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

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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.

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References

  1. Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, Lalloo F (2010) Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A 152A(2):327–332

    Article  CAS  PubMed  Google Scholar 

  2. Asthagiri AR, Parry DM, Butman JA, Kim HJ, Tsilou ET, Zhuang Z, Lonser RR (2009) Neurofibromatosis type 2. Lancet 373(9679):1974–1986

    Article  CAS  PubMed  Google Scholar 

  3. Peyre M, Goutagny S, Bah A, Bernardeschi D, Larroque B, Sterkers O, Kalamarides M (2013) Conservative management of bilateral vestibular schwannomas in neurofibromatosis type 2 patients: hearing and tumor growth results. Neurosurgery 72(6):907–913

    Article  PubMed  Google Scholar 

  4. Mathieu D, Kondziolka D, Flickinger JC, Niranjan A, Williamson R, Martin JJ, Lunsford LD (2007) Stereotactic radiosurgery for vestibular schwannomas in patients with neurofibromatosis type 2: an analysis of tumor control complications and hearing preservation rates. Neurosurgery 60(3):460–468

    PubMed  Google Scholar 

  5. Mallory GW, Pollock BE, Foote RL, Carlson ML, Driscoll CL, Link MJ (2014) Stereotactic radiosurgery for neurofibromatosis 2-associated vestibular schwannomas: toward dose optimization for tumor control and functional outcomes. Neurosurgery 74(3):292–301

    Article  PubMed  Google Scholar 

  6. Plotkin SR, Stemmer-Rachamimov AO, Barker FG, Halpin C, Padera TP, Tyrrell A, Sorensen AG, Jain RK, di Tomaso E (2009) Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med 361(4):358–367

    Article  CAS  PubMed  Google Scholar 

  7. Mautner V-F, Nguyen R, Knecht R, Bokemeyer C (2010) Radiographic regression of vestibular schwannomas induced by bevacizumab treatment: sustain under continuous drug application and rebound after drug discontinuation. Ann Oncol 21(11):2294–2295

    Article  PubMed  Google Scholar 

  8. Plotkin SR, Merker VL, Halpin C, Jennings D, McKenna MJ, Harris GJ, Barker FG 2nd (2012) Bevacizumab for progressive vestibular schwannoma in neurofibromatosis type 2: a retrospective review of 31 patients. Otol Neurotol 33(6):1046–1052

    Article  PubMed  Google Scholar 

  9. Goutagny S, Raymond E, Sterkers O, Colombani JM, Kalamarides M (2011) Radiographic regression of cranial meningioma in a NF2 patient treated by bevacizumab. Ann Oncol 22(4):990–991

    Article  CAS  PubMed  Google Scholar 

  10. Nunes FP, Merker VL, Jennings D, Caruso PA, di Tomaso E, Muzikansky A, Barker FG 2nd, Stemmer-Rachamimov AO, Plotkin SR (2013) Bevacizumab treatment for meningiomas in NF2: a retrospective analysis of 15 patients. PLoS ONE 8(3):e59941

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Slusarz KM, Merker VL, Muzikansky A, Francis SA, Plotkin SR (2014) Long-term toxicity of bevacizumab therapy in neurofibromatosis 2 patients. Cancer Chemother Pharmacol 73(6):1197–1204

    Article  CAS  PubMed  Google Scholar 

  12. Plotkin SR, Halpin C, McKenna MJ, Loeffler JS, Batchelor TT, Barker FG (2010) Erlotinib for progressive vestibular schwannoma in neurofibromatosis 2 patients. Otol Neurotol 31(7):1135–1143

    Article  PubMed Central  PubMed  Google Scholar 

  13. Karajannis MA, Legault G, Hagiwara M, Ballas MS, Brown K, Nusbaum AO, Hochman T, Goldberg JD, Koch KM, Golfinos JG, Roland JT, Allen JC (2012) Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro Oncol 14(9):1163–1170

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. James MF, Stivison E, Beauchamp R, Han S, Li H, Wallace MR, Gusella JF, Stemmer-Rachamimov AO, Ramesh V (2012) Regulation of mTOR complex 2 signaling in neurofibromatosis 2-deficient target cell types. Mol Cancer Res 10(5):649–659

