Managing Toxicities of BRAF-MEK Inhibitors in Non-Small Cell Lung Cancer – Dr. Melissa Johnson

Hello and welcome back to the Oncology Brothers Podcast. I'm Rohit Gossane, alongside my brother and co-host Rahul Gossane. In our ongoing talk check series, our focus today is to focus on two available treatment options from BRAF and MEK inhibitor standpoint. These combinations are rather critical for our patients with BRAF V600 emutated non-small cell lung cancer and even in other solid tumors. For this discussion, we are excited to have Dr. Melissa Johnson, a thoracic medical oncologist and director of lung cancer research at Sarah Cannon Research Institute. Melissa, welcome. Thanks so much. I'm thrilled to be here. Melissa, thank you so much for joining us. To set the stage for our BRAF V600 e non-small cell lung cancer, here we have two BRAF MEK inhibitors available, the Brafnib and Tremi, which is a proof way back when in 2017, based off open label study and there we saw 64% response trait in treatment naive and medium PFAS of roughly 11 months with median OS around 17 to 24 months. Then more recently came along Ferris study, which led to the approval of Encorrafinib and Binnie in 2023. And here we saw that response trait of 75%, but median progression free survival of 30.2 months, an updated overall survival of almost four years, 47.6 months. These updated numbers are looking very promising. Melissa, before we dive into side effects, here your preferred combination out of the two options in hand. You know, I'll have to tell you that Dubrafinib Tremetinib is a very well-established regimen in particular for melanoma. I've used it plenty over the last few years. Encorrafinib and Binnie Mettinib is the punk kid on the block. It's newer. And we have found it to be very well tolerated in lung cancer patients. Probably because of my experiences participating in the trial that led to the approval of Encorbinnie, I'm using that more in my practice. We see BRAF V600E in a small number of patients with non-small cell lung cancer, as you said, only about 2% to 5%. So we don't see it every day, even those of us that focus in lung cancer. But I am reaching for Encorbinnie. Well, Dr. Greg Riley, when we touched on a BRAF specific podcast, had a similar choice. So for the audience, if you've not checked out that episode, we focused on BRAF V600E mutated metastatic non-small cell lung cancer and how to manage and pick the appropriate option in the space. Please check that out where the option is, BRAF Mettinib or chemo-immunotherapy. All right. When picking one drug over the other, we have to keep two things in mind. One, we have to make sure that this particular drug has better survival data at hand and also favorable side effect profile. With that theme in mind, it will assess starting out with Encorbinnie here. Common side effects would keep in mind and importantly, clinical pearls with this combination. You know, part of the appeal of Encorbinnie is that it's better tolerated in many patients than the older Dabraffin-Eptometinib. We see vague GI side effects, but importantly, much less fever, which is one of the characteristics, side effects of Dabraffin-Eptometinib. Anytime that we're giving an oral medicine more than once a day, there's the chance for nausea, upset stomach and diarrhea. And I think we do see that here. Well, second, I push you a little more here with these side effects for GI side effects. Are you affron giving anti-emetics anything for that diarrhea? Well, it's an important part of practice. I certainly don't see the need to give upfront anti-diarrheals often. Any drug on an empty stomach can cause nausea, so I do tend to give a prescription for anti-emetics. And in general, how does this one differs from depth to any, as depth to any is supposed to be taken with empty stomach with this one, there is no such restriction with that. Yes, that's right. So that's another advantage. Thank you. I can't take a multivitamin on an empty stomach, so I am looking for always a piece of food or a cracker or something. So that's an advantage for sure. Absolutely. And again, we'll have both here in Melissa Tuchtandas that these combinations are not only available for lung cancer, but out in community settings, we're using this for melanoma. And grapheneb is also proof for colon cancer, but just to re-treat a few things, GI side effects, a little more anemia as well with this combination, but when it comes to rash or pyrexia, we tend to see that more with depth tremey. With binometeineb label, there's also recommendation to monitor echo, because of that left ventricular ejection fraction effect. Recommendations are usually affront than every two to three months. Melissa, before we move on to depth tremey combination with enquiraphineb binometeineb, if we