Safety, Clinical Activity, and Pharmacokinetics of Al flutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation

doi:10.1016/j.jtho.2020.01.010

	Safety, Clinical Activity, and Pharmacokinetics of Al flutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation
	Shi, Yuankai 2; Zhang, Shucai 3; Hu, Xingsheng 2; Feng, Jifeng 4,5; Ma, Zhiyong 6; Zhou, Jianying 7; Yang, Nong 8; Wu, Lin 9; Liao, Wangjun 10; Zhong, Dafang 11
刊名	JOURNAL OF THORACIC ONCOLOGY
	2020-06-01
卷号	15 期号:6 页码:1015-1026
关键词	Alflutinib NSCLC EGFR T790M mutation Efficacy Safety
ISSN号	1556-0864
DOI	10.1016/j.jtho.2020.01.010
通讯作者	Shi, Yuankai(syuankai@cicams.ac.cn)
英文摘要	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/).
资助项目	Shanghai Allist Pharmaceuticals Co., Ltd. ; China National Major Project for New Drug Innovation[2017ZX09304015] ; China National Major Project for New Drug Innovation[2018ZX09301014009] ; China National Major Project for New Drug Innovation[2019ZX09201-002] ; Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS)[2016-I2M-1-001]
WOS关键词	CELL LUNG-CANCER ; OPEN-LABEL ; OSIMERTINIB ; THERAPY ; RESISTANCE ; ICOTINIB ; PHASE-3
WOS研究方向	Oncology ; Respiratory System
语种	英语
出版者	ELSEVIER SCIENCE INC
WOS记录号	WOS:000550011000015
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/292018]
专题	中国科学院上海药物研究所
通讯作者	Shi, Yuankai
作者单位	1.Shanghai Allist Pharmaceut Co Ltd, Clin Affairs & Regulatory Dept, Shanghai, Peoples R China 2.Chinese Acad Med Sci & Peking Union Med Coll, Beijing Key Lab Clin Study Anticanc Mol Targeted, Natl Clin Res Ctr Canc, Dept Med Oncol,Natl Canc Ctr,Canc Hosp, Beijing 100021, Peoples R China 3.Capital Med Univ, Beijing Chest Hosp, Beijing TB & Thorac Oncol Inst, Dept Oncol, Beijing, Peoples R China 4.Nanjing Med Univ, Affiliated Canc Hosp, Jiangsu Canc Hosp, Nanjing, Peoples R China 5.Nanjing Med Univ, Affiliated Canc Hosp, Jiangsu Inst Canc Res, Nanjing, Peoples R China 6.Zhengzhou Univ, Affiliated Canc Hosp, Henan Canc Hosp, Dept Med Oncol, Zhengzhou, Peoples R China 7.Zhejiang Univ, Coll Med, Affiliated Hosp 1, Dept Resp Med, Hangzhou, Peoples R China 8.Cent South Univ, Affiliated Canc Hosp, Hunan Canc Hosp,Xiangya Sch Med, Dept Med Oncol,Lung Canc & Gastrointestinal Unit, Changsha, Peoples R China 9.Hunan Canc Hosp, Dept Gastroenterol, Changsha, Peoples R China 10.Nanfang Med Univ, Nanfang Hosp, Dept Med Oncol, Guangzhou, Peoples R China
推荐引用方式 GB/T 7714	Shi, Yuankai,Zhang, Shucai,Hu, Xingsheng,et al. Safety, Clinical Activity, and Pharmacokinetics of Al flutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation[J]. JOURNAL OF THORACIC ONCOLOGY,2020,15(6):1015-1026.
APA	Shi, Yuankai.,Zhang, Shucai.,Hu, Xingsheng.,Feng, Jifeng.,Ma, Zhiyong.,...&Jiang, Yong.(2020).Safety, Clinical Activity, and Pharmacokinetics of Al flutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation.JOURNAL OF THORACIC ONCOLOGY,15(6),1015-1026.
MLA	Shi, Yuankai,et al."Safety, Clinical Activity, and Pharmacokinetics of Al flutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation".JOURNAL OF THORACIC ONCOLOGY 15.6(2020):1015-1026.