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Clinical Trial
. 2023 Aug 3;25(8):1498-1506.
doi: 10.1093/neuonc/noad066.

Multicenter, prospective, phase II study of maintenance bevacizumab for children and adults with NF2-related schwannomatosis and progressive vestibular schwannoma

Scott R Plotkin  1 , Jeffrey Allen  2 , Girish Dhall  3 , Jian L Campian  4 , D Wade Clapp  5 , Michael J Fisher  6 , Rakesh K Jain  1 , James Tonsgard  7 , Nicole J Ullrich  8 , Coretta Thomas  9 , Lloyd J Edwards  9 , Bruce Korf  9 , Roger Packer  10 , Matthias A Karajannis  2 , Jaishri O Blakeley  11
Affiliations
Clinical Trial

Multicenter, prospective, phase II study of maintenance bevacizumab for children and adults with NF2-related schwannomatosis and progressive vestibular schwannoma

Scott R Plotkin et al. Neuro Oncol. .

Abstract

Background: Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS).

Methods: Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants were monitored for changes in hearing, tumor size, and quality of life (QOL), and for adverse events. Hearing loss was defined as a statistically significant decline in word recognition score (WRS) or pure-tone average compared to the study baseline; tumor growth was defined as >20% increase in volume compared to baseline.

Results: Twenty participants with NF2-SWN (median age 23.5 years; range, 12.5-62.5 years) with hearing loss in the target ear (median WRS 70%, range 2%-94%) received maintenance bevacizumab. Freedom from hearing loss in the target ear was 95% after 48 weeks, 89% after 72 weeks, and 70% after 98 weeks. Freedom from tumor growth in the target VS was 94% after 48 weeks, 89% after 72 weeks, and 89% after 98 weeks. NF2-related QOL remained stable for 98 weeks whereas tinnitus-related distress decreased. Maintenance bevacizumab was well tolerated, with 3 participants (15%) discontinuing treatment due to adverse events.

Conclusions: Maintenance bevacizumab (5 mg/kg every 3 weeks) is associated with high rates of hearing and tumor stability during 18 months of follow-up. No new unexpected adverse events related to bevacizumab were identified in this population.

Keywords: NF2; bevacizumab; maintenance; neurofibromatosis 2; vestibular schwannoma.

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Conflict of interest statement

Scott Plotkin: co-founder of NF2 Therapeutics; consultant for Akouos. Jeffrey Allen: No conflicts to report. Girish Dhall: No conflicts to report. Jian Campian: research support from Merck, NeoimmuneTech, Incyte, and GI Innovation. D. Wade Clapp: No conflicts to report. Michael Fisher: Advisory Board for AstraZeneca and Springworks; research support from AstraZeneca, Array Biopharma, and Exelixis. Rakesh Jain: Consultant fees from BMS, Elpis, Innocoll, SPARC, SynDevRx; owns equity in Accurius, Enlight, SynDevRx; Serves on the Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund, and received Research Grants from Boehringer Ingelheim and Sanofi. James Tonsgard: No conflicts to report. Nicole Ullrich: No conflicts to report. Coretta Thomas: No conflicts to report. Lloyd Edwards: No conflicts to report. Bruce Korf: Medical Advisory boards: Genome Medical, Infixion, Healx, and SpringWorks, Recursion. Roger Packer: No conflicts to report. Matthias Karajannis: consultant for CereXis, Recursion. Jaishri Blakeley: Medical Advisory Board for SpringWorks.

Figures

Figure 1.
Figure 1.
Study schema highlighting dosing for induction therapy (left) and maintenance therapy (right).
Figure 2.
Figure 2.
Speech intelligibility in target ears (left panel) and non-target ears (right panel) during maintenance therapy as measured by word recognition score (N = 20). One adult and 2 pediatric participants (15%) lost hearing in a target ear during maintenance (circles). Higher scores represent better hearing discrimination.
Figure 3.
Figure 3.
Perceptual thresholds in target ears (left panel) and non-target ears (right panel) during maintenance therapy as measured by pure tone average (N = 20). One adult and 1 pediatric participant (10%) lost hearing transiently during maintenance therapy where 1 adult and 1 pediatric participant (10%) experienced sustained improved hearing during maintenance therapy. Positive scores represent worse hearing sensitivity.
Figure 4.
Figure 4.
Maximum change in tumor volume during maintenance therapy for target VS (left panel) and non-target VS (right panel). For target VS, 2 pediatric participants experienced tumor growth during maintenance therapy, whereas 2 adult participants experienced tumor shrinkage during maintenance therapy. For non-target VS, 3 pediatric and 3 adult participants experienced tumor growth during maintenance therapy, whereas 2 adult participants experienced tumor shrinkage during maintenance therapy.
Figure 5.
Figure 5.
Change in quality of life during bevacizumab treatment. (Left panel) NFTI-QOL scores, a measure of NF2-related quality of life with lower scores representing less disease-related morbidity, decreased nonsignificantly during treatment. (Right panel) TRQ scores, a measure of tinnitus-related distress with lower scores representing less distress, decreased significantly through week 49 and then increased slightly to remain below baseline.
See this image and copyright information in PMC

References

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    1. Plotkin SR, Merker VL, Muzikansky A, et al. Natural history of vestibular schwannoma growth and hearing decline in newly diagnosed neurofibromatosis type 2 patients. Otol Neurotol. 2014;35:e50–e56. - PubMed
    1. Plotkin SR, Stemmer-Rachamimov AO, Barker FG, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009;361:358–367. - PMC - PubMed
    1. Blakeley JO, Ye X, Duda DG, et al. Efficacy and biomarker study of bevacizumab for hearing loss resulting from neurofibromatosis type 2-associated vestibular schwannomas. J Clin Oncol. 2016;34(14):1669–1675. - PMC - PubMed

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Supplementary concepts