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Advances in cerebrospinal fluid (CSF)\u2010based diagnostics, improved molecular characterization, and the development of central nervous system (CNS)\u2010penetrant targeted therapies have begun to reshape both disease assessment and treatment expectations, particularly in oncogene\u2010driven 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\u2010active therapies. In selected patients, especially those with epidermal growth factor receptor\u2010 or anaplastic lymphoma kinase\u2010altered disease, contemporary targeted agents have demonstrated meaningful leptomeningeal and intracranial activity, supporting more durable and compartment\u2010specific 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\u2010associated LMD, while emphasizing persistent limitations in diagnostic standardization, response assessment, and clinical trial design. It also underscores the need for leptomeningeal\u2010specific end points, longitudinal CSF\u2010based biomarker integration, and more inclusive trial strategies to improve evidence generation and patient outcomes.<\/jats:p>","DOI":"10.1002\/cncr.70624","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:20:47Z","timestamp":1791292847000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Redefining leptomeningeal metastasis in non\u2013small cell lung cancer: From terminal complication to molecularly managed disease"],"prefix":"10.1002","volume":"132","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7705-3926","authenticated-orcid":false,"given":"K\u00fcbra","family":"Canaslan","sequence":"first","affiliation":[{"name":"Department of Translational Oncology Dokuz Eylul University Oncology Institute  Izmir Turkey"},{"name":"Department of Medical Oncology Mehmet Akif \u0130nan Training and Research Hospital  \u015eanl\u0131urfa Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9687-5677","authenticated-orcid":false,"given":"Kelsey","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology Winship Cancer Institute of Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3735-9063","authenticated-orcid":false,"given":"Ticiana","family":"Leal","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology Winship Cancer Institute of Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.20272"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/curroncol30060442"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2016.06.029"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2025.108806"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.ANNONC.2025.09.140"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470\u20102045(17)30689\u20107"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538\u20107445.AM2025\u20101155"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(06)70443\u20104"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568\u2010024\u201000700\u2010y"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.02.025"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.10.693"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.17925\/OHR.2025.21.1.5"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2024.10.019"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2024.09.1385"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2023.101624"},{"key":"e_1_2_12_17_1","unstructured":"National Comprehensive Cancer Network.NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers (Version 3.2025). 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