Purpose: Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic 
profile that is distinct from that of other clinically active BRAFis. We 
evaluated encorafenib in a phase I study in patients with BRAFi treatment-naïve 
and pretreated BRAF-mutant melanoma.Experimental Design: The pharmacologic 
activity of encorafenib was first characterized preclinically. Encorafenib 
monotherapy was then tested across a range of once-daily (50-700 mg) or 
twice-daily (75-150 mg) regimens in a phase I, open-label, dose-escalation and 
-expansion study in adult patients with histologically confirmed 
advanced/metastatic BRAF-mutant melanoma. Study objectives were to determine the 
maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), 
characterize the safety and tolerability and pharmacokinetic profile, and assess 
the preliminary antitumor activity of encorafenib.Results: Preclinical data 
demonstrated that encorafenib inhibited BRAF V600E kinase activity with a 
prolonged off-rate and suppressed proliferation and tumor growth of BRAF 
V600E-mutant melanoma models. In the dose-escalation phase, 54 patients (29 
BRAFi-pretreated and 25 BRAFi-naïve) were enrolled. Seven patients in the 
dose-determining set experienced dose-limiting toxicities. Encorafenib at a dose 
of 300 mg once daily was declared the RP2D. In the expansion phase, the most 
common all-cause adverse events were nausea (66%), myalgia (63%), and 
palmar-plantar erythrodysesthesia (54%). In BRAFi-naïve patients, the overall 
response rate (ORR) and median progression-free survival (mPFS) were 60% and 
12.4 months [95% confidence interval (CI), 7.4-not reached (NR)]. In 
BRAFi-pretreated patients, the ORR and mPFS were 22% and 1.9 months (95% CI, 
0.9-3.7).Conclusions: Once-daily dosing of single-agent encorafenib had a 
distinct tolerability profile and showed varying antitumor activity across 
BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic melanoma. 
Clin Cancer Res; 23(18); 5339-48. ©2017 AACR.