Results from an international phase 3 study show that the targeted therapy combination of encorafenib and cetuximab with mFOLFOX6 chemotherapy helps patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC) live longer.

After early results from the BREAKWATER trial showed 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 for patients with BRAF V600E-mutant mCRC.

The research was presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place May 30-June 3 in Chicago. 

“BRAF V600E-mutant metastatic colorectal cancer is characterised 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, Vall d’Hebron Institute of Oncology, Barcelona, Spain. 

The BREAKWATER randomised clinical trial was designed to test the targeted therapy drugs encorafenib and cetuximab, with or without mFOLFOX6, for BRAF V600E-mutant mCRC.

Encorafenib is a BRAF inhibitor.

Cetuximab is an EGFR inhibitor. The mFOLFOX6 chemotherapy regimen combines multiple drugs to treat colorectal cancer, including folinic acid, fluorouracil, and oxaliplatin.

The encorafenib/cetuximab combination with and without mFOLFOX6 was compared to the current standard of care treatment of chemotherapy with or without bevacizumab. 

The BREAKWATER 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 (ORR), enrollment in the encorafenib/cetuximab alone arm was closed in a protocol amendment. 
• Overall survival was 30.3 months in the encorafenib/cetuximab with mFOLFOX6 arm, 19.5 months in the encorafenib/cetuximab alone arm, 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. 
• ORR, which is the percentage of people who have a partial or complete response to the treatment, was 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 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, anaemia, and diarrhoea. 

“This trial continues to move the needle forward to a more personalised approach to care based on the molecular and genetic characteristics of metastatic colon cancer. This trial establishes frontline 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. 

Next Steps

Researchers will continue to study the encorafenib/cetuximab combination with another chemotherapy regimen called FOLFIRI, which combines the common chemotherapy drugs folinic acid, fluorouracil and irinotecan. 

Source: ASCO