Real-world comparative safety of first-line lorlatinib versus alectinib in metastatic ALK-rearranged non-small cell lung cancer: A propensity score-matched analysis.

Abstract

283 Background: Lorlatinib and alectinib are both NCCN-preferred first-line therapies for ALK-positive metastatic NSCLC, yet no head-to-head randomized trials exist. Lorlatinib carries a distinct safety profile including hyperlipidemia and CNS effects, while alectinib is associated with hepatotoxicity and GI toxicities. Real-world comparative safety data are needed to inform treatment selection. Methods: We conducted a retrospective propensity score-matched (PSM) cohort study using the TriNetX Global Collaborative Network (171 healthcare organizations). Adults with metastatic NSCLC (ICD-10: C34 + C78/C79) receiving first-line lorlatinib (Cohort A) or alectinib (Cohort B) were identified. PSM was performed on age, sex, race/ethnicity, brain metastases (C79.31), Charlson comorbidity components, and baseline labs (albumin, hemoglobin, creatinine, LDH). Safety outcomes were assessed using risk analysis (odds ratios) and Kaplan-Meier survival analysis (hazard ratios) with outcomes occurring prior to the index event excluded. Results: After PSM, 844 patients were matched per cohort. Median follow-up was 350 days (lorlatinib) vs 697 days (alectinib). Baseline characteristics were well-balanced (all standardized differences < 0.1). Key safety findings are in the Table. Notably, the divergence between risk-based and time-to-event analyses for several outcomes (cognitive disorders, mood disorders, bradycardia) reflects the substantial follow-up imbalance, with alectinib patients having nearly double the observation time. Conclusions: In this large real-world PSM analysis, lorlatinib was associated with significantly higher hypercholesterolemia risk but lower cumulative rates of mood disorders, bradycardia, constipation, and weight gain compared with alectinib. CNS-related effects and time to new intracranial metastases were comparable between the two agents. These findings suggest distinct but manageable safety trade-offs and support individualized first-line ALK-TKI selection. Sensitivity analyses are warranted to account for the observed follow-up asymmetry. Outcome Lorlatinib (%) Alectinib (%) OR (95% CI) HR (95% CI) Hypercholesterolemia 11.1 7.7 1.48 (1.04–2.11)* 2.20 (1.55–3.11)* Cognitive disorders 10.8 14.8 0.70 (0.51–0.94)* 1.06 (0.80–1.42) Mood disorders 5.1 8.7 0.56 (0.37–0.85)* 0.83 (0.55–1.24) Peripheral neuropathy 7.5 8.2 0.91 (0.63–1.32) 1.37 (0.96–1.96) Weight gain 5.6 8.3 0.66 (0.44–0.99)* 1.05 (0.70–1.57) Bradycardia 3.4 6.3 0.53 (0.32–0.85)* 0.76 (0.47–1.23) Intracranial mets 13.5 15.9 0.83 (0.56–1.23) 1.19 (0.83–1.71) Elevated AST/ALT 3.4 5.1 0.65 (0.40–1.07) 0.85 (0.52–1.38) Constipation 13.2 21.1 0.57 (0.43–0.77)* 0.80 (0.61–1.05)