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Ref Type Journal Article
PMID (42219860)
Authors Kopetz S, Tabernero J, Lonardi S, Shen L, Wasan HS, Yoshino T, Van Cutsem E, Kim TW, Eng C, Ciardiello F, Desai J, Maughan TS, Yaeger R, Usari T, Zhang X, Beyzarov E, Mori A, Whalley E, Zhang X, Elez E
Title A randomised study of encorafenib, cetuximab, and FOLFIRI versus FOLFIRI with or without bevacizumab in BRAF V600E-mutant colorectal cancer: BREAKWATER Cohort 3.
Journal Vol Issue Date Pages Journal Short Title
Annals of oncology : official journal of the European Society for Medical Oncology 2026 May 31 Ann Oncol
URL
Abstract Text Encorafenib + cetuximab (EC) and mFOLFOX6 or irinotecan, leucovorin, and fluorouracil (FOLFIRI) is approved in several countries for BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on results from the BREAKWATER trial.In BREAKWATER Cohort 3, eligible patients with previously untreated BRAF V600E-mutant mCRC were randomly assigned 1:1 to receive EC+FOLFIRI or FOLFIRI with or without bevacizumab (control). The primary endpoint was objective response rate (ORR) by blinded independent central review (BICR), and the key secondary endpoint was progression-free survival (PFS) by BICR. Other secondary endpoints included overall survival (OS) and safety.A total of 147 patients were randomly allocated in Cohort 3 (EC+FOLFIRI, n = 73; control, n = 74) with similar baseline demographics and disease characteristics across arms. EC+FOLFIRI demonstrated clinically meaningful and statistically significant improvement in ORR by BICR {64.4% versus 39.2%, odds ratio = 2.756 [95% confidence interval (CI) 1.420-5.348], one-sided P-value = 0.0011}, meeting the primary endpoint (1 March 2025, data cutoff). At the 6 January 2026 data cutoff, the key secondary endpoint was met, with EC+FOLFIRI demonstrating a clinically meaningful and statistically significant PFS [hazard ratio = 0.44 (95% CI 0.27-0.70), one-sided P-value = 0.0002, 15.2 versus 8.3 months]. Prolonged OS was also observed with EC+FOLFIRI (hazard ratio = 0.56 [95% CI 0.34-0.94], not estimable versus 20.3 months). Serious adverse event rates were 49.3% versus 44.1% for the EC+FOLFIRI versus control arms, respectively. The safety profile was consistent with that known for each agent.EC+FOLFIRI demonstrated clinically meaningful and statistically significant improvements in ORR and PFS, with prolonged OS versus control in BRAF V600E-mutant mCRC. The safety profile was generally manageable, with no new safety signals. These data support EC+FOLFIRI as an additional new standard of care for patients with BRAF V600E-mutant mCRC, enabling treatment personalisation.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E colorectal cancer sensitive Cetuximab + Encorafenib + Fluorouracil + Irinotecan + Leucovorin FDA approved - On Companion Diagnostic Actionable In a Phase III trial (BREAKWATER) that supported FDA approval, Braftovi (encorafenib) in combination with Erbitux (cetuximab) and FOLFIRI significantly improved objective response rate (64.4%, 47/73 vs 39.2%, 29/74; OR=2.756, p=0.0011) and progression-free survival (15.2 vs 8.3 mo; HR=0.44, p=0.0002) compared to FOLFIRI with or without bevacizumab in metastatic colorectal cancer patients harboring BRAF V600E, and median overall survival was not estimable vs 20.3 mo (HR=0.56) (PMID: 42219860; NCT04607421). detail... detail... detail... 42219860