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Triplet therapy shows early promise in BRAF V600E-mutant metastatic colorectal cancer
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A regimen of encorafenib, binimetinib and cetuximab demonstrated acceptable safety and tolerability among patients with previously treated BRAF V600E-mutant metastatic colorectal cancer in the safety lead-in of the randomized, phase 3 BEACON trial, according to results published in Journal of Clinical Oncology.
The triplet therapy also showed promising efficacy compared with available treatments and, if confirmed in the randomized phase of the study that is currently underway, could be a new standard of care for this patient population.
“Results from a recent phase 3 study in patients with BRAF V600E-mutant [metastatic colorectal cancer] who received at least one prior regimen showed that the doublet of encorafenib plus cetuximab resulted in a confirmed [overall response rate] of 24%, a PFS of 4.2 months, and an OS of 9.3 months, with a tolerable safety profile,” Eric Van Cutsem, MD, PhD, head of the division of digestive oncology at University Hospital Gasthuisberg in Leuven, Belgium, and colleagues wrote. “Relative to the standard of care and to other BRAF, MEK and EGFR inhibitor triplet combinations, the promising results with the encorafenib and cetuximab double supported the initiation of the phase 3 BEACON study.”
In the lead-in phase of the open-label, randomized, phase 3 trial, Van Cutsem and colleagues evaluated data from 30 patients (median age, 59 years; 43% men; 97% white) with colorectal cancer, all but one of whom had BRAF V600E-mutant disease. All participants failed treatment with at least one but no more than two previous regimens.
Patients received encorafenib (Braftovi, Array Pharmaceuticals) 300 mg daily, binimetinib (Mektovi, Array Pharmaceuticals) 45 mg twice daily and cetuximab (Erbitux, Bristol-Myers Squibb) 400 mg/m2 followed by 250 mg/m2 IV weekly in cycles of 28 days.
Safety, including occurrences of dose-limiting toxicities, served as the primary endpoint. ORR, PFS and OS among patients with a BRAF V600E mutation served as efficacy endpoints.
Among the 30 patients treated, five experienced dose-limiting toxicities. These included serous retinopathy (n = 2), reversible decreased left ventricular ejection fraction (n = 1) and cetuximab-related infusion reactions (n = 2).
The most prevalent grade 3 or grade 4 adverse events included fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased aspartate aminotransferase (10%) and urinary tract infections (10%).
Among the 29 patients with BRAF V600E-mutant disease, with median follow-up of 18.2 months (range, 16.6-19.8), researchers observed a confirmed ORR of 48% (95% CI, 29.4-67.5) median PFS of 8 months (95% CI, 5.6-9.3) and median OS of 15.3 months (95% CI, 9.6 months to not reached).
“The randomized portion of the BEACON [colorectal cancer] study is ongoing, and if results approximate those from the safety lead-in, the combination of binimetinib, encorafenib and cetuximab may become a new standard of care for patients with previously treated BRAF V600E-mutated [colorectal cancer],” the researchers wrote. “To maximize the potential for benefit to patients, results warrant additional investigation of this regimen in the first-line and potentially the adjuvant settings.” – by Jennifer Byrne
Disclosures: Van Cutsem reports consultant/advisory roles with AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Eli Lilly, Merck KGaA, Merck Sharp & Dohme and Novartis; and research funding to his institution from Amgen, Bayer. Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck, Merck KGaA, Roche and Servier. Please see the study for all other authors’ relevant financial disclosures.
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