In an interim analysis of the phase III BEACON CRC trial reported at the European Society for Medical Oncology (ESMO) Congress 2019 (Abstract LBA32) and in The New England Journal of Medicine, Scott Kopetz, MD, PhD, and colleagues found improved overall survival and overall response rate in patients with BRAF V600E–mutated metastatic colorectal cancer treated with encorafenib/binimetinib/cetuximab vs either cetuximab/irinotecan or cetuximab/FOLFIRI (leucovorin, fluorouracil, and irinotecan).

Scott Kopetz, MD, PhD

Study Details

In the open-label trial, 665 patients with disease progression after one or two prior regimens were randomly assigned 1:1:1 between May 2017 and January 2019 to receive encorafenib/binimetinib/cetuximab (triplet-therapy group, n = 224), encorafenib/cetuximab (doublet-therapy group, n = 220); or investigators’ choice of either cetuximab/irinotecan or cetuximab/FOLFIRI (control group, n = 221). Treatment was given in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer therapy, or death. Crossover was not permitted before the data cutoff date.

The primary endpoints were overall survival and objective response rate in the triplet-therapy group vs the control group. Response rates were assessed in the first 331 randomized patents (111 in triple-therapy group, 113 in doublet-therapy group, and 107 in the control group). Findings reported are those of a prespecified interim analysis.

Overall Survival and Response Rates

Median follow-up for survival was 7.8 months at time of analysis.

Median overall survival was 9.0 months in the triplet-therapy group vs 5.4 months in the control group (hazard ratio [HR] = 0.52, P < .001). The confirmed response rate was 26% vs 2% (P < .001).

Median overall survival in the doublet-therapy group—a secondary endpoint of the trial—was 8.4 months (HR = 0.60, P < .001). The objective response rate in the doublet-therapy group was 20% (P < .001 vs control).

Median progression-free survival was 4.3 months in the triplet-therapy group, 4.2 months in the doublet-therapy group, and 1.5 months in the control group (P < .001 for both triplet- and doublet-therapy groups vs control).

Adverse Events

Adverse events of grade ≥ 3 occurred in 58% of patients in the triplet-therapy group, 50% of the doublet-therapy group, and 61% of the control group; the most common in the three groups were diarrhea (10%), fatigue (4%), and diarrhea (10%), respectively. Discontinuation of therapy due to adverse events occurred in 7%, 8%, and 11% of patients, respectively. Fatal adverse events occurred in 4%, 3%, and 4%, respectively.

The investigators concluded, “A combination of encorafenib/cetuximab/binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation.”

Disclosure: The study was supported by Array BioPharma, Merck (for sites outside North America), ONO Pharmaceutical, and Pierre Fabre. For full disclosures of the study authors, visit nejm.org.