Comparative effectiveness of first-line targeted therapies in ALK-positive non-small cell lung cancer: real-world evidence of tyrosine kinase inhibitors

Abstract

Objective: To estimate the comparative effectiveness of first-line (1 L) anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in ALK-positive non-small cell lung cancer (NSCLC) in the United States. Methods: We conducted a retrospective cohort study using Optum's de-identified Clinformatics® Data Mart Database (2016–2024). Patients with lung cancer ICD-10 codes and pharmacy claims for ALK TKIs were eligible if aged ≥ 18 years, continuously enrolled ≥ 6 months before initiation, and treated after each drug's FDA approval. Outcomes included time-to-next (targeted) treatment or death (TTNTD) and overall survival (OS). Propensity scores were constructed for pairwise comparisons and applied using overlap weighting (OW) as the primary specification and inverse probability of treatment weighting (IPTW) as alternative specification. Results: Among 940 patients initiating 1 L therapy (crizotinib n = 449, alectinib n = 417, brigatinib n = 30, ceritinib n = 8, lorlatinib n = 36), alectinib had the longest reached median TTNTD (33.5 months; 95% CI, 24.6–46.3) and OS (46.5 months; 95% CI, 39.0–NR) in unadjusted analyses. In overlap-weighted analyses, alectinib was associated with significantly longer TTNTD (HR 0.50; 95% CI, 0.41–0.61) and OS (HR 0.58; 95% CI, 0.47–0.71) versus crizotinib. Comparison of alectinib vs lorlatinib statistically insignificantly favored lorlatinib (TTNTD HR 2.02; 95% CI, 0.92–4.46; OS HR 1.29; 95% CI, 0.58–2.83). Conclusion: Alectinib demonstrated a clear survival advantage over crizotinib, consistent with trial findings. Lorlatinib showed potential benefit over alectinib, though limited by sample size and wide confidence intervals. This study provides the largest claims-based analysis of 1 L ALK TKIs and may help guide differentiation among agents with equivalent guideline placement.