do run into these GI side effects or cardiac side effects, do you tend to dose reduce one drug or both at the same time? And importantly, when we're reducing the dose, are we compromising any efficacy here? Good question. The first answer that I have is that I typically do dose-reduced stepwise, and I tend to start with the mech inhibitor, regardless of the combination, by the way, the mech inhibitor is the more challenging drug to tolerate and in combination, it's the more likely to sort of increase the adverse event profile. Some of the scarier side effects for that matter, the decreased ejection fraction, we can talk some about the blurred vision and the risk of a demon and rabdo, because those are very uncommonly seen. But those are all the ones for which the mech inhibitor is implicated, and so I'm starting with going down on the binometeineb first. And with regards to the cardiac toxicity, we also see the QTC prolongation aspect. Along with echocardiogram, do you go for serial EKG monitoring for these patients as well, or just initially if things are looking good and nothing to follow up after that? Initially, I will get an EKG, but not again until there's a problem. And with regards to, as you mentioned, mech inhibitors is rather the one which is sort of the cumbersome one, especially with the side effect profile. Is there a patient population where you would just consider B-raff inhibitor by itself? Yeah, that's a good question. I would extrapolate from what we know from de-braphenic and preventative when I answer that. Of course, the response rates and the duration of response PFS was prolonged and better for patients that got the combo, the de-braphenib and tremetinib, as compared to de-braphenib alone. So I am of the mindset, at least in lung cancer, the combination is important. And getting rid of the mech inhibitor completely would make me a little squeamish. Melissa, can I push a little here around that dose reduction of mech? When we're doing that, you're keeping the same dose for that B-raffenib. Are we compromising any efficacy? Do we have any data here with these B-raffenib. I know when it comes to anti-EJFR, we have strong data that when we're dos-reducing these medications for side effects, we're not compromising any efficacy. Is that what we are extrapolating here as well? You know, if there is data, I'm not aware of it. I think that there are, and why might that be, just the smaller numbers of patients with de-ref, V600, e-mutations. But I tend to think of these oncogenes as similar to EGFR in that it's still worth trying dose reduction as opposed to stopping the combination completely. You know, I will say, and it sounds like you talked about this with Greg Riley, that the rub here for B-raffenib. Lunkance, or like B-raffenib melanoma, is that chemo and immune therapy also works really well. So, I think I probably am a little bit less persistent in making the dose reduction's thick, if the patient is still not tolerating, then I'm going to move on to chemo and immune therapy and not feel bad about it. Absolutely. Unlike other targeted mutations, this is one place where we can start using chemo and immunotherapy. Okay, now on to the B-raffenib and Tremi. Here Pyrexia is common. We briefly alluded to that. And again, we've seen this play out in multiple disease sites for us. Around two to four weeks after starting that therapy, it can be episodic, but holding treatment here or steroids can be very helpful. We can also see cardiac side effects with all these combinations. And then the one that we all struggle with almost with all our interventions. Fatigue. Melissa, can you touch on what to expect with this combination and clinical pearls around that? Yeah, I think your summary was really good. I do think the fever is the most vexing. who have cancer are taught that fevers are bad and they should call. and they probably need to come in. And so in the development of de-graph and imptment, and Sarah Cannon played a large role in the clinical trials, we were a little confused with what to do when these patients were on trial. And so we learned over time that the steroids were really helpful in sort of suppressing the fever. I actually try to do that without stopping the drug just for the improved absorption and drug levels that that will provide sometimes you can't. And so that's different from the counsel that we give for a fever for every other medicine that we prescribe. And with your court, Sarah, I'm sorry. Go on. Sorry, I was just going to move on to the Tremet nibs. And just mention, here again, the Mech inhibitor has liability. And the venus ocular occlusion, the retinal detachment, like these are significant things. I tend to do one eye exam early on, and then watch until there's problems, rather than continuing to send a