Results from an international phase III study showed that the targeted therapy combination of encorafenib and cetuximab with mFOLFOX6 (leucovorin, fluorouracil, and oxaliplatin) chemotherapy may help patients with BRAF V600E–mutant metastatic colorectal cancer live longer. After early results from the BREAKWATER trial demonstrated a significant benefit, the U.S. Food and Drug Administration (FDA) granted accelerated approval of encorafenib/cetuximab with mFOLFOX6 chemotherapy as a first-line treatment of patients with BRAF V600E–mutant metastatic colorectal cancer. The research will be presented at the 2025 ASCO Annual Meeting (Abstract LBA3500).
Study Details
“BRAF V600E–mutant metastatic colorectal cancer is characterized by its aggressive nature, and the standard therapeutic options have limited efficacy. Despite the high unmet need in this subtype, prior to the accelerated FDA approval based on initial overall response rates from the BREAKWATER study, there were no approved biomarker-driven therapies specifically indicated for people with previously untreated BRAF V600E–mutant metastatic colorectal cancer,” said lead study author Elena Elez, MD, PhD, of Vall d’Hebron Institute of Oncology, Barcelona, who will be presenting the study.
The BREAKWATER randomized clinical trial was designed to test the BRAF inhibitor encorafenib and the EGFR inhibitor cetuximab, with or without mFOLFOX6, for BRAF V600E-mutant metastatic colorectal cancer. The encorafenib/cetuximab combination with and without mFOLFOX6 was compared with the current standard-of-care treatment of chemotherapy with or without bevacizumab.
The study included 637 participants. The median age of the participants was approximately 60 years, and about half were women.
Key Findings
The study originally included three treatment arms: encorafenib/cetuximab alone (158 patients), encorafenib/cetuximab with mFOLFOX6 (236 patients), and the control arm of chemotherapy with or without bevacizumab (243 patients). When early results showed that the encorafenib/cetuximab with mFOLFOX6 arm had a statistically significant improvement in objective response rates, enrollment in the encorafenib/cetuximab alone arm was closed in a protocol amendment.
Overall survival was 30.3 months with encorafenib/cetuximab and mFOLFOX6, 19.5 months with encorafenib/cetuximab alone, and 15.1 months in the control arm. Patients treated with encorafenib/cetuximab with mFOLFOX6 had a 51% lower risk of dying than patients treated with the standard-of-care chemotherapy with or without bevacizumab.
Progression-free survival was 12.8 months in the encorafenib/cetuximab plus mFOLFOX6 arm, 6.8 months in the encorafenib/cetuximab alone arm, and 7.1 months in the control arm. Patients treated with encorafenib/cetuximab with mFOLFOX6 had a 47% lower risk of cancer progression than patients treated with the standard-of-care chemotherapy with or without bevacizumab.
The objective response rates were 65.7% in the encorafenib/cetuximab plus mFOLFOX6 arm, 45.6% in the encorafenib/cetuximab alone arm, and 37.4% in the control arm.
Most of the side effects for these treatments were reported to be manageable. Serious side effects caused by the treatments occurred in 30% of patients in the encorafenib/cetuximab alone arm, 46% of the encorafenib/cetuximab with mFOLFOX6 arm, and 39% of the control arm. The most common side effects for the encorafenib/cetuximab with mFOLFOX6 treatment were nausea, anemia, and diarrhea.
‘The New Standard of Care’
“This trial continues to move the needle forward to a more personalized approach to care based on the molecular and genetic characteristics of metastatic colon cancer. This trial establishes front-line encorafemib, cetuximab, and FOLFOX as the new standard of care for BRAF V600E–mutant metastatic colorectal cancer,” said Joel Saltzman, MD, Vice Chair of Regional Oncology at Taussig Cancer Center, Cleveland Clinic, and an ASCO expert in gastrointestinal cancers.
Researchers will continue to study the encorafenib/cetuximab combination with the FOLFIRI (leucovorin, fluorouracil, and irinotecan) regimen.
Disclosure: This study was funded by Pfizer. For full disclosures of the study authors, visit coi.asco.org.
