BREAKWATER Expands First-Line Treatment Options for Patients With BRAF V600E–Mutant Metastatic Colorectal Cancer
Clinical Summary:
- Design/Population: In cohort 3 of the BREAKWATER study previously untreated patients with BRAF V600E-mutant mCRC were randomly assigned to receive encorafenib plus cetuximab and FOLFIRI or standard chemotherapy.
- Key Outcomes: Encorafenib plus cetuximab plus FOLFIRI significantly improved objective response rate, progression-free survival, and overall survival compared with standard chemotherapy.
- Clinical Relevance: These findings expand first-line treatment options for patients with BRAF V600E-mutant mCRC and further support incorporation of targeted therapy into frontline management.
Results from Cohort 3 of the BREAKWATER trial demonstrated that encorafenib plus cetuximab and FOLFIRI significantly improves survival compared with standard chemotherapy among previously untreated patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC).
These results were presented by Scott Kopetz, MD, PhD, MD Anderson Cancer Center, Houston, Texas, at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.
In this study, 147 patients were randomized 1:1 to receive either encorafenib plus cetuximab and FOLFIRI (n = 73) or standard chemotherapy (n = 74). Primary end points included progression-free survival (PFS), overall survival (OS), and safety.
At analysis, median PFS was 15.2 months in the encorafenib plus cetuximab and FOLFIRI arm and 8.3 months in the standard arm (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.27 to 0.70; P = .0002). Median OS was not reached in the encorafenib plus cetuximab and FOLFIRI arm and 20.3 months in the standard arm, with 18-month OS rates of 72% and 54.5%, respectively.
The median duration of study treatment was 67.9 weeks in the encorafenib plus cetuximab and FOLFIRI arm and 32.1 weeks in the standard arm. Serious treatment-emergent adverse events were reported in 49% of patients and 44% of patients, respectively. Grade 3/4 treatment-emergent adverse events were reported in 70% of patients in the encorafenib plus cetuximab and FOLFIRI arm and 81% of patients in the standard arm. Adverse events led to chemotherapy discontinuation in 14% and 10% of patients, respectively.
“[Encorafenib plus cetuximab and FOLFIRI] expands practice-changing standard-of-care options to deliver pt-centered care for pts with BRAF V600E-mutant mCRC.”
Source:
Kopetz S, Tabernero J, Lonardi S, et al. BREAKWATER: Progression-free and overall survival analyses of first-line (1L) encorafenib + cetuximab (EC) + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer (mCRC). Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. LBA3503.
