BREAKWATER phase 3: Post hoc subgroup analyses by age in patients (pts) with BRAF V600E-mutant metastatic colorectal cancer (mCRC).

Abstract

122 Background: Most mCRC occurs in pts ≥50 y old but increasingly pts <50 y are being diagnosed with mCRC. Evidence regarding their outcomes is conflicting. BREAKWATER (Phase 3; NCT04607421) demonstrated statistically significant and clinically meaningful improvements in ORR, PFS by blinded independent central review (BICR), and OS with encorafenib + cetuximab (EC)+mFOLFOX6 vs control (chemotherapy±bevacizumab) in 1L BRAF V600E-mutant mCRC, making EC+mFOLFOX6 a new standard of care. We report analyses by age. Methods: Eligible pts with untreated BRAF V600E-mutant mCRC were randomized 1:1:1 to EC (n=158; enrollment closed after protocol amendment), EC+mFOLFOX6 (n=236), or control (n=243). Dual primary endpoints (EPs) were ORR and PFS by BICR; the key secondary EP was OS for EC+mFOLFOX6 vs control. Here, exploratory efficacy, safety, and biomarker analyses were performed by age at diagnosis (<50 y, early onset [EOCRC] or ≥50 y, average age onset [AOCRC]). A genAI tool (08/06/25; Pfizer; GPT-4o) assisted with the 1st draft; authors assume content responsibility. Results: As of Jan 6, 2025, 39, 66, and 59 EOCRC pts (~25% of each arm) were enrolled in the EC, EC+mFOLFOX6, and control arms, respectively, with 119, 170, and 184 AOCRC pts in each arm, respectively (Table). Median age (range) was 41 (24, 49) y for EOCRC pts and 64 (50, 84) y for AOCRC pts. Results for EC+mFOLFOX6 in EOCRC and AOCRC pts, respectively, were 69.7% and 64.1% for confirmed ORR by BICR, 10.9 and 14.0 mo for mPFS by BICR, and 23.8 and 30.3 mo for mOS. Results for the control arms in EOCRC and AOCRC pts, respectively, were 45.8% and 34.8% for confirmed ORR by BICR, 7.1 mo in both groups for mPFS by BICR, and 15.1 and 14.9 mo for mOS. See table for EC data. Incidence of grade 3/4 AEs was 80.0% and 82.0% for EC+mFOLFOX6, 64.8% and 67.4% for control, and 35.1% and 44.8% for EC in EOCRC and AOCRC pts, respectively. Biomarker data will be reported. Conclusions: All pts with BRAF V600E-mutant mCRC receiving 1L EC+mFOLFOX6, including EOCRC pts, showed improved ORR, PFS, and OS vs control. The safety profile of EC+mFOLFOX6 was similar for both age groups. Clinical trial information: NCT04607421 . EOCRC EOCRC EOCRC AOCRC AOCRC AOCRC EC n=39 EC+ mFOLFOX6 n=66 Control n=59 EC n=119 EC+ mFOLFOX6 n=170 Control n=184 Confirmed ORR, a % (95% CI) 56.4(41.0, 70.7) 69.7(57.8, 79.4) 45.8(33.7, 58.3) 42.0(33.5, 51.0) 64.1(56.7, 70.9) 34.8(28.3, 41.9) Odds ratio vs control (95% CI) 1.53(0.68, 3.46) 2.73(1.31, 5.68) 1.36(0.85, 2.18) 3.35(2.17, 5.18) Median PFS, a mo(95% CI) 5.4(4.2, 5.7) 10.9(9.7, 16.8) 7.1(6.7, 11.1) 8.3(6.4, 9.2) 14.0(11.3, 16.6) 7.1(5.9, 8.8) HR vs control(95% CI) 1.84(1.08, 3.13) 0.57(0.34, 0.95) 0.94(0.70, 1.27) 0.49(0.37, 0.65) Median OS, mo(95% CI) 18.9(14.6, 23.4) 23.8(21.1, NE) 15.1(13.2, 19.5) 19.5(17.6, 24.5) 30.3(21.0, NE) 14.9(13.7, 18.2) HR vs control(95% CI) 0.68(0.40, 1.16) 0.42(0.25, 0.71) 0.70(0.52, 0.95) 0.51(0.38, 0.68) NE, not estimable. a By BICR.