Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors.

8503 Background: GSK2118436 is a highly potent and selective ATP competitive BRAF inhibitor with > 100-fold selectivity for mutant (mut) BRAF over wild type (wt) in cell lines. It displays dose-dependent inhibition of MEK and ERK phosphorylation in mut BRAF cell lines and tumor regression in xenograft models. Methods: This is a first-time in human, dose escalation study to identify the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in cohorts of 1 to 20 patients (pts). Pts were treated with oral GSK2118436 once to three times daily. Once safety was established in cohorts of 3 to 4 pts, cohorts were expanded to determine the optimal dose based on efficacy and tolerability. Results: 61 pts (52 mut BRAF melanoma) received 12–400 mg daily. Plasma concentrations were dose-proportional and exceeded the minimal therapeutic target at doses > 35 mg BID. 1 pt reported dose-limiting toxicity of syncope (200 mg BID) and resumed reduced dosing. AEs included skin changes (23 pts, 1 gr 3), low grade cutaneous SCC (2 pts), headache (12 pts, 1 gr 3), nausea (11 gr 1), fatigue (9 gr 1), and vomiting (8 pts, 4 gr 2). MTD has not yet been determined. Concentration-dependent pERK inhibition was seen in tumor (max 93% inhibition) at GSK2118436 concentration of 140 ng/mL. In pts with mut BRAF melanoma: exposure-related decrease in FDG-PET metabolic uptake was noted with 11/14 (79%) pts showing a decrease from baseline (range −5 to −100%). In pts with mut BRAF melanoma (without brain mets) 18/ 30 (60%) pts have a > 20% tumor decrease by RECIST at first restaging (8–9 wks). Conclusions: MTD has not yet been reached. Clinical activity with minimal toxicity was observed at multiple dose levels in mut BRAF tumors. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline