BREAKWATER Study for BRAF V600E Mutated Colorectal Cancer – Encorafenib + Cetuximab + Chemotherapy

Hello and welcome back to the oncology brothers podcast. I'm Rahul Gossane here with my brother in New York, co-host Rohit Gossane. This is the second episode in our three part series on colorectal cancer. In the first episode, we covered the broad treatment landscape for early stage colon cancer and metastatic colorectal cancer. Today, we're zooming in on the B-Raff V600 e-story to appreciate the prevalence, outcomes, and the recent advances for this particular subset. And in our third episode, we'll focus on toxicity management and some practical clinical pearls around our available treatment options. Right, Rahul. Today, the focus of the discussion is going to be on current treatment options for metastatic B-Raff V600 e-colorectal cancer, which has rather changed from the initial presentation of breakwater data at GISCO 2025. In general, in oncology, we would see some incremental advancements and only a handful of times we see a new treatment or combination rather double the overall survival. And this is one of those stories. We will cover that study today here that is breakwater for B-Raff V600 e-mutation in colorectal cancer. To cover all this, we are thrilled to have Dr. Scott Coppets, a leading GI medical oncologist from MD Anderson Cancer Center. Scott, thanks so much for joining us. Oh, delighted. Scott, welcome. To set the stage in our first episode, we touched on the importance of NGS testing to appreciate RAS status and B-Raff V600 e-mutation biomarker testing to know MSI and her two expressions is also critical. And then our treatment decision is also based off-sightedness. Focusing on B-Raff disease today, Scott, how common is this in metastatic settings? Is this seen more commonly with right-sided tumor or left-sided tumor? And how frequently do we see this overlap with MSI high disease? Yeah, so I think the point you made is this spectacular one. That the first thing you need to do is just test. And if I could leave you with one message, it's when you have a newly diagnosed patient, just get that testing done. This is a bit of a shift. We used to think, oh, well, let's test later. Like we'll start on full Fox Bev. And then we'll figure out the molecular later. We've got time. But really, the treatment paradigms are shifting. You need to know this information before you get started. Now, within that for the Fishing Auto's, B-Raff, that's about 6% to 8%. Little more right-sided than left-sided, little more female than male. But you know what, there's plenty of young male left-sided patients with B-Raff mutation. So you really can't rely on the clinical characteristics that much to guide you on this. So it's a critical thing to test. Knowing your B-Raff status as well as MSI status is critical for that first treatment decision. We think that the MSI, if you see it, 2% to 3% at the time, that really kind of trumps it and dictates how you should be managing the patients. That's down the PD1, CTLA4 direction, for example. But there is some overlap. More than you would think by chance, but plenty of patients out there microcentalite stable, but then have your B-Raff V600E mutation. Now, you'll note that we say V600E, so just to remind you, you'll get a report back with some non-V600E mutations, some class 2s and 3s for the fishy noddles out there. We don't know what to do with those yet. I wish we did. We just treat those as if it were B-Raff wild type. What we're talking about today is the V600s. Well, thanks so much for that background, Scott. I must echo what you said that please test. So then we can only decide if we have to use the targeted options at hand. In general, B-Raff V600E has been associated with poor prognosis. Now, these mutations we have seen in lung and melanoma, and we have combinations available there. For colon cancer specifically, we have used Cytoxamab and Kuraafnib in second line. And the hope with breakwater was, can we do better outside of full fox and RNA-T-can combination here? And that's what breakwater was all about. Scott, can you touch on the study design and the findings that led to the approval of full fox plus N-Kuraafnib, Cytoxamab, or full theory plus Cytoxamab N-Kuraafnib? Yeah, absolutely. So the breakwater study was the idea that targeted therapy is working for B-Raff V600E. This is a combination of the N-Kuraafnib, B-Raffnib, and Abyssinus, the Tuxamab EGFR. Now, it's a little counterintuitive, right? Because we're used to the idea if you have a B-Raff or K-Raff mutation, EGFR inhibitor doesn't work alone. And that's still absolutely the case. So this is a really fascinating biology where you target B-Raff and now you uncover a vulnerability. These tumors now start to depend on EGFR signaling to get around that B-Raff inhibition alone. And the combination is really kind of what's driving. We've seen the same thing applied to the K-Raffs inhibitors that are coming down the pipes. So stay tuned there. But B-Raff is really sending the stage for that. So the idea is how do we move that combination up and a chemo therapy backbone to improve upon that? And indeed, that was what the breakwater design was. So standard care, which is full fox, a theory could be full fox-yribev versus an A-Raffnib, C-Tuxamab, full fox arm. Now, there's a third arm of A-Raffnib, C-Tuxamab alone that we'll briefly mention. But the A-Raffnib, C-Tuxamab, full fox, well tolerated, higher response rates out of the gate, longer progression-free survival. What we saw is a doubling of the overall survival in that population. Recognizing that our standard care therapy does not work all that well, full fox-yribev doesn't work all that well in this population. Even our most aggressive cytotoxic regimen isn't as effective. And so to be able to go from that 15 month overall survival to out to 30 months, we think some meaningful improvement. Now, full