Lorlatinib in Tyrosine Kinase Inhibitor-Naive Advanced ROS1-Positive Non-Small Cell Lung Cancer: A Phase 2 Nonrandomized Clinical Trial.

Abstract

ROS1 rearrangement is rare but is an attractive therapeutic target in advanced non-small cell lung cancer (NSCLC). Crizotinib, entrectinib, and repotrectinib have been approved by the US Food and Drug Administration for treatment of ROS1-positive NSCLC. Lorlatinib, a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI), targets ROS1 and ALK; however, its efficacy and safety for patients with advanced ROS1-positive remains unknown. To evaluate the efficacy and safety of lorlatinib for patients with advanced ROS1-positive NSCLC never treated with any TKI. This multicenter phase 2 nonrandomized clinical trial enrolled patients with advanced ROS1-positive NSCLC who were TKI-naive with an Eastern Cooperative Oncology Group performance status of 2 or less, and 1 or no prior platinum-based chemotherapy. Participants were recruited from June 2019 to April 2023 and followed up through August 2024. Data analysis was performed from April 5 to August 30, 2025. Lorlatinib, 100 mg daily, was administered until disease progression, toxic effects, consent withdrawal, or death. Objective response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival, and safety. The analysis included 32 patients (mean [IQR] age, 59 [11] years; 20 female [63%] and 12 male [37%] individuals), all of whom had adenocarcinoma histologic findings. There were 21 patients (66%) who were treatment-naive, and 11 (34%) who had prior chemotherapy. The median (SD) follow-up duration was 22.1 (15.4-46.8) months; ORR was 73% (95% CI, 56%-86%; 22 of 30 patients), and disease control rate was 90% (95% CI, 74%-97%; 27 of 30 patients). Median (IQR) PFS was 53.6 (95% CI, 27.8-79.5) months, and overall survival was not reached. For treatment-naive vs previously treated patients, the ORR was 90% vs 60%, and PFS was not reached vs 35.8 months. Grade 3 to 4 adverse effects were hypertriglyceridemia (5 patients [16%]) and hypercholesterolemia (8 patients [25%]). No treatment-related deaths occurred. In this nonrandomized clinical trial, lorlatinib demonstrated durable efficacy and manageable safety in TKI-naive advanced ROS1-positive NSCLC, supporting the potential for using lorlatinib in earlier treatment settings. ClinicalTrials.gov Identifier: NCT03612154.