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Clinical Trial
. 2025 Mar;31(3):901-908.
doi: 10.1038/s41591-024-03443-3. Epub 2025 Jan 25.

Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial

Scott Kopetz  1 , Takayuki Yoshino  2 , Eric Van Cutsem  3 , Cathy Eng  4 , Tae Won Kim  5 , Harpreet Singh Wasan  6 , Jayesh Desai  7 , Fortunato Ciardiello  8 , Rona Yaeger  9 , Timothy S Maughan  10 , Elena Beyzarov  11 , Xiaoxi Zhang  11 , Graham Ferrier  11 , Xiaosong Zhang  12 , Josep Tabernero  13
Affiliations
Clinical Trial

Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial

Scott Kopetz et al. Nat Med. 2025 Mar.

Abstract

Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study. Historically, first-line treatment of BRAF V600E-mutant mCRC with chemotherapy regimens has had limited efficacy. The phase 3 BREAKWATER study investigated EC+mFOLFOX6 versus standard of care (SOC) in patients with previously untreated BRAF V600E mCRC. The dual primary endpoint of progression-free survival is event driven; data were not mature at data cutoff. BREAKWATER met the other dual primary endpoint of objective response rate, demonstrating significant and clinically relevant improvement in objective response rate (EC+mFOLFOX6: 60.9%; SOC: 40.0%; odds ratio, 2.443; 95% confidence interval (CI): 1.403-4.253; 99.8% CI: 1.019-5.855; one-sided P = 0.0008). Median duration of response was 13.9 versus 11.1 months. At this first interim analysis of overall survival, the hazard ratio was 0.47 (95% CI: 0.318-0.691; repeated CI: 0.166-1.322). Serious adverse event rates were 37.7% versus 34.6%. The safety profiles were consistent with those known for each agent. BREAKWATER demonstrated a significantly improved response rate that was durable for first-line EC+mFOLFOX6 versus SOC in patients with BRAF V600E mCRC. ClinicalTrials.gov identifier: NCT04607421 .

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Conflict of interest statement

