A phase 1b/2 study of the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib in patients with BRAF V600E/K-mutant solid tumors
Mené sur 126 patients atteints d'une tumeur solide présentant la mutation V600E/K du gène BRAF, cet essai de phase IB/II évalue la dose maximale tolérée de l'encorafénib (un inhibiteur de BRAF) en combinaison avec le binimétinib (un inhibiteur de MEK) et analyse les caractéristiques pharmacocinétiques de cette combinaison
Purpose : This open-label, dose-finding phase 1b/2 study reports the safety and activity of the first combination use with BRAF inhibitor (BRAFi) encorafenib plus MEK inhibitor (MEKi) binimetinib in patients with BRAF V600E-mutant solid tumors. (NCT01543698). Methods : In phase 1, the recommended phase 2 doses (RP2D) were established (primary objective). In phase 2, the clinical activity of the combination at the RP2D was assessed (primary objective) in patients with BRAF-mutant metastatic colorectal cancer (mCRC), BRAFi-treated BRAF-mutant melanoma, and BRAFi-naïve BRAF-mutant melanoma. Results : 126 patients with BRAF mutant solid tumors were enrolled (phase 1: 47 patients; phase 2: 79 patients). The RP2D was encorafenib 450 mg QD plus binimetinib 45 mg BID and pharmacokinetic (PK) data suggest that drug-exposures of each agent were similar in combination compared with single-agent studies. In the phase 2 cohorts, confirmed responses were seen in 2 of 11 (18%) evaluable mCRC patients, 11 of 26 (42%) evaluable BRAFi-pretreated melanoma patients, and 28 of 42 (67%) BRAFi-naïve melanoma patients. The most common grade 3/4 adverse event in phase 2 was increased alanine aminotransferase. Conclusion : The combination of encorafenib (450 mg) plus binimetinib (45 mg) showed acceptable tolerability and encouraging activity in patients with BRAF V600-mutant tumors, which led to the dose selection for the melanoma COLUMBUS study. The safety profile of the combination was consistent with other approved BRAFi plus MEKi regimens, with several differences, including lower rates of dose-limiting pyrexia, arthralgia, and photosensitivity.