Safety, Clinical Activity and Pharmacokinetics of Alflutinib (AST2818) in Advanced NSCLC Patients with EGFR T790M Mutation.
J Thorac Oncol. 2020 Jan 30;:
Authors: Shi Y, Zhang S, Hu X, Feng J, Ma Z, Zhou J, Yang N, Wu L, Liao W, Zhong D, Han X, Wang Z, Zhang X, Qin S, Ying K, Feng J, Fang J, Liu L, Jiang Y
INTRODUCTION: Alflutinib (AST2818) is a newly developed third-generation EGFR tyrosine kinase inhibitor (TKI) selective for EGFR sensitizing and T790M resistant mutations. We assessed the safety, efficacy and pharmacokinetics (PK) of alflutinib in advanced NSCLC patients with conﬁrmed T790M mutation, who progressed after the first- or second-generation EGFR-TKI therapy.
METHODS: In the dose-escalation (NCT02973763) and dose-expansion (NCT03127449) studies, patients received alflutinib orally until disease progression, unacceptable toxicity, or subject withdrawal. Primary endpoints were the safety, tolerability, and PK for the dose-escalation study, and the objective response rate (ORR, assessed by an independent radiological review committee) for the dose-expansion study.
RESULTS: Between Nov 30, 2016, and Jul 24, 2018, 130 patients (14 in dose-escalation, 116 in dose-expansion) received alflutinib treatment (20, 40, 80, 160, or 240 mg once daily). By Oct 30, 2018, 79 (61%) patients remained on treatment. No dose limiting toxicities were observed in the dose-escalation study. In the dose-expansion study (40 – 240 mg), the overall ORR was 76.7% (89/116), and it was 70.6% (12/17) in patients with CNS metastases. 79% (103/130) of all patients had possibly treatment-related adverse events (AEs); 8% (11/130) had treatment-related grade ≥3 AEs. Serious adverse events (SAEs) were reported in 15% (20/130) of patients, and two SAEs were treatment related. 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 advanced NSCLC patients (including those with CNS metastases) with EGFR T790M mutation. Further investigation is ongoing.
PMID: 32007598 [PubMed – as supplied by publisher]