Iruplinalkib (WX-0593) is a new-generation, potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) and has shown systemic and central nervous system (CNS) efficacy in ALK-positive non-small-cell lung cancer (NSCLC). We compared the efficacy and safety of iruplinalkib with crizotinib in ALK TKI-naïve, locally advanced or metastatic ALK-positive NSCLC patients.In this open-label, randomized, multicenter, phase III study, patients with ALK-positive NSCLC were randomly assigned to receive iruplinalkib 180 mg once daily (7-day run-in at 60 mg once daily) or crizotinib 250 mg twice daily. The primary endpoint was progression-free survival (PFS) assessed by Independent Review Committee (IRC) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included PFS by investigator, objective response rate (ORR), time to response, duration of response, intracranial ORR and time to CNS progression by IRC and investigator, overall survival and safety. An interim analysis was planned after approximately 70% (134 events) of all 192 expected PFS events assessed by IRC were observed. Efficacy was analyzed in the intention-to-treat (ITT) population. Safety was assessed in the safety population, which included all randomized patients who received at least one dose of study drugs. This study is registered with Center for Drug Evaluation of China NMPA (CTR20191231) and Clinicaltrials.gov (NCT04632758).From 4 September 2019 to 2 December 2020, a total of 292 patients were randomized and treated; 143 with iruplinalkib and 149 with crizotinib. At this interim analysis (145 events), the median follow-up time was 26.7 months (range, 3.7-37.7) in the iruplinalkib group and 25.9 months (range, 0.5-35.9) in the crizotinib group. The PFS assessed by IRC was significantly longer among patients in the iruplinalkib group (median PFS, 27.7 months [95% CI, 26.3-NE] versus 14.6 months [95% CI, 11.1-16.5] in the crizotinib group; HR, 0.34 [98.02% CI, 0.23-0.52]; p<0.0001). The ORR assessed by IRC was 93.0% (95% CI, 87.5-96.6) in the iruplinalkib group and 89.3% (95% CI, 83.1-93.7) in the crizotinib group. The intracranial ORR was 90.9% (10/11, 95% CI, 58.7-99.8) in the iruplinalkib group and 60.0% (9/15, 95% CI, 32.3-83.7) in the crizotinib group for patients with measurable baseline CNS metastases. Incidence of grade 3 or 4 treatment-related adverse events was 51.7% in the iruplinalkib group and 49.7% in the crizotinib group.Iruplinalkib demonstrated significantly improved PFS and improved intracranial antitumor activity versus crizotinib. Iruplinalkib may be a new treatment option for patients with advanced ALK positive and ALK TKI-naïve NSCLC.Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.