title: Efficacy and Biomarker Study of Bevacizumab for Hearing Loss Resulting From Neurofibromatosis Type 2-Associated Vestibular Schwannomas.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Jaishri O. Blakeley, Xiaobu Ye, Amanda L. Bergner, Laura M. Fayad, Shivani Ahlawat, and Michael A. Jacobs, Johns Hopkins University, Baltimore; Christopher Zalewski, National Institute on Deafness and Other Communication Disorders; Eva Dombi and Brigitte C. Widemann, National Cancer Institute, Bethesda, MD; Dan G. Duda, Alona Muzikansky, Vanessa L. Merker, Elizabeth R. Gerstner, Rakesh K. Jain, and Scott R. Plotkin, Massachusetts General Hospital; and Chris F. Halpin, Massachusetts Eye and Ear Infirmary, Boston, MA. jblakel3@jhmi.edu.
authors.forename: Jaishri O
authors.initials: JO
authors.lastname: Blakeley
authors.affiliation: Jaishri O. Blakeley, Xiaobu Ye, Amanda L. Bergner, Laura M. Fayad, Shivani Ahlawat, and Michael A. Jacobs, Johns Hopkins University, Baltimore; Christopher Zalewski, National Institute on Deafness and Other Communication Disorders; Eva Dombi and Brigitte C. Widemann, National Cancer Institute, Bethesda, MD; Dan G. Duda, Alona Muzikansky, Vanessa L. Merker, Elizabeth R. Gerstner, Rakesh K. Jain, and Scott R. Plotkin, Massachusetts General Hospital; and Chris F. Halpin, Massachusetts Eye and Ear Infirmary, Boston, MA.
authors.forename: Xiaobu
authors.initials: X
authors.lastname: Ye
authors.affiliation: Jaishri O. Blakeley, Xiaobu Ye, Amanda L. Bergner, Laura M. Fayad, Shivani Ahlawat, and Michael A. Jacobs, Johns Hopkins University, Baltimore; Christopher Zalewski, National Institute on Deafness and Other Communication Disorders; Eva Dombi and Brigitte C. Widemann, National Cancer Institute, Bethesda, MD; Dan G. Duda, Alona Muzikansky, Vanessa L. Merker, Elizabeth R. Gerstner, Rakesh K. Jain, and Scott R. Plotkin, Massachusetts General Hospital; and Chris F. Halpin, Massachusetts Eye and Ear Infirmary, Boston, MA.
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.affiliation: Jaishri O. Blakeley, Xiaobu Ye, Amanda L. Bergner, Laura M. Fayad, Shivani Ahlawat, and Michael A. Jacobs, Johns Hopkins University, Baltimore; Christopher Zalewski, National Institute on Deafness and Other Communication Disorders; Eva Dombi and Brigitte C. Widemann, National Cancer Institute, Bethesda, MD; Dan G. Duda, Alona Muzikansky, Vanessa L. Merker, Elizabeth R. Gerstner, Rakesh K. Jain, and Scott R. Plotkin, Massachusetts General Hospital; and Chris F. Halpin, Massachusetts Eye and Ear Infirmary, Boston, MA.
authors.forename: Chris F
authors.initials: CF
authors.lastname: Halpin
authors.affiliation: Jaishri O. Blakeley, Xiaobu Ye, Amanda L. Bergner, Laura M. Fayad, Shivani Ahlawat, and Michael A. Jacobs, Johns Hopkins University, Baltimore; Christopher Zalewski, National Institute on Deafness and Other Communication Disorders; Eva Dombi and Brigitte C. Widemann, National Cancer Institute, Bethesda, MD; Dan G. Duda, Alona Muzikansky, Vanessa L. Merker, Elizabeth R. Gerstner, Rakesh K. Jain, and Scott R. Plotkin, Massachusetts General Hospital; and Chris F. Halpin, Massachusetts Eye and Ear Infirmary, Boston, MA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Bergner
authors.affiliation: Jaishri O. Blakeley, Xiaobu Ye, Amanda L. Bergner, Laura M. Fayad, Shivani Ahlawat, and Michael A. Jacobs, Johns Hopkins University, Baltimore; Christopher Zalewski, National Institute on Deafness and Other Communication Disorders; Eva Dombi and Brigitte C. Widemann, National Cancer Institute, Bethesda, MD; Dan G. Duda, Alona Muzikansky, Vanessa L. Merker, Elizabeth R. Gerstner, Rakesh K. Jain, and Scott R. Plotkin, Massachusetts General Hospital; and Chris F. Halpin, Massachusetts Eye and Ear Infirmary, Boston, MA.
