Redefining leptomeningeal metastasis in non–small cell lung cancer: From terminal complication to molecularly managed disease

Leptomeningeal disease (LMD) is one of the most devastating complications of advanced non-small cell lung cancer (NSCLC), historically associated with profound neurologic morbidity and poor survival. Advances in cerebrospinal fluid (CSF)-based diagnostics, improved molecular characterization, and the development of central nervous system (CNS)-penetrant targeted therapies have begun to reshape both disease assessment and treatment expectations, particularly in oncogene-driven NSCLC. Available data suggest that outcomes in LMD are highly heterogeneous and are influenced by molecular subtype, performance status, systemic disease control, and access to effective CNS-active therapies. In selected patients, especially those with epidermal growth factor receptor- or anaplastic lymphoma kinase-altered disease, contemporary targeted agents have demonstrated meaningful leptomeningeal and intracranial activity, supporting more durable and compartment-specific disease control. At the same time, diagnosis still relies on imperfect but complementary modalities, including magnetic resonance imaging and CSF cytology, whereas emerging liquid biopsy approaches may improve detection and longitudinal monitoring. Treatment failure is further shaped by the pharmacokinetic constraints of the leptomeningeal compartment, where limited drug penetration contributes to therapeutic resistance. This review highlights the evolving biology, diagnosis, prognostic determinants, and therapeutic landscape of NSCLC-associated LMD, while emphasizing persistent limitations in diagnostic standardization, response assessment, and clinical trial design. It also underscores the need for leptomeningeal-specific end points, longitudinal CSF-based biomarker integration, and more inclusive trial strategies to improve evidence generation and patient outcomes.