Lorlatinib in advanced ALK-positive non-small cell lung cancer: Efficacy, safety and exploration of predictive biomarkers for therapeutic response

Background: Lorlatinib is approved as first-line therapy for advanced ALK-positive non-small cell lung cancer (NSCLC); however, some patients fail to achieve optimal responses. This study aimed to explore the real-world efficacy of lorlatinib in Chinese patients with advanced ALK-positive NSCLC and identify predictive biomarkers for treatment response. Methods: A total of 60 patients with advanced ALK-positive NSCLC treated with lorlatinib (100 mg once daily) at Cancer Hospital of the Chinese Academy of Medical Sciences from June 2023 to October 2025 were enrolled. Peripheral blood samples were collected at baseline, 1 month post-treatment, and at disease progression. The primary endpoint was objective response rate (ORR). Results: First-line lorlatinib achieved an ORR of 87.9%, disease control rate (DCR) of 100%, and unreached median progression-free survival (mPFS). Second-line treatment showed an ORR of 38.5%, DCR of 92.3%, and mPFS of 35.93 months; third-line treatment had an ORR of 33.3%, DCR of 100%, and mPFS of 9.87 months. For the overall population, the ORR was 67.3%, DCR 98.2%, and mPFS 35.93 months. Paired baseline and 1-month post-treatment blood samples from 26 patients (51 samples total) underwent liquid chromatography-mass spectrometry (LC-MS) lipid metabolomics analysis, detecting 1,077 lipid species. After 1 month of lorlatinib treatment, phosphatidylethanolamine (PE) and phosphatidylcholine (PC) were upregulated, while ceramides were downregulated. Based on best overall response (BOR), patients were stratified into the good response (GR, n=20) and limited response (LR, n=6) groups. 100 differential lipid species were identified in the GR group (notably HexCer 18:1;20/24:0, P =0.018), with no significant differences in the LR group. Further analysis showed that low baseline HexCer 18:1;20/24:0 expression correlated with longer PFS ( P =0.02). Consistently, non-progressive disease (non-PD) patients also had low baseline HexCer 18:1;20/24:0 expression ( P =0.015), suggesting its potential as a predictive biomarker. For safety, among the patients evaluable for safety (n=51), hyperlipidemia was observed in all cases, with 22 patients (43.1%) experiencing grade ≥III hyperlipidemia. Additionally, 17 patients (33.3%) had edema, 8 patients (15.7%) had abnormal liver function, and 8 patients (15.7%) suffered from neurological adverse reactions. Conclusions: Lorlatinib exhibits favorable efficacy in Chinese patients with advanced ALK-positive NSCLC, with overall mPFS of 35.93 months, ORR of 67.3%, and unreached first-line mPFS. Adverse reactions were manageable. Low baseline HexCer 18:1;20/24:0 expression may serve as a predictive biomarker, which requires further validation.