    Article  CAS  PubMed  Google Scholar 

  15. Giovannini M, Bonne NX, Vitte J, Chareyre F, Tanaka K, Adams R, Fisher LM, Valeyrie-Allanore L, Wolkenstein P, Goutagny S, Kalamarides M (2014) mTORC1 inhibition delays growth of neurofibromatosis type 2 schwannoma. Neuro Oncol 16(4):493–504

    Article  CAS  PubMed  Google Scholar 

  16. Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Whittemore VH, Thiele EA, Ford JP, Shah G, Cauwel H, Lebwohl D, Sahmoud T, Jozwiak S (2013) Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre randomised placebo-controlled phase 3 trial. Lancet 381(9861):125–132

    Article  CAS  PubMed  Google Scholar 

  17. Dombi E, Ardern-Holmes SL, Babovic-Vuksanovic D, Barker FG, Connor S, Evans DG, Fisher MJ, Goutagny S, Harris GJ, Jaramillo D, Karajannis MA, Korf BR, Mautner V, Plotkin SR, Poussaint TY, Robertson K, Shih CS, Widemann BC, RESIC (2013) Recommendations for imaging tumor response in neurofibromatosis clinical trials. Neurology 81(21 Suppl 1):S33–S40

    Article  PubMed Central  PubMed  Google Scholar 

  18. American Academy of Otolaryngology-Head and Neck Surgery Foundation Committee on Hearing and Equilibrium (1995) Guidelines for the evaluation of hearing preservation in acoustic neuroma (vestibular schwannoma). Otolaryngol Head Neck Surg 113(3):179–180

    Article  Google Scholar 

  19. Mawrin C, Sasse T, Kirches E, Kropf S, Schneider T, Grimm C, Pambor C, Vorwerk CK, Firsching R, Lendeckel U, Dietzmann K (2005) Different activation of mitogen-activated protein kinase and Akt signaling is associated with aggressive phenotype of human meningiomas. Clin Cancer Res 11(11):4074–4082

    Article  CAS  PubMed  Google Scholar 

  20. Pachow D, Andrae N, Kliese N, Angenstein F, Stork O, Wilisch-Neumann A, Kirches E, Mawrin C (2013) mTORC1 inhibitors suppress meningioma growth in mouse models. Clin Cancer Res 19(5):1180–1189

    Article  CAS  PubMed  Google Scholar 

  21. AHern RP (2001) Sample size tables for exact single-stage phase II designs. Stat Med 20(6):859–866

    Article  CAS  Google Scholar 

  22. Bates D, Maechler M, Bolker B, WalkerS (2014) lme4: Linear mixed-effects models using Eigen and S4. R package version 1.1-6. http://CRAN.R-project.org/package=lme4. Accessed May 2014

  23. Verbeke G, Molenberghs G (2005) Models for discrete longitudinal data. Springer, New York

    Google Scholar 

  24. James MF, Han S, Polizzano C, Plotkin SR, Manning BD, Stemmer-Rachamimov AO, Gusella JF, Ramesh V (2009) NF2/merlin is a novel negative regulator of mTOR complex 1 and activation of mTORC1 is associated with meningioma and schwannoma growth. Mol Cell Biol 29(15):4250–4261

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Widemann BC, Dombi E, Gillespie A, Wolters PL, Belasco J, Goldman S, Korf BR, Solomon J, Martin S, Salzer W, Fox E, Patronas N, Kieran MW, Perentesis JP, Reddy A, Wright JJ, Kim A, Steinberg SM, Balis FM (2014) Phase 2 randomized flexible crossover double-blinded placebo-controlled trial of the farnesyltransferase inhibitor tipifarnib in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. Neuro Oncol 16(5):707–718

    Article  CAS  PubMed  Google Scholar 

  26. Plotkin SR, Merker VL, Muzikansky A, Barker FG 2nd, Slattery W 3rd (2014) Natural history of vestibular schwannoma growth and hearing decline in newly diagnosed neurofibromatosis type 2 patients. Otol Neurotol 35(1):e50–e56

    Article  PubMed  Google Scholar 

  27. Karajannis MA, Legault G, Hagiwara M, Giancotti FG, Filatov A, Derman A, Hochman T, Goldberg JD, Vega E, Wisoff JH, Golfinos JG, Merkelson A, Roland JT, Allen JC (2014) Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro Oncol 16(2):292–297

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN (2008) Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 358(2):140–151

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Dirks MS, Butman JA, Kim HJ, Wu T, Morgan K, Tran AP, Lonser RR, Asthagiri AR (2012) Long-term natural history of neurofibromatosis type 2-associated intracranial tumors. J Neurosurg 117(1):109–117

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Chantal Dreyer, Jean Michel Colombani, Mustapha Smail, and Philippe Grenier for their contribution to the study.

