Encorafenib and Cetuximab Plus FOLFIRI Demonstrates Superior Response Rates for Patients With BRAF V600E-Mutant Metastatic Colorectal Cancer
Key Clinical Summary
- Population and Design: Phase 3 BREAKWATER Cohort 3 enrolled 147 untreated patients with BRAF V600E-mutant mCRC (ECOG 0 to 1), randomized 1:1 to encorafenib plus cetuximab plus FOLFIRI (n = 73) or standard chemotherapy FOLFIRI plus or minus bevacizumab (n = 74); median follow-up 10.5 months.
- Efficacy: The ORR was 64.4% with encorafenib plus cetuximab + FOLFIRI versus 39.2% with control (OR 2.76; 95% CI, 1.42 to 5.35; P = 0.001); 57.4% maintained response ≥ 6 months vs 34.5% with control; median TTR 6.9 vs 7.1 weeks.
- Safety: Serious treatment-emergent adverse events occurred in 39.4% vs 36.8% of patients, with no new safety signals and manageable toxicity profile.
- Clinical Relevance: EC plus FOLFIRI produced rapid, durable, and significantly higher response rates than standard chemotherapy, supporting its adoption as a potential new first-line standard of care for BRAF V600E-mutant mCRC.
In the primary analysis of cohort 3 from the phase 3 BREAKWATER trial, encorafenib plus cetuximab (EC) in combination with FOLFIRI showed statistically significant and clinically meaningful improvements in response rates compared to standard chemotherapy regimens among patients with previously untreated BRAF V600E-mutant metastatic colorectal cancer (mCRC).
These results were presented at the ASCO Gastrointestinal Cancers Symposium in San Francisco, California, by Scott Kopetz, MD, PhD, FASCO, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Researchers conducted a phase 3 trial to determine the safety and efficacy of encorafenib plus cetuximab in combination with FOLFIRI compared with the control of FOLFIRI plus or minus bevacizumab (bev). The primary end point was overall response rate (ORR) and secondary end points included progression-free survival (PFS), overall survival (OS), duration of response (DOR), time to response (TTR), and safety.
The trial enrolled 147 patients with untreated BRAF V600E-mutant mCRC and ECOG performance status of 0 or 1. Patients were randomized 1:1 to receive encorafenib and cetuximab plus FOLFIRI (n=73) or investigator’s choice of FOLFIRI plus or minus bevacizumab (n=74) as the control. The median age of patients was 62 years.
At a median follow-up of approximately 10.5 months, encorafenib and cetuximab plus FOLFIRI achieved a significantly higher ORR (64.4%) compared to the control arm (39.2%; odds ratio [OR] 2.76; 95% confidence interval [CI], 1.42 to 5.35; P = 0.001). At 6 months or more, 57.4% of patients who received encorafenib and cetuximab plus FOLFIRI and 34.5% of patients in the control arm still had a response. The median TTR was slightly lower among patients treated with encorafenib and cetuximab plus FOLFIRI (6.9 weeks (range, 5.4 to 36.1) than patients in the control arm (7.1 (range, 5.9 to 25.3).
Serious treatment-emergent adverse events occurred in 39.4% of patients in the encorafenib and cetuximab plus FOLFIRI arm versus 36.8% in the control arm.
The researchers concluded, “BREAKWATER Cohort 3 demonstrated a clinically meaningful and statistically significant improved response rate that was rapid and durable with EC+FOLFIRI vs control in 1L BRAF V600E-mutant mCRC, with manageable toxicities and no new safety signals.”
They added, “These data support EC+FOLFIRI as a potential new standard of care in BRAF V600E-mutant mCRC.”
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 2026 ASCO Genitourinary Cancers Symposium. January 8-10, 2026; San Francisco, CA. Abstract 13.
