The BRAF inhibitor encorafenib plus the monoclonal antibody cetuximab combined with mFOLFOX (modified folinic acid, fluorouracil, and oxaliplatin) significantly improved overall response in BRAF V600E–mutant metastatic colorectal cancer, according to data presented at the 2025 ASCO Gastrointestinal Cancers Symposium1 and published simultaneously in Nature Medicine.2 These findings were presented by lead investigator Scott Kopetz, MD, PhD, FACP, Deputy Chair for Translational Research and Professor of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center.
Results of the phase III BREAKWATER trial, which compared the experimental regimen of encorafenib, cetuximab, and mFOLFOX against standard chemotherapy in patients with previously untreated, BRAF V600E–mutated metastatic colorectal cancer, showed a 60.9% overall response rate in the experimental arm vs 40% in the standard-of-care arm. The median duration of response reached 13.9 months in the experimental arm, compared with 11.1 months in the standard-of-care arm. The proportion of patients whose response persisted for at least 6 months or 12 months was roughly double in the experimental group relative to those on standard chemotherapy.
Scott Kopetz, MD, PhD, FACP
“These findings establish encorafenib plus cetuximab and mFOLFOX as a new first-line standard of care for patients with BRAF V600E–mutated metastatic colorectal cancer,” said Dr. Kopetz.
As Dr. Kopetz explained, patients with BRAF V600E mutations, which occur in roughly 8% to 12% of metastatic colorectal cancers, have long been recognized as having a more aggressive disease course. Historically, outcomes have been poorer for these patients than for those with BRAF wild-type tumors, he said, and standard chemotherapy regimens have demonstrated limited efficacy in this setting.
Encorafenib, an ATP-competitive BRAF inhibitor, combined with cetuximab—a monoclonal antibody targeting the EGFR—had already shown efficacy in preclinical models and gained approval in the second- and later-line settings for BRAF V600E–mutant metastatic colorectal cancer, based on the BEACON CRC trial. However, there remained a critical unmet need for an effective, targeted first-line treatment strategy.
Study Design
The BREAKWATER trial was designed as an open-label, multicenter, phase III study to evaluate the addition of encorafenib and cetuximab to standard mFOLFOX (EC-FOLFOX) in untreated BRAF V600E–mutant metastatic colorectal cancer. Patients were required to have microsatellite-stable tumors and proficient mismatch repair. They were randomly assigned to one of three groups: standard-of-care chemotherapy (with or without bevacizumab), EC-FOLFOX, or a dual combination of encorafenib plus cetuximab without chemotherapy.
The co-primary endpoints for this trial were progression-free survival and overall response rate. Overall survival was examined as a key secondary endpoint.
Overall Survival Results
At interim analysis, both overall response rate and duration of response were significantly higher in the experimental arm vs standard chemotherapy. Of note, 68.7% of responding patients in the EC-FOLFOX arm maintained their responses for at least 6 months, said Dr. Kopetz, compared with 34.1% in the standard-of-care arm. At 12 months, response was maintained by 22.4% in the experimental arm and 11.1% with standard chemotherapy. The median time to response was approximately 7 weeks in both arms, suggesting responses occurred relatively early with the experimental therapy.
In addition, investigators reported a trend favoring EC-FOLFOX in terms of overall survival, although these data remain immature. Median overall survival was not reached in the experimental arm, compared with 14.6 months in the standard-of-care arm (hazard ratio = 0.47).
At 6 months, 92.3% of patients randomly assigned to the experimental regimen were alive, compared with 87.1% in the standard-of-care group. At 12 months, 79.5% were alive in the experimental arm vs 66.1% in the standard-of-care arm.
“The prespecified statistical threshold for overall survival significance was not reached at this interim analysis, because only a fraction of the required overall survival events had accumulated, so further planned analyses will help to clarify the definitive survival benefit,” Dr. Kopetz reported.
Nevertheless, investigators emphasized that the difference in clinical response was sufficient for the U.S. Food and Drug Administration (FDA) to grant approval of the EC-FOLFOX regimen in 2024 for the treatment of patients with BRAF V600E–mutant metastatic colorectal cancer, including use in the first-line setting, as part of the FDA Project FrontRunner initiative. This initiative was designed to facilitate the development of new cancer drugs for earlier lines of therapy. (For more on Project FrontRunner, visit https://www.fda.gov/about-fda/oncology-center-excellence/project-frontrunner.)
