PMID- 32007598 OWN - NLM STAT- MEDLINE DCOM- 20210106 LR - 20210106 IS - 1556-1380 (Electronic) IS - 1556-0864 (Linking) VI - 15 IP - 6 DP - 2020 Jun TI - Safety, Clinical Activity, and Pharmacokinetics of Alflutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation. PG - 1015-1026 LID - S1556-0864(20)30031-9 [pii] LID - 10.1016/j.jtho.2020.01.010 [doi] AB - 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 con fi rmed 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. CI - Copyright (c) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. FAU - Shi, Yuankai AU - Shi Y AD - Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, People's Republic of China. Electronic address: syuankai@cicams.ac.cn. FAU - Zhang, Shucai AU - Zhang S AD - Department of Oncology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Oncology Institute, Beijing, People's Republic of China. FAU - Hu, Xingsheng AU - Hu X AD - Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, People's Republic of China. FAU - Feng, Jifeng AU - Feng J AD - Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, People's Republic of China. FAU - Ma, Zhiyong AU - Ma Z AD - Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou, People's Republic of China. FAU - Zhou, Jianying AU - Zhou J AD - Department of Respiratory Medicine, the First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, People's Republic of China. FAU - Yang, Nong AU - Yang N AD - Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People's Republic of China. FAU - Wu, Lin AU - Wu L AD - Department of Gastroenterology, Hunan Cancer Hospital, Changsha, People's Republic of China. FAU - Liao, Wangjun AU - Liao W AD - Department of Medical Oncology, Nanfang Hospital, Nanfang Medical University, Guangzhou, People's Republic of China. FAU - Zhong, Dafang AU - Zhong D AD - Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China. FAU - Han, Xiaohong AU - Han X AD - Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, People's Republic of China. FAU - Wang, Ziping AU - Wang Z AD - Department of Thoracic Oncology, Unit I, Peking University Cancer Hospital, Beijing, People's Republic of China. FAU - Zhang, Xiaodong AU - Zhang X AD - Department of Medical Oncology, Nantong Cancer Hospital, Nantong, People's Republic of China. FAU - Qin, Shukui AU - Qin S AD - Department of Medical Oncology, PLA Cancer Center of Bayi Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, People's Republic of China. FAU - Ying, Kejing AU - Ying K AD - Department of Respiratory Medicine, Sir Run Shaw Hospital, Affiliated With Zhejiang University School of Medicine, Hangzhou, People's Republic of China. FAU - Feng, Jian AU - Feng J AD - Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong, People's Republic of China. FAU - Fang, Jian AU - Fang J AD - Department of Thoracic Oncology, Unit II, Peking University Cancer Hospital, Beijing, People's Republic of China. FAU - Liu, Li AU - Liu L AD - Department of Thoracic Oncology, Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. FAU - Jiang, Yong AU - Jiang Y AD - Clinical Affairs and Regulatory Department, Shanghai Allist Pharmaceuticals Co., Ltd., Shanghai, People's Republic of China. LA - eng SI - ClinicalTrials.gov/NCT03127449 SI - ClinicalTrials.gov/NCT02973763 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200130 PL - United States TA - J Thorac Oncol JT - Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer JID - 101274235 RN - 0 (Indoles) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyridines) RN - 0 (Pyrimidines) RN - A49A7A5YN4 (aflutinib) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM CIN - J Thorac Oncol. 2020 Jun;15(6):881-883. PMID: 32471561 EIN - J Thorac Oncol. 2020 Oct 16;:. PMID: 33077354 MH - *ErbB Receptors/genetics MH - Humans MH - Indoles MH - *Lung Neoplasms/drug therapy/genetics MH - Mutation MH - Protein Kinase Inhibitors/adverse effects MH - Pyridines MH - Pyrimidines OTO - NOTNLM OT - Alflutinib OT - EGFR T790M mutation OT - Efficacy OT - NSCLC OT - Safety EDAT- 2020/02/03 06:00 MHDA- 2021/01/07 06:00 CRDT- 2020/02/03 06:00 PHST- 2019/10/20 00:00 [received] PHST- 2020/01/14 00:00 [revised] PHST- 2020/01/15 00:00 [accepted] PHST- 2020/02/03 06:00 [pubmed] PHST- 2021/01/07 06:00 [medline] PHST- 2020/02/03 06:00 [entrez] AID - S1556-0864(20)30031-9 [pii] AID - 10.1016/j.jtho.2020.01.010 [doi] PST - ppublish SO - J Thorac Oncol. 2020 Jun;15(6):1015-1026. doi: 10.1016/j.jtho.2020.01.010. Epub 2020 Jan 30.