Elena Elez, Barcelona, ASCO: BRAF Inhibitor Encorafenib Delays Progression, Extends Survival in Patients with Inoperable BRAF V600E Mutant Colorectal Cancer

Audio Journal of Oncology Podcast

An interview with:

Elena Elez MD PhD, Vall d’Hebron Institute of Oncology, Barcelona, Spain

CHICAGO, USA—Adding the BRAF inhibitor encorafenib (partnered with EGFR-inhibitor cetuximab) to standard chemotherapy as initial therapy markedly delayed progression and extended life in patients whose inoperable metastatic colorectal cancers had tested positive for the BRAF V600E (found in around ten per cent of patients). This was in the randomized open label phase three BREAKWATER study reported at the 2025 Annual Meeting of the American Society of Clinical Oncology (ASCO).

After the ASCO conference, the Audio Journal of Oncology’s correspondent Peter Goodwin asked study leader Elena Elez from the Vall d’Hebron Institute of Oncology in Barcelona for the details.

INTERVIEW with Elena Elez MD PhD, Vall d’Hebron Institute of Oncology, Barcelona

ASCO ABSTRACT:

LBA3500: “First-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer (BREAKWATER): Progression-free survival and updated overall survival analyses”

Background:

BREAKWATER (NCT04607421) is an open-label, global, randomized, phase 3 study evaluating first-line (1L) encorafenib + cetuximab (EC) ± chemotherapy (chemo) vs standard of care (SOC; chemo ± bevacizumab) in BRAF V600E-mutant metastatic colorectal cancer (mCRC). The study previously met one of its dual primary endpoints (EPs) demonstrating clinically meaningful and statistically significant improvement in confirmed objective response rate (ORR) by blinded independent central review (BICR) in the ORR subset. These results were the basis for the FDA accelerated approval of EC+mFOLFOX6 for BRAF V600E-mutant mCRC, including in the 1L, under Project Frontrunner. Here, we report the primary analysis of progression-free survival (PFS) by BICR, updated interim analysis of OS, updated safety, and other analyses.

Methods:

Eligible patients (pts) with untreated BRAF V600E-mutant mCRC were randomized 1:1:1 to receive EC, EC+mFOLFOX6, or SOC; EC arm enrollment was closed after a protocol amendment. Dual primary EPs: ORR and PFS by BICR (EC+mFOLFOX6 vs SOC); key secondary EP: OS (EC+mFOLFOX6 vs SOC).

Results:

637 pts were randomized to EC, EC+mFOLFOX6, or SOC. Baseline demographics and disease characteristics were generally balanced between arms. EC+mFOLFOX6 (data cutoff: Jan 6, 2025) demonstrated a clinically meaningful and statistically significant PFS improvement vs SOC, meeting the other dual primary EP; HR = 0.53 (95% CI 0.407, 0.677; P < 0.0001); median PFS 12.8 vs 7.1 mo. OS was clinically meaningful and statistically significant vs SOC; HR = 0.49 (95% CI 0.375, 0.632; P < 0.0001); median OS 30.3 vs 15.1 mo. Median PFS and OS in the EC arm were 6.8 and 19.5 mo. These data and response data for all randomized pts are shown in the table. Serious treatment-emergent adverse events occurred in 30%, 46%, and 39% of pts in the safety analysis set. Safety was consistent with that known for each agent.

Conclusions: BREAKWATER demonstrated clinically meaningful and statistically significant PFS and OS improvements with EC+mFOLFOX6 vs SOC and manageable toxicities. EC+mFOLFOX6 is potentially practice changing as the new SOC.