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…
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