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.

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阿氟替尼 (AST2818) 在具有 EGFR T790M 突变的晚期 NSCLC 患者中的安全性、临床活性和药代动力学

简介 阿氟替尼 (AST2818) 是一种新开发的第三代 EGFR 酪氨酸激酶抑制剂 (TKI)，对 EGFR 致敏和 T790M 耐药突变具有选择性。我们评估了阿氟替尼在经第一代或第二代 EGFR-TKI 治疗后进展的具有确认的 T790M 突变的晚期 NSCLC 患者中的安全性、有效性和药代动力学 (PK)。方法 在剂量递增 (NCT02973763) 和剂量扩展 (NCT03127449) 研究中，患者口服阿氟替尼直至疾病进展、出现不可接受的毒性或受试者退出。主要终点是剂量递增研究的安全性、耐受性和 PK，以及剂量扩展研究的客观反应率（ORR，由独立放射学审查委员会评估）。2016年11月30日至2018年7月24日期间的结果，130 名患者（14 名剂量递增，116 名剂量扩展）接受了阿氟替尼治疗（20、40、80、160 或 240 毫克，每天一次）。到 2018 年 10 月 30 日，79 名（61%）患者仍在接受治疗。在剂量递增研究中未观察到剂量限制性毒性。在剂量扩展研究 (40 - 240 mg) 中，总体 ORR 为 76.7% (89/116)，在 CNS 转移患者中为 70.6% (12/17)。79% (103/130) 的所有患者有可能与治疗相关的不良事件 (AE)；8% (11/130) 有治疗相关的 ≥ 3 级 AE。15% (20/130) 的患者报告了严重不良事件 (SAE)，其中两个 SAE 与治疗相关。没有观察到明确的剂量反应（抗肿瘤活性和 AE）关系。阿氟替尼及其活性代谢物 (AST5902) 在稳态时的暴露量相当。结论 阿氟替尼在具有 EGFR T790M 突变的晚期 NSCLC 患者（包括具有 CNS 转移的患者）中具有临床有效性和可接受的毒性特征。进一步调查正在进行中。