Patients with metastatic colorectal cancer (mCRC) carrying BRAF V600E mutations showed significant benefits from a first-line treatment combining the targeted therapies encorafenib and cetuximab with the mFOLFOX6 chemotherapy regimen. Results from the Phase III BREAKWATER trial, presented at the ASCO GI Annual Symposium and published in Nature Medicine, revealed an overall response rate (ORR) of 60.9% for the combination therapy, compared to 40% with standard-of-care (SOC) treatment (chemotherapy with or without bevacizumab).
In the experimental group, 68.7% of patients maintained a response for at least six months, compared to 34.1% in the SOC group. These findings supported the FDA's December 2024 approval of the therapy, offering a new first-line option for patients with BRAF V600E-mutant mCRC.
Key Highlights
- Prevalence of Colorectal Cancer: More than 150,000 cases are diagnosed annually in the U.S., with BRAF mutations occurring in 8–12% of cases. These mutations are associated with aggressive tumor growth and poor prognosis.
- BREAKWATER Trial Overview:
- Conducted across 28 countries.
- Enrolled patients aged 16+ with untreated BRAF V600E-mutant mCRC.
- Compared three groups: SOC, dual therapy (encorafenib + cetuximab), and triple therapy (encorafenib + cetuximab + mFOLFOX6).
- Clinical Impact: The triple combination therapy showed improved outcomes across key patient subgroups, including those with extensive metastases or liver involvement.
Dr. Scott Kopetz, the trial’s co-principal investigator, emphasized the importance of identifying molecular subtypes of colorectal cancer at diagnosis to optimize treatment strategies.
Safety and Future Directions
The combination therapy’s safety profile aligned with existing data, with no new safety concerns identified. Common side effects included nausea, rash, fatigue, vomiting, abdominal pain, diarrhea, and decreased appetite.
Further analysis is planned to evaluate progression-free and overall survival, as well as predictive biomarkers for this treatment.