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My name is Doctor Zev Weinberg. I'm a professor of medicine at UCLA. Here are my relevant disclosures. So we'll begin with the case. This is a 68 year old male who presented with fatigue and a change in bowel habits. A colonoscopy revealed a large mass in the right colon, the ascending colon. The biopsy confirmed adenocarcinoma. The CAT scans, unfortunately, showed multiple liver meta metastatic disease, and the tumor was deemed unresectable. On the genomic profile of the tumor, there was a BRAFV600E mutation detected with no mutation seen in KRAS and the microsatellite status was stable, so no mismatch repair deficiency. He had a good performance status, the ECOG of 1. Discussion questions center on considering his molecular profile and performance status, what are his treatment options? What is the evidence for using a triplet combination of chemo plus targeted therapy in this context? And how do the efficacy and safety outcomes of this regimen compare to the current standard of care? So we'll walk through BRAF mutated colon cancer, which represents about 8%. It seems to represent a little higher and earlier stages of disease. But an advanced disease, in those with stage 4 metastatic colon cancer, we're probably talking about 8%. You can see here how we are increasingly able to divide the pie of metastatic colon cancer, as we'll talk about lung cancer as well, into subgroups with about half having a RAS mutation. And then a whole bunch of other smaller ones. MSI high represents about 2 to 3%, but BRATV 600E represents a decent number of patients, 8% annually. The clinical relevance of this is quite unique, as we all know, um, the context of how it presents is similar to the patient's case. More likely to be in the right side of the colon, more likely to present with a large mass, often is poorly differentiated histology, and has sometimes mucinous cells. About 15 to 20% of the time, they also have a deficiency and mismatched repair. There are um different classes of BRAF mutation. The, the main class, the one we'll be discussing, represents uh V600E, and there are other classes with non-V600E mutations where the targeted therapies are not effective, it seems. Now we, we first recognized that BRAF mutated colon cancer had a poorer prognosis than the other groups in which the progression-free survival and overall survival were lower than the other subtypes of colon cancer. So there's a few important things to keep in mind. When should we test, how should we test, and why. Uh, the when is now standard. It should be tested at the diagnosis of metastatic disease. So the first onset of advanced disease, we should be doing a test, and, and you can do PCR which is the basic, or you could do next-generation sequencing, which of course has become a much more common tool because it captures mutations beyond V6000. The why is that we can now incorporate therapy into the plan. So it's critical to know in advance, ideally of first-line metastatic disease, whether the patient has a BRAFV 600A mutation. There is pretty good evidence that most of the time, you can pick this up by liquid biopsy. There have been a few studies done. I, I highlighted one here, in which the correlation between tissue and liquid was reasonably high. It's not perfect, of course, but there is concordance upwards of 90% that can be identified on a liquid-based biopsy. So if, for example, there is No tissue specimen with which to determine the BRAF mutation status, one can certainly do it on a liquid biopsy. Now in the beginning, there were some studies that looked at what is the role of chemotherapy. And one of the first clues was that there was this tribe study which used a triplet chemotherapy regimen, FOLFOoxiri plus Bev. It was a study that compared folfiribev to FOLFOiribev, but in the group of patients who have BRAF mutation, they showed a very large benefit in the group of patients who had Uh, full fox series. So that led some people to use that regimen, more likely in front line, knowing that they had a poor prognosis. This is before, of course, the advent of targeted therapy. Um, ultimately, in a meta-analysis, it really wasn't clear whether this mattered at the end of the day. And of course, the advent of targeted therapy has changed the paradigm significantly. The other thing to keep in mind is that most of the time, as I mentioned, but not exclusively, BRAFE 600Es fall on the right side of the colon, which we already know is a poor prognostic subgroup. So thinking about your patient, you have a right-sided big bulky tumor, that's the time you should start thinking about a BRAFE 600E mutation. Now the first trial, to really look at this in front line, was called the Breakwater trial. And the Breakwater trial combined encarafenib and cetuximab, and we'll talk about those two drugs individually, encarafenib is a BRAF inhibitor directly blocking BRAFE 600E and cetuximab, of course, is an EGFR inhibitor. And there was a safety lead-in, that was about 30 patients that combined this with Folfiri and with FOLFO in two separate cohorts each, and showed reasonable uh tolerability profile and encouraging early activity. So they launched what was called the randomized phase 3 breakwater trial, which you can see the scheme of here. ARM A had no chemotherapy, just encarafenib and cetuximab, so chemo-free. ARM B had encarafenib, tuximab, and FOLFO, and ARM C was the control arm, and the control arm could be any chemotherapy with or without bevacizumab. Now we should know that the reason arm A was done without chemo is because there had already been at that point, an approval of that regimen and second line colon cancer. The safety lead-in I'll show here very quickly, look, very nice waterfall plots, uh, encouraging responses in the safety cohort. Uh, you saw, regardless of whether it was Fol Fox or Folfiri, encouraging safety and efficacy in that the media and PFS far exceeded what we might have expected. Now, this came based on some science, uh, as I mentioned, um, why combined with chemotherapy? Well, the reason to combined with chemotherapy is that we know that drugs have synergy. And synergy doesn't just mean between individual agents, it also means in combinations with chemotherapy. And this was a nice pre-clinical paper that commented a little bit on the value of combining with chemotherapy regimens. So that in fact, if you combine with chemotherapy upfront, rather than waiting until the tumor has some degree of progression, a better outcome might be foreseen. So here again was the study schema. Um, it had uh 637 patients. It was in patients with no prior therapy, again, randomizing originally to one of three arms, and graphene potuximab in the top arm, and graphene cetuximab and Folfox in R&B, and the standard of care. Now, you'll see, you'll notice the numbers are a little different, because in the first arm, in graffenib postuximab alone, That's that arm was closed. And, and the reason it was closed is that at that point, like I said, there was some interest in looking at that arm, but it was quickly deemed inferior to the chemotherapy combination arm. So at that point, the study changed to be a randomization to only the bottom two arms. The co-primary endpoint was overall response rate, and progression-free survival, with secondary endpoints including overall survival. So first, the overall response rate, you can see on the left, the overall response rate by blinded Independent Central Review was 66% with a combination of FOLFOox andrafenib and stuximab, and only 37% with chemotherapy, so significantly improved. Interestingly, with in prafenib and tuximab, the response rate was 45%. So some responses were indeed seen. When you looked at median progression-free survival, you could see that the study met its primary endpoint. There was improvement from the standard of care arm, which was chemotherapy alone, of 7 months to 12.8 months median progression-free survival in the investigational arm. This was, of course, statistically significant, and met its co-primary endpoints of both response rate and progression-free survival. They also looked at interim overall survival at that point. And here too, the higher the ratio is 0.49, with the median overall survival of 30 months in the investigational arm compared to 15 months in the control chemotherapy arm. So, again, uh, this was something quite impressive, doubling the overall survival in the group of patients who got FOLFox and carafenib and tuximab compared to chemotherapy alone. This led ultimately to an FDA approval. When we go over a toxicity profile, what was noticed is that when compared to the chemotherapy arm, which was often FOO.