Signal Transduction and Targeted Therapy (Jan 2022)

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

  • Yuankai Shi,
  • Jian Fang,
  • Xuezhi Hao,
  • Shucai Zhang,
  • Yunpeng Liu,
  • Lin Wang,
  • Jianhua Chen,
  • Yi Hu,
  • Xiaosheng Hang,
  • Juan Li,
  • Chunling Liu,
  • Yiping Zhang,
  • Zhehai Wang,
  • Yanping Hu,
  • Kangsheng Gu,
  • Jian’an Huang,
  • Liangming Zhang,
  • Jinlu Shan,
  • Weiwei Ouyang,
  • Yanqiu Zhao,
  • Wu Zhuang,
  • Yan Yu,
  • Jun Zhao,
  • Helong Zhang,
  • Pei Lu,
  • Weidong Li,
  • Meimei Si,
  • Mingjing Ge,
  • Huaize Geng

DOI
https://doi.org/10.1038/s41392-021-00841-8
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 10

Abstract

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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.