Safety, Efficacy, and Biomarker Analysis of Deulorlatinib (TGRX-326) in Anaplastic Lymphoma Kinase-Positive NSCLC: A Multicenter, Open-Label, Phase 1/1b Trial.

Abstract

Introduction: Patients with anaplastic lymphoma kinase (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.

Methods: This three-part (dose-escalation/dose-expansion/cohort-expansion), open-label, phase 1/1b trial was conducted at 22 sites in the People's Republic of China (ClinicalTrials.gov, NCT05441956). Patients who were eligible had advanced ALK/ROS1-positive NSCLC. Patients enrolled in dose-escalation/dose-expansion parts were previously treated with one or more second-generation ALK inhibitors (ALK-positive) or crizotinib (ROS1-positive) and received deulorlatinib 5 to 125 mg once per day. Patients enrolled in cohort-expansion parts were either crizotinib-treated, second-generation tyrosine kinase inhibitor (TKI)-treated, or TKI-naïve; and received deulorlatinib at the recommended phase 2 dose (RP2D). The primary outcomes were safety and tolerability. Here, we report safety analysis in all patients and efficacy analysis in patients who were ALK-positive.

Results: Between April 2021 and March 2023, 198 patients were enrolled (ALK-positive = 171, ROS1-positive = 27). The 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 or higher TRAEs. Meanwhile, TRAE-associated dose interruptions, reduction, and discontinuation occurred in 11.1%, 3.0%, and 1.5% of patients, respectively. The RP2D was set at 60 mg once per day. A total of 144 patients who were ALK-positive were treated at RP2D. For crizotinib-treated (n = 14), second-generation TKI-treated (n = 97), and TKI-naïve (n = 33) patients, the objective response rate to deulorlatinib at RP2D was 71.4%, 38.1%, and 87.9%, respectively. Intracranial objective response rate was 50%, 70.4%, and 75%, respectively. The median duration of response was 18.0 months for second-generation TKI-treated patients, and not reached for patients who were crizotinib-treated and TKI-naïve. Biomarker analyses identified undetectable ALK alterations at baseline and ALK circulating tumor DNA clearance at week 6 as potential predictive biomarkers.

Conclusions: Deulorlatinib reported desirable tolerability and efficacy in ALK-positive NSCLC, demonstrating the potential to become a new treatment option in this population.