Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas

J Neurooncol. 2015 Apr;122(2):313-20. doi: 10.1007/s11060-014-1710-0. Epub 2015 Jan 8.

Abstract

Neurofibromatosis type 2 (NF2) is a genetic disorder with bilateral vestibular schwannomas (VS) as the most frequent manifestation. Merlin, the NF2 tumor suppressor, was identified as a negative regulator of mammalian target of rapamycin complex 1. Pre-clinical data in mice showed that mTORC1 inhibition delayed growth of NF2-schwannomas. We conducted a prospective single-institution open-label phase II study to evaluate the effects of everolimus in ten NF2 patients with progressive VS. Drug activity was monitored every 3 months. Everolimus was administered orally for 12 months and, if the decrease in tumor volume was >20 % from baseline, treatment was continued for 12 additional months. Other patients stopped when completed 12 months of everolimus but were allowed to resume treatment when VS volume was >20 % during 1 year follow-up. Nine patients were evaluable. Safety was evaluated using CTCAE 3.0 criteria. After 12 months of everolimus, no reduction in volume ≥20 % was observed. Four patients had progressive disease, and five patients had stable disease with a median annual growth rate decreasing from 67 %/year before treatment to 0.5 %/year during treatment. In these patients, tumor growth resumed within 3-6 months after treatment discontinuation. Everolimus was then reintroduced and VS decreased by a median 6.8 % at 24 months. Time to tumor progression increased threefold from 4.2 months before treatment to > 12 months. Hearing was stable under treatment. The safety of everolimus was manageable. Although the primary endpoint was not reached, further studies are required to confirm the potential for stabilization of everolimus.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers, Tumor / metabolism
  • Cranial Nerve Neoplasms / drug therapy*
  • Cranial Nerve Neoplasms / pathology
  • Cranial Nerve Neoplasms / physiopathology
  • Disease Progression
  • Disease-Free Survival
  • Everolimus / adverse effects
  • Everolimus / therapeutic use*
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes / antagonists & inhibitors
  • Multiprotein Complexes / metabolism
  • Neurilemmoma / drug therapy*
  • Neurilemmoma / pathology
  • Neurilemmoma / physiopathology
  • Neurofibromatosis 2 / drug therapy*
  • Neurofibromatosis 2 / pathology
  • Neurofibromatosis 2 / physiopathology
  • Prospective Studies
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Treatment Outcome
  • Tumor Burden
  • Vestibulocochlear Nerve Diseases / drug therapy*
  • Vestibulocochlear Nerve Diseases / pathology
  • Vestibulocochlear Nerve Diseases / physiopathology
  • Young Adult

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Multiprotein Complexes
  • Everolimus
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1