Safety, Clinical Activity, and Pharmacokinetics of Alflutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation
Yuankai Shi, Shucai Zhang, Xingsheng Hu, Jifeng Feng, Zhiyong Ma, Jianying Zhou, Nong Yang, Lin Wu, Wangjun Liao, Dafang Zhong, Xiaohong Han, Ziping Wang, Xiaodong Zhang, Shukui Qin, Kejing Ying, Jian Feng, Jian Fang, Li Liu, Yong Jiang, Yuankai Shi, Shucai Zhang, Xingsheng Hu, Jifeng Feng, Zhiyong Ma, Jianying Zhou, Nong Yang, Lin Wu, Wangjun Liao, Dafang Zhong, Xiaohong Han, Ziping Wang, Xiaodong Zhang, Shukui Qin, Kejing Ying, Jian Feng, Jian Fang, Li Liu, Yong Jiang
Abstract
Introduction: Alflutinib (AST2818) is a newly developed third-generation EGFR tyrosine kinase inhibitor selective for EGFR-sensitizing and T790M-resistant mutations. We assessed the safety, efficacy, and pharmacokinetics of alflutinib in patients with advanced NSCLC with confirmed EGFR T790M mutation, whose status progressed after the first- or second-generation EGFR tyrosine kinase inhibitor therapy.
Methods: In the dose-escalation (NCT02973763) and dose-expansion (NCT03127449) studies, patients received alflutinib orally until disease progression, unacceptable toxicity, or subject withdrawal. The primary end points were safety, tolerability, and pharmacokinetics for the dose-escalation study and the objective response rate (assessed by an independent radiological review committee) for the dose-expansion study.
Results: Between November 30, 2016, and July 24, 2018, a total of 130 patients (14 in dose escalation, 116 in dose expansion) received alflutinib treatment (20 mg, 40 mg, 80 mg, 160 mg, or 240 mg once daily). On October 30, 2018, 79 patients (61%) remained on the treatment. No dose-limiting toxicities were observed in the dose-escalation study. In the dose-expansion study (40-240 mg), the overall objective response rate was 76.7% (89 of 116), and it was 70.6% in patients with central nervous system metastases (12 of 17). A total of 79% of all patients had possibly treatment-related adverse events (AEs) (103 of 130); 8% had treatment-related grade 3 or higher AEs (11 of 130). Serious AEs were reported in 15% of patients (20 of 130), and two serious AEs were related to treatment. No clear dose-response (antitumor activity and AEs) relationships were observed. Exposures to alflutinib and its active metabolite (AST5902) were comparable at steady state.
Conclusions: Alflutinib was clinically effective with an acceptable toxicity profile in patients with advanced NSCLC (including those with central nervous system metastases) with EGFR T790M mutation. Further investigation is ongoing.
Keywords: Alflutinib; EGFR T790M mutation; Efficacy; NSCLC; Safety.
Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Source: PubMed