First-line treatment with the targeted therapies encorafenib and cetuximab plus a modified leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) chemotherapy regimen may be effective in patients with BRAF V600E–mutated metastatic colorectal cancer, according to recent findings presented by Kopetz et al at the 2025 ASCO Gastrointestinal Cancers Symposium (Abstract 16) and simultaneously published in Nature Medicine.
Background
More than 150,000 patients are diagnosed with colorectal cancer per year, making it the fourth most common cancer type in the United States, according to the National Cancer Institute. BRAF mutations occur in approximately 8% to 12% of cases and are associated with aggressive tumor growth, low efficacy from standard-of-care treatments, and a poor prognosis—with a median overall survival of less than 12 months. Previously, there were no first-line targeted therapies approved to treat patients with BRAF V600E–mutated metastatic colorectal cancer.
“Chemotherapy has had limited efficacy as a first-line treatment in controlling the aggressive tumor growth we see in patients with this mutation,” stressed lead study author Scott Kopetz, MD, PhD, Professor of Gastrointestinal Medical Oncology and Associate Vice President of Translational Integration at The University of Texas MD Anderson Cancer Center.
Study Methods and Results
The phase III BREAKWATER trial involved a multi-institutional collaboration of researchers across 28 countries. They randomly assigned patients aged 16 or older with previously untreated BRAF V600E–mutated metastatic colorectal cancer to receive a triple combination of encorafenib and cetuximab plus mFOLFOX6, a dual combination of encorafenib and cetuximab, or standard-of-care chemotherapy with or without bevacizumab.
The trial used the U.S. Food and Drug Administration’s (FDA) Project FrontRunner, an initiative to encourage the evaluation of therapies in earlier clinical settings for advanced cancers rather than after patients received numerous previous treatments. The researchers found that patients who received the triplet demonstrated a 60.9% overall response rate, and 68.7% of them experienced a duration of response of at least 6 months compared with a respective 40% and 34.1% among those who received the standard-of-care treatment.
When researchers analyzed patient subgroups, the triplet showed benefits across groups, including those with cancer spread to three or more organs and those with liver metastases.
The safety profile of the triplet was consistent with the known safety profile of each respective drug. No new safety signals were identified. The most common adverse effects included nausea, rash, fatigue, vomiting, abdominal pain, diarrhea, and decreased appetite—all of which were reported in at least 25% of the patients and were similar between treatment groups.
Final calculations of progression-free survival and overall survival will be formally assessed in the next phase of the trial.
Conclusions
Data from the study supported the accelerated FDA approval of the novel treatment combination in December 2024, providing an effective new first-line treatment option in patients with BRAF V600E–mutated metastatic colorectal cancer.
“This new regimen highlights the importance of combining dual-targeted therapy with chemotherapy to improve patient outcomes in the first-line setting, and the durable responses are a significant development as we work to improve quality of life for these patients,” Dr. Kopetz stated. “These results support this combination as a new first-line standard of care for patients with BRAF V600E–[mutated] metastatic colorectal cancer. [This study] also [indicates the significance] of swiftly identifying molecular subtypes of colorectal cancer at diagnosis to optimize treatment strategies for our patients,” he underscored.
The researchers proposed that future analyses of this trial may illuminate predictive biomarkers for the combination of encorafenib and cetuximab plus mFOLFOX6.
Disclosure: The research in this study was sponsored by Pfizer. For full disclosures of the study authors, visit meetings.asco.org and nature.com.
