Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas With Somatic NF2 Mutations

Abstract

Purpose: Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (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 1-3 meningiomas.

Patients and methods: Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy.

Results: Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events.

Conclusion: GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Trial registration: ClinicalTrials.gov NCT02523014.

FIG 1.

CONSORT diagram of patient population. ^aEighty-nine patients were identified as having NF2 mutation while the NF2 arm was opened to accrual and 12 were allowed to be registered while the NF2 arm was closed to accrual as they were already in preregistration. From May 8, 2016 to April 14, 2017 (when the NF2 arm closed to accrual for grade 2/3 tumors), NF2 mutation testing was performed if the patient had a grade 1 tumor. ^bBecause of having resection after registration and tumor was multifocal. ^cOne grade 2/3 cohort patient received only one cycle of treatment, then went off study treatment because of grade 3 AST and grade 3 ALT (both deemed probably related to study treatment). This patient had a baseline scan and no other scans until 1 year from study entry (because of patient follow-up visits cancellations) and was excluded from primary end point analysis. End of study treatment reasons (all enrolled patients): 1 grade 1 cohort patient and 3 grade 2/3 cohort patients withdrew/refused further treatment, 3 grade 1 cohort patients and 1 grade 2/3 cohort patient ended study treatment because of adverse events/side effects/complications, and 8 grade 1 cohort patients and 21 grade 2/3 cohort patients ended study treatment because of disease progression. One grade 2/3 cohort patient remains in study treatment 4 years from study initiation.

FIG 2.

KM curves of OS and PFS for patients treated with GSK2256098. (A) KM curve of OS (note that a total of 13 censors were observed after month 30). The median OS for the grade 1 cohort was not yet reached and for the grade 2/3 cohort was 21.5 months. (B) KM curve of PFS. The median PFS was 12.8 months for the grade 1 cohort and 3.7 months for the grade 2/3 cohort. KM, Kaplan-Meier; NE, not evaluable; OS, overall survival; PFS, progression-free survival.

FIG 3.

Mutational landscape in meningioma trial patients. CoMut plot displaying grade, genetic variants, and best response at 6 months. The top and side histograms (green) represent total number and fraction of reported variants per sample or gene, respectively. For a detailed list of variant annotations, see the Data Supplement. CoMut plot, Comutation plot; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.