BREAKWATER: Primary analysis of first-line (1L) encorafenib + cetuximab (EC) + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer (mCRC).

Abstract

13 Background: Leucovorin/5-FU in combination with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are common chemotherapies used in 1L mCRC. In patients (pts) with BRAF V600E-mutant mCRC, the Phase 3 portion of BREAKWATER (NCT04607421) demonstrated clinically meaningful and statistically significantly improved ORR by blinded independent central review (BICR), PFS by BICR, and OS with 1L EC + mFOLFOX6 vs chemotherapy ± bevacizumab (bev) (Kopetz Nat Med 2025; Elez N Engl J Med 2025). The safety lead-in portion of BREAKWATER previously showed that EC+FOLFIRI was tolerable with promising antitumor activity. The primary analysis results for EC+FOLFIRI vs FOLFIRI ± bev (control) from BREAKWATER Cohort 3 are reported here. Methods: Eligible pts in Cohort 3 had untreated BRAF V600E-mutant mCRC, measurable disease (RECIST 1.1), and ECOG PS 0-1. Pts were randomized 1:1 to receive EC+FOLFIRI or control. The primary endpoint (EP) is ORR by BICR; key secondary EP is PFS by BICR; and other secondary EPs include OS, DOR, time to response (TTR), and safety. Results: In Cohort 3, 147 pts were randomized (EC+FOLFIRI, n=73; control, n=74). Baseline demographics and disease characteristics were similar between arms (median age: 62 yrs; male: 46%; ECOG PS 0: 60%). At data cutoff (Mar 1, 2025), EC+FOLFIRI demonstrated a clinically meaningful and statistically significant improvement in confirmed ORR by BICR vs control (Table), meeting the primary EP. Responses observed with EC+FOLFIRI were rapid and durable. OS data were immature (median follow-up: 10.5 mo [EC+FOLFIRI] and 10.3 mo [control]) but suggested a potential survival benefit with EC+FOLFIRI vs control. Serious treatment-emergent adverse events (EC+FOLFIRI: n=71; control: n=68) occurred in 39.4% vs 36.8% of pts, respectively. The safety profile was consistent with that known for each agent. The addition of EC to FOLFIRI did not lead to substantial increases in FOLFIRI discontinuation (FOLFIRI [or bev] discontinuation: 9.9% vs 8.8%, respectively). Conclusions: BREAKWATER Cohort 3 demonstrated a clinically meaningful and statistically significant improved response rate that was rapid and durable with EC+FOLFIRI vs control in 1L BRAF V600E-mutant mCRC, with manageable toxicities and no new safety signals. These data support EC+FOLFIRI as a potential new standard of care in BRAF V600E-mutant mCRC. Clinical trial information: NCT04607421 . EC+FOLFIRI n=73 Controln=74 ORR, a % 64.4 39.2 Odds ratio (95% CI) P -value b 2.76 (1.42-5.35)0.001 Estimated medianresponse duration a,c (95% CI), mo NE (NE-NE) NE (7.0-NE) Pts with a response duration of ≥6 mo, a,c % 57.4 34.5 Median TTR a,c (range), weeks 6.9 (5.4-36.1) 7.1 (5.9-25.3) Median OS (95% CI), mo NE (NE-NE) NE (12.1-NE) OS hazard ratio (95% CI) 0.49 (0.24-1.03) a By BICR. b One-sided α=0.025. c In responders: n=47 and n=29, respectively. NE, not estimable.