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Triplet Therapy for BRAF V600E-Mutated Metastatic Colorectal Cancer

Mouse model of human colorectal cancer.

In metastatic colorectal cancer, the BRAF V600E mutation, which affects around 10% of patients, portends a poor outcome. Initial standard chemotherapy often fails, and after it does, patients survive for a median of only 4 to 6 months. A phase 3 trial reports a significant improvement in overall survival with two different treatments: a triplet therapy consisting of encorafenib (BraftoviTM, Array BioPharma), binimetinib (MektoviTM, Array BioPharma), and cetuximab (Erbitux®, Eli Lilly); and a doublet therapy consisting of encorafenib and cetuximab.

As a monotherapy, BRAF inhibition has limited activity in BRAF V600E-mutated colorectal cancer, despite its effectiveness in BRAF V600E-mutated melanoma and non-small cell lung cancer.

"Preclinical and clinical studies showed that the lack of efficacy of single-agent BRAF or dual BRAF and MEK inhibition in BRAF V600E–mutated colorectal cancer is related to EGFR-mediated adaptive feedback—a finding that led to the development of a combination of BRAF, MEK, and EGFR inhibition through a series of iterative studies," write the researchers in their publication in The New England Journal of Medicine, led by first author Scott Kopetz, MD, PhD, Associate Professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. "Analyses of mechanisms of resistance in several studies reiterated the dependency of BRAF V600E-mutated metastatic colorectal cancer on the MAPK pathway, which is composed most prominently of KRAS, NRAS, BRAF, and MEK." For this reason, suppressing MAPK signaling through a combination of a BRAF inhibitor (encorafenib), a MEK inhibitor (binimetinib), and an anti-EGFR monoclonal antibody (cetuximab) "represented the logical therapeutic strategy to address this persistent dependency."

For the open-label trial, 665 patients with BRAF V600E-mutated metastatic colorectal cancer with disease progression following one or two prior regimens were randomized in a 1:1:1 ratio to either the triplet therapy group, for which they received encorafenib/binimetinib/cetuximab; the doublet therapy group, for which they received encorafenib/cetuximab; or the control group, for which they received investigators' choice of either cetuximab/irinotecan or cetuximab/FOLFIRI (folinic acid/fluorouracil/irinotecan). The study's primary end points compared overall survival and objective response rates between the triplet therapy group and the control group, with a secondary end point comparing overall survival between the doublet therapy group and the control group.

In this prespecified interim analysis, the triplet therapy improved both median overall survival (9.0 vs 5.4 months) and confirmed response rate (26% vs 2%) compared with control. The doublet therapy also increased median overall survival compared with control (8.4 vs 5.4 months). Grade 3 or higher adverse events were experienced by 58% of patients receiving the triplet therapy, 50% of those receiving the doublet therapy, and 61% of those in the control group.

"Despite the documented activity of the triplet regimen, resistance ultimately develops in many patients, and further characterization of these mechanisms is needed to further improve outcomes," note Dr. Kopetz and colleagues. In addition, the authors remark that since the trial was not designed to directly compare the doublet and triplet therapies, further research is needed to better determine the two regimens' relative benefits.

Nevertheless, the significant improvements in overall survival for both encorafenib/binimetinib/cetuximab and encorafenib/cetuximab in comparison with standard therapy represent a substantial step towards better outcomes for patients with BRAF V600E-mutated metastatic colorectal cancer.

For More Information

Kopetz S, Grothey A, Yaeger R, et al (2019). Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. New Engl J Med. [Epub ahead of print] DOI:10.1056/NEJMoa1908075

Image credit: Thomas Ried. Courtesy of the National Cancer Institute (NCI) Center for Cancer Research

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