EC Plus FOLFIRI Improves Response Rates in First-Line BRAF V600E–Mutant Metastatic Colorectal Cancer
Results from Cohort 3 of the phase 3 BREAKWATER trial show that encorafenib plus cetuximab (EC) combined with FOLFIRI significantly improves response rates in previously untreated patients with BRAF V600E–mutant metastatic colorectal cancer (mCRC), supporting its use as a new first-line option for this high-risk population.
FOLFOX- or FOLFIRI-based chemotherapy remains standard in first-line mCRC, but outcomes for BRAF V600E–mutant disease have historically been poor. In BREAKWATER Cohort 3, 147 patients with untreated, measurable BRAF V600E–mutant mCRC and ECOG performance status 0–1 were randomized to receive EC plus FOLFIRI or FOLFIRI with or without bevacizumab. The primary endpoint was objective response rate (ORR) by blinded independent central review.
At the March 1, 2025, data cutoff, EC plus FOLFIRI met the primary endpoint, demonstrating a “clinically meaningful and statistically significant improvement in confirmed ORR” compared with control therapy. Responses in the EC plus FOLFIRI arm were described as both rapid and durable, addressing a key unmet need in this aggressive molecular subtype.
Progression-free survival was a key secondary endpoint and favored the EC plus FOLFIRI arm. Overall survival data were immature at a median follow-up of approximately 10 months but suggested a potential survival benefit with the combination. Additional secondary endpoints, including duration of response and time to response, further supported the antitumor activity of EC plus FOLFIRI.
Safety outcomes were consistent with known profiles of the individual agents. Serious treatment-emergent adverse events occurred in 39.4% of patients receiving EC plus FOLFIRI and 36.8% of those in the control arm. Importantly, the addition of EC did not meaningfully increase chemotherapy discontinuation rates. “The addition of EC to FOLFIRI did not lead to substantial increases in FOLFIRI discontinuation,” the investigators reported.
The authors concluded that BREAKWATER Cohort 3 demonstrated “a clinically meaningful and statistically significant improved response rate that was rapid and durable with EC+FOLFIRI vs control,” with manageable toxicities and no new safety signals.
Reference
Kopetz S. BREAKWATER: Primary analysis of first-line (1L) encorafenib + cetuximab (EC) + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer (mCRC). Presented at: American Society of Clinical Oncology. May 30-June 5, 2025. Chicago, Illinois.
