BREAKWATER: Randomized phase 3 study of encorafenib (enco) + cetuximab (cetux) ± chemotherapy for first-line (1L) treatment (tx) of <i>BRAF</i> V600E-mutant (<i>BRAF</i><sup>V600E</sup>) metastatic colorectal cancer (mCRC).
Scott Kopetz, Axel Grothey, Rona Yaeger, Fortunato Ciardiello, Jayesh Desai, Tae Won Kim, Tim Maughan, Eric Van Cutsem, Harpreet Wasan, Takayuki Yoshino, Michelle L. Edwards, Adele Golden, Ashwin Gollerkeri, Josep Tabernero
Abstract
TPS3619 Background: Approximately 10% of patients (pts) with mCRC have BRAF mutations (mostly V600E). 1L tx options for BRAF V600E 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 cetux is approved for tx of BRAF V600E mCRC after prior therapy. In BEACON CRC, enco + cetux 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 BRAF V600E mCRC (median follow-up: 12.8 months); 57.4% of pts had grade 3/4 adverse events (AEs); 9% discontinued due to AEs. Given the poor prognosis of pts with BRAF V600E mCRC and based on the efficacy and tolerability of enco + cetux from BEACON CRC, BREAKWATER will evaluate efficacy and safety of enco + cetux ± chemotherapy in tx-naive pts with BRAF V600E 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 BRAF V600E mCRC (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 6 January 2021. Clinical trial information: NCT04607421. [Table: see text]