Bevacizumab plus encorafenib-cetuximab in BRAF V600E mutated metastatic colorectal cancer (mCRC): A phase II study with a safety lead-in cohort (the BRAVE trial).

Abstract

TPS3681 Background: Encorafenib plus cetuximab is the standard of care for patients with BRAF V600E mutant, microsatellite-stable (MSS) mCRC, BRAF inhibitor-naïve, whose disease has progressed after 1-2 prior lines of chemotherapy. However, all patients eventually experience disease progression, and progression-free survival (PFS) remains modest. Therefore, there is an unmet need to enhance the efficacy of encorafenib-based combinations in BRAF -mutant mCRC. Preclinical data from rodent models treated with BRAF inhibitors have demonstrated upregulation of hypoxia-related genes (VEGFA, ADM, and CXCR4), and alterations in tumor vessel architecture. Based on these observations, rodent models treated with BRAF inhibitors in combination with anti-VEGF therapy achieved a meaningful improvement in PFS. In this trial, we hypothesize that encorafenib–cetuximab with bevacizumab will result in synergistic activity leading to durable responses in patients with refractory BRAF -mutant mCRC. Methods: The BRAVE trial (NCT06411600) is a multicenter, single-arm, phase Ib/II study evaluating the safety and efficacy of encorafenib–cetuximab–bevacizumab. Patients must have progressed to 1-2 previous lines and have a BRAF V600E-mutant, MSS tumor. Previous treatment with BRAF inhibitors or antiEGFR was not allowed. All patients receive encorafenib 300 mg vo QD, cetuximab 500 mg iv Q2W, and bevacizumab 5 mg/kg iv Q2W, administered in 28-day cycles. The primary endpoints are dose-limiting toxicities (DLTs) and 6-month PFS (6mPFS). The study follows a Simon two-stage design. A sample size of 89 evaluable patients is required to detect an increase in 6mPFS to 49% in the study population, compared with a 36% 6mPFS achieved with encorafenib plus cetuximab in the BEACON trial, using a one-sided type I error of 0.05 and 80% statistical power. As there was no prior evidence on the safety of this combination, a safety lead-in (SLI) phase (n=9) was included to evaluate potential DLTs. An Independent Data Safety Monitoring Board (IDSMB) reviewed the toxicity profile and DLTs granted continuation of the study on April 1, 2025. Following completion of the SLI phase and IDSMB evaluation, the study proceeded to two subsequent stages. Stage I enrolled 41 additional patients (completed on December 12, 2025). A preplanned interim analysis (IA) is being performed before proceeding to Stage II. If fewer than 19 of the first 50 patients achieve 6mPFS, the study will be discontinued due to lack of efficacy. If 19 or more of the first 50 patients achieve 6mPFS, Stage II will enroll an additional 39 patients. Recruitment is currently on hold pending the planned IA. Biomarker analyses include plasma sample collection at screening, on C1D15, and at end of treatment, as well as tumor biopsies (optional) at baseline and at disease progression to study mechanism of sensitivity and resistance. Clinical trial information: NCT06411600 .