Yunpeng Yang1, Jianya Zhou2, Jianying Zhou2, Jifeng Feng3, Wu Zhuang4, Jianhua Chen5, Jun Zhao6, Wei Zhong7, Yanqiu Zhao8, Yiping Zhang9, Yong Song10, Yi Hu11, Zhuang Yu12, Youling Gong13, Yuan Chen14, Feng Ye15, Shucai Zhang16, Lejie Cao17, Yun Fan9, Gang Wu18, Yubiao Guo19, Chengzhi Zhou20, Kewei Ma21, Jian Fang6, Weineng Feng22, Yunpeng Liu23, Zhendong Zheng24, Gaofeng Li25, Ning Wu26, Wei Song27, Xiaoqing Liu28, Shijun Zhao26, Lieming Ding29, Li Mao29, Giovanni Selvaggi30, Xiaobin Yuan29, Yuanqing Fu29, Tao Wang31, Shanshan Xiao31, Li Zhang32. 1. Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. 2. Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. 3. Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China. 4. Department of Thoracic Oncology, Fujian Provincial Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, China. 5. Department of Medical Oncology-Chest, Hunan Cancer Hospital, Changsha, China. 6. Department of Thoracic Oncology, Beijing Cancer Hospital, Beijing, China. 7. Department of Pulmonary Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China. 8. Respiratory Department of Internal Medicine, Henan Provincial Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China. 9. Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China. 10. Division of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China. 11. Department of Oncology, Chinese PLA General Hospital, Beijing, China. 12. Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China. 13. Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China. 14. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 15. Department of Medical Oncology, Cancer Hospital, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, China. 16. Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China. 17. Respiratory Medicine, The First Affiliated Hospital of the University of Science and Technology of China, Anhui Provincial Hospital, Hefei, China. 18. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 19. Pulmonary & Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 20. Respiratory Medicine Department, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. 21. Cancer Center, The First Hospital of Jilin University, Changchun, China. 22. Department of Head and Neck and Thoracic Medical Oncology, The First People's Hospital Of Foshan, Foshan, China. 23. Oncology Medicine, The First Hospital of China Medical University, Shenyang, China. 24. Oncology Department, General Hospital of Northern Theater Command, Shenyang, China. 25. 2nd Department of Thoracic Surgery, Yunnan Cancer Hospital, Kunming, China. 26. Department of Diagnostic Radiology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China. 27. Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China. 28. Department of Pulmonary Oncology, The Fifth Medical Centre Chinese PLA General Hospital, Beijing, China. 29. Betta Pharmaceuticals, Hangzhou, China. 30. X-covery Holdings, Palm Beach Gardens, FL, USA. 31. Hangzhou Repugene Technology, Hangzhou, China. 32. Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Electronic address: zhangli@sysucc.org.cn.
Abstract
BACKGROUND: Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range of known crizotinib-resistant ALK mutations and CNS metastases. We aimed to assess the efficacy and safety of ensartinib in ALK-positive patients with non-small-cell lung cancer (NSCLC), in whom crizotinib therapy was unsuccessful. The associations between ensartinib efficacy and crizotinib-resistant mutations were also explored. METHODS: We did a single-arm, open-label, phase 2 study at 27 centres in China. Patients were aged 18 years or older, had stage IIIb or stage IV ALK-positive NSCLC that had progressed while they were on crizotinib therapy, an Eastern Cooperative Oncology Group performance status of 2 or less, had measurable disease, and had received fewer than three previous treatments. Patients with CNS metastases were included if these metastases were asymptomatic and did not require steroid therapy. All patients received 225 mg ensartinib orally once daily on a continuous dosing schedule. The primary outcome was the proportion of patients with an objective response according to the Response Evaluation Criteria in Solid Tumors (version 1.1), as assessed by an independent review committee in all patients who received at least one dose of ensartinib with no major violations of the inclusion criteria (ie, the full analysis set). Safety was assessed in all enrolled patients who received at least one dose of ensartinib. This trial was registered with ClinicalTrials.gov, NCT03215693. FINDINGS:Between Sept 28, 2017, and April 11, 2018, 160 patients were enrolled and had at least one dose of ensartinib (safety analysis set). Four patients had inclusion violations and were excluded from the efficacy analysis, which thus included 156 patients (full analysis set). 97 (62%) patients in the full analysis set had brain metastases. 76 (52% [95% CI 43-60]) of 147 patients in the full analysis set, with responses that could be assessed by the independent review committee, had an objective response. 28 (70% [53-83]) of 40 patients with measurable brain metastases as assessed by the independent review committee had an intracranial objective response. 145 (91%) of 160 patients had at least one treatment-related adverse event, which were mostly grade 1 or 2. The most common treatment-related adverse events were rash (89 [56%]), increased alanine aminotransferase concentrations (74 [46%]), and increased aspartate aminotransferase concentrations (65 [41%]). INTERPRETATION: Ensartinib has activity and is well tolerated in patients with crizotinib-refractory, ALK-positive NSCLC, including those with brain metastases. The role of ensartinib in patients in whom other second-generation ALK inhibitors have been unsuccessful warrants further studies. FUNDING: Betta Pharmaceuticals.
