Safety, Clinical Activity, and Pharmacokinetics of Al flutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation
Safety, Clinical Activity, and Pharmacokinetics of Al flutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation
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DOI：
10.1016/j.jtho.2020.01.010
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发表时间：
2020-06-01
影响因子：
20.4
通讯作者：
Jiang, Yong
中科院分区：
文献类型：
--
作者：
Shi, Yuankai;Zhang, Shucai;Jiang, Yong
前言：阿氟替尼(AST2818)是新近开发的第三代EGFR酪氨酸激酶抑制剂，选择性抑制EGFR增敏和T790M耐药突变。我们评估了阿氟替尼在确诊为EGFR T790M突变的晚期非小细胞肺癌患者中的安全性、有效性和药代动力学，这些患者在第一代或第二代EGFR酪氨酸激酶抑制剂治疗后病情恶化。方法：在剂量递增(NCT02973763)和剂量扩大(NCT03127449)研究中，患者口服阿氟替尼直到疾病进展、不可接受的毒性或受试者停药。主要终点是剂量递增研究的安全性、耐受性和药代动力学，以及剂量扩大研究的客观反应率(由独立的放射学审查委员会评估)。结果：从2016年11月30日到2018年7月24日，共有130名患者(剂量递增14例，剂量扩大116例)接受阿氟替尼治疗(20 mg、40 mg、80 mg、160 mg或240 mg，每天一次)。2018年10月30日，79例(61%)患者仍在接受治疗。在剂量递增研究中没有观察到剂量限制毒性。在剂量扩展研究(40-240 mg)中，总的客观有效率为76.7%(89/116)，其中中枢神经系统转移患者的客观有效率为70.6%(12/17)。总共79%的患者可能有与治疗相关的不良事件(AEs)(130人中有103人)；8%的患者有与治疗相关的3级或更高的不良事件(11人在130人中)。严重不良反应发生率为15%(20/130)，2例严重不良反应与治疗有关。没有观察到明确的剂量-反应关系(抗肿瘤活性和AEs)。结论：阿氟替尼对EGFR T790M突变的晚期非小细胞肺癌患者(包括中枢神经系统转移患者)具有较好的临床疗效和可接受的毒性。进一步的调查正在进行中。(C)2020年国际肺癌研究协会。由爱思唯尔公司出版。这是CC BY-NC-ND许可证(http://creativecommons.org/licenses/by-nc-nd/4.0/).下的一篇开放获取文章
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. (C) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).