patient, too. Thanks for touching on that. With regards to pyrexia, I'll dive into the ocular talk study right after that. With regards to pyrexia, if it is a recurrent pattern, of course, for a short period of time we are relying on steroids. But if it's a recurrent pattern, are you dose reducing or rather dose interrupting at that point in time? I will dose reduce rather than dose interrupt. I think it is-- also we found in the trials that the fevers do tend to attenuate over time. And so you don't always get it forever. So trying to treat through, if patients are otherwise feeling OK, you can do that. And for patients that are not, there are after-dose reduction, it's easy to start to think about what the next option will be. Indeed. And here again, you go for Mech inhibitor first before touching the Dubroffinib arm. Yes, that's right. And as I'm sitting here thinking about my practice, I can think of a patient early on who was randomized to Dubroffinib alone, rather than Dubroffinib, Tremetinib. And I saw her for years after the trial was completed. So I guess I got to eat my words a little bit. There is an opportunity potentially to drop the Tremetinib, sorry, and keep the Dubroffinib going for some. I wouldn't say that that's the wrong option either, but I do think about the combo being more effective. Indeed. Would your courts do the ocular toxicity, though most of it or some of it is still self-limiting for our oncologists practicing in rural community or there is no ophthalmologist readily available? Any clinical pearls would regards to this particular toxicity. And how common is that? How common is it? Yeah. Not common. I've looked for it for-- I've looked at it for it in a lot of patients. I don't think I've caused it, not good. And it's really going to be symptoms that are your guide that there's something wrong. Dock, I'm not seeing. I can't see out of this eye. I can't see out of part of this eye. And of course, by then, it's happened. No, certainly at that point in time, I'm a pharmacological or even prior to that, it gets to that stage off the neurological evaluation is very much needed. But have you seen when this happens with dose interruption or dose reduction this certainly resolves? In my experience, we stopped. Once the central venous occlusion happened, I think the protocol guidance was always to discontinue. OK. Well, so sorry. Is that the case with both the combinations? I have not seen this in my practice. So I just want to learn a little more. Are we seeing the same thing with enquiraffinabinni in the same amount with the braffinabin tremi? Again, my sense-- and we probably would need to go to the clinical experiences in large, large numbers of patients. But I haven't ever seen this with Benny either to know. If it happened, again, I would be loved to restart. Well, again, at the end of the day, we're glad that we have that chemo-IO combination and just a quick question with regards to that, Melissa. If a patient come in into CEU with braff v600 emutated and non-smolcell lung cancer, you have the choice of braff making a bit of a combination or chemo-IO, how are you picking amongst the two options? I will say that I'm a mutationist. And so I do like to go for the mutation first. And we spend a lot of time with patients early on after their diagnosis before we know what they're going to get. And so I think most oncologists have a spiel. That includes lung cancer, can be treated with chemotherapy, immune therapy, or targeted therapy. So I've talked about the difference in those treatments. And the targeted therapy is a pill. And that is so appealing to patients. So I usually start with that and save the chemo-immune therapy, either for those that need a different approach because adverse events are significant, or when the braffinib, trometinib, and chiroffinib, biny-metinib, combos are no longer working. I'll just also say that in both trials, and maybe there was more attention to it with the end-combinny trial because, of course, all the-- there was a group of patients who had been previously treated with immune therapy. There is always this risk when patients are treated with immune therapy. And then you stop and put them on a targeted therapy that there'll be an interaction between the PD1 inhibitor that they had before and the small molecule inhibitor that you're starting, where that doesn't happen the other way around because the half-life of the small molecule inhibitors is so short, that it clears as you're getting started on the chemo-immune therapy. So in my head, that's another reason that I do the braffinib, trometinib, or anchro-enchro-phenib, biny-metinib, first. And with regards to getting an idea about the sequencing approach, if you do get started on targeted therapy, though that is a low risk, but there