Patients with metastatic colorectal cancer (mCRC) that have BRAF V600E mutations experienced significant benefits from the first-line treatment comprising the targeted therapies encorafenib and cetuximab, in conjunction with the mFOLFOX6 chemotherapy regimen, according to findings from the Phase III BREAKWATER trial conducted by researchers at The University of Texas MD Anderson Cancer Center.
Patients diagnosed with metastatic colorectal cancer (mCRC) harboring BRAF V600E mutations experienced positive outcomes from first-line treatment using the targeted therapies encorafenib and cetuximab alongside the mFOLFOX6 chemotherapy regimen, as indicated by results from the Phase III BREAKWATER trial led by researchers at The University of Texas MD Anderson Cancer Center.
The results were shared today at the American Society of Clinical Oncology Gastrointestinal Cancers (ASCO GI) Annual Symposium and published in Nature Medicine. They revealed an overall response rate (ORR) of 60.9% with the three-drug combination compared to 40% with the standard treatment, which consists of chemotherapy either with or without bevacizumab. Additionally, 68.7% of patients in the experimental group had a response duration of at least six months, contrasted with 34.1% in the standard treatment group.
This multi-center study, which included participation from 28 countries, supported the accelerated approval of this combination by the Food and Drug Administration (FDA) in December 2024, thus providing a new, effective first-line treatment option for patients suffering from BRAF V600E-mutant mCRC.
“Conventional chemotherapy has shown limited success as a first-line treatment for controlling the rapid tumor growth seen in patients with this mutation,” stated co-principal investigator Scott Kopetz, M.D., Ph.D., a professor of Gastrointestinal Medical Oncology and associate vice president of Translational Integration at MD Anderson. “This innovative treatment regimen underscores the need for integrating dual-targeted therapy with chemotherapy to enhance patient outcomes in initial treatments, and the lasting responses signify a meaningful advancement in improving these patients’ quality of life.”
According to the National Cancer Institute, over 150,000 individuals are diagnosed with colorectal cancer yearly, making it the fourth most prevalent cancer in the United States. BRAF mutations are detected in around 8-12% of colorectal cancer cases and are linked to aggressive tumor proliferation, limited effectiveness of standard treatments, and a bleak prognosis, with a median overall survival of under 12 months. Historically, patients with BRAF V600E-mutant mCRC lacked approved first-line targeted therapies.
The BREAKWATER trial was one of the initial studies to leverage the FDA’s Project FrontRunner, which aims to facilitate the examination of therapies in earlier clinical phases for advanced cancers instead of post extensive prior treatments.
The trial enrolled participants aged 16 and older who had not previously received treatment for BRAF V600E-mutant mCRC. Patients were randomly assigned to one of three treatment groups: standard chemotherapy with or without bevacizumab; a dual therapy of encorafenib and cetuximab; or a three-drug combination of encorafenib, cetuximab, and mFOLFOX6.
When researchers examined the various patient subgroups in the trial, the triple therapy displayed advantages across crucial demographics, including patients with cancer metastasized to three or more organs and those with liver metastases.
“These findings advocate for this combination to be recognized as a new standard of care for first-line treatment in patients with BRAF V600E-mutant metastatic colorectal cancer,” Kopetz remarked. “They also underscore the need for rapid identification of molecular cancer subtypes upon diagnosis, which can optimize treatment plans for our patients.”
The safety profile for this combination matched the established safety records of each medication involved. No novel safety concerns were reported. The most prevalent side effects included nausea, rash, fatigue, vomiting, abdominal pain, diarrhea, and reduced appetite, all noted in at least 25% of patients and were similar across the treatment groups.
Final evaluations of progression-free survival and overall survival will be formally analyzed in the subsequent phase of the trial. Future evaluations may provide insights into predictive biomarkers for this combined therapy.
This study was sponsored by Pfizer Inc., and Kopetz disclosed his consulting role and research funding received from Pfizer.
