Abemaciclib in meningiomas with somatic NF2 or CDK pathway alterations: the phase 2 Alliance A071401 trial.

Systemic treatments are limited for patients with meningiomas that have progressed after surgery or radiation. Loss of NF2 and CDKN2A/CDKN2B is common in higher-grade meningiomas and promotes progression in preclinical models. We evaluated the efficacy of abemaciclib, a cyclin-dependent kinase 4/6 inhibitor, as one arm of the Alliance umbrella trial A071401, a genomically driven phase 2 study in recurrent and progressive meningiomas. Eligible patients with grade 2 or 3 tumors and NF2 mutations or CDK pathway alterations were treated with abemaciclib. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate as defined by local review; the trial would be declared positive if either endpoint was met. The success threshold for PFS6 was 8 or more of 24 patients; for the response rate, it was 3 or more of 24 patients. Ninety-six patients were screened and 36 patients received treatment. The mean number of treatment cycles was nine and the median follow-up was 21 months. The first 24 patients who met the eligibility criteria and began treatment could be evaluated for the primary endpoint. The observed PFS6 rate was 58% (14 of 24 patients, 95% confidence interval = 37-78%), thus meeting the PFS6 criteria for promising activity. The best response was stable disease in 16 of 24 patients. Of the 36 patients who started treatment, nine had a grade 3 and two had grade 4 adverse events at least possibly related to treatment. Grade 4 toxicities included alanine aminotransferase elevation (1), aspartate aminotransferase elevation (1) and vomiting (1). The trial met its primary endpoint. Abemaciclib was well tolerated and resulted in improved PFS6. Abemaciclib warrants further investigation for patients with progressive grade 2 or 3 meningiomas harboring NF2 or CDK pathway alterations. ClinicalTrials.gov registration no. NCT02523014 .