Yuankai Shi1, Shucai Zhang2, Xingsheng Hu3, Jifeng Feng4, Zhiyong Ma5, Jianying Zhou6, Nong Yang7, Lin Wu8, Wangjun Liao9, Dafang Zhong10, Xiaohong Han3, Ziping Wang11, Xiaodong Zhang12, Shukui Qin13, Kejing Ying14, Jian Feng15, Jian Fang16, Li Liu17, Yong Jiang18. 1. 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. 2. Department of Oncology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Oncology Institute, Beijing, People's Republic of China. 3. 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. 4. Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, People's Republic of China. 5. Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou, People's Republic of China. 6. Department of Respiratory Medicine, the First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, People's Republic of China. 7. 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. 8. Department of Gastroenterology, Hunan Cancer Hospital, Changsha, People's Republic of China. 9. Department of Medical Oncology, Nanfang Hospital, Nanfang Medical University, Guangzhou, People's Republic of China. 10. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China. 11. Department of Thoracic Oncology, Unit I, Peking University Cancer Hospital, Beijing, People's Republic of China. 12. Department of Medical Oncology, Nantong Cancer Hospital, Nantong, People's Republic of China. 13. Department of Medical Oncology, PLA Cancer Center of Bayi Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, People's Republic of China. 14. Department of Respiratory Medicine, Sir Run Shaw Hospital, Affiliated With Zhejiang University School of Medicine, Hangzhou, People's Republic of China. 15. Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong, People's Republic of China. 16. Department of Thoracic Oncology, Unit II, Peking University Cancer Hospital, Beijing, People's Republic of China. 17. Department of Thoracic Oncology, Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. 18. Clinical Affairs and Regulatory Department, Shanghai Allist Pharmaceuticals Co., Ltd., Shanghai, People's Republic of China.
Abstract
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.
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 EGFRT790M 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 EGFRT790M mutation. Further investigation is ongoing.
Authors: P Xing; X Zheng; Y Wang; T Chu; S Wang; J Jiang; J Qian; X Han; L Ding; Y Wang; L Cui; H Li; L Li; X Chen; B Han; P Hu; Y Shi Journal: ESMO Open Date: 2022-05-06