Clinical Summary: 

• Design/Population: Cohort 3 of the phase 3 BREAKWATER trial randomized previously untreated patients with BRAF V600E–mutant metastatic colorectal cancer to receive encorafenib plus cetuximab with FOLFIRI or FOLFIRI with or without bevacizumab.
• Key Outcomes: Encorafenib plus cetuximab and FOLFIRI significantly improved objective response rates and nearly doubled response duration compared with standard chemotherapy. Early overall survival results favored the experimental regimen, although follow-up remains immature, and the safety profile was consistent with the known toxicities of FOLFIRI and targeted therapy.
• Clinical Relevance: These findings support FOLFIRI as an additional chemotherapy backbone for encorafenib plus cetuximab, expanding frontline treatment options for patients with BRAF V600E–mutant metastatic colorectal cancer.

Scott Kopetz, MD, PhD, MD Anderson Cancer Center, Houston, Texas, discusses results from cohort 3 of the phase 3 BREAKWATER trial evaluating encorafenib plus cetuximab with a FOLFIRI backbone in patients with previously untreated BRAF V600E–mutant metastatic colorectal cancer.

The study demonstrated higher response rates and more durable responses with the targeted combination compared with standard chemotherapy, extending the clinical benefit previously observed with the FOLFOX-based BREAKWATER regimen. These results provide greater flexibility in selecting chemotherapy backbones while reinforcing the role of encorafenib plus cetuximab as a cornerstone of frontline therapy for BRAF V600E–mutant metastatic colorectal cancer.

These findings were presented at the 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