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. 2023 Apr 17;5(1):vdad041.
doi: 10.1093/noajnl/vdad041. eCollection 2023 Jan-Dec.

Prospective phase II trial of the dual mTORC1/2 inhibitor vistusertib for progressive or symptomatic meningiomas in persons with neurofibromatosis 2

Justin T Jordan  1 , Christina C Orr  1 , Raquel D Thalheimer  1 , Josephine V Cambillo  1 , Roberta L Beauchamp  2 , Ghalib Shaikh  2 , Alona Muