma world and now just replicating that in lung cancer space. What we know is both of these combinations are active. However, we don't have any head-to-head comparison amongst the two. As you stated, we are left with retrospective comparisons here. What we saw from Esmo open article, which looked at the match-adjusted indirect treatment comparison, which showed and graphinib binomethneb combination is better when compared to de-b tremetneb. However, question is, how are you picking one or the other in your real practice? And more importantly, who gets that immunotherapy or immunochemotherapy combination versus targeted therapy? - Yeah, I think it's difficult to pick amongst the targeted therapies. And so I think it's like with many drugs, we all kind of pick one and get used to it and go with that. So for me, the data aren't crystal clear, but they're suggestive that anchor-affinib binomethneb might be a bit better tolerable and longer duration. So when I'm picking targeted therapy, that's the target of therapy I pick. But I think the important question that you raised is since these patients are a little different than other oncogenic driven cancers, they have a higher rate of smoking. Sometimes they have high PDL1 scores. How does that really factor into our decision-making? And I think the biggest piece of data that we've had recently added to the mix was a paper from last year in annals of oncology by Alessandro DiFerrico, where he collected data from 17 different sites, 285 patients, large number of patients. Now this is retrospective, so it's got all the caveats associated with the retrospective analysis. But he looked at patients with B-Rap B600E who got immunotherapy-based treatments, so that included single-age and IO or IO plus chemo compared to patients who got first line targeted therapy. From that end. analysis actually surprising to me, he showed the patients who got the immunotherapy based regimen did a little bit better. The caveats of course were the, it was retrospective so the patients weren't balanced in some of their clinical characteristics. And as when he looked at patients who got that immunotherapy based approach up front, turns out those patients were more likely to be heavy cigarette smokers, more likely to have high PDL-1 scores. And so they were kind of biased. In the end analysis they said the things that most likely predicted better outcomes were high PDL-1 score and smoking history in the past. I think those factors can come into play as we think about this. And I tell you that for sure when I'm seeing patients and meet a new patient with a B-Rap-V6 100 emutation, if they're an ever smoker, if their PDL-1 is negative, it's obvious that that patient gets targeted there, be up front. When they have a modest smoking history and their PDL-1 is positive, it gets much more complicated in my decision making. I don't have as big a challenge as I have for a lot of oncogenic drivers, but at the same time a waiver a little bit on what my best approach is here. But I have to say before, Alessandro's paper, I would have never not given target there. I would always do that for these patients with B-Rap-V6 100 emutation. But based on this paper, I think about a little bit more starting with immunotherapy. And I think you guys see this too when you meet a new patient with not small cell lung cancer and they have a high PDL-1 score, we're kind of salivating a little bit with the idea that this is going to be one of those patients that is going to do so well and they're going to have a year or two of checkpoint inhibitor and they're going to stop and they're going to be off treatment and they're going to do very, very well. And so it's hard not to hope for that when you see that high PDL-1 score. And so that always makes me think a little bit about doing it that way. Good. Thinking into that story about immunotherapy, Greg, if PDL-1 score is more than 50, we tend to favor the immunotherapy. However, if it's PDL-1 is negative or 1-49, in that case, are you going with chemo, immunotherapy, combination or dual checkpoint inhibitor? Yeah, I think that's my general rule of thumb as well is to go with immunotherapy with the high PDL-1. For me, I don't think of it as a real dichotomy of 50%. You meet that patient with modest performance status and has a PDL-1 of 30. You know, I might go one way or another. If they have a PDL-1 of 95%, then it's a home run. I'm just going to use checkpoint inhibitor. So I kind of take that approach, but I do a little bit of thinking through it. That's right. You know, out in community, Royce, you brought this up outside just these retrospective studies where often also extrapolating data from melanoma studies. And there we have two studies, right? I'm sick and sick, come back and take a message from those two studies, was if you're looking for a quick response, if you have heavy tumor burden or high LDH, then start with your B-raft Mech inhibitors. And then you switch to immunotherapy after that initial response. And then you're still coming back to that B-raft Mech inhibitor at the time of progression. This was for melanoma. But for lung cancer, I/O affront, here likely is for someone with that tobacco exposure. Higher PDL-1 expression and low tumor burden. Royce, for that 1 to 49% or PDL-1 negative, likely I am leaning into B-raft Mech inhibitors. Greg, the other thing to keep in mind here ends up being CNS disease. How prevalent is that? And is that swaying you one way or the other to use immunotherapy or B-raft Mech inhibitor? Yeah, my sense is that for B-raft Mutant Disease, the frequency of CNS metastasis is not as high as, say, with out positive disease. It's probably in the same ballpark