Therapeutic progress in leptomeningeal metastasis from EGFR mutant non-small cell lung cancer: a clinical medicine review

Leptomeningeal metastasis in patients with Epidermal Growth Factor Receptor-mutant non-small cell lung cancer carries a dismal prognosis and is associated with profound neurological morbidity. Historically, therapeutic efficacy has been severely limited, leading to poor overall survival. This review aims to synthesize the recent, albeit incremental, advances in the multidisciplinary management of this devastating complication. We delve into the evolving landscape of treatment modalities, with a particular focus on the latest generation of tyrosine kinase inhibitors and their superior central nervous system penetration. The roles of conventional approaches, including radiotherapy (both whole-brain and focal) for symptom palliation and tumor control, and intrathecal chemotherapy, are critically re-evaluated in the modern context. Furthermore, we explore the rationale and early evidence for novel combination strategies. A significant portion of our analysis is dedicated to evaluating the pharmacodynamic mechanisms of action, optimizing dosing strategies, and interpreting clinical outcomes from key trials and real-world evidence. Central to the discussion are the persistent challenges of adequate blood-brain barrier penetration, the emergence of therapeutic resistance, and the management of overlapping toxicities. We also address the parallel progress in diagnostic neuro-imaging and cerebrospinal fluid liquid biopsies, which are enhancing early detection and disease monitoring. Finally, this review outlines future research directions, emphasizing the need for randomized controlled trials and a deeper understanding of the tumor microenvironment to foster a paradigm shift in the care of patients with leptomeningeal metastasis.