Triplet Regimen Offers Improved Outcomes in BRAF-Mutant Colorectal Cancer

The combination of encorafenib (Braftovi), cetuximab (Erbitux), and binimetinib (Mektovi), offered significantly better overall survival (OS) than either of two standard therapy regimens in patients with BRAF V600E-mutated metastatic colorectal cancer (CRC), according to the results of a phase III trial¹. The mutation occurs in approximately 10% of all metastatic CRC patients, with some estimates ranging as high as 21%. 

“This mutation identifies a distinct subtype of colorectal cancer that has a poor prognosis,” wrote study authors led by Scott Kopetz, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston. “Initial standard chemotherapy for BRAF V600E–mutated colorectal cancer results in poor outcomes and attempts to intensify therapy have met with limited success.”

The new study was an open-label phase III trial, including a total of 665 patients with metastatic colorectal cancer and a BRAF V600E mutation. They were randomized to receive 1 of 3 regimens: the triple therapy group received encorafenib, cetuximab, and binimetinib (224 patients); the doublet therapy group received encorafenib and cetuximab (220 patients); or investigator’s choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (223 patients). 

Baseline characteristics were well balanced between the 3 groups. Most patients in all 3 groups had received 1 previous line of therapy (approximately 66%), and more than half the cohort had liver metastases.

The median overall survival with triplet therapy was 9.0 months, compared with 5.4 months in the control group who received investigator’s choice of the 2 regimens. This yielded a hazard ratio (HR) of 0.52 (95% CI, 0.39-0.70; P < 0.001). In the doublet therapy group the median OS was 8.4 months, which was also significantly better than the control group, with an HR of 0.60 (95% CI, 0.45-0.79; P < 0.001).

The investigators conducted a descriptive analysis comparing the triplet and doublet therapy groups. The estimated 6-month survival with triplet therapy was 71%, compared with 65% with doublet therapy, for an HR of 0.79 (95% CI, 0.59-1.06). The rate in the control group was 47%.

The objective response rate was also better with triplet therapy, at 26% in the triplet therapy group compared with 2% in the control group (P < 0.001). The ORR in the doublet group was 20%, which also significantly better than the control group (P < 0.001).

Grade 3 or higher adverse events (AEs) occurred in 58% of patients in the triplet therapy group, 50% of those receiving doublet therapy, and in 61% of patients in the control group. In the 3 groups, 7%, 8%, and 11%, respectively, discontinued therapy due to AEs. The most frequent AEs in the triplet group included gastrointestinal-related and skin-related AEs.

 “The side-effect profiles of both combination regimens allowed maintenance of high dose intensity for the majority of patients and are consistent with the known profile of each agent,” the authors concluded. “Further follow-up is needed to better define the relative benefits of the triplet and doublet regimens.”

References:

Bertelsen, C., Neuenschwander, A., Jansen, J., Tenma, J., Wilhelmsen, M., Kirkegaard-Klitbo, A., Iversen, E., Bols, B., Ingeholm, P., Rasmussen, L., Jepsen, L., Born, P., Kristensen, B. and Kleif, J. (2019). 5-year outcome after complete mesocolic excision for right-sided colon cancer: a population-based cohort study. Lancet Oncology.