Results from the Phase III BREAKWATER trial, which was conducted by researchers at The University of Texas MD Anderson Cancer Center, showed that patients with metastatic colorectal cancer (mCRC) who had BRAF V600E mutations benefited from first-line treatment with the targeted therapies Cetuximab and Encorafenib in addition to a mFOLFOX6 chemotherapy regimen.
Their findings were published in the journal Nature Medicine.
In contrast to the standard-of-care (SOC) treatment of chemotherapy with or without bevacizumab, which had an ORR of 40%, their trial showed a 60.9% ORR with the three-drug combination. Compared to 34.1% of patients in the SOC arm, 68.7% of patients in the experimental arm experienced a duration of response of at least six months.
Data from this 28-country multi-institutional effort helped the Food and Drug Administration (FDA) approve this combination more quickly in December 2024, giving patients with BRAF V600E-mutant mCRC a new and effective first-line treatment choice.
Chemotherapy has had limited efficacy as a first-line treatment in controlling the aggressive tumor growth we see in patients with this mutation,
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.
Scott Kopetz
According to the National Cancer Institute, colorectal cancer is the fourth most frequent disease in the United States, with over 150,000 new cases reported each year. About 8–12% of patients had BRAF mutations, which are linked to aggressive tumor development, poor response to SOC therapies, and a poor prognosis with a median overall survival of fewer than 12 months. Prior to now, patients with BRAF V600E-mutant mCRC had no approved first-line targeted treatments.
One of the first studies to make use of the FDA’s Project FrontRunner program, which aims to promote the assessment of medicines in earlier clinical settings for advanced tumors rather than after patients have undergone multiple prior treatments, was the BREAKWATER experiment.
Patients with untreated BRAF V600E-mutant mCRC who were at least 16 years old were eligible to participate in the experiment. Three treatment arms—SOC chemotherapy with or without bevacizumab, a dual combination of Encorafenib and Cetuximab, or a triple combination of Encorafenib, Cetuximab, and mFOLFOX6—were randomly assigned to each patient.
Researchers examined the trial’s patient subgroups and found that the triple combination was beneficial for patients with liver metastases and cancer that had spread to three or more organs.
These results support this combination as a new first-line standard of care for patients with BRAF V600E-mutant metastatic colorectal cancer,
It also highlights the importance of swiftly identifying molecular subtypes of colorectal cancer at diagnosis to optimize treatment strategies for our patients.
Scott Kopetz
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The combination’s safety profile aligned with the established safety profile of each individual medication. There were no new warning signs found. The most frequent adverse events, which were similar across arms and reported in at least 25% of patients, were nausea, rash, exhaustion, vomiting, abdominal discomfort, diarrhea, and decreased appetite.
The next stage of the trial will formally evaluate the final progression-free survival and overall survival calculations. Predictive biomarkers for this combo therapy might be revealed by further study studies.
Kopetz revealed consulting for Pfizer and getting research cash from the corporation, which financed the study.
Source: The University of Texas, MD Anderson Cancer Center – News
Journal Reference: Kopetz, Scott, et al. “Encorafenib, Cetuximab and Chemotherapy in BRAF-mutant Colorectal Cancer: A Randomized Phase 3 Trial.” Nature Medicine, 2025, pp. 1-8, DOI: https://doi.org/10.1038/s41591-024-03443-3.
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Graduated from the University of Kerala with B.Sc. Botany and Biotechnology. Attained Post-Graduation in Biotechnology from the Kerala University of Fisheries and Ocean Science (KUFOS) with the third rank. Conducted various seminars and attended major Science conferences. Done 6 months of internship in ICMR – National Institute of Nutrition, Hyderabad. 5 years of tutoring experience.
