Efficacy and Biomarker Study of Bevacizumab for Hearing Loss Resulting From Neurofibromatosis Type 2-Associated Vestibular Schwannomas

Abstract

Purpose: Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by bilateral vestibular schwannomas (VSs) resulting in deafness and brainstem compression. This study evaluated efficacy and biomarkers of bevacizumab activity for NF2-associated progressive and symptomatic VSs.

Patients and methods: Bevacizumab 7.5 mg/kg was administered every 3 weeks for 46 weeks, followed by 24 weeks of surveillance after treatment with the drug. The primary end point was hearing response defined by word recognition score (WRS). Secondary end points included toxicity, tolerability, imaging response using volumetric magnetic resonance imaging analysis, durability of response, and imaging and blood biomarkers.

Results: Fourteen patients (estimated to yield > 90% power to detect an alternative response rate of 50% at alpha level of 0.05) with NF2, with a median age of 30 years (range, 14 to 79 years) and progressive hearing loss in the target ear (median baseline WRS, 60%; range 13% to 82%), were enrolled. The primary end point, confirmed hearing response (improvement maintained ≥ 3 months), occurred in five (36%) of 14 patients (95% CI, 13% to 65%; P < .001). Eight (57%) of 14 patients had transient hearing improvement above the 95% CI for WRS. No patients experienced hearing decline. Radiographic response was seen in six (43%) of 14 target VSs. 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 vascular endothelial growth factor (not bound to bevacizumab) and increased placental growth factor in plasma. Hearing responses were inversely associated with baseline plasma hepatocyte growth factor (P = .019). Imaging responses were associated with high baseline tumor vessel permeability and elevated blood levels of vascular endothelial growth factor D and stromal cell-derived factor 1α (P = .037 and .025, respectively).

Conclusion: Bevacizumab treatment resulted in durable hearing response in 36% of patients with NF2 and confirmed progressive VS-associated hearing loss. Imaging and plasma biomarkers showed promising associations with response that should be validated in larger studies.

Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2016 by American Society of Clinical Oncology.

Figures

Fig 1.

Trial schema. IV, intravenous; MRI, magnetic resonance imaging; NF2, neurofibromatosis type 2.

Fig 2.

Changes in (A) word recognition score and (B) tumor volume during (through week 49) and after treatment (weeks 60 and 72) for target ears by best confirmed response: (A) yellow line, hearing response; grey line, stable disease; (B) grey line, stable disease; blue line, minor response; yellow line, partial response.

Fig 3.

Line graphs showing changes over time in plasma (A) free vascular endothelial growth factor (VEGF), (B) total VEGF (free plus bound), (C) placental growth factor (PlGF), (D) VEGF-D, (E) stromal cell–derived factor 1α (SDF1α), and (F) angiopoietin 2 for all participants (N = 14). Anti-VEGF therapy with bevacizumab decreased the plasma levels of free VEGF and increased the levels of antibody-bound VEGF, PlGF, and SDF1α in patients with neurofibromatosis type 2. Vertical bars indicate interquartile range; (*) indicates P < .05.

Fig A1.

Scattergrams of (A) baseline hearing function for all target ears, as recommended by the Hearing Committee of the American Academy of Otolaryngology-Head and Neck Society, and (B) best change in hearing for all target ears after treatment with bevacizumab. Color code: gray, class A; gold, class B; red, class C; blue, class D. Classes A and B are considered serviceable, and classes C and D are considered unserviceable.

Fig A2.

Line graphs for (A to D) patients with confirmed hearing response (HR; n = 5) versus nonresponders (n = 9) and (E to H) confirmed radiographic responders (n = 9) versus nonresponders (n = 5) showing changes over time in (A, E) relative free vascular endothelial growth factor (VEGF), (B, F) total VEGF (free plus bound), (C, G) soluble VEGF receptor 2, and (D, H) carbonic anhydrase IX. Data are presented as median values with interquartile ranges; (*) indicates a significant difference between relative biomarker concentrations in responders and nonresponders (P < .05).