Encorafenib Plus Cetuximab and Chemotherapy for BRAF V600E-Mutant Metastatic Colorectal Cancer
According to results from the BREAKWATER trial, encorafenib plus cetuximab and FOLFOX (oxaliplatin, leucovorin, fluorouracil) demonstrated a significant improvement in response rate among patients with BRAF V600E-mutant metastatic colorectal cancer when compared with standard of care.
These data were presented by Scott Kopetz, MD, MD Anderson Cancer Center at The University of Texas, Houston, Texas at the 2025 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.
This open-label, global, randomized, phase 3 study enrolled patients with BRAF V600E-mutant metastatic colorectal cancer who have not undergone treatment. Patients were randomized on a 1-to-1-to-1 basis to receive encorafenib plus cetuximab; encorafenib plus cetuximab and FOLFOX (n = 236); or standard of care (chemotherapy with or without bevacizumab; n = 243). Following a protocol amendment, the encorafenib plus cetuximab arm was closed to enrollment. The dual primary end points were objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review, and as assessed in the first 110 patients randomized to each arm. A key secondary end point was overall survival and other secondary end points included response duration and time to response.
The confirmed ORR of the encorafenib plus cetuximab and FOLFOX arm was 60.9% vs 40.0% in the standard of care arm, representing a statistically significant improvement (odds ratio = 2.443; one-sided P = .0008). Dr Kopetz et al, noted the response seen with encorafenib plus cetuximab and FOLFOX was “rapid and durable.” While OS data were immature, there was trend toward a sustained survival benefit with encorafenib plus cetuximab and FOLFOX. Serious treatment-emergent adverse events were observed in 37.7% of patients in the encorafenib plus cetuximab and FOLFOX vs 34.6% in the standard of care arm.
Dr Kopetz et al concluded, “BREAKWATER demonstrated a substantially improved response rate that was rapid and durable with [encorafenib plus cetuximab] and FOLFOX in BRAF V600E-mutant [metastatic colorectal cancer] with manageable toxicities and no new safety signals.”
Source:
Kopetz S, Yoshino T, Van Cutsem E, et al. BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer. Presented at 2025 ASCO Gastrointestinal Cancers Symposium. January 23-25, 2025; San Francisco, CA. Abstract 16.