RCT Entities:
BACKGROUND: Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range of known crizotinib-resistant ALK mutations and CNS metastases. We aimed to assess the efficacy and safety of ensartinib in ALK-positive patients with non-small-cell lung cancer (NSCLC), in whom crizotinib therapy was unsuccessful. The associations between ensartinib efficacy and crizotinib-resistant mutations were also explored. METHODS: We did a single-arm, open-label, phase 2 study at 27 centres in China. Patients were aged 18 years or older, had stage IIIb or stage IV ALK-positive NSCLC that had progressed while they were on crizotinib therapy, an Eastern Cooperative Oncology Group performance status of 2 or less, had measurable disease, and had received fewer than three previous treatments. Patients with CNS metastases were included if these metastases were asymptomatic and did not require steroid therapy. All patients received 225 mg ensartinib orally once daily on a continuous dosing schedule. The primary outcome was the proportion of patients with an objective response according to the Response Evaluation Criteria in Solid Tumors (version 1.1), as assessed by an independent review committee in all patients who received at least one dose of ensartinib with no major violations of the inclusion criteria (ie, the full analysis set). Safety was assessed in all enrolled patients who received at least one dose of ensartinib. This trial was registered with ClinicalTrials.gov, NCT03215693. FINDINGS: Between Sept 28, 2017, and April 11, 2018, 160 patients were enrolled and had at least one dose of ensartinib (safety analysis set). Four patients had inclusion violations and were excluded from the efficacy analysis, which thus included 156 patients (full analysis set). 97 (62%) patients in the full analysis set had brain metastases. 76 (52% [95% CI 43-60]) of 147 patients in the full analysis set, with responses that could be assessed by the independent review committee, had an objective response. 28 (70% [53-83]) of 40 patients with measurable brain metastases as assessed by the independent review committee had an intracranial objective response. 145 (91%) of 160 patients had at least one treatment-related adverse event, which were mostly grade 1 or 2. The most common treatment-related adverse events were rash (89 [56%]), increased alanine aminotransferase concentrations (74 [46%]), and increased aspartate aminotransferase concentrations (65 [41%]). INTERPRETATION: Ensartinib has activity and is well tolerated in patients with crizotinib-refractory, ALK-positive NSCLC, including those with brain metastases. The role of ensartinib in patients in whom other second-generation ALK inhibitors have been unsuccessful warrants further studies. FUNDING: Betta Pharmaceuticals.
Authors: Flávia Melo Cunha de Pinho Pessoa; Caio Bezerra Machado; Emerson Lucena da Silva; Laudreísa da Costa Pantoja; Rodrigo Monteiro Ribeiro; Maria Elisabete Amaral de Moraes; Manoel Odorico de Moraes Filho; Raquel Carvalho Montenegro; André Salim Khayat; Caroline Aquino Moreira-Nunes Journal: Int J Mol Sci Date: 2022-03-30 Impact factor: 5.923