Key Clinical Summary:

• Design/Population: This real-world study evaluated lorlatinib in patients with advanced ALK-positive NSCLC, treated in both the first- and later-line settings.  
• Key Outcomes: Lorlatinib achieved high response rates, particularly in the first-line setting, with durable progression-free survival. Lipid metabolomics identified a potential biomarker associated with improved outcomes.
• Clinical Relevance: Lorlatinib remains a highly effective option for ALK-positive NSCLC. Emerging biomarker data may help refine patient selection and guide personalized treatment strategies.

Results from a real-world study demonstrate that lorlatinib is associated with high response rates and durable disease control among patients with advanced ALK-positive non-small cell lung cancer (NSCLC), with exploratory biomarker analyses suggesting a potential role for lipid metabolomics in predicting treatment response.

These findings were presented by Fang Wei, MD, National Cancer Center, Beijing, China, at the 2026 American Association for Cancer Research (AACR) Annual Meeting in San Diego, California.

In this single-center study, researchers collected data from 60 patients who received 100 mg of once daily lorlatinib. Peripheral blood samples were collected at baseline, 1 month after treatment initiation, and at disease progression. Samples underwent liquid chromatography-mass spectrometry lipid metabolomics analysis to detect lipid species. The primary end point was objective response rate (ORR). Key secondary end points included progression-free survival (PFS), disease control rate, and safety. 

At analysis, ORR was 67.3%, disease control rate was 98.2%, and median PFS was 35.93 months in the intention-to-treat population. Patients who received first-line lorlatinib achieved an ORR of 87.9%, a disease control rate of 100%, and median PFS not reached. Patients who received second-line lorlatinib achieved an ORR of 38.5%, a disease control rate of 92.3%, and a median PFS of 35.93 months. Patients who received third-line lorlatinib achieved an ORR of 33.3%, a disease control rate of 100%, and a median PFS of 9.87 months. 

Lipid metabolomics analysis detected 1,077 liquid species across 56 samples (collected from 26 patients). Following 1 month of treatment, phosphatidylethanolamine and phosphatidylcholine levels increased and ceramide levels decreased. Lower baseline expression of HexCer 18:1;20/24:0 was associated with improved PFS (P = 0.02) and better treatment response (P = 0.015), suggesting potential as a predictive biomarker.

Among 51 patients evaluable for safety, the safety profile was consistent with known toxicities. Hyperlipidemia was reported in all patients, including grade ≥3 hyperlipidemia in 43.1% of patients. Other frequently reported adverse events included edema (33.3%), abnormal liver function (15.7%), and neurological toxicities (15.7%).

“Lorlatinib exhibits favorable efficacy… [and] adverse reactions were manageable,” concluded Dr Wei. “Low baseline HexCer 18:1;20/24:0 expression may serve as a predictive biomarker, which requires further validation.”

Source:

Wei F, Tian L, Shi H, et al. Lorlatinib in advanced ALK-positive non-small cell lung cancer: Efficacy, safety and exploration of predictive biomarkers for therapeutic response. Presented at AACR Annual . April 17 - 22, 2026; San Diego, California. LB013.