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

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.

• Authors: Stéphane Goutagny, Eric Raymond, Marina Esposito-Farese, Stéphanie Trunet, Christian Mawrin, Daniele Bernardeschi, Béatrice Larroque, Olivier Sterkers, Marco Giovannini, Michel Kalamarides
• Journal: Journal of neuro-oncology (J Neurooncol) Vol. 122 Issue 2 Pg. 313-20 (Apr 2015) ISSN: 1573-7373 [Electronic] United States
• PMID: 25567352 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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