still exists a risk of pneumonitis with B-raff-mechanibitor combination. Now, if the disease was to progress and one did have pneumonitis, when initiating chemo-immune therapy, does that pneumonitis mechanism in fact, and works the same way? Would you avoid immunotherapy in that scenario? That's a really good question. I think that there's several reasons for pneumonitis. Obviously, we talk about it more and more. And the mechanism of the one versus the other doesn't seem to matter as much as the presence of the pneumonitis itself, the state of inflammation in the lungs. So I have to say that if-- and I've not done this, but if your B-raff-mechanibitor combination is pneumonitis, I would think twice about immunotherapy, at least at first. Maybe you give some chemo-immune therapy. Maybe you start at the once every three week dose theoretically, or less. But I would be worried, especially in the same time interval, right? If there's a time period, a time lag that goes by, and so you really feel like the inflammation is gone, then maybe it's OK. Makes sense. Again, the grade would also matter here, Rohit. But these patients were often getting these scans, so that grade one shows up and what to make out of that. I might feel comfortable with introducing IO versus a patient being symptomatic, and I clearly worry that it was the targeted agent that drove this, and I'm likely going to hold off IO. But the good thing here is we have options, B-raff-mechanibitters, chemo or chemo-IO. One thing to keep in mind, based on the recent publication with high PDI-1, or with tobacco exposure, maybe IO, might be the right way to do it, versus if you have high tumor burden, you're looking for that quick response, or even CNS disease. Perhaps that B-raff-mechanibitter is the better approach. Melissa, one thing that you brought up, and I think we've seen this play out, even with our K-raff-sympitters, of course, with our anti-EGFR saying if you use immunotherapy upfront, not only in some of those cases, you're bluntening the response, but you're seeing higher toxicities with our oral agents, so something to keep in mind when we're doing that sequence upfront. I know we've covered a lot. Melissa, any final thoughts on this whole discussion? It just-- we'd love to underscore for the general oncologist that we'll see one or two of these in a five-year period, maybe. The B-raff-V600E is a special one, because it is a mutation that can develop in patients that smoked, and maybe is even more common in those patients than the never smokers, minimal smokers. And so this is one not to forget in your smokers, and another reason that NGF is-- testing is still applicable for smokers in your patient population. And you know that it's okay to play with sequence and it's okay to go with chemo and immune therapy. I will say that I have some patients who have just tolerated chemo and immune therapy better. And again, Bradley NGS here is the standard of care. An RN educating and managing these predictable toxicities proactively give us a chance to keep our patients on these active targeted therapies for longer while preserving their quality of life. Melissa, thank you for walking us through all this. On RN, let's do a quick recap. In today's Talks Check discussion, we're Dr. Melissa Johnson. We focused on side effect management for two main B-Raff Meckin and bitter combinations, debrafinab plus chromatinab and encarrafinab plus benemetinab, which are used in B-Raff V600 E mutated non-small saloon cancer and other solid tumors. Rahul, what is your preferred combination here? Yeah, for me, from efficacy standpoint, that updated ferros data with encarrafinab benemetinab is showing impressive PFS and OS. The medium PFS was roughly 30 months and OS of almost four years. This ends up being my go-to, but of course, side effect profile is also playing a role here. In terms of side effects and clinical pearls, Rahul, what are you walking away with? Right, Rahul, a few things to keep in mind. Debrafinab, chromatinab is associated with a lot more Pyrexia. As a result, stopping and restarting medication or even continuing on with medication while adding prednisone can help. Encarrafinab benemetinab, we don't see too much of Pyrexia here, but we have to keep GI side effects in mind. And also, with these combinations, we have to monitor for left ventricular ejection fraction. I do get a front echo here before starting any of these medications. And let's not forget, a common side effect which is fatigue. Key to all this ends up being education, education, education, and looking out for these side effects and intervening as early as possible. Thanks for tuning in. Make sure to check out our other treatment algorithm episodes, conference highlights, and talk-check discussions. We are The Oncology Brothers.