theory, backbone also can be seen. So full theory, obviously we know that we patients had prior adjuvant full fox. Maybe they have diabetes, had neuropathy, or you know what, I kind of like just to give full theory as a first line chemotherapy anyway, right? I think it's just a good fit for a lot of patients. So is there data here? Cohort three, as we call it, it really was a cohort that was enrolled after the primary full fox study was done. Kudos to the study sponsors actually asked these really practical questions that we want to know when we treat our patients, right? As many companies would have just stopped and said, "Great, we've got full fox." But now we have data that really says, "Yeah, it looks good." The response rates are much higher. The overall survival trends are very similar. It's a little less mature. We'll have more data and ask go this year to share. The FDA took a look at everything and they said, just last week, full approval for either a full fox or a full theory backbone when combined with anchor effinements and toxin. And just to reiterate a few things, we're through brought up that historically this particular disease was aggressive. Now with full fox or full theory with Cytoxemab and anchor effinem, this is indeed that new standard of care for B-Rap V600E because of that doubling of overall survival from 15 months to 13 months. And coming back to that combination of Cytoxemab and anchor effinem, it's that combination for lung cancer or for melanoma. We're using that B-Rap and Mechin a bit of combinations. Different if you have heard two positive disease in those settings, we're trying to run away from using Cytoxemab because we feel there is that resistance to anti-EGFR. Here, it's this combination with chemotherapy that's playing a big role. Scott coming back to that overlap of MSI and B-Rap V600E positive disease. A small number, but in those settings, what are you prioritizing? Immunotherapy? We have data from APNIVO, single agent immunotherapy, immunotherapy chemotherapy. Or is there a particular patient where you would still lean into the breakwater regimen? Yeah, I mean, unless there's an absolute contraindication for immunotherapy, in which case we do lean into the breakwater, we're really just diving into the immunotherapy. The doublet PD1, CTLA IV is kind of our go-to higher plateau and better outcomes. If now the disease was to progress on immunotherapy, in that case, would you rely on the breakwater regimen? We do in that setting. So that is another area. I will say there is a study ongoing PD1 versus PD1 plus an end-cos-the-tux. So the idea could you combine them is being explored, but you have to stay tuned for that one. Well, we await for that. And just want to dive in a bit on the TalkS Study profile, though we have a third episode dedicated for TalkScheck, where we will talk about into clinical pearls aspect of it. But here's Scott, what we are seeing is overlapping side effects. That is rash. That can be seen with CITUXAMAB or NKRAFNAB. Fatigue, that can be seen with any of these agents or even underlying malignancy. And then we also have diarrhea and marrow suppression with all that in mind, Scott. How do you decide which of these agents is causing some of these overlapping side effects? So what we see is, you can appreciate in this, is that a lot of them are very similar, right? So the GI TalkS Study is same, right? You're not adding much there at all. But it is that the big three are, there is some anemia. That we see so higher rates of anemia that's associated with the BRAF. But in that situation, where I'm usually kind of coming back on the BOLUS 5FU, for example, I'll throw off if the patient was still on in order to maintain the intensity of the others. The arthralges tend to be, they can be still problematic for patients. Usually they respond to like a Cox inhibitor and said short breaks if needed. The rash is what you'd expect from a CITUXAMAB rash. actually with a little. bit less. So there's some interesting data that B-Raff and EGFR gives you lower rates of EGFR rash than the EGFR alone. There's actually company making a topical B-Raff inhibitor to treat EGFR inhibitor rash. So it's another fascinating biology, but we see that as less of an issue and actually is better tolerated rash-wise. So Scott here pushing around the idea of rash, if someone is on Doxysyclin already to begin with and you are running into grade one, grade two rash, are you often decreasing the dose for end-corraphinet? Do you think this is more likely from Cetuximab? What is that management like? Yeah, it's typically Cetuximab that's doing that. You know, short holidays if you really need it, you know, what we also recognize is we've all gotten, you know, proficient at treating EGFR rashes that you know there's phases of it and if you can kind of get a patient pass that acute inflammatory phase at the beginning, that things become better tolerated and moving forward. You know, given such profound benefit here, we have to get better in addressing these side effects on our end to ensure our patients can stay on these active treatments for longer. Scott, I know we briefly touched on sequencing for that MSI disease with overlapping B-Raff, but outside that, if we're starting on full fox, encorraph, and Cetuximab, if the disease was to progress on this frontline settings, what next? Are you keeping up with encorraphneb, Cetuximab, and switching to full theory, or vice versa, where you still continue with encorraphneb and Cetuximab, but if you started with full theory, now switching on to full fox, the idea ends up being, are we maintaining that backbone of Cetuximab and encorraphneb at the time of progression? We just don't have any data on that yet, so it's not something that we can do routinely and it's a huge unmet need. What do you do after that? So we are switching side of toxic backbone. There are studies looking at how we can try to reverse-resistant, but