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.
Kopetz et al. (Fri,) studied this question.
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