BREAKWATER Cohort 3: encorafenib plus cetuximab with FOLFIRI as a first-line option in BRAF V600E-mutant mCRC

In this in-depth discussion at ASCO 2026, Prof Dr Eric Van Cutsem, GI oncologist at University Hospitals Leuven, speaks with Dr Elena Elez, medical oncologist at Vall d’Hebron Institute of Oncology (VHIO). They discussed the results of BREAKWATER Cohort 3 presented during ASCO 2026.^1,2

Cohort 3 of the BREAKWATER trial evaluated first-line encorafenib plus cetuximab combined with FOLFIRI in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC). This molecular subgroup has historically been associated with poor prognosis, and the broader BREAKWATER programme has already established encorafenib plus cetuximab with mFOLFOX6 as a new first-line standard.

In Cohort 3, patients with previously untreated BRAF V600E-mutant, microsatellite-stable mCRC were randomised to encorafenib plus cetuximab and FOLFIRI, or to FOLFIRI with or without bevacizumab. The objective response rate was significantly improved with the encorafenib-cetuximab combination (64.4% versus 39.2% for the control arm). Treatment with encorafenib-cetuximab plus FOLFIRI resulted in a statistically significant and clinically meaningful improvement in progression-free survival (PFS), with median PFS of 15.2 months versus 8.3 months in the control arm, corresponding to a hazard ratio of 0.44. Overall survival also favoured encorafenib plus cetuximab and FOLFIRI. Median OS was not reached in the experimental arm compared with 20.3 months in the control arm, with an 18-month OS rate of 72.0% versus 54.5%. Longer follow-up will further clarify the magnitude of survival benefit.

The safety profile was consistent with the known toxicities of the individual treatment components. No new safety signals were identified. These data support FOLFIRI as an additional chemotherapy backbone for encorafenib plus cetuximab in first-line BRAF V600E-mutant mCRC, offering another treatment option for patients, particularly when irinotecan-based therapy is clinically preferred.