Safety and pharmacokinetics of DS-6051b in Japanese patients with non-small cell lung cancer harboring <i>ROS1</i> fusions: a phase I study

Abstract

Oncogenic <i>ROS1</i> and <i>NTRK</i> fusions were reported in solid tumors, including non-small cell lung cancer (NSCLC). DS-6051b is an oral, potent selective small molecule tyrosine kinase inhibitor. We report the safety, tolerability, efficacy, and pharmacokinetics of DS-6051b in 15 Japanese patients with NSCLC harboring <i>ROS1</i> fusions. Patients received DS-6051b once daily (400 mg <i>n</i> = 6; 600 mg <i>n</i> = 6; or 800 mg <i>n</i> = 3) for cycles of 3 weeks. Safety, tolerability, maximum-tolerated dose, pharmacokinetics, and recommended dose for phase II were determined. Common treatment-related adverse events were increased: aspartate aminotransferase and alanine aminotransferase (80.0% each), diarrhea (53.3%), and nausea (46.7%). Dose-limiting toxicities (two grade-3 alanine aminotransferase increases) were seen in the 800 mg cohort. The maximum-tolerated dose and recommended phase II dose was 600 mg once daily. Plasma concentrations of free DS-6051b and DS-6051a increased with dose. Compared with a US phase I study, AUC_{0-24 h} on day 15 was higher but narrowed after body weight correction. Objective response rate was 58.3% in patients with target lesions (<i>n</i> = 12) and 66.7% in crizotinib-naïve patients (<i>n</i> = 9). Disease control rate was 100%. DS-6051b is well tolerated and effective in Japanese patients with NSCLC harboring <i>ROS1</i> fusions and might be a targeted therapy for advanced NSCLC.