Several small molecule inhibitors, such as osimertinib and lorlatinib, demonstrate high penetrance into the cerebrospinal fluid, potent leptomeningeal activity, and superior survival outcomes relative to historical controls.

Immune checkpoint inhibitors can induce leptomeningeal responses in select patients with immunotherapy-responsive cancers, though the bioactivity of these agents may be hampered by a dysfunctional leptomeningeal immune microenvironment and relatively low cerebrospinal fluid drug penetrance with intravenous administration.

Clinical trials designed specifically for patients with leptomeningeal metastases, with inclusion of cerebrospinal fluid pharmacokinetic analyses, are needed to define the leptomeningeal bioactivity of novel agents in this patient population.