Multicenter, phase 2 study of bevacizumab in children and adults with neurofibromatosis 2 and progressive vestibular schwannomas: an NF Clinical Trials Consortium study (S23.004)

Objective: The primary aim of this study was to determine the hearing response rate during induction therapy with bevacizumab at 10 mg/kg every 2 weeks; secondary aims included radiographic response rate. Background: Vestibular schwannomas (VSs) in patients with neurofibromatosis 2 (NF2) are associated with hearing loss. Recently published data from a prospective clinical trial showed that bevacizumab treatment at a fixed dose of 7.5 mg/kg every 3 weeks was associated with hearing improvement and tumor shrinkage in 36% and 43% of patients, respectively. The optimal treatment dose and schedule, however, are unknown. Design/Methods: This multicenter, phase II, open label study evaluated children and adults (≥6 years of age) with NF2 and progressive VSs treated with bevacizumab. Subjects received bevacizumab 10 mg/kg every 2 weeks during induction therapy (6 months), and 5 mg/kg every 3 weeks during maintenance therapy (18 months). Hearing response was defined as a significant increase in word recognition score above baseline. Radiographic response was defined as ≥20% decrease in tumor volume from baseline. The primary endpoint was hearing response rate in the target ear at 6 months. Results: We enrolled 22 subjects (9M;13F) with a median age of 23 years (range 12–62 years). Nineteen subjects have completed induction therapy. 8/19 (42%) subjects had hearing response and 4/19 subjects (21%) had a radiographic response in the target VS. Bevacizumab was well tolerated. Adverse events included hypertension, proteinuria, arthralgias, AST/bilirubin elevation, delayed wound healing, fatigue, and irregular menstruation. 11/13 female subjects had elevated FSH and underwent evaluation for premature ovarian insufficiency. All continued treatment with bevacizumab. Conclusions: Bevacizumab treatment at 10 mg/kg every 2 weeks is associated with hearing and radiographic response rates at 6 months that are similar to previous studies using lower doses. Future analyses will address the durability of hearing and radiographic responses during 18 months of maintenance therapy. Study Supported by: Genentech and the Department of Defense Disclosure: Dr. Plotkin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with NFlection, Novartis. Dr. Tonsgard has nothing to disclose. Dr. Ullrich has nothing to disclose. Dr. Allen has nothing to disclose. Dr. Blakeley has nothing to disclose. Dr. Rosser has nothing to disclose. Dr. Clapp has nothing to disclose. Dr. Campion has nothing to disclose. Dr. Fisher has nothing to disclose. Dr. Cutter has nothing to disclose. Dr. Korf has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis Pharmaceuticals Corporation. Dr. Packer has nothing to disclose. Dr. Thomas has nothing to disclose. Dr. Karajannis has nothing to disclose.