BREAKWATER: An open-label, multicenter, randomized, phase 3 study, with a safety lead-in (SLI), of first-line (1L) encorafenib (E) + cetuximab (C) ± chemotherapy (CT) vs standard-of-care (SOC) CT for BRAF V600E-mutant metastatic colorectal cancer (mCRC).

TPS3627 Background: Globally, 8-12% of patients (pts) with mCRC have BRAF V600E mutations, which confer poor prognosis. Based on BEACON (NCT02928224), EC was approved for the treatment (tx) of previously treated pts with BRAF V600E-mutant mCRC. BREAKWATER (NCT04607421) is evaluating EC ± CT vs SOC CT in pts with BRAF V600E-mutant mCRC. In the BREAKWATER SLI (N = 57), EC + CT showed encouraging antitumor activity. Confirmed ORR by BICR (95% CI) with EC + mFOLFOX6 and EC + FOLFIRI, respectively, was 68.4% (46.0, 84.6) and 75.0% (46.8, 91.1) in 1L, and 37.5% (13.7, 69.4) and 44.4% (24.6, 66.3) in 2L. mPFS by BICR (95% CI) with EC + mFOLFOX6 and EC + FOLFIRI, respectively, was 11.1 months [mo] (8.5, NE) and NE (13.8, NE) in 1L, and 10.8 mo (4.3, NE) and 12.6 mo (6.9, NE) in 2L. These results support the continued evaluation of EC + CT. Based on the SLI, EC + mFOLFOX6 was selected for the phase 3 portion. Here we present the updated study design. Methods: BREAKWATER is an ongoing, open-label, multicenter, randomized, phase 3 study evaluating 1L EC ± CT vs SOC CT alone in pts with BRAF V600E-mutant mCRC. Approximately 620 pts will be enrolled in the phase 3 portion and an additional 135 in cohort 3 (Table). Phase 3 and cohort 3 inclusion criteria are age ≥16 (or ≥18 based on country); no prior systemic tx for metastatic disease; measurable disease (RECIST 1.1); BRAF V600E-mutant mCRC (blood or tumor tissue); ECOG PS 0 or 1; and adequate bone marrow, hepatic, and renal function. Pts who received prior BRAF or EGFR inhibitors, those with symptomatic brain metastases (unless stable for ≥4 weeks prior to randomization), or with MSI-H/dMMR tumors (unless ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition) are excluded. Study treatments and endpoints are shown in the Table. Phase 3 enrollment began in November 2021. Clinical trial information: NCT04607421 . [Table: see text]