they're all experimental in that space. A lot of epigenetics doubling down on MAP kinase and habition, topogen modulator. So there's some creative solutions being explored, but nothing ready, unfortunately, for prime time. Outside clinical trials, what is your practice today if the disease was to progress on that frontline, chemo, and encorraphneb, Cetuximab? And mostly switching backbones in that setting, there is not unreasonable to try just like we do with EGFR, we're given enough time away from an EGFR inhibitor, we can rechallenge and obtain benefit for those patients. So at least some sense that if the disease biology allows and you're able to have some period of time off of encorraphneb and Cetuximab that there may be value going back on. We don't have the data yet to try it, but in my practice, that's kind of what we're doing. Scott, let me push you a little on another case, though, how about that oligometastatic disease, with a curative intent, especially with isolated lesion and lung or liver, where we're thinking about full-fox, any role of adding breakwater regimen in perioperative setting at all? Yeah, so in a kind of oligometastatic disease, there was a period of time not that long ago when many surgeons would look at a patient that had a B-Raph and say, "That's it, like that's it." Exactly. We're not taking a patient's B-Raph. So these treatments, using the encorraphneb to touch some of combine with chemo, I think has opened up more options for patients. And I think showing these greater regressions, and now we have the surgeons are very willing to take these patients who've shown that the disease is able to be controlled with these regimens. So, yes, we're doing that routinely. Breakwater did not require that they'd be unresectable metastatic disease, really took all comers, and we're able to show the benefit there. Scott, in that particular patient, if you've gone through surgery, how long are you continuing in caraphaneps? The toxin lab where the treatment was with curative intent? Yeah, again, not a whole lot of data there. For lack of data, what we've been doing is just, you know, if the plan was a total of six-month perioperative treatment, we're just continuing that same regimen that they were on, pre-op, and to post-op, whether that's adding benefit or not, I think, hard to know, but that's kind of been our practice pattern. Scott, after the completion of six months of therapy, as you described, how are you monitoring these patients? Do you utilize CTDNA, along with imaging modality? So we're using CTDNA for almost all of our surgical patients across stage and setting, just for MRD monitoring. So these patients likewise are getting tested. That's been part of our practice for a few years. And here, given the aggressive nature of this disease, we're often extrapolating the data via from CTDNA or this periop post-op approach. Scott, any final thoughts here when it comes to treating B-Raf-V600-E disease? Yeah, I just want to reiterate that, you know, the one kind of key point, and even showing how that, you know, the tumors evolving, that the idea that, oh, we have an aggressive tumor, therefore we need to aggressive side of toxic regimen, like, full-foxyere that had kind of gotten ingrained in our minds. We really have to break away from that. Remember, we looked at some groups. Full-foxyere-beam did worse than EC-full-fox, right? So there really isn't an option based on the level one data that we should really be thinking about the targeted therapy first. The other is that, you know, starting with without targeted therapy, almost all the patients had access to B-Raf-EGFR and the breakwater study in the control arm and second line and beyond, right? So what breakwater was testing is actually the sequencing of this, right? That starting EC-full-fox or EC-chemophers doubled survival, comparing with chemo followed by a regimen that included EC, right? So we really have to think about that. You want to get started with the patient on a regimen. You don't have a mutation data back. This is a big temptation to put them on a chemo regimen and circle back to target a therapy later, but that's really not our best way to manage these patients. So, again, the idea is to break away from cytotoxic chemotherapy as our only answer, because now we have breakwater data. Again, not too often we see doubling overall survival from our interventions and graphene with cytotoxamab along with chemo therapy is now the standard of care for B-Raf-V600-E mutated metastatic colorectal cancer. Scott, thank you so much for walking us through the data that led to this approval. And congratulations for this tremendous effort for a lessoners. Let's go over a quick recap. Today with Dr. Scott Coppets, we focused on B-Raf-V600-E mutant metastatic colorectal cancer, which in past has been associated with poor outcomes, but given breakwater regimen, which is N-Graphenib with cytotoxamab combined with full fox or full theory. We are seeing doubling of overall survival benefit. That is from 15 months to rather 30 months. Besides the overall survival, we also touched on the sequencing here. Should we continue on with cytotoxamab and N-Graphenib here and just switch our chemo partner or perhaps switch the whole systemic treatment option? For it to grow ahead, another thing to learn from this conversation ends up being, how long to continue to toxinab and chloraphneib if you're using this in olicometastatic disease where the disease has been resected? For everyone tuning in, if you missed part one of this series on the overall colorectal cancer treatment landscape, definitely go back and give that a listen. And stay tuned for part three, where we'll shift gears to toxicity management, including how to manage some of the unique adverse events we're seeing with these targeted combinations and for our available options in colorectal cancer. See you soon. We are the oncology brothers.