BREAKWATER: Randomized phase 3 study of encorafenib (enco) + cetuximab (cet) ± chemotherapy for first-line treatment (tx) of BRAF V600E-mutant (BRAFV600) metastatic colorectal cancer (mCRC).

Abstract

TPS211 Background: Approximately 10% of patients (pts) with mCRC have BRAF mutations (mostly V600E). First-line tx options for BRAFV600E mCRC are limited to cytotoxic chemotherapy ± anti-VEGF or anti-EGFR; or immune checkpoint inhibitors in pts with MSI-H tumors. In Europe, Japan, and USA, the combination of BRAF inhibitor enco + EGFR inhibitor cet is approved for tx of BRAFV600E mCRC after prior therapy. In BEACON CRC, enco + cet resulted in a median overall survival (OS) of 9.3 months (95% confidence interval [CI]: 8.0–11.3) and an objective response rate (ORR) of 19.5% (95% CI: 14.5%–25.4%) in previously treated pts with BRAFV600E mCRC (median follow-up: 12.8 months); 57.4% of pts had grade 3/4 adverse events (AEs), and 9% discontinued due to AEs. Given the poor prognosis of pts with BRAFV600E mCRC and based on the efficacy and tolerability of enco + cet from BEACON CRC, the BREAKWATER study will evaluate the efficacy and safety of enco + cet ± chemotherapy in tx-naive pts with BRAFV600E mCRC. Methods: BREAKWATER is an open-label, global, multicenter, randomized, phase 3 study with a safety lead-in (SLI). Approximately 60 and 870 pts will be enrolled in the SLI and phase 3 parts of the study, respectively. Pts must have mCRC with BRAF V600E-mutation (determined using tumor tissue or blood); ECOG performance status 0/1; and adequate bone marrow, hepatic, and renal function. Pts in the SLI must have evaluable disease (RECIST v1.1) and have received ≤ 1 prior tx regimen; those previously treated with a BRAF or EGFR inhibitor, or both oxaliplatin and irinotecan, will be excluded. Pts in the phase 3 study must have measurable disease and be tx naive for metastatic disease. Study tx and endpoints are shown in the table. Enrollment began on 06-Jan-2021. Clinical trial information: NCT04607421. [Table: see text]