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).
Scott Kopetz, Takayuki Yoshino, Tae Won Kim, Harpreet Wasan, Eric Van Cutsem, Fortunato Ciardiello, Tim Maughan, Cathy Eng, Rona Yaeger, Jayesh Desai, Xiaosong Zhang, Tiziana Usari, A. Mori, Josep Tabernero
Abstract
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]