Efficacy and safety of entrectinib in locally advanced/metastatic ROS1 fusion-positive NSCLC: An updated integrated analysis

Abstract

Background: Entrectinib is a potent, selective, CNS active, ROS1 tyrosine kinase inhibitor (TKI). In a preliminary analysis (data cut-off: 31 May 2018) of pts with ROS1 fusion-positive (ROS1-fp) NSCLC enrolled in phase 1/2 studies (ALKA-372-001, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88, NCT02097810, NCT02568267), treatment with entrectinib produced clinically meaningful and durable systemic responses with a manageable safety profile. We report on an updated integrated analysis in a larger patient population with longer follow-up (data cut-off: 1 May 2019). Methods: Enrolled pts were ROS1 TKI naïve with measurable disease; most received entrectinib 600mg once daily. Tumours were assessed by blinded independent central review using RECIST v1.1, after 4 wks and every 8 wks thereafter. Primary endpoints were objective response rate (ORR) and duration of response (DoR). Progression-free survival (PFS), overall survival (OS), efficacy in pts with/without baseline CNS metastases, and safety were also assessed. Results: The efficacy-evaluable population comprised 161 pts with ROS1-fp NSCLC; baseline characteristics are shown (Table). Median follow-up: 15.8 months (range 0.1e43.2). ORR, 67.1% (95% CI 59.3e74.3); 14 pts (8.7%) achieved complete response, 94 (58.4%) partial response, 14 (8.7%) stable disease, 15 (9.3%) disease progression. Median DoR, 15.7 months (95% CI 13.9e28.6); median PFS, 15.7 months (95% CI 11.0e21.1); median OS, not estimable (NE) (95% CI 28.3eNE). In the subgroup with prior immunotherapy (n¼24), ORR, 70.8% (95% CI 48.9e87.4). In pts with investigator-assessed CNS metastases at baseline, ORR, 62.5% (95% CI 48.6e75.1). The safety profile was similar to that previously reported. Conclusions: This updated analysis, using a larger dataset with longer follow-up, shows that entrectinib induces clinically meaningful responses in pts with ROS1-fp NSCLC, including pts with CNS metastases at baseline.