Bevacizumab Impact on Hearing Loss Due to Neurofibromatosis Type 2 Associated Vestibular Schwannomas and Associated Biomarkers (S34.004)

OBJECTIVE: Investigate the efficacy and biomarkers of bevacizumab activity for neurofibromatosis type 2 (NF2) -associated symptomatic vestibular schwannomas (VS).BACKGROUND: NF2 is a genetic tumor predisposition syndrome characterized by bilateral VS resulting in deafness and brainstem compression. Pre-clinical and anecdotal clinical evidence suggest benefit with antiangiogenesis agents.DESIGN/METHODS: Bevacizumab (7.5mg/kg) was given every 3 weeks for 54 weeks, followed by 24-weeks of surveillance off drug. The primary endpoint was hearing response defined by word recognition score (WRS). Secondary endpoints included toxicity, tolerability, imaging response using volumetric MRI analysis, durability of response, and imaging and blood biomarkers.RESULTS: Fourteen patients (10 female) with NF2, median age 30 (range, 14-79 years) with progressive hearing loss in the target ear (median baseline WRS 60[percnt], range 13-82[percnt]) were enrolled. The primary endpoint, confirmed hearing response (improvement maintained u003e3 months), occurred in 5/14 patients (36[percnt]; 95[percnt]CI, 13-65[percnt]). 8/14 patients (57[percnt]) had transient hearing improvement above the 95[percnt]CI for WRS. No patients experienced hearing decline. Radiographic response was seen in 6/14 (43[percnt]) target VS. Three grade 3 adverse events, hypertension (N=2) and immune-mediated thrombocytopenic purpura (N=1), were possibly related to bevacizumab. Bevacizumab treatment was associated with decreased free VEGF (not bound to bevacizumab) and increased PlGF in plasma. Hearing responses were inversely associated with baseline plasma HGF (p=0.019). Imaging responses were associated with high baseline tumor vessel permeability and elevated blood levels of VEGF-D and SDF1α (p=0.037 and p=0.025, respectively).CONCLUSIONS: Bevacizumab resulted in durable hearing response in 36[percnt] of patients with NF2 VS-associated progressive hearing loss. Imaging and plasma biomarkers showed promising associations with response that should be validated in larger studies.Study Supported by: Galloway Family Foundation, the Cancer Therapy Evaluation Program, NCI, NIDCD, CCR intramural research program. Disclosure: Dr. Blakeley has received personal compensation for activities with Abbvie. Dr. Blakeley has received research support from GlaxoSmithKline. Dr. Ye has nothing to disclose. Dr. Duda has received personal compensation for activities with Hexal as a consultant. Dr. Halpin has nothing to disclose. Dr. Bergner has nothing to disclose. Dr. Muzikansky has nothing to disclose. Dr. Merker has nothing to disclose. Dr. Gerstner has nothing to disclose. Dr. Fayad has nothing to disclose. Dr. Ahlawat has nothing to disclose. Dr. Jacobs has nothing to disclose. Dr. Jain has received personal compensation for activities with Dyax, MedImmune, Roche, Dyax, Noxxon, Enlight, Hu0026Q Capital Management, Tuit Pharmaceuticals as a consultant, Scientific Advisory Board u0026 Equity and Board of Trustees. Dr. Dombi has nothing to disclose. Dr. Widemann has nothing to disclose. Dr. Plotkin has nothing to disclose.