Objective. To evaluate whether the combination of encorafenib plus cetuximab with or without the MEK inhibitor binimetinib would lead to longer overall survival (OS) than standard therapy in patients with metastatic BRAF V600E–mutated colorectal cancer.
Design. Global, multicenter, randomized, open-label, phase 3 trial.
Intervention. Patients were randomized in a 1:1:1 fashion to 1 of 3 groups: triplet-therapy group (encorafenib 300 mg daily, binimetinib 45 mg twice daily, and cetuximab 400 mg/m2 of body surface area initially, then 250 mg/m2 weekly), doublet-therapy group (encorafenib and cetuximab in same doses and schedule as the triplet-therapy group), and control group (investigators choice of cetuximab and irinotecan or cetuximab and FOLFIRI). The randomization was stratified by performance status and prior irinotecan use. Treatment was given until progression or unacceptable toxicities on a 28-day cycle. No crossover was permitted.
Setting and participants. 665 patients underwent randomization: 224 patients to triplet-therapy, 220 to doublet-therapy, and 221 to the control group. Eligible patients had histologically confirmed metastatic colorectal cancer with a BRAF V600E mutation. Patients all had disease progression after 1 or 2 previous lines of therapy.
Main outcome measures. The primary end point of the study was OS and objective response rate (ORR) in the triplet-therapy group compared with the control group. Secondary endpoints included OS in the doublet-therapy group compared with the control group, as well as progression-free survival (PFS), duration of response (DOR), and safety. Assessments were performed every 6 weeks for the first 24 weeks and then every 12 weeks thereafter.
Results. The baseline characteristics were well balanced between the treatment arms. At the time of data cutoff, the median duration of follow-up was 7.8 months for each group. The median OS was 9 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio [HR] for death, 0.52; 95% confidence interval [CI], 0.39-0.70; P < 0.001). The median OS was 8.4 months for the doublet-therapy group, resulting in a significant reduction in the risk of death compared with the control group (HR, 0.6; 95% CI, 0.45-0.79; P < 0.001). The estimated 6-month survival was 71% for the triplet-therapy group, 65% for the doublet-therapy group, and 47% for the control group. The triplet-therapy group had a higher ORR compared with the control group (26% versus 2%, P < 0.001). The ORR in the doublet-therapy group was also significantly higher than that in the control group (20% versus 2%, P < 0.001). Complete responses were seen in 4% of patients in the triplet-therapy group, 5% of the doublet-therapy group, and no patients in the control group. PFS was significantly longer in both the triplet-therapy and doublet-therapy groups compared with the control group (median PFS: 4.3 months, 4.2 months, 1.5 months, respectively). This translated into a 62% and 60% reduction in the risk for disease progression or death in the triplet-therapy and doublet-therapy groups, respectively, compared to the control group.
The most common adverse event reported in the triplet-therapy group was gastrointestinal (GI) related (diarrhea, nausea, and vomiting), with grade 3 or higher GI toxicity seen in 10% of patients. Skin toxicity in the form of acneiform dermatitis was seen in almost 50% of those in the triplet-therapy arm; however, grade 3 or higher skin toxicity was uncommon (2%). Overall, adverse events grade 3 or higher were observed in 58% of those in the triplet-therapy group, 50% in the doublet-therapy group, and 61% in the control group. Adverse events leading to drug discontinuation occurred in 7% in the triplet-therapy group, 8% in the doublet-therapy group, and 11% in the control group. Three deaths were considered treatment related: 1 in the triplet-therapy group (bowel perforation) and 2 in the control group (anaphylaxis and respiratory failure).