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.affiliation: Jaishri O. Blakeley, Xiaobu Ye, Amanda L. Bergner, Laura M. Fayad, Shivani Ahlawat, and Michael A. Jacobs, Johns Hopkins University, Baltimore; Christopher Zalewski, National Institute on Deafness and Other Communication Disorders; Eva Dombi and Brigitte C. Widemann, National Cancer Institute, Bethesda, MD; Dan G. Duda, Alona Muzikansky, Vanessa L. Merker, Elizabeth R. Gerstner, Rakesh K. Jain, and Scott R. Plotkin, Massachusetts General Hospital; and Chris F. Halpin, Massachusetts Eye and Ear Infirmary, Boston, MA.
authors.forename: Vanessa L
authors.initials: VL
authors.lastname: Merker
authors.affiliation: Jaishri O. Blakeley, Xiaobu Ye, Amanda L. Bergner, Laura M. Fayad, Shivani Ahlawat, and Michael A. Jacobs, Johns Hopkins University, Baltimore; Christopher Zalewski, National Institute on Deafness and Other Communication Disorders; Eva Dombi and Brigitte C. Widemann, National Cancer Institute, Bethesda, MD; Dan G. Duda, Alona Muzikansky, Vanessa L. Merker, Elizabeth R. Gerstner, Rakesh K. Jain, and Scott R. Plotkin, Massachusetts General Hospital; and Chris F. Halpin, Massachusetts Eye and Ear Infirmary, Boston, MA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Gerstner
authors.affiliation: Jaishri O. Blakeley, Xiaobu Ye, Amanda L. Bergner, Laura M. Fayad, Shivani Ahlawat, and Michael A. Jacobs, Johns Hopkins University, Baltimore; Christopher Zalewski, National Institute on Deafness and Other Communication Disorders; Eva Dombi and Brigitte C. Widemann, National Cancer Institute, Bethesda, MD; Dan G. Duda, Alona Muzikansky, Vanessa L. Merker, Elizabeth R. Gerstner, Rakesh K. Jain, and Scott R. Plotkin, Massachusetts General Hospital; and Chris F. Halpin, Massachusetts Eye and Ear Infirmary, Boston, MA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Fayad
authors.affiliation: Jaishri O. Blakeley, Xiaobu Ye, Amanda L. Bergner, Laura M. Fayad, Shivani Ahlawat, and Michael A. Jacobs, Johns Hopkins University, Baltimore; Christopher Zalewski, National Institute on Deafness and Other Communication Disorders; Eva Dombi and Brigitte C. Widemann, National Cancer Institute, Bethesda, MD; Dan G. Duda, Alona Muzikansky, Vanessa L. Merker, Elizabeth R. Gerstner, Rakesh K. Jain, and Scott R. Plotkin, Massachusetts General Hospital; and Chris F. Halpin, Massachusetts Eye and Ear Infirmary, Boston, MA.
