Leptomeningeal Metastasis in Non-Small-Cell Lung Cancer with Actionable Genomic Alterations: Pathogenesis, Diagnosis, and Emerging Therapeutic Strategies

Leptomeningeal metastasis (LM) is a severe and increasingly recognized complication of advanced non-small-cell lung cancer (NSCLC), particularly in patients with actionable genomic alterations. Although LM has historically been associated with poor outcomes, molecularly targeted systemic therapies with improved central nervous system (CNS) activity are reshaping its therapeutic landscape. This review summarizes current concepts in the pathogenesis, diagnosis, and risk stratification of LM, focusing on systemic treatment strategies for NSCLC harboring actionable driver alterations. We highlight the rationale and emerging evidence for next-generation tyrosine kinase inhibitors targeting EGFR, ALK, and other oncogenic drivers, and discuss their role as the cornerstone of LM management. Intrathecal chemotherapy, immunotherapy, and radiotherapy are also reviewed within a risk-adapted treatment framework. An individualized approach integrating molecular profiling, neurological status, and disease distribution is essential to optimize outcomes. Prospective studies are needed to refine systemic treatment strategies and establish evidence-based algorithms for this high-risk population.