Alliance A071401: phase II trial of focal adhesion kinase inhibition in meningiomas with somatic NF2 mutations
In the first trial to match meningioma patients to a drug by their tumour's mutation, a FAK-blocking tablet kept 83 percent of low-grade and 33 percent of higher-grade NF2-mutant tumours from progressing for six months, clearing the bar the trial had set.
Overview
Report of the NF2 cohort of Alliance A071401 (NCT02523014), the first genomically driven phase 2 study in recurrent or progressive grade 1 to 3 meningioma. Patients whose tumours screened positive for NF2 mutations received the focal adhesion kinase inhibitor GSK2256098, 750 mg orally twice daily, until progression. Coprimary endpoints were progression-free survival at six months, evaluated separately in grade 1 and grade 2 or 3 tumours, and response rate by Macdonald criteria; the drug would be considered promising if either met its decision criterion.
Of 322 patients screened for all mutation cohorts, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated (12 grade 1, 24 grade 2 or 3). One patient had a partial response and 24 had stable disease. Six-month progression-free survival was 83 percent in grade 1 (10 of 12; 95 percent CI 52 to 98) and 33 percent in grade 2 or 3 (8 of 24; 16 to 55), meeting the endpoint in both cohorts. Seven patients had a maximum grade 3 adverse event at least possibly related to treatment; there were no grade 4 or 5 events.
- Six-month progression-free survival 83 percent (10 of 12) in grade 1 and 33 percent (8 of 24) in grade 2 or 3 NF2-mutant meningioma; both met the decision criteria.
- One partial response and 24 stable disease among 36 patients.
- Seven grade 3 adverse events at least possibly related; no grade 4 or 5.
Meningioma had no systemic therapy with proven activity; this cohort shows that matching a drug to the NF2 mutation can slow progression, and it validates the synthetic-lethal idea that NF2-deficient cells depend on FAK. It is a signal-finding result against historical controls, not yet a change to standard care.
- Single-arm cohort compared with historical controls; no randomised comparison.
- Small numbers, especially in the grade 1 group (12 patients), so the confidence intervals are wide.
- Response by Macdonald criteria was rare (one partial response); the benefit is disease stabilisation.