Triple therapy shows strong response in BRAF V600E metastatic colorectal cancer

Triple therapy shows strong response in BRAF V600E metastatic colorectal cancer

Patients with metastatic colorectal cancer (MCRC) harboring BRAF V600E mutations benefited from first-line treatment with the targeted therapies encorafenib and cetuximab plus an MFOLFOX6 chemotherapy regimen, according to Phase III Cancer Center results.

The findings, presented today at the American Society of Clinical Oncology Gastrointestinal Cancer (ASCO GI) annual symposium and will be published inNatural medicinedemonstrated a 60.9% overall response rate (ORR) with the three-gland combination compared to 40% with SOC treatment (SOC) chemotherapy with or without bevacizumab. In the experimental arm, 68.7% of patients had a response duration of at least six months, compared to 34.1% of patients in the SoC arm.

Data from this multi-institutional collaboration in 28 countries supported accelerated approval of this combination by the Food and Drug Administration (FDA) in December 2024, providing an effective new first-line treatment option for patients with BRAF V600E mutant MCRC.

Chemotherapy had limited effectiveness as a first-line treatment in controlling the aggressive tumor growth that we see in patients with this mutation. This new regimen demonstrates the importance of combining dual 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 the quality of life of these patients. “

Scott Kopetz, MD, Ph.D., co-principal investigator, professor of gastrointestinal medical oncology and associate vice president for translational integration at MD Anderson

More than 150,000 people are diagnosed with colorectal cancer each year, which is the fourth most common cancer in the United States, according to the National Cancer Institute. BRAF mutations occur in approximately 8-12% of cases and are associated with aggressive tumor growth, low efficacy of SOC treatments, and poor prognosis with a median overall survival of less than 12 months. Previously, no initial targeted therapies were approved for patients with BRAF V600E mutant MCRC.

The Breakwater study was one of the first studies to utilize the FDA's project, an initiative to promote evaluation of therapies in earlier clinical settings for advanced cancers, rather than after patients have received numerous previous treatments.

The study included patients at least 16 years old with previously untreated BRAF V600E mutant MCRC. Patients were equally randomized to one of three treatment arms: SOC chemotherapy with or without bevacizumab; a double combination of encorafenib plus cetuximab; or a triple combination of encorafenib, cetuximab and Mfolfox6.

When researchers analyzed the subgroups of patients in the study, the triple combination showed benefits in key groups, including patients with cancer that spread to three or more organs and patients with liver metastases.

“These results support this combination as a new first-line standard for patients with BRAF V600E mutant metastatic colorectal cancer,” said Kopetz. “It also highlights the importance of quickly identifying molecular subtypes of colorectal cancer at diagnosis to optimize treatment strategies for our patients.”

The safety profile of this combination was consistent with the known safety profile of each respective drug. No new safety signals were identified. The most common adverse reactions included nausea, rash, fatigue, vomiting, abdominal pain, diarrhea, and decreased appetite, all of which were similar between arms in at least 25% of patients.

The final calculations of progression-free survival and overall survival will be formally evaluated in the next phase of the trial. Future analyzes of this study could provide information about predictive biomarkers for this combination therapy.

The study was sponsored by Pfizer Inc., and Kopetz disclosed consulting for Pfizer and receiving research funding from the company.

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