Competing interests: S.K. has stock and other ownership interests in Lylon, Lutris, MolecularMatch and Navire; a consulting or advisory role at 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, Iylon, Jacobio, Jazz Pharmaceuticals, Lilly, Lutris, Merck, Mirati Therapeutics, Natera, Novartis, Numab, Pfizer, Pierre Fabre, Redx Pharma, Repare Therapeutics, Servier and Xilis and received research funding from Amgen, Array BioPharma, Biocartis, Daiichi Sankyo, EMD Serono, Genentech/Roche, Guardant Health, Lilly, MedImmune, Novartis and Sanofi. T.Y. receives honoraria from Bayer Yakuhin, Chugai Pharma, Merck KGaA, MSD, Ono Pharmaceutical, Sumitomo and Takeda and research funding from Amgen, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, Eisai, FALCO Biosystems, Genomedia, Molecular Health, MSD, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Pfizer, Roche Diagnostics, Sanofi, Sumitomo Dainippon, Sysmex and Taiho Pharmaceutical. E.V.C. has a consulting or advisory role at AbbVie, Agenus, ALX, Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, Bayer, BeiGene, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Debiopharm, ElmediX, Eisai, GSK, Hookipa Biotech, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seagen, Servier, Simcere, Takeda, Taiho Pharmaceutical and Terumo. C.E. has a consulting role at Bayer, Boston Scientific, GlaxoSmithKline, HalioDx, Merck, Mirati, Hookipa, J&J, Natera, Roche, Seagen, Taiho and Veloxis and receives research funding (to VUMC) from Elevar, Hutchinson, Merck and Pfizer. T.W.K. receives research funding (institutional) from AstraZeneca, Sanofi and Roche/Genentech. H.S.W. has a consulting or advisory role at Amgen, Bayer, Bristol Myers Squibb (Celgene), Boehringer Ingelheim (DMC), BTG, EXACT Therapeutics, Erytech Pharma, Incyte, Merck KGaA, Oaktree Life Sciences, OncoSil, Pfizer, Pierre Fabre, Roche/Genentech, Seagen, Servier, Shire, Sirtex Medical, Takeda (Hutchinson Med) and Zymeworks and recieves research funding (institutional) from Merck KGaA, MSD, Pfizer and Sirtex Medical. J.D. has a consulting or advisory role at Amgen, Bayer, BeiGene, Daiichi Sankyo, Eisai, GSK, Merck KGaA and Pierre Fabre and receives research funding from AstraZeneca/MedImmune, BeiGene, Bionomics, Bristol Myers Squibb, GSK, Lilly, Novartis and Roche. F.C. has a consulting or advisory role at Amgen, Bayer, Merck KGaA, Pfizer and Roche/Genentech and receives research funding from Amgen, Bayer, Bristol Myers Squibb, Ipsen, Merck KGaA, MSD, Roche/Genentech, Servier and Symphogen. R.Y. has a consulting or advisory role at Array BioPharma/Pfizer, Mirati Therapeutics, Zai Lab and Amgen and receives research funding from Array BioPharma, Boehringer Ingelheim, Mirati Therapeutics, Pfizer and Daiichi Sankyo. T.S.M. has a consulting or advisory role at AstraZeneca, Pierre Fabre and Vertex; receives research funding (institutional) from Almac Diagnostics, AstraZeneca, Merck KgAA and PsiOxus Therapeutics; and has a patent pending. E.B., Xiaoxi Zhang and G.F. are employees of and have stock and other ownership interests in Pfizer. Xiaosong Zhang is an employee of and has stock and other ownership interests in Pfizer and has patents, royalties or other intellectual property via Johns Hopkins University. J.T. has a consulting or advisory role at Array BioPharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, F. Hoffmann-La Roche, Genentech, HalioDx, Hutchison MediPharma, Ikena Oncology, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, Mirati Therapeutics, MSD, NeoPhore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seagen, Servier, Taiho Pharmaceutical, Tessa Therapeutics and TheraMyc and has other relationships with Amgen, Array Biopharma, BeiGene, Boehringer Ingelheim, BMS, Cancer Research UK, Celgene, Debiopharm, F. Hoffman-La Roche, Fundación Científica de la Asociación Española Contra el Cáncer, Genentech, HalioDx, Hutchinson Medipharma, Imedex, Janssen-Cilag, MedImmune, Medscape, Menarini, Merck Health KGaA, MJH Life Sciences, MSD, Merus, Mirati, Novartis, Oniria Therapeutics, PeerView Institute for Medical Education, Pfizer, PharmaMar, Physicans’ Education Resource, Sanofi-Aventis, Servier and Taiho Pharmaceutical.

Figures

Fig. 1
Fig. 1. Patient disposition.
CAPOX, oxaliplatin and capecitabine; EC, encorafenib and cetuximab; mFOLFOX6, oxaliplatin, leucovorin and 5-FU; FOLFOXIRI, irinotecan, oxaliplatin, leucovorin and 5-FU; mCRC, metastatic colorectal cancer; SOC, standard of care. aOne participant who was randomized to the EC+mFOLFOX6 arm (but never treated) was inadvertently entered as withdrawal by subject on the screening case report form page. bFollowing closure of the EC arm, randomization was 1:1 to the EC+mFOLFOX6 and SOC arms.
Fig. 2
Fig. 2. Subgroup analyses of confirmed objective response rate by blinded independent central review.
Odds ratios (center) are presented with 95% CI (error bars). EC+mFOLFOX6, encorafenib and cetuximab plus oxaliplatin, leucovorin and 5-FU. aPercentages were calculated based on the number of participants in the objective response rate subset of all randomized patients in each treatment group. bObjective response rate calculated based on the number of participants in the objective response rate subset of all randomized patients within each treatment group and subgroup. The odds ratio was estimated using the Mantel–Haenszel method. The exact CI was calculated.
Fig. 3
Fig. 3. Overall survival.
Hazard ratio repeated CI: 0.166–1.322.
See this image and copyright information in PMC

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