BEACON CRC shines spotlight on triplet, doublet regimens for BRAF V600E-mutated disease

Use of the triplet regimen containing encorafenib, cetuximab and binimetinib, or a doublet regimen containing the first two, confers significant benefits for overall survival (OS) and response as compared with standard therapy in the treatment of metastatic colorectal cancer (CRC) harbouring the BRAF V600E mutation, according to the initial results of the phase III, open-label BEACON CRC trial.

“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 investigators said.

BEACON CRC randomly assigned 665 patients with BRAF V600E–mutated metastatic disease who had had disease progression after one or two previous regimens to the following treatment groups: encorafenib, binimetinib and cetuximab (triplet therapy; n=224), encorafenib plus cetuximab (doublet therapy; n=220), or the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil and irinotecan; control; n=221).

The triplet-therapy vs control group had significantly better OS (median 9.0 vs 5.4 months; hazard ratio [HR] for death, 0.52, 95 percent confidence interval [CI], 0.39–0.70; p<0.001) and objective response rate (26 percent, 95 percent CI, 18–35 vs 2 percent, 95 percent CI, 0–7; p<0.001). [N Engl J Med 2019;381:1632-1643]

Likewise, the doublet therapy provided longer median OS compared with control therapy (8.4 months; HR for death, 0.60, 95 percent CI, 0.45–0.79; p<0.001).

In terms of safety, grade ≥3 adverse events were documented in 58 percent of patients in the triplet-therapy group, 50 percent in the doublet-therapy group and 61 percent in the control group. Median duration of exposure was 21, 19 and 7 weeks, respectively. Median relative dose intensities were 91 percent with the triplet and 98 percent with the doublet regimen for encorafenib, 87 percent with the triplet for binimetinib, and 91 percent with the triplet and 93 percent with the doublet regimen for cetuximab.

“The triplet regimen was designed to be a combination of agents that would provide the most effective inhibition of the MAPK pathway,” the investigators noted.

“Analyses of mechanisms of resistance in several studies reiterated the dependency of BRAF V600E–mutated metastatic CRC on the MAPK pathway, which is composed most prominently of KRAS, NRAS, BRAF and MEK. Suppression of MAPK signaling with encorafenib, binimetinib and cetuximab represented the logical therapeutic strategy to address this persistent dependency,” they added. [J Clin Oncol 2015;33:4032-4038; Cancer Discov 2018;8:428-443; Cancer Res 2017;77:6513-6523]

However, the investigators warned that resistance ultimately develops in many patients regardless of the documented activity of the triplet regimen, underscoring a need for additional characterization of underlying mechanisms to further improve outcomes.

One important limitation of the trial is that it was not powered to directly compare the triplet and doublet regimens, with the interim nature of the analysis further limiting such a comparison, the investigators acknowledged.

“Further follow-up is needed to better define the relative benefits of the triplet and doublet regimens,” they said.