Safety Profile
Safety data from BREAKWATER showed that although the incidence of adverse events was high in both arms—99.6% with EC-FOLFOX and 97.8% with the standard of care—the spectrum of these events was consistent with the known profiles of the individual agents.
Common adverse events included nausea, anemia, diarrhea, appetite reduction, vomiting, and decreased neutrophil counts. Grade 3 or 4 treatment-emergent adverse events were recorded in 74.0% of patients receiving EC-FOLFOX and in 61.0% of the comparator arm, and grade 3 or 4 treatment-related adverse events were noted in 69.7% vs 53.9%, respectively.
There were no fatal adverse events in the experimental arm, and treatment discontinuations or dose reductions as a result of adverse events were similar between the two arms.
“Overall, the BREAKWATER trial provides a critical step forward in the management of BRAF V600E–mutant metastatic colorectal cancer,” said Dr. Kopetz. “Encorafenib and cetuximab combined with mFOLFOX appears to overcome a therapeutic challenge that has long perplexed clinicians, offering new hope for patients historically hindered by poor prognoses.”
Expert Point of View
Invited discussant Wells Messersmith, MD, FASCO, FACP, Professor and Head, Division of Medical Oncology, University of Colorado Cancer Center, underscored the significance of the BREAKWATER study.
Wells Messersmith, MD, FASCO, FACP
“The 21% increase in the overall response rate is quite remarkable, and many of these responses were durable,” said Dr. Messersmith. “We all know BRAF V600E is a difficult-to-treat, aggressive patient population, so these results are, in my view, practice-changing.”
Dr. Messersmith noted that treatment with encorafenib plus cetuximab combined with mFOLFOX (modified folinic acid, fluorouracil, and oxaliplatin) doubled the rate of durable responses while demonstrating “a nice separation of the curves” for interim overall survival. However, the bar for statistical significance at this early point was exceedingly high, he said, so the survival advantage did not fully clear the prespecified threshold. Further analyses are planned and are likely to provide greater clarity on long-term outcomes, Dr. Messersmith added.
In discussing toxicity, Dr. Messersmith explained that adverse events such as gastrointestinal, rashes, and arthralgia are unsurprising class effects when incorporating encorafenib and cetuximab. However, he cautioned that increased duration of therapy naturally heightens the risk of cytopenias and neuropathy. Nevertheless, the overall rates of treatment discontinuations, dose reductions, and interruptions did not differ notably between the experimental and standard arms.
Despite the early-stage nature of the data, the U.S. Food and Drug Administration has already approved this combination regimen, Dr. Messersmith concluded.
DISCLOSURE: The BREAKWATER study was supported by Pfizer; with additional support from Ono Pharmaceutical, Merck KGaA, Darmstadt, Germany, and Eli Lilly. Dr. Kopetz reported financial relationships with Iylon, Lutris, MolecularMatch, Navire, AbbVie, Amal Therapeutics, AstraZeneca/MedImmune, Bayer Health, Bicara Therapeutics, Boehringer Ingelheim, Boston Biomedical, Carina Biotech, Daiichi Sankyo, EMD Serono, Endeavor BioMedicines, Flame Biosciences, Genentech, Gilead Sciences, GSK, HalioDx, Holy Stone Healthcare, Inivata, Ipsen, Jacobio, Jazz Pharmaceuticals, Eli Lilly, Merck, Mirati Therapeutics, Natera, Novartis, Numab, Pfizer, Pierre Fabre, Redx Pharma, Repare Therapeutics, Servier Pharmaceuticals, Xilis, Amgen, Array BioPharma, Biocartis, Daiichi Sankyo, EMD Serono, Genentech/Roche, Guardant Health, MedImmune, and Sanofi. Dr. Messersmith reported institutional relationships with, and/or support from, Amgen, Criterium, Experimental Drug Development Centre, Agenus, ALX Oncology, AstraZeneca/Medimmune, BeiGene, CanBas, Exelixis, FATE Therapeutics, Mirati Therapeutics, Nurix, Pfizer, PureTech, RasCal, and Revolution Medicines.
REFERENCES
1. Kopetz S, Yoshino T, Van Cutsem E, et al: BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E–mutant metastatic colorectal cancer. 2025 ASCO Gastrointestinal Cancers Symposium. Abstract 16. Presented January 25, 2025.
2. Kopetz S, Yoshino T, Van Cutsem E, et al: Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: A randomized phase 3 trial. Nat Med. January 25, 2025 (early release online).
