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Ref Type Journal Article
PMID (39551469)
Authors Zhao S, Zhou H, Yang N, Wang Z, Jin W, Ma Y, Xue J, Li X, Liu Y, Meng R, Zhou J, Cheng Y, Wang Y, Yu Z, Cao Y, Zhao Y, Huang Y, Fang W, Zhang Y, Hong S, Wu B, Shi Y, Cao J, Xu M, Zhang X, Hu L, Peng B, Yang Y, Zhang L, Zhao H
Title Safety, efficacy and biomarker analysis of deulorlatinib (TGRX-326) in ALK-positive non-small-cell lung cancer: a multicentre, open-label, phase 1/1b trial.
Journal Vol Issue Date Pages Journal Short Title
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2024 Nov 15 J Thorac Oncol
URL
Abstract Text Patients with ALK-positive NSCLC developing resistance to second-generation inhibitors have limited treatment options. Deulorlatinib is a highly brain-penetrant, new-generation ALK/ROS1 inhibitor. We evaluated the safety, efficacy and pharmacokinetics of deulorlatinib in ALK-positive NSCLC.This 3-part (dose-escalation/dose-expansion/cohort-expansion), open-label, phase 1/1b trial was conducted at 22 sites in China (ClinicalTrials.gov, NCT05441956). Eligible patients had advanced ALK/ROS1-positive NSCLC. Patients enrolled into dose-escalation/dose-expansion parts were previously treated with ≥1 second-generation ALK inhibitors (ALK-positive) or crizotinib (ROS1-positive); received deulorlatinib 5-125mg once daily. Patients enrolled into cohort-expansion parts were either crizotinib-treated, second-generation TKI-treated or TKI-naïve; received deulorlatinib at recommended phase 2 dose (RP2D). Primary outcomes were safety and tolerability. Here, we report safety analysis in all patients and efficacy analysis in ALK-positive patients.Between April 2021 and March 2023, 198 patients were enrolled (ALK-positive=171, ROS1-positive=27). Most common treatment-related adverse events (TRAEs) were hypercholesterolemia (79.3%), hypertriglyceridemia (77.3%) and weight gain (53.0%). 40.4% of patients had grade≥3 TRAEs. TRAE-associated dose interruptions, reduction and discontinuation occurred in 11.1%, 3.0% and 1.5% of patients, respectively. The RP2D was set at 60mg once daily. A total of 144 ALK-positive patients were treated at RP2D. For crizotinib-treated (n=14), second-generation TKI-treated (n=97) and TKI-naïve (n=33) patients, ORR to deulorlatinib at RP2D was 71.4%, 38.1%, and 87.9%, respectively. Intracranial ORR was 50%, 70.4%, and 75%. Median duration of response was 18.0 months for second-generation TKI-treated patients, and not reached for crizotinib-treated and TKI-naïve patients. Biomarker analyses identified undetectable ALK alterations at baseline and ALK ctDNA clearance at week 6 as potential predictive biomarkers.Deulorlatinib showed desirable tolerability and efficacy in ALK-positive NSCLC, demonstrating the potential to become a new treatment option in this population.

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