Key Clinical Takeaways: 

• Encorafenib plus cetuximab with FOLFIRI significantly improved confirmed objective response rate compared with control, meeting the primary endpoint in previously untreated BRAF V600E-mutant metastatic colorectal cancer.
• Responses were rapid and durable, with early overall survival data suggesting a potential survival benefit despite immature follow-up.
• The safety profile was manageable and consistent with known toxicities, with no substantial increase in chemotherapy discontinuation and no new safety signals observed.

Scott Kopetz, MD, PhD, MD Anderson Cancer Center, Houston, Texas, discusses results from Cohort 3 of the phase 3 BREAKWATER study evaluating encorafenib plus cetuximab with FOLFIRI versus control therapy in previously untreated BRAF V600E-mutant metastatic colorectal cancer. 

Results showed that encorafenib plus cetuximab with FOLFIRI demonstrated a statistically significant and clinically meaningful improvement in objective response rate, with responses that were rapid and durable. Safety was manageable and consistent with known profiles, supporting this regimen as a potential new first-line standard of care.

This study was presented at the 2026 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in San Francisco, California.

Transcript: 

Hi, my name is Scott Kopetz, professor of GI medical oncology at MD Anderson Cancer Center, and I’m delighted to share with you some of the work that we presented at GI ASCO on behalf of my coauthors and the amazing BREAKWATER clinical trial team. 

We have previously shown in the BREAKWATER study in colorectal cancer patients that are metastatic and previously untreated that have a BRAF V600E mutation, remembering that's the most common and the oncogenic mutation within BRAF, that FOLFOX when combined with encorafenib and cetuximab compared with FOLFOX and bevacizumab had a doubling of overall survival– really redefining the standard of care for first-line patients with BRAF V600E mutation. The reality, of course, is that about a quarter of our patients don't receive adjuvant therapy or receive adjuvant therapy and may have prior exposure to oxaliplatin, for example, or may have some neuropathy or patient provider preferences to utilize a FOLFIRI backbone, so the cohort 3 that we presented at GI ASCO was really designed to look at this FOLFIRI backbone. 

This was randomized EC, encorafenib [plus] cetuximab, with FOLFIRI compared with FOLFIRI with or without bevacizumab at provider's choice. There were about 140 patients that were enrolled, the primary end point was response rate with a key secondary end point of progression-free survival reported out later, it was event-driven, and a secondary end point of overall survival that we reported out at GI ASCO. 

What we saw was that indeed the response rates were substantially higher with EC and FOLFIRI. This was 64% compared to 39% for the control arm, and those responses not only were early and deep, but they were durable. We saw almost a doubling in the duration of response in the experimental arm as well, and this is consistent with what we saw in the FOLFOX arm previously. 

We also shared some updates on the overall survival and early look at this, this was a secondary end point and therefore unpowered. After a median of about 10 months of follow-up, so not a ton of duration of follow-up yet for overall survival, but the P-value there was not significant, but the hazard ratio was 0.49, identical numerically to what we saw before with the FOLFOX arm. Curves are separating, we await further follow-up with mature data there. Safety, very similar to what was seen with FOLFOX, obviously with a different toxicity profile associated with FOLFIRI, but really no augmentation of GI toxicity, rash, or other toxicities. 

We think that this data is very compelling and builds on the FOLFOX and EC backbone and tells us that we now have options for our patients, which is just what we need. We want to be able in the right patient to utilize FOLFIRI backbone, and indeed this data now supports that and I think gives us another option for standard of care management of these patients where we're combining cytotoxic chemotherapy with encorafenib and cetuximab.

Source: 

Kopetz S, Wasan HS, Yoshino T, et al. BREAKWATER: Primary analysis of first-line (1L) encorafenib + cetuximab (EC) + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer (mCRC). Presented at ASCO Gastrointestinal Cancers Symposium. January 8 - 12, 2026; San Francisco, California. Abstract 13