NCI-Funded Study Finds Triple Therapy Packs a Punch in Metastic Colorectal Cancer


Adding vemurafenib, known to target a mutation affecting 10% of metastatic colorectal cancers, made a big difference.

A triplet drug combination of irinotecan, cetuximab, and vemurafenib proved more potent in fighting tumors and keeping patients with metastatic colon cancer disease free than a combination of irinotecan and cetuximab, according to results published today in the Journal of Clinical Oncology. The findings are expected to change clinical practice.

Researchers from SWOG Cancer Research Network, a group funded by the National Cancer Institute (NCI), led by Scott Kopetz, MD, PhD, of MD Anderson Cancer Center, studied the combination for patients with tumors that carry a mutation in the BRAF gene, V600E; when this mutation is present, which occurs in about 10% of metastatic colorectal cancers, the patient rarely responds to treatment.

Kopetz, an expert in BRAF-mutated colorectal cancer, had previously found in the BEACON trial that 2 targeted therapies—cetuximab and encorafenib—caused tumors to shrink significantly and helped patients live longer, relative to standard treatment. In the current study, Kopetz and his team tested 106 patients whose metastatic colorectal cancer includes the deadly V600E mutation. All the patients had been previously treated with chemotherapy without success. The team randomly assigned study participants to 1 of 2 treatment groups—those who received irinotecan and cetuximab and those who received that combination with a third drug, vemurafenib, whose name comes “V600E mutated BRAF inhibition.”

The team found that patients who received the triplet combination had better tumor response rates, 17% compared with 4%, and stayed cancer-free longer. Kopetz explained how the triplet works:

The chemotherapy irinotecan kills cancer cells.

The monoclonal antibody cetuximab blocks cancer growth by targeting a well-known protein, epidermal growth factor receptor, or EGFR.

The BRAK inhibitor vemurafenib attacks the BRAF protein directly and further slows tumor growth.

“That 1-2-3 action, that triple threat, shuts off a powerful growth pathway in these cancers," Kopetz said. "In this trial, unlike in BEACON, we added chemo and found that it makes for a more effective way to treat this aggressive form of colorectal cancer.

Also of note, the results showed an 87% decline in circulating tumor DNA (ctDNA) of the BRAFV600E variant allele frequency in patients receiving all 3 drugs, compared with no ctDNA drop in patients receiving the 2-drug combination. Kopetz said this is strong evidence that measuring the presence of ctDNA can be a good way to detect short-term response to treatment; this can be done with a simple blood test.


Kopetz S, Guthrie KA, Morris VK, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutated metastatic colorectal cancer (SWOG S1406). J Clin Oncol. Published online December 23, 2020. DOI: 10.1200/JCO.20.01994

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