Abstract
Oncogenic ROS1 and NTRK 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 ROS1 fusions. Patients received DS-6051b once daily (400 mg n = 6; 600 mg n = 6; or 800 mg n = 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, AUC0–24 h on day 15 was higher but narrowed after body weight correction. Objective response rate was 58.3% in patients with target lesions (n = 12) and 66.7% in crizotinib-naïve patients (n = 9). Disease control rate was 100%. DS-6051b is well tolerated and effective in Japanese patients with NSCLC harboring ROS1 fusions and might be a targeted therapy for advanced NSCLC.
Highlights
Driver gene mutations and chromosomal gene rearrangements lead to oncogenic tyrosine kinase activation [1, 2]
Tolerability, efficacy, and pharmacokinetics of DS-6051b in 15 Japanese patients with non-small cell lung cancer (NSCLC) harboring receptor tyrosine kinase gene (ROS1) fusions
ROS1 fusion has been reported in glioblastoma multiforme [3, 4], non-small cell lung cancer (NSCLC) [5], cholangiocarcinoma [6], gastric cancer [7], and colorectal cancer [8], and neurotrophic receptor tyrosine kinase (NTRK) fusion proteins have been reported in thyroid carcinoma [9], colorectal cancer [10], melanoma [11], breast cancer [12], and NSCLC [13, 14]
Summary
Driver gene mutations and chromosomal gene rearrangements lead to oncogenic tyrosine kinase activation [1, 2]. The ROS1 inhibitor crizotinib showed a high response rate (objective response rate [ORR] of 72%; median duration of response: 17.6 months, n = 50) [17], and it is approved globally for use in advanced NSCLC patients with ROS1 fusions. Resistance to crizotinib, caused by a G2032R or other mutation within the kinase domain, has been reported in ROS1 fusion-positive NSCLC [18]. A phase II study reported that ceritinib, an anaplastic lymphoma kinase and ROS1 inhibitor, had efficacy in patients with ROS1-rearranged NSCLC who were previously treated with multiple chemotherapy [19]
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