LBA3503 Background: Leucovorin/5-FU in combination with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are common chemotherapies (chemo) used in 1L treatment (tx) of mCRC. In patients (pts) with BRAF V600E-mutant mCRC, BREAKWATER Phase 3 demonstrated clinically meaningful and statistically significantly improved ORR by blinded independent central review (BICR), PFS by BICR, and OS with 1L EC+mFOLFOX6 vs chemo ± bevacizumab (bev) (Kopetz Nat Med 2025; Elez N Engl J Med 2025). The BREAKWATER safety lead-in previously showed that EC+FOLFIRI was tolerable with promising antitumor activity. BREAKWATER Cohort 3 was therefore conducted to study EC+FOLFIRI. The primary endpoint (EP) of BREAKWATER Cohort 3 was met, demonstrating clinically meaningful and statistically significant improvement in confirmed ORR by BICR with EC+FOLFIRI (64.4%) vs FOLFIRI±bev (39.2%; control) (odds ratio 2.76 95% CI 1.42, 5.35; one-sided P =0.001) (Kopetz ASCO GI 2026). Reported here are PFS by BICR (key secondary EP), and updated OS and safety data from BREAKWATER Cohort 3. 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 EP was ORR by BICR. The key secondary EP was PFS by BICR; other secondary EPs included OS and safety. Results: 147 pts were randomized to EC+FOLFIRI or control; the median follow-up for PFS was 18.0 and 14.4 mo, respectively, for OS it was 20.6 and 20.7 mo, respectively (data cutoff: Jan 6, 2026). Baseline demographics and disease characteristics were generally balanced between arms. EC+FOLFIRI demonstrated a clinically meaningful and statistically significant PFS improvement vs control, meeting the key secondary EP (Table). Prolonged OS was observed (Table). The median duration of study tx was 67.9 wk for EC+FOLFIRI and 32.1 wk for control. Discontinuation of chemo (± bev as appropriate for the respective tx arms) due to AEs was similar between arms (14% EC+FOLFIRI vs 10% control). Conclusions: BREAKWATER Cohort 3 demonstrated clinically meaningful and statistically significant ORR and PFS improvements and prolonged OS with EC+FOLFIRI vs control. The safety profile was consistent with that known for each agent with no new safety signals. EC+FOLFIRI expands practice-changing standard-of-care options to deliver pt-centered care for pts with BRAF V600E-mutant mCRC. Clinical trial information: NCT04607421 . EC+FOLFIRI (n=73) Control (n=74) mPFS (95% CI), mo 15.2 (13.6, NE) 8.3 (6.9, 9.8) PFS HR a (95% CI) 0.44 (0.27, 0.70)One-sided P =0.0002 mOS (95% CI), mo NE (21.0, NE) 20.3 (13.2, NE) OS HR a (95% CI) 0.56 (0.34, 0.94) 18-mo OS rate (95% CI), % 72.0 (60.0, 80.9) 54.5 (42.0, 65.4) n=71 n=68 Serious TEAEs, % 49 44 Maximum Grade 3/4 TEAEs, % 70 81 NE, not estimable; TEAE, tx-emergent adverse event. a Stratified by ECOG PS (0 vs 1) at randomization.
Kopetz et al. (Wed,) studied this question.