Safety and activity of WX-0593 (Iruplinalkib) in patients with ALK- or ROS1-rearranged advanced non-small cell lung cancer: a phase 1 dose-escalation and dose-expansion trial

  • Signal Transduct Target Ther. 2022 Jan 28;7(1):25. doi: 10.1038/s41392-021-00841-8.
Yuankai Shi  1 ,  Jian Fang  2 ,  Xuezhi Hao  3 ,  Shucai Zhang  4 ,  Yunpeng Liu  5 ,  Lin Wang  3 ,  Jianhua Chen  6 ,  Yi Hu  7 ,  Xiaosheng Hang  8 ,  Juan Li  9 ,  Chunling Liu  10 ,  Yiping Zhang  11 ,  Zhehai Wang  12 ,  Yanping Hu  13 ,  Kangsheng Gu  14 ,  Jian'an Huang  15 ,  Liangming Zhang  16 ,  Jinlu Shan  17 ,  Weiwei Ouyang  18 ,  Yanqiu Zhao  19 ,  Wu Zhuang  20 ,  Yan Yu  21 ,  Jun Zhao  2 ,  Helong Zhang  22 ,  Pei Lu  23 ,  Weidong Li  24 ,  Meimei Si  25 ,  Mingjing Ge  25 ,  Huaize Geng  25
Affiliations
  • 1. 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, 100021, Beijing, P.R. China. [email protected].
  • 2. Beijing Cancer Hospital, 100142, Beijing, P.R. China.
  • 3. 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, 100021, Beijing, P.R. China.
  • 4. Beijing Chest Hospital, Capital Medical University, 101149, Beijing, P.R. China.
  • 5. The First Hospital of China Medical University, 110001, Shenyang, P.R. China.
  • 6. Hunan Cancer Hospital, 410000, Changsha, P.R. China.
  • 7. Chinese PLA General Hospital, 100853, Beijing, P.R. China.
  • 8. Affiliated Hospital of Jiangnan University, 214062, Wuxi, P.R. China.
  • 9. Sichuan Cancer Hospital, 610041, Chengdu, P.R. China.
  • 10. Affiliated Tumour Hospital of Xinjiang Medical University, 830000, Urumqi, P.R. China.
  • 11. Zhejiang Cancer Hospital, 310022, Hangzhou, P.R. China.
  • 12. Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 250117, Jinan, P.R. China.
  • 13. Hubei Cancer Hospital, 430079, Wuhan, P.R. China.
  • 14. The First Affiliated Hospital of Anhui Medical University, 230022, Hefei, P.R. China.
  • 15. The First Affiliated Hospital of Soochow University, 215006, Suzhou, P.R. China.
  • 16. Yantai Yuhuagding Hospital, Yantai, 264000, P.R. China.
  • 17. Army Medical Center of People's Liberation Army, 400042, Chongqing, P.R. China.
  • 18. Guizhou Cancer Hospital, 520100, Guiyang, P.R. China.
  • 19. Henan Cancer Hospital, 450008, Zhengzhou, P.R. China.
  • 20. Fujian Province Cancer Hospital, 350014, Fuzhou, P.R. China.
  • 21. Harbin Medical University Cancer Hospital, 150081, Harbin, P.R. China.
  • 22. Tangdu Hospital of the Fourth Military Medical University, 710038, Xi'an, P.R. China.
  • 23. Liuzhou People's Hospital, 545006, Liuzhou, P.R. China.
  • 24. Cancer Center of Guangzhou Medical University, 510095, Guangzhou, P.R. China.
  • 25. Qilu Pharmaceutical Co., Ltd, 250101, Jinan, P.R. China.
PMID: 35087031 DOI: 10.1038/s41392-021-00841-8
Abstract

WX-0593 (Iruplinalkib) is a novel, highly selective oral ALK and ROS1 tyrosine kinase inhibitor (TKI). In this study, the safety, antitumor activity, and pharmacokinetics of WX-0593 were evaluated in advanced Non-Small Cell Lung Cancer (NSCLC) patients with ALK or ROS1 rearrangement. In the dose-escalation phase and dose-expansion phase, patients were treated with WX-0593 until disease progression, unacceptable toxicity, or subject withdrawal. In the dose-escalation phase, the primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety assessed by investigators. In the dose-expansion phase, the primary endpoint was objective response rate (ORR) assessed by investigators. Between September 25, 2017 and October 15, 2018, a total of 153 patients received WX-0593 treatment. Two dose-limiting toxicities (DLTs) including one grade 3 QT interval prolonged and one grade 2 chronic Heart Failure were reported at the dose of 300 mg in one patient. MTD was not reached. Overall, 140 of the 152 (92%) patients experienced treatment-related adverse events (TRAEs) and 35 of the 152 (23%) patients had TRAEs ≥grade 3. The overall ORR was 59.3% (32 of 54) for the dose-escalation phase and 56.6% (56 of 99) for the dose-expansion phase. For patients who were ALK-rearranged and ALK TKI naive, the ORR were 81.0% (17 of 21) in the dose-escalation phase and 76.3% (29 of 38) in the dose-expansion phase, and for patients who previously received crizotinib as the only ALK TKI, the ORR were 38.1% (8 of 21) and 45.7% (21 of 46) for the two phases, respectively. For patients who were ROS1-rearranged, the ORR were 30.0% (3 of 10) in the dose-escalation phase and 44.4% (4 of 9) in the dose-expansion phase. WX-0593 showed favorable safety and promising antitumor activity in advanced NSCLC patients with ALK or ROS1 rearrangement.

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