Delayed Occurrence of Lung Cancer Leptomeningeal Metastasis and Era-Associated Post-LM Survival: A 14-Year Single-Center Cohort Study.

INTRODUCTION: Leptomeningeal metastasis (LM) is a devastating complication of lung cancer. We investigated the clinical and molecular evolution of LM in the modern targeted-therapy era and factors associated with post-LM survival. METHODS: We retrospectively analyzed 201 patients with cytologically confirmed lung cancer LM diagnosed between November 2012 and May 2026. Patients were classified by LM diagnosis date (2012-2016 vs. 2017-2026). Intervals from lung cancer and Stage IV diagnosis to LM were compared using the Mann-Whitney U test. Paired primary tumor and cerebrospinal fluid (CSF) molecular profiles were assessed in 80 patients. Overall survival (OS) was evaluated using Kaplan-Meier and prespecified multivariable cox analyses. RESULTS: Adenocarcinoma accounted for 93.0% of cases. The intervals from lung cancer and Stage IV diagnosis to LM were longer in the later cohort (23.7 vs. 13.8 months, p < 0.001; 17.4 vs. 10.4 months, p = 0.002). Unadjusted OS from LM diagnosis did not differ significantly between eras (9.8 vs. 11.3 months, p = 0.864). Tissue-CSF driver discordance occurred in 7/80 patients (8.75%). In multivariable analysis, later diagnostic era, smoking, and ECOG PS ≥ 2 were associated with higher mortality (adjusted HR, 1.826, p = 0.014; 1.847, p = 0.014; and 1.674, p = 0.007, respectively), whereas post-LM third-generation EGFR-TKI exposure was associated with lower mortality (adjusted HR, 0.385; p < 0.001). CONCLUSION: The later era was associated with a longer interval to LM diagnosis but no statistically significant improvement in unadjusted post-LM OS. Adjusted associations require cautious interpretation because of residual confounding and post-baseline treatment bias. CSF profiling may provide clinically relevant information beyond primary tumor genotyping.