as what we see with EGFR Mutant Lung Cancer. So definitely something we've got to be looking for and check in on from time to time. My sense is in terms of efficacy, that there's not, you know, we don't have a lot of prospective data in this space for even for the targeted therapy. So I can't tell you for sure that they have good efficacy. My experience is that they do relatively well in the CNS space. Similarly, as we all know, and have done this in clinic, the Platinum-Based Chema with checkpoint inhibitor has a reasonable response rate in the CNS and those patients who have brain majestases. So to me, it's not a real differentiator, but I do have a little bit more confidence with that high response rate for the Braft Mutant Nebancraffin of many metaniv. Coming in with that high response rate gives me a little bit more comfort with patients with CNS disease. Absolutely. Again, I'm going to put my community oncology hat here. We know that these agents can be active as we've seen that from melanoma side of things. Greg, coming back to sequencing, if someone got immunotherapy, a front or chemo immunotherapy, and then at the time of progression, are you still sticking with your same combination of Enco-Binney? Does that change at all? You know, it hasn't for me. I'm always happy to learn from you guys in your experience for melanoma. But for me, the thing we think a lot about in lung cancer is finding that patient with EGF-ar mutation after they've started on immun checkpoint inhibitor and recognizing that there's a lot of toxicity barriers to adding in Osemarritinib after checkpoint inhibitor. It's less of an issue in my sense for B-Raph-Mec inhibition because we have had trials that have combined them and it's not been a mess in the case of melanoma, unlike in the case of EGF-ar inhibitors in lung cancer. So I don't have a preference based on that. I'd say for me, at least even in front line or even disease progression, I'm sticking with Encro-Binney-Metney. Especially with the impressive data that we have seen. That is impressive in treatment eye-eve setting, very comparable amongst Deb Trem and Encro-Binney -Metney in progression post-immunotherapy. All right, as we start to close here, is there any patient, Greg, where you would utilize single agent B-Raph-Inhibitor? That is Encro-Raph-Nib or Deb Raph-Nib or Remi-Raph-Nib? I don't start there in truth. For a lot of patients, all patients, I'm starting with target therapy, I start with both. But every patient demands their own course. And as you see what toxicity develop, sometimes we find that there is a role for ending the Mech-Nibitor and Continuant Singlesion B-Raph-Inhibition. And I feel honestly comfortable with that approach. I think that particularly after you've shown that the tox is too much for a combo, I'm pretty clear that single agent B-Raph-Nibitor has a reasonable efficacy. Of course, we have all these skin toxicities and other toxicities that benefit from the addition of that second drug. So it's a balancing act of say, at least. I love that you brought that up. When you're taking that Mech-Nibitor, you might see a little more of those skin-cutaneous toxicities just with the B-Raph-Nibitor. Can I quickly go back to our experience of challenging the disease after chemo-immune therapy with B-Raph-Mech-Nibitor? I think this is still a very good viable option. From melanoma, we're seeing that this is not increasing toxicity unlike what you touched on for our anti-UGF-armutations. So still, this ends up being a viable option if you've used chemo-immune therapy upfront. But the big thing here ends up being, often our patients are not seeing that second and third line treatment, and we have strong data for that. Greg, I know we've touched on quite a bit here, but before we close, any final thoughts? I think as all of you know, the most important thing in lung cancer is doing the testing for all of these oncogenic drivers, doing the testing for PDL-1. This is how we treat lung cancer today, understanding that these characteristics is critical to making our decisions. You know, again, a few things that I'm walking away with here for B-Raph-Mech-Nibitor E. This is rare, but we still have to look for it. And we have few options that are very active. There's no head to head comparison between the two B-Raph-Mech-Nibitor combinations, but at least my preferred combination is similar to what you mentioned, Greg and Karafa and Aben-Binney. Greg, thank you so much for taking the time to walk us through the data here and your treatment approach for our listeners. Let's go over a quick recap. In today's discussion with Dr. Greg Riley, we focused on B-Raph-V600E-driven non-smolsa lung cancers. We see this roughly in about 1 to 3% of non-smolsa lung cancer. Yes, it's rare, but definitely actionable. We have two approved B-Raph-Mech-Nibitor combinations. That is, and Karafa-Nib, B-Nib, based off of Ferris trial. Here, we are seeing stronger signal of PFS and overall survival when we are doing cross-trial comparison with the Braf-Nib and Tramitinib, as we do not have head-to-head comparisons available here. Rahul, what do you want to add here? Yeah, right. I think it is very important to reiterate that unlike EGFR and ALC positive disease, B-Raph-V600E patients can benefit from immunotherapy. But B-Raph-Mech-Nibitors offer high response rates, and this might be our way to go, especially for that, never smoker and those with CNS disease. And of course, side effects, how we manage these are critical. This will be covered in our next episode of TalkShack, where we walk through these available combinations. See you soon, and let's continue to learn together. We are the oncology brothers.