authors.forename: Shivani
authors.initials: S
authors.lastname: Ahlawat
authors.affiliation: Jaishri O. Blakeley, Xiaobu Ye, Amanda L. Bergner, Laura M. Fayad, Shivani Ahlawat, and Michael A. Jacobs, Johns Hopkins University, Baltimore; Christopher Zalewski, National Institute on Deafness and Other Communication Disorders; Eva Dombi and Brigitte C. Widemann, National Cancer Institute, Bethesda, MD; Dan G. Duda, Alona Muzikansky, Vanessa L. Merker, Elizabeth R. Gerstner, Rakesh K. Jain, and Scott R. Plotkin, Massachusetts General Hospital; and Chris F. Halpin, Massachusetts Eye and Ear Infirmary, Boston, MA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jacobs
authors.affiliation: Jaishri O. Blakeley, Xiaobu Ye, Amanda L. Bergner, Laura M. Fayad, Shivani Ahlawat, and Michael A. Jacobs, Johns Hopkins University, Baltimore; Christopher Zalewski, National Institute on Deafness and Other Communication Disorders; Eva Dombi and Brigitte C. Widemann, National Cancer Institute, Bethesda, MD; Dan G. Duda, Alona Muzikansky, Vanessa L. Merker, Elizabeth R. Gerstner, Rakesh K. Jain, and Scott R. Plotkin, Massachusetts General Hospital; and Chris F. Halpin, Massachusetts Eye and Ear Infirmary, Boston, MA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: Jaishri O. Blakeley, Xiaobu Ye, Amanda L. Bergner, Laura M. Fayad, Shivani Ahlawat, and Michael A. Jacobs, Johns Hopkins University, Baltimore; Christopher Zalewski, National Institute on Deafness and Other Communication Disorders; Eva Dombi and Brigitte C. Widemann, National Cancer Institute, Bethesda, MD; Dan G. Duda, Alona Muzikansky, Vanessa L. Merker, Elizabeth R. Gerstner, Rakesh K. Jain, and Scott R. Plotkin, Massachusetts General Hospital; and Chris F. Halpin, Massachusetts Eye and Ear Infirmary, Boston, MA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Zalewski
authors.affiliation: Jaishri O. Blakeley, Xiaobu Ye, Amanda L. Bergner, Laura M. Fayad, Shivani Ahlawat, and Michael A. Jacobs, Johns Hopkins University, Baltimore; Christopher Zalewski, National Institute on Deafness and Other Communication Disorders; Eva Dombi and Brigitte C. Widemann, National Cancer Institute, Bethesda, MD; Dan G. Duda, Alona Muzikansky, Vanessa L. Merker, Elizabeth R. Gerstner, Rakesh K. Jain, and Scott R. Plotkin, Massachusetts General Hospital; and Chris F. Halpin, Massachusetts Eye and Ear Infirmary, Boston, MA.
authors.forename: Eva
authors.initials: E
authors.lastname: Dombi
authors.affiliation: Jaishri O. Blakeley, Xiaobu Ye, Amanda L. Bergner, Laura M. Fayad, Shivani Ahlawat, and Michael A. Jacobs, Johns Hopkins University, Baltimore; Christopher Zalewski, National Institute on Deafness and Other Communication Disorders; Eva Dombi and Brigitte C. Widemann, National Cancer Institute, Bethesda, MD; Dan G. Duda, Alona Muzikansky, Vanessa L. Merker, Elizabeth R. Gerstner, Rakesh K. Jain, and Scott R. Plotkin, Massachusetts General Hospital; and Chris F. Halpin, Massachusetts Eye and Ear Infirmary, Boston, MA.
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
authors.affiliation: Jaishri O. Blakeley, Xiaobu Ye, Amanda L. Bergner, Laura M. Fayad, Shivani Ahlawat, and Michael A. Jacobs, Johns Hopkins University, Baltimore; Christopher Zalewski, National Institute on Deafness and Other Communication Disorders; Eva Dombi and Brigitte C. Widemann, National Cancer Institute, Bethesda, MD; Dan G. Duda, Alona Muzikansky, Vanessa L. Merker, Elizabeth R. Gerstner, Rakesh K. Jain, and Scott R. Plotkin, Massachusetts General Hospital; and Chris F. Halpin, Massachusetts Eye and Ear Infirmary, Boston, MA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Plotkin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000068258:Bevacizumab / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D004334:Drug Administration Schedule; D005260:Female; D034381:Hearing Loss / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016518:Neurofibromatosis 2 / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D009464:Neuroma, Acoustic / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D000068258:Bevacizumab