Multicenter, Prospective, Phase II and Biomarker Study of High-Dose Bevacizumab as Induction Therapy in Patients With Neurofibromatosis Type 2 and Progressive Vestibular Schwannoma

J Clin Oncol. 2019 Dec 10;37(35):3446-3454. doi: 10.1200/JCO.19.01367. Epub 2019 Oct 18.


Purpose: Bevacizumab treatment at 7.5 mg/kg every 3 weeks results in improved hearing in approximately 35%-40% of patients with neurofibromatosis type 2 (NF2) and progressive vestibular schwannomas (VSs). However, the optimal dose is unknown. In this multicenter phase II and biomarker study, we evaluated the efficacy and safety of high-dose bevacizumab in pediatric and adult patients with NF2 with progressive VS.

Patients and methods: Bevacizumab was given for 6 months at 10 mg/kg every 2 weeks, followed by 18 months at 5 mg/kg every 3 weeks. The primary end point was hearing response defined by word recognition score (WRS) at 6 months. Secondary end points included toxicity, radiographic response, quality of life (QOL), and plasma biomarkers.

Results: Twenty-two participants with NF2 (median age, 23 years) with progressive hearing loss in the target ear (median baseline WRS, 53%) were enrolled. Nine (41%) of 22 participants achieved a hearing response at 6 months (1 of 7 children and 8 of 15 adults; P = .08). Radiographic response was seen in 7 (32%) of 22 patients with VS at 6 months (7 of 15 adults and 0 of 7 children; P = .05). Common mild to moderate adverse events included hypertension, fatigue, headache, and irregular menstruation. Improvement in NF2-related QOL and reduction in tinnitus-related distress were reported in 30% and 60% of participants, respectively. Paradoxically, high-dose bevacizumab treatment was not associated with a significant decrease in free vascular endothelial growth factor but was associated with increased carbonic anhydrase IX, hepatocyte growth factor, placental growth factor, stromal cell-derived factor 1α, and basic fibroblast growth factor concentrations in plasma.

Conclusion: High-dose bevacizumab seems to be no more effective than standard-dose bevacizumab for treatment of patients with NF2 with hearing loss. In contrast to adults, pediatric participants did not experience tumor shrinkage. However, adult and pediatric participants reported similar improvement in QOL during induction. Novel approaches using bevacizumab should be considered for children with NF2.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Angiogenesis Inhibitors / therapeutic use*
  • Bevacizumab / therapeutic use*
  • Biomarkers, Tumor / blood*
  • Child
  • Dose-Response Relationship, Drug
  • Female
  • Follow-Up Studies
  • Humans
  • Induction Chemotherapy / mortality*
  • Male
  • Middle Aged
  • Neurofibromatosis 2 / blood
  • Neurofibromatosis 2 / drug therapy
  • Neurofibromatosis 2 / pathology*
  • Neuroma, Acoustic / blood
  • Neuroma, Acoustic / drug therapy
  • Neuroma, Acoustic / pathology*
  • Prognosis
  • Prospective Studies
  • Survival Rate
  • Young Adult


  • Angiogenesis Inhibitors
  • Biomarkers, Tumor
  • Bevacizumab