A randomised study of encorafenib, cetuximab, and FOLFIRI versus FOLFIRI with or without bevacizumab in BRAF V600E-mutant colorectal cancer: BREAKWATER Cohort 3

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

Author(s): 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;
Details: Publication Year 2026-08,Volume 37,Issue #8,Page 1133-1143
Journal Title: Annals of Oncology
Publication Type: Research article
Abstract: BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Publisher: Elsevier
Keywords: Humans; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/administration &; dosage/adverse effects; *Colorectal Neoplasms/drug therapy/genetics/pathology/mortality; *Proto-Oncogene Proteins B-raf/genetics; Fluorouracil/administration & dosage/adverse effects; Cetuximab/administration & dosage/adverse effects; Leucovorin/administration & dosage/adverse effects; *Camptothecin/analogs & derivatives/administration & dosage/adverse effects; Bevacizumab/administration & dosage/adverse effects; Carbamates/administration & dosage/adverse effects; Female; Middle Aged; Male; Sulfonamides/administration & dosage/adverse effects; Mutation; Aged; Adult; BRAF mutant; Folfiri; cetuximab; colorectal cancer; encorafenib
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1016/j.annonc.2026.04.017
Open Access at Publisher's Site: https://doi.org/10.1016/j.annonc.2026.04.017
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-06-23 03:42:07

Last Modified: 2026-08-11 05:52:44