Triplet Targeted Therapy Regimen Improves Survival in BRAF+ Metastatic Colorectal Cancer

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A new combination may be key to improving tumor response rates and overall survival in colorectal cancer.

Triplet targeted therapy with encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) improved tumor response rates and overall survival (OS) in patients with BRAF-mutated metastatic colorectal cancer, according to the results of the BEACON trial1. The results were presented at the European Society for Medical Oncology (ESMO) Congress 2019 meeting in Barcelona, Spain and were published in the New England Journal of Medicine. The BEACON study was funded by Array BioPharma, Merck, ONO Pharmaceutical, and Pierre Fabre.

“This targeted therapy combination should be a new standard of care for this patient group,” said study coauthor Scott Kopetz, MD, PhD, Associate Professor of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston in a press release. “Further investigation is needed to determine if this combination may also benefit those with less advanced disease or as a first-line treatment.” 

The BRAF inhibitor encorafenib, MEK inhibitor binimetinib, and EGFR inhibitor cetuximab together represent “a rational combination to address the vulnerabilities unique to this tumor,” Kopetz said.BRAF-mutant colorectal cancers frequently show deficient DNA mismatch repair that results in microsatellite instability (MSI).

The open-label, phase III trial enrolled 665 patients with BRAFV600E-mutation-positive metastatic colorectal cancer who experienced disease progression after one or two treatment regimens. Patients were randomly assigned them 1:1:1 to receive the triplet regimen, a doublet encorafenib plus cetuximab regimen, or investigator’s choice of cetuximab plus either irinotecan or FOLFIRI (folinic acid, fluorouracil, and irinotecan). The latter represented the study’s control group.

Median OS was 9.0 months among patients receiving the triplet therapy, compared to 5.4 months in the control group, and 8.4 months for doublet therapy (hazard ratio for death, triplet vs. control: 0.52; 95% CI: 0.39-0.70; <.001). The confirmed response rate was 26% for triplet therapy versus 2% in the control group (<.001).

BRAFV600E mutant colorectal cancers are an aggressive subgroup that respond poorly to standard chemotherapy and for which novel therapies are a major unmet need,” said Frank A. Sinicrope, MD, FACP, Professor of Medicine and Oncology Co-director, GI Cancer Program, at the Mayo Clinic and Mayo Comprehensive Cancer Center in Rochester, Minnesota, commenting on the study for CancerNetwork. “The results of the BEACON study interim analysis show an impressive increase in response rate and prolongation of patient median overall survival for the triplet therapy group compared to the control group. Importantly, the targeted treatment regimens were not associated with higher rates of major toxicities compared to control treatment. These data support use of the triplet of encorafenib, binimetinib and cetuximab as a new standard treatment of this patient molecular subgroup.”

“The relatively similar benefit seen in the doublet arm is of interest and further follow-up of the data from this and the other study arms are eagerly awaited,” Sinicrope added.

Grade 3 or higher adverse events were reported for 58% of patients receiving triplet therapy compared to 50% in the doublet therapy study group and 61% in the control group. Treatment discontinuation due to adverse events occurred in 7%, 8% and 11% of patients in the triplet, doublet, and control groups. Grade 3 or higher diarrhea affected 10% of patients in the triplet regimen group.

Disclosures:

1. Coleman, R. (2019). Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer | NEJM. [online] New England Journal of Medicine. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa1909707

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