Computer generated transcript

Warning!
The following transcript was generated automatically from the content and has not been checked or corrected manually.

My name is Doctor Zeev Weinberg. I'm a professor of medicine at UCLA. Here are my relevant disclosures. Now we'll go back in time a little earlier and talk about what led to this. And this is going back almost 10 years. First showing that single agents, BRAF inhibitors had very, very low activity. That was vimmirafenib, and even debrafenib and remetinib had low activity. But as we started to get to more modern therapies, we started to see good activity culminating in the beacon trial, which we'll talk about, and carafenib, tuximab and binimenib. Now this was a second line study. This was a study in patients who already progressed on frontline chemo. They did a safety reading of this combination, and carafenib, tuximab, and binimetinib. Now binimetinib is a MC inhibitor, so it's downstream of BRAAF. And in this study, the control arm was also chemotherapy with or without cetuximab. With the main investigational arm being encarafenib and cetuximab. There was also a third arm, as I mentioned, Binny Metniben Karafenib and cetuximab. You could see that the primary endpoint of the study, which was survival, was met in the Narrafenib tuximab arm over the control arm with a hazard ratio of 0.61. So the combination of the BRAF plus EGFR in second line was superior to the standard chemotherapy at that time. Both when it came to overall survival and progression-free survival. The adverse events on the beacon trial were very similar to what we just talked about with the breakwater study. On the beacon study, there was uh obviously a little more rash, and, and, and some degree of cytopenias as well, were a little more common than in the controller. Quality of life study was done. A, a maintenance quality of life using an EORTC scale was done on that study and showed that uh indeed there was an improvement in the quality of life scale in the group of patients who got the combination of those two drugs over chemotherapy. So that led to the approval in 2nd line of Narrafenib and Stuximett. And as you can see here, the guidelines were immediately changed, both from ESMO and from ASCO and from NCCN. So what do we do? Uh, we also know that, um, we now have frontline approval and second line approval, but it wouldn't make sense to use the drug in second line if it was already received in frontline. So the standard of care remains frontline. Uh, FOfox and rafenibtuximab, if they didn't receive rafenib tuximab in second line, and they're BRAF mutin, I would do it then, possibly without chemotherapy, that would depend on the individual characteristics. Now, one of the interesting things to come out of these studies is you can try to understand a little more about the biomarkers, try to understand a little bit more about optimizing patient selection even beyond BRAFE 600E. And as I mentioned, there's about 15 to 20% of patients who also have microsatellite instability. And again, there were no immunotherapy used in this agent. So one of the interesting biomarkers studies was looking at Characteristics such as MSI high and something called the RIN 43, which is a possible isolated biomarker that was looked at in this nice study. There was a trial that was launched, interestingly, with Enarrafenib and Vinny Metneb and tuximab in front line. Uh, this is called the Anchor trial, you can see it here. It was ultimately abandoned, as I mentioned. But what was more interesting was a recent study called Narrafenib tuximab and devolumab, which was the combination of the BRAAF, EGFR, and of course, the checkpoint inhibitor NO in BRAFE 600 mutation. And you can see here, small study, but in 22 valuable patients, the response rate was over 50%. This is in uh refractory disease, so not first line. This is second line and third line. And this is, this was somewhat encouraging, I have an overall survival of 15 months. There was a similar study, uh, done with a different common backbone, dobrafenib and remetinib, which is also a, we'll talk about that a little later, a BRAF and a MEC inhibitor, and another anti-PD1 antibody also showing a, a nice response rate. So the question is, do we um need the checkpoint inhibitor? Uh, should we add it to the group of patients with, who are BRAFV 600E who have co-occurring mutations? You can sort of look through in the pivotal, this is the pivotal uh checkpoint inhibitor study in metastatic colon cancer. This was in, um, the, uh, the study of uh keynote 177. And when you looked at BRAF mutated patients, there was, uh, certainly small numbers, but there was a suggestion of benefits to a checkpoint inhibitor. But how do we sequence these things? Should we start with a checkpoint inhibitor, then go to rafenib cetuximab, and then only do chemotherapy later? I think that's how most people would, would, uh, consider the scenario. Start with a checkpoint inhibitor and use encarafenib and stuximab in second line. The question is being addressed right now in a randomized study called the CMA study. Patients are randomized to either pembrolizumab, which was the standard of care. Now many people use Epinivo and newly diagnosed MSI high, or pembrolizumab plus encarafenib and cetuximab. The primary endpoint is progression-free survival in those patients that have co-occurrence of MSI high and BRAFE 6000. We'll wait for the results. So overall, when it comes to BRAFV600D mutated colon cancer, we're talking about a diagnosis that's present in 8 to 12% of cases. The first line chemotherapy. Uh, plus Bev was very ineffective for those patients. So now we have a full FDA approval. This, this slide actually should be changed from accelerated to full FDA approval for patients based on the breakwater study with the combination of FOLFox. Uh, and encarafenib and cetuximab. We also have a secondary approval of for metastatic colon cancer after progression on chemotherapy, if they haven't received it already, of encarafenib and cetuximab alone. Now moving on to non-small cell lung cancer. Non-small cell lung cancer also has a very common pie chart. I didn't even put in the PD1 expression that is uh one of the most important biomarkers in that disease, certainly, that's all intermixed here, of course. But you can see here a smaller group. It's probably 2 to 3% of metastatic non-small cell lung cancer has BRAF mutations. Those mutations are not even. About half of them are V600E, so only about 2% are V600E. The other are those non-V600D mutations. The first trial to look at this was in a refractory group of patients where they combined dobrafenib and tremetinib. And again, dobrafenib is a BRAF inhibitor, remetinib is a MEC inhibitor, so you're blocking successive parts of the pathway. The EGFR inhibitors, tuximab, less important in lung cancer and colon cancer, of course. So these weren't tested initially. But the combination was tested, and, and actually a number of years ago. In 36 untreated patients. And ultimately 36 patients were valuable. Here you can see a very nice waterfall plot with about a 40 to 50% response rate. Uh, you can see that the very large majority of patients had a response. Many of them were sustainable, uh, with median PFSs, which were encouraging. And this was the first trial to look at the combination of BRAF plus Mac. More recently, the Narrafenib plus Binni Metnib trial was done. Again, N Karafenib plus Binni Metnib, same thing. Bra plus Mech, no EGFR. And um this is the overall study design. You can see on the bottom, this enrolled patients who had BRAFE 600E mutant non-small cell lung cancer with no secondary mutations, no EGFR, no ALK, no ROS1. No more than one prior line. Patients were treated, uh, who were treatment naive and uh previously treated. So two different cohorts were actually enrolled with the combination of encarafenib 450 once a day and bimetani 45 mg BID. The primary endpoint was the overall response rate. Here are the two cohorts of patients, you can sort of see in this table. On the left, there were 59 patients who are treatment naive. On the right, 39 patients who were previously treated. Uh, you can sort of get a feel for whether they had received immunotherapy or not. And, uh, obviously, in the treatment naive none had. But in the previously treated, about 60% had received, uh, checkpoint inhibitors at some point, and about half haven't received chemotherapy. The overall response rate, which you can be seen on