Funding

The study was designed and the protocol written by academic investigators, and sponsored by the Assistance Publique Hôpitaux de Paris (APHP). The data were monitored and analyzed by the sponsor (Direction de la Recherche Clinique, APHP). Novartis (France) provided the drug and a grant to support the study. The corresponding author made the final decision about where to submit the paper for publication.

Conflict of interest

The authors declare they have no conflict of interest.

Ethical standards

The experiments comply with the current laws in France.

Author information

Authors and Affiliations

  1. Neurochirurgie, Hôpital Beaujon, Assistance Publique Hôpitaux de Paris, 100 boulevard du General Leclerc, 92100, Clichy, France

    Stéphane Goutagny

  2. Service interhospitalier de Cancérologie, Hôpital Beaujon, Assistance Publique Hôpitaux de Paris, 100 boulevard du General Leclerc, 92100, Clichy, France

    Eric Raymond

  3. Départment d’Épidémiologie et de Recherche Clinique, Hôpital Beaujon, Assistance Publique Hôpitaux de Paris, 100 boulevard du General Leclerc, 92100, Clichy, France

    Béatrice Larroque

  4. Département d’Épidémiologie et de Recherche Clinique, Hôpital Bichat, Institut National de la santé et de la recherche médicale CIC-EC 1425, Assistance Publique Hôpitaux de Paris, 46 rue Henri Huchard, 75018, Paris, France

    Marina Esposito-Farese

  5. Neuroradiologie, Hôpital Pitié Salpêtrière, Assistance Publique Hôpitaux de Paris, 47-83, boulevard de l’Hôpital, 75013, Paris, France

    Stéphanie Trunet

  6. Otolaryngologie, Hôpital Pitié Salpêtrière, Assistance Publique Hôpitaux de Paris, 47-83, boulevard de l’Hôpital, 75013, Paris, France

    Daniele Bernardeschi & Olivier Sterkers

  7. Neurochirurgie, Hôpital Pitié Salpêtrière, Assistance Publique Hôpitaux de Paris, 47-83, boulevard de l’Hôpital, 75013, Paris, France

    Michel Kalamarides

  8. Faculté de Médecine, Université Pierre et Marie Curie, 91-105, boulevard de l’Hôpital, 75013, Paris, France

    Stéphanie Trunet, Olivier Sterkers & Michel Kalamarides

  9. Department of Neuropathology, Institute of Biology, Otto-von-Guericke University, Leipziger Strasse 44, 39120, Magdeburg, Germany

    Christian Mawrin

  10. Department of Head and Neck Surgery, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Ave, Los Angeles, CA, 90095-1624, USA

    Marco Giovannini

  11. Institut National de la santé et de la recherche médicale, U1127, Institut cerveau moelle, 47-83, boulevard de l’Hôpital, 75013, Paris, France

    Michel Kalamarides

Authors
  1. Stéphane Goutagny
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  2. Eric Raymond
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  3. Marina Esposito-Farese
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  4. Stéphanie Trunet
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  5. Christian Mawrin
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  6. Daniele Bernardeschi
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  7. Béatrice Larroque
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  8. Olivier Sterkers
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  9. Marco Giovannini
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  10. Michel Kalamarides
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Corresponding author

Correspondence to Michel Kalamarides.

Additional information

To the memory of Beatrice Larroque, who died accidentally as this paper was written.

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Goutagny, S., Raymond, E., Esposito-Farese, M. et al. Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas. J Neurooncol 122, 313–320 (2015). https://doi.org/10.1007/s11060-014-1710-0

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  • DOI: https://doi.org/10.1007/s11060-014-1710-0

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