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

Priscilla K. Brastianos, Erin L. Twohy, Elizabeth R. Gerstner, Timothy J. Kaufmann, A. John Iafrate, Jochen Lennerz, Suriya Jeyapalan, David E. Piccioni, Varun Monga, Camilo E. Fadul, David Schiff, Jennie W. Taylor, Sajeel A. Chowdhary, Chetan Bettegowda, George Ansstas, Macarena De La Fuente, Mark D. Anderson, Nicole Shonka, Denise Damek, Jose CarrilloLara J. Kunschner-Ronan, Rekha Chaudhary, Kurt A. Jaeckle, Francis M. Senecal, Thomas Kaley, Tara Morrison, Alissa A. Thomas, Mary R. Welch, Fabio Iwamoto, David Cachia, Adam L. Cohen, Shivangi Vora, Michael Knopp, Ian F. Dunn, Priya Kumthekar, Jann Sarkaria, Susan Geyer, Xiomara W. Carrero, Maria Martinez-Lage, Daniel P. Cahill, Paul D. Brown, Caterina Giannini, Sandro Santagata, Frederick G. Barker, Evanthia Galanis

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

PURPOSEPatients 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 METHODSEligible 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.RESULTSOf 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.CONCLUSIONGSK2256098 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.

Original languageEnglish
Pages (from-to)618-628
Number of pages11
JournalJournal of Clinical Oncology
Volume41
Issue number3
DOIs
StatePublished - Jan 20 2023

Fingerprint

Dive into the research topics of 'Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas with Somatic NF2 Mutations'. Together they form a unique fingerprint.

Cite this