Triplet Regimen Significantly Improves OS in BRAF V600E-Mutated Metastatic CRC

A triplet regimen comprising encorafenib, cetuximab and binimetinib significantly improved OS and response rates compared with standard therapy in patients with metastatic colorectal cancer (CRC) harboring the BRAF v600E mutation, according to results from a recent phase 3 trial (N Engl J Med. 2019 Sep 30. Epub ahead of print).

“Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy,” explained Scott Kopetz, MD, PhD, University of Texas MD Anderson Cancer Center, Houston, and co-investigators.

“Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling,” they added.

This led Dr Kopetz and colleagues to investigate the triplet combination of encorafenib, cetuximab and binimetinib in BRAF V600E-mutated metastatic CRC in a phase 3 trial. A total of 665 patients who experienced disease progression after 1 or 2 prior therapies were enrolled.

Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet therapy arm); encorafenib and cetuximab (doublet therapy arm); or either cetuximab and irinotecan or cetuximab and FOLFIRI (control arm).

The co-primary endpoints of the trial were OS and objective response rate in the triplet-therapy arm versus the control arm. A secondary endpoint was OS in the doublet-therapy arm versus the control arm.

The median OS observed in the triplet-therapy arm was 9 months versus 5.4 months in the control arm (HR 0.52, 95% CI, 0.39 to 0.70; P<0.001). The confirmed response rates were 26% and 2% in the triplet-therapy arm and control arm, respectively. In the doublet-therapy arm, median OS was 8.4 months (HR 0.60; 95% CI, 0.45 to 0.79; P<0.001).

Notably, patients in both the triplet-therapy arm (58%) and doublet-therapy arm (51%) experienced less grade ≥3 adverse events than the control arm (61%).

“A combination of encorafenib, cetuximab, and 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,” Dr Kopetz et al concluded.—Kaitlyn Manasterski