Efficacy and safety of lorlatinib in first-line and subsequent-line treatments for patients with ALK-positive non-small cell lung cancer: a single-center real-world study in China

Background: Current evidence on the efficacy and safety of lorlatinib as first-line or subsequent-line therapy for patients with anaplastic lymphoma kinase (ALK)-positive (ALK+) non-small cell lung cancer (NSCLC) in real-world clinical settings remains insufficient. We aim to further evaluate the efficacy and safety of lorlatinib through a real-world cohort study and investigate potential mechanisms of resistance. Methods: This study is a single-center cohort study in China. We retrospectively and prospectively collected data on patients with advanced or metastatic ALK+ NSCLC who initiated lorlatinib treatment at National Cancer Center from December 1, 2020. Patients were categorized into two groups based on lorlatinib treatment sequence: first-line cohort and subsequent-line cohort. Demographic characteristics, efficacy, and safety outcomes were comprehensively documented. Survival curves were generated using the Kaplan-Meier method, and group comparisons were performed with the log-rank test. Continuous variables were analyzed using Student’s t-tests. The endpoints of this study included measures of both treatment efficacy and safety. Results: As of July 18, 2025, a total of 36 patients were enrolled in the lorlatinib first-line treatment cohort, and 43 patients were enrolled in the lorlatinib subsequent-line treatment cohort for analysis. For the first-line treatment cohort, the median follow-up time was 12.7 months and the median progression-free survival (PFS) had not yet been reached; the objective response rate (ORR) was 82.9%, and the disease control rate (DCR) was 100%. For the subsequent-line treatment cohort, the median follow-up time was 19.9 months and the median PFS was 16.8 months; the ORR was 40.5%, and the DCR was 92.9%. Among all patient groups included in this study, the adverse events associated with lorlatinib treatment predominantly comprised hypercholesterolemia, hypertriglyceridemia, edema, cognitive impairment/mood disorders, elevated transaminases, weight gain, and peripheral neuropathy. No cases of interstitial lung disease were observed. The overall safety profile of lorlatinib is manageable. Analysis of next-generation sequencing (NGS) test results from patients with lorlatinib resistance demonstrated that ALK compound mutations, novel ALK fusions, and MET gene amplification may be potential mechanisms contributing to lorlatinib resistance. Conclusions: Lorlatinib has shown remarkable efficacy in both first-line and subsequent-line treatment settings for patients with locally advanced or metastatic ALK+ NSCLC. Effective management of lorlatinib-related adverse events, through close monitoring and timely intervention, is essential to enhance patient tolerance. Lorlatinib has progressively transformed the therapeutic landscape for patients with ALK+ NSCLC.