BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer.
Authors: Scott Kopetz, Takayuki Yoshino, Eric Van Cutsem, Cathy Eng, Tae Won Kim, Harpreet Singh Wasan, Jayesh Desai, Fortunato Ciardiello, Rona Yaeger, Timothy S. Maughan, Elena Beyzarov, Xiaoxi Zhang, Graham Ferrier, Xiaosong Zhang, Josep Tabernero
Journal: Journal of Clinical Oncology (2025)

16 Background: Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study (NCT02928224). Historically, first-line (1L) treatment of BRAF V600E-mutant mCRC with chemotherapy (chemo) regimens has had limited efficacy.BREAKWATER (NCT04607421) is an open-label, global, randomized, phase 3 study evaluating 1L EC with or without chemo vs standard of care (SOC; chemo with or without bevacizumab). Reported here are the primary analysis of objective response rate by blinded independent central review (ORR by BICR; dual primary endpoint [EP]), the first interim analysis of overall survival (OS; key secondary EP), other secondary EPs, and safety for the EC+FOLFOX (oxaliplatin, leucovorin, and 5-FU) vs SOC arms. Methods: Eligible patients (pts) had untreated BRAF V600E-mutant mCRC, measurable disease (RECIST 1.1), and ECOG PS 0-1. Pts were randomized 1:1:1 to receive EC, EC+FOLFOX, or SOC; EC arm enrollment was closed after a protocol amendment. Dual primary EPs were ORR (assessed in the first 110 pts randomized to each of the EC+FOLFOX and SOC arms) and progression-free survival by BICR (EC+FOLFOX vs SOC); OS was a key secondary EP (EC+FOLFOX vs SOC), other secondary EPs included response duration and time to response (TTR). Results: Four hundred seventy-nine pts were randomized to the EC+FOLFOX and SOC arms (EC+FOLFOX: n=236; SOC: n=243). Baseline demographics and disease characteristics were similar across arms (median age: 61.0 years; male: 50.5%; ECOG PS 0: 54.3%). At data cutoff (Dec 22, 2023), the EC+FOLFOX arm demonstrated a clinically meaningful and statistically significant improvement in confirmed ORR vs the SOC arm, 60.9% vs 40.0%, odds ratio=2.443, one-sided P -value=0.0008, meeting this dual primary EP. The response observed with EC+FOLFOX was rapid and durable. OS data were immature but indicated a sustained survival benefit with EC+FOLFOX vs SOC arm. Serious treatment-emergent adverse events (EC+FOLFOX: n=231; SOC: n=228) occurred in 37.7% vs 34.6% of pts in the respective arms. The safety profile was consistent with that known for each agent. Conclusions: BREAKWATER demonstrated a substantially improved response rate that was rapid and durable with EC+FOLFOX in BRAF V600E-mutant mCRC with manageable toxicities and no new safety signals. Clinical trial information: NCT04607421 . EC+FOLFOXn=110 SOCn=110 ORR by BICR % (95% CI) 60.9 (51.6, 69.5) 40.0 (31.3, 49.3) Odds ratio (95% CI) P -value a 2.443 (1.348, 4.380) 0.0008 n=67 n=44 Estimated median response duration by BICR (95% CI), mo 13.9 (8.5, NE) 11.1 (6.7, 12.7) Pts with a response duration of ≥6 mo, n (%)Pts with a response duration of ≥12 mo, n (%) 46 (68.7)15 (22.4) 15 (34.1)5 (11.4) Median TTR by BICR (range), weeks 7.1 (5.7-53.7) 7.3 (5.4-48.0) n=236 n=243 OS (95% CI), mo NE (19.8, NE) 14.6 (13.4, NE) Hazard ratio (95% CI) 0.47 (0.318, 0.691) a One-sided α=0.001. NE, not estimable.