Abstract
BACKGROUND: Leptomeningeal metastatic disease (LMD) represents a devastating complication of non-small-cell lung cancer (NSCLC) with a poor prognosis. Our understanding of LMD is limited in the era of molecular testing and emerging therapeutic options for lung cancer. PATIENTS AND METHODS: We conducted an international, multicenter, retrospective study involving eight institutions across Asia, United States, and Europe. Patients diagnosed with LMD from advanced NSCLC were identified (2007-2024). Clinicopathological characteristics, treatment patterns, and outcomes were analyzed. The primary endpoint was overall survival from the LMD diagnosis (LMOS). RESULTS: A total of 2052 patients with NSCLC and LMD were included and analyzed by molecular subtypes: epidermal growth factor receptor (EGFR) (n = 1610), ALK (n = 141), other actionable genomic alterations (other AGA; n = 137), and non-AGA (n = 164). The cumulative prevalence of LMD by molecular subgroups was EGFR, 11.1%; ALK, 11.2%; ROS1, 16%; ERBB2, 12.3%, non-AGA, 3.6%. A higher proportion of LMD was diagnosed >3 years after initial metastatic diagnosis. By the European Association of Neuro-Oncology (EANO)-European Society for Medical Oncology (ESMO) diagnostic criteria, type I (cerebrospinal fluid cytology positive) had significantly shorter LMOS than type II (magnetic resonance imaging and/or symptom positive). Median LMOS was 10.9 months [95% confidence interval (CI) 10.0-11.8 months] in all patients. Compared with historical cohorts, patients demonstrated improved LMOS in contemporary cohorts (7.3 versus 11.5 months, P < 0.0001), across all molecular subtypes. In AGA NSCLC, tyrosine kinase inhibitors (TKIs) were associated with improved LMOS [hazard ratio (HR) 0.39, 95% CI 0.31-0.48, P < 0.0001]. Immune checkpoint inhibitors (ICIs) conferred survival benefit in non-AGA patients (HR 0.45, 95% CI 0.25-0.84, P = 0.012). For the EGFR-mutated cohort, central nervous system (CNS)-penetrant TKI usage delayed LMD onset (P < 0.0001). Continued CNS-penetrant TKIs after LMD diagnosis were associated with longer LMOS (12.4 versus 6.0 months, P < 0.0001). CONCLUSIONS: The prevalence of LMD is rising, largely due to prolonged survival in advanced NSCLC. Contemporary systemic treatments, including TKIs and ICIs, were the main contributors to delayed LMD onset and improved LMD survival.