Phase 1/2 mirdametinib MEK1/2 inhibitor tests MAPK-driven CNS tumors, perioperative glioma cohort

This Phase 1/2, multicenter, open-label Memorial Sloan Kettering (MSK) study evaluates mirdametinib, an oral small-molecule inhibitor of MEK1 and MEK2 in the MAPK pathway, in two biologically selected CNS tumor cohorts. Cohort A treats refractory neurohistiocytosis with continuous-cycle mirdametinib to define safety, tolerability, and preliminary activity in MAPK pathway–mutant disease (MAPK alterations are common drivers in several histiocytic disorders). Cohort B randomizes recurrent NF1-mutant glioma patients 2:1 to 5 days of perioperative mirdametinib vs no pre-op drug before standard-of-care surgery, then treats all patients post-op with continuous mirdametinib until progression—an efficient design to probe target engagement and early signals while keeping surgery central. The commercial/scientific angle is MEK inhibition in the CNS setting (including a perioperative “window” exposure) with a drug developed by SpringWorks Therapeutics, here run as an investigator-led MSK trial. Today’s care for recurrent glioma remains maximal safe re-resection when feasible plus radiation and/or systemic therapies depending on grade and prior treatments, while refractory neurohistiocytosis typically relies on steroids, chemo/immunosuppressants, and increasingly targeted agents when a driver is found—this study tests whether MEK blockade can be a rational targeted option across both.