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Impact of Encorafenib Approval for BRAF V600E Mutant Colorectal Cancer

 

Scott Kopetz, MD, PhD, University of Texas, MD Anderson Cancer Center, Houston, Texas, discusses results from the BREAKWATER trial which led to the recent FDA approval of encorafenib with cetuximab and modified FOLFOX6 (fluorouracil, leucovorin, and oxaliplatin; mFOLFOX6) for patients with metastatic colorectal cancer and a BRAF V600E mutation. 

Transcript: 

My name is Scott Kopetz, physician and professor of GI medical oncology at MD Anderson Cancer Center. I’m delighted to be able to share updates from GI ASCO and the new recent FDA approval of encorafenib and cetuximab combined with FOLFOX in first-line BRAF V600E-mutated metastatic colorectal cancer. 

This is based on some data that was presented at the GI ASCO meeting, of the BREAKWATER study. This is an international randomized phase 3 [study] really addressing a population of patients with BRAF V600E mutation that is an aggressive subset of colorectal cancer where standard cytotoxic chemotherapy, FOLFOX-BEV [bevacizumab], even FOLFOX-[enfortumab vedotin]-BEV, have not been as effective as in other molecular subtypes, so there really is a need for trying to improve therapy. We know that encorafenib and cetuximab is approved in second- and third-line therapy, but there's good preclinical data and then clinical desire to try to move up this treatment and evaluating the combination, and that was the BREAKWATER study. This is microsatellite-stable patients that were previously untreated, that randomized to 2 arms that were reported out of FOLFOX and encorafenib-cetuximab versus standard of care, it could be FOLFOX, FOLFOX-BEV, FOLFOX-EV-BEV, at the discretion of the treating provider. 

There were 2 co-primary endpoints for the study: overall response rate and progression-free survival. This is a little unusual for a phase 3 study, this was because this was part of the FDA Project Front Runner. Project Front Runner is a brand new initiative [and] this is one of the first studies to take advantage of it that's really trying to get therapies into first-line setting sooner and this uses a rate readout with the duration of response for an accelerated approval of a therapy, which then is confirmed with progression-free survival and turned into a full approval in the future hopefully. 

The BREAKWATER study read out its first co-primary end point of response rate and that demonstrated a statistically significant and clinically meaningful improvement from 40% to 60.9% response rate, there's an odds ratio of 2.4 and a P value of .0008, which met the pre-specified boundaries. Importantly, the durability of this was meaningful and long and what we saw was that the number of patients that had maintained responses at 6 and 12 months was twice as high in the experimental arm as it was in the control arms and this certainly was encouraging data. 

Now, as part of the report out is a very early interim look at the overall survival. Despite the fact that only a minority of patients had events at this point, there was an early separation of the curves that was appreciated, where the median overall survival was not reached yet in the experimental arm and was 14.3 months in the control arm. The hazard ratio was 0.47, a very strong hazard ratio, P value of 4.5x10-5, which is certainly a very small P value. The interim was designed that had to beat 8x10-8 at this first interim, so it did not meet its pre-specified end point and therefore is not yet statistically significant differences, but we're certainly encouraged by that. The safety is as expected with encorafenib and cetuximab, some grade 1/2 arthralgias and rash that we're seeing and some anemia but overall, what we'd expect with the agents and was manageable. 

On the basis of this, the FDA did approve encorafenib and cetuximab in combination with FOLFOX and this is a new standard of care for this population as a result. We look forward to reporting out more data on this and some additional conferences upcoming. 

What does this mean practically, in practice–well, it does tell us that we need to know the molecular subtype of patients in first-line therapies. That when we start therapy appropriately, it improves outcomes compared to more sequential traditional design. Remember in the BREAKWATER study patients had access to second- and third-line BRAF inhibitors and the majority of them took advantage of that but, still we saw this really substantial improvement in overall response rate and this really strong early signal with the overall survival. Practically what we would recommend is that you try to rapidly obtain molecular testing results on your patients, you can use ctDNA, for example, if that's available in order to get their results quickly but even then, sometimes we don't have that information back and in my practice and starting patients with a cycle or 2 of FOLFOX alone and then once I have that molecular testing back, then I can adjust the treatment regimen appropriately by either adding in encorafenib and cetuximab in the setting of BRAF, or bevacizumab or cetuximab alone based on their molecular subtypes.


Source:

Kopetz, K. Yoshino T, Van Cutsem E, et al. BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer. Presented at the 2025 ASCO Gastrointestinal Cancers Symposium. January 23-25, 2025; San Francisco, CA. Abstract 16.

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