Background: Patients with progressive or recurrent meningiomas have limited treatment options. Clinical trials of systemic therapies for meningiomas have failed to demonstrate benefit. FAK inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically-driven phase II study in recurrent or progressive grade I-III meningiomas. Methods: Eligible patients (pts) whose tumors screened positively for NF2 mutations were treated with GSK2256098 750mg po bid until progressive disease in 2 separate cohorts: grade I or II/III meningiomas. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR) by Macdonald criteria; per study design, the trial would be declared positive if either endpoint was met. RR was evaluated across the overall cohort; PFS6 was evaluated within each subgroup. Historical benchmark data was obtained from Kaley et al. Neuro Oncol 2014. In the grade I group, 12 evaluable pts provided >79% power to detect a PFS6 rate >65% (vs. null hypothesis of 25%; alpha=0.014). In the grade II/III group, 24 evaluable pts provided >85% power to detect a PFS6 >41.5% (vs. null 15%; alpha=0.02). The threshold for promising results for PFS6 was: 7+/12(grade I) and 8+/24(grade II/III) pts. For RR, 36 evaluable pts provided >94% power to detect RR >20% (vs. null 2.5%; alpha= 0.012). Results: Of 322 pts screened for all mutation cohorts of the study, 36 eligible and evaluable pts with NF2 mutations were enrolled. Across all grades, one pt had a partial response and 24 had stable disease as best response to treatment. In Grade I pts, the observed PFS6 rate was 83% (10/12 pts; 95% CI: 52-98%). In Grade II/III pts, the observed PFS6 rate was 33% (8/24 pts; 95% CI: 16-55%). The study met PFS6 efficacy endpoint both for the Grade I and the Grade II/III cohorts. Treatment was well tolerated. Only 7 patients had a maximum grade-3 adverse event that was at least possibly related to treatment; toxicities across these pts included: proteinuria (2), rash (1), pain (1), ALT (1), AST (1), cholecystitis (1), hypertriglyceridemia (1), apraxia (1), and lymphopenia (1) with no grade 4 or 5 events. Conclusions: GSK2256098 had excellent tolerability andresulted in an improved PFS6 rate in pts with recurrent or progressive NF2-mutated meningiomas. Trial endpoint was met. FAK inhibition warrants further evaluation in this patient population. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org Clinical trial information: NCT02523014.