Dr Morris Talks Approaches to BRAF, RAS Mutant CRC

Van Morris, MD, MD Anderson Cancer Center, talks approaches in treating patients with BRAF and RAS mutant colorectal cancer at the 2022 GDU GI Meeting. 

Transcript

My name is Van Morris. I'm an associate professor in the Department of Gastrointestinal Medical Oncology at MD Anderson Cancer Center in Houston, Texas. The first talk that I gave today was updating the audience on approaches to the management of BRAF mutated and KRAS mutated, colorectal cancer. And we know starting with the BRAF mutated patients, that this is a population of patients who don't fare as well when a patient has a BRAF mutation relative to those who do not. And not only is their survival not as long, but unfortunately they don't respond to standard treatments in the same way that their BRAF wild-type counterparts with metastatic colorectal cancer may otherwise do. So there's definitely a need for new therapeutic approaches for this group of patients.

And while there are agents out there which can target the BRAF V600e onco-protein and other targets along the MAP-kinase pathway, such as MEK inhibitors, we know in other cancer types for BRAF mutated non-small cell lung cancer or melanoma... seen very good response rates with BRAF inhibitors alone with BRAF plus MEK inhibitor approaches. Unfortunately this just doesn't happen as commonly when you have the same exact BRAF mutation in the context of colorectal cancer. And there are scientific reasons for this. We know that EGFR gets unregulated when BRAF is blocked in the context of BRAF mutated CRC. And this led the way to pivotal clinical trials, which have shown that BRAF, EGFR combinations specifically in the phase 3 Beacon trial, that encorafenib and cetuximab improves survival outcomes, specifically for patients with BRAF mutated metastatic colorectal cancer.

So while that's an initial promising step forward, the reality though, is that although this is an FDA approved double combination, the responses are fairly short lived. So the median progression-free survival is only four months. So before these patients would come off study and come off treatment. So definitely a need to do better and build upon that. And we presented some of our data that we first shared at ASCO GI earlier this year, where we looked at a single institution trial at MD Anderson, where we looked at patients with micro-satellite stable BRAF mutated metastatic colorectal cancer. And we treated them with encorafenib, cetuximab, and the anti-PD-1 antibody nivolumab. And what we saw in our initial cohort of patients that was that not only was this combination well tolerated, but on top of that, there was a very early promising signal of encorafenib, cetuximab and nivolumab, an overall response rate of 50% in the 22 patients who had been restaged in a median progression-free survival (PFS) of seven months.

So while these results are certainly promising for the BRAF mutated subgroup, we have to exercise caution and generalizing these early on, thus, the reason for doing prospective trials, which look at this and interrogate this combination more formally, we have the SWOG 2107 trial, which we expect to activate within the next two to three months likely across the United States. This is a randomized phase 2 trial in this setting of MSS, BRAF mutated, CRC patients will be randomized to either in encorafenib cetuximab, or encorafenib cetuximab and nivolumab. And here participants will have a two-thirds chance of being able to receive the addition of immunotherapy to that BRAF-EGFR combination as part of the study. So I think this will be the first prospective study to look formally at, "is there survival benefit with the addition of immunotherapy?" We certainly hope that will be the case and excited to share these results. So here's down the road.