Treatment options for second-generation (2nd-gen) anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) resistant patients are limited. We evaluated the safety, pharmacokinetics, and efficacy of ficonalkib (SY-3505), a third-generation (3rd-gen) ALK TKI.This first-in-human, phase I/Ⅱ study (Chinese Clinical Trial Registry identifier: ChiCTR1900025619; ClinicalTrials.gov identifier: NCT05257512) had two parts. Phase I included a dose-escalation phase (25-800 mg quaque die [QD]) and a dose-expansion phase (500 mg QD or 600 mg QD). Phase Ⅱ enrolled patients treated at recommended phase Ⅱ dose (RP2D). Primary endpoints were safety in phase I and objective response rate (ORR) in phase Ⅱ.Between Apr 21, 2020, and Aug 31, 2023, a total of 127 patients were enrolled, with 62 in phase I. Ficonalkib was well absorbed and tolerated, with one dose limited toxicity event occurring at 800 mg QD. Treatment-related adverse events (TRAEs) occurred in 85.5% of patients, with 19.4% experienced ≥ grade 3 events. The ORR was 38.3% (23/60, 95% confidence interval [CI] 26.1-51.8%) in phase I, and 600 mg QD was established as RP2D. In phase Ⅱ, a total of 65 patients received ficonalkib at 600 mg QD. Totally 88 patients received ficonalkib at 600 mg QD in phase I/Ⅱ, and all had received prior 2nd-gen ALK TKI treatment. 90.9% of patients experienced TRAEs and 14.8% experienced ≥ grade 3 events. The ORR in efficacy-evaluable patients received ficonalkib at 600 mg QD was 47.5% (38/80, 95% CI 36.2-59.0%), with an intracranial ORR of 37.5% (12/32, 95% CI 21.1-56.3%) in these patients with measurable brain lesions at baseline.Ficonalkib (SY-3505) was well tolerated, with favorable safety profiles and promising efficacy in patients resistant to prior 2nd-gen ALK TKI.Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.