Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer

Authors

Elena Elez
Takayuki Yoshino
Lin Shen
Sara Lonardi
Eric Van Cutsem
Cathy Eng
Tae Won Kim
Harpreet Singh Wasan
Jayesh Desai
Fortunato Ciardiello
Rona Yaeger
Timothy S Maughan
Van K Morris
Christina Wu
Tiziana Usari
Robert Laliberte
Samuel S Dychter
Xiaosong Zhang
Josep Tabernero
Scott Kopetz
BREAKWATER Trial Investigators

Language

English

Publication Date

6-26-2025

Journal

The New England Journal of Medicine

DOI

10.1056/NEJMoa2501912

PMID

40444708

PMCID

PMC12197837

PubMedCentral® Posted Date

6-26-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Background: First-line treatment with encorafenib plus cetuximab (EC) with or without chemotherapy (oxaliplatin, leucovorin, and fluorouracil [mFOLFOX6]) for BRAF V600E-mutated metastatic colorectal cancer, an aggressive subtype with a poor prognosis, was compared with standard care (chemotherapy with or without bevacizumab) in an open-label, phase 3 trial, which showed significance regarding one of the two primary end points, objective response according to blinded independent central review (odds ratio for EC+mFOLFOX6 vs. standard care, 2.44; one-sided P< 0.001). This result led to accelerated Food and Drug Administration approval of this investigational combination therapy for BRAF V600E-mutated metastatic colorectal cancer, including as first-line therapy. Data on progression-free survival (the second primary end point) and an updated interim analysis of overall survival are now available.

Methods: We randomly assigned patients with untreated BRAF V600E-mutated metastatic colorectal cancer to receive EC, EC+mFOLFOX6, or standard care. The two primary end points were objective response (reported previously) and progression-free survival according to blinded independent central review in the EC+mFOLFOX6 group and the standard-care group. The key secondary end point was overall survival.

Results: Significantly longer progression-free survival was seen with EC+mFOLFOX6 than with standard care (median, 12.8 vs. 7.1 months; hazard ratio for progression or death, 0.53; 95% confidence interval [CI], 0.41 to 0.68; P< 0.001). In an interim analysis, overall survival was significantly longer with EC+mFOLFOX6 than with standard care (median, 30.3 vs. 15.1 months; hazard ratio for death, 0.49; 95% CI, 0.38 to 0.63; P< 0.001). The incidence of serious adverse events during treatment was 46.1% with EC+mFOLFOX6 and 38.9% with standard care. Safety profiles were consistent with those known for each agent.

Conclusions: This trial showed significantly longer progression-free survival and overall survival with first-line treatment with EC+mFOLFOX6 than with standard care among patients with BRAF V600E-mutated metastatic colorectal cancer. (Funded by Pfizer and others; BREAKWATER ClinicalTrials.gov number, NCT04607421.).

Keywords

Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Antineoplastic Combined Chemotherapy Protocols, Carbamates, Cetuximab, Colorectal Neoplasms, Mutation, Neoplasm Metastasis, Progression-Free Survival, Proto-Oncogene Proteins B-raf, Sulfonamides, Treatment Outcome, Young Adult, Leucovorin, Fluorouracil, Organoplatinum Compounds

Published Open-Access

yes

Recommended Citation

Elez, Elena; Yoshino, Takayuki; Shen, Lin; et al., "Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer" (2025). Faculty, Staff and Student Publications. 6015.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6015