Phase I Clinical Trial Evaluating Safety, Tolerability, and Early Activity of Exarafenib (KIN-2787), a Highly Selective Pan-RAF Inhibitor, in BRAF -Altered Solid Tumors or NRAS -Mutant Melanoma

PURPOSE Exarafenib is an investigational, next-generation pan-RAF inhibitor. This phase I study evaluated the safety, tolerability, and activity of exarafenib in patients with BRAF -altered solid tumors or NRAS -mutated melanoma. PATIENTS AND METHODS In this international, multicenter, 3 + 3 design, phase I, dose escalation and expansion study, adult patients with advanced or metastatic solid tumors harboring BRAF class 1, 2, or 3 alterations or with NRAS -mutant melanoma received escalating doses of exarafenib (65 patients) or a fixed exarafenib dose in expansion cohorts (42 patients). RESULTS Exarafenib's maximal tolerated dose was 300 mg twice a day, which was selected as the RP2D for expansion; dose-limiting toxicities included reversible skin adverse events (AEs). Treatment-related AEs (TRAEs) were mostly G1 or 2. The most common grade 3 or 4 TRAEs were reversible, asymptomatic elevations of ALT (11%) and AST (8%), rash (6%), and dermatitis acneiform (2%). TRAEs led to exarafenib discontinuation in 10% of patients. Exarafenib had linear pharmacokinetic up to 300 mg twice a day and accumulated three-fold at steady state. Tumor responses were observed in 15 patients, primarily at either the 200 mg twice a day or 300 mg twice a day doses, and across several tumor types and different genomic alterations; the overall response rate (ORR) was 8.4%. Activity was notable in patients with BRAF class 2 alterations; in the fusion-driven class 2 subset, the ORR, disease control rate, and duration of response were 30%, 90%, and 6.7 months, respectively. CONCLUSION Exarafenib is a novel pan-RAF inhibitor with an acceptable safety profile and encouraging antitumor activity in patients with BRAF class 2 and NRAS -mutated cancers. Further exploration of exarafenib alone and in combination with mitogen activated protein kinase kinase inhibitor therapy is warranted in patients with BRAF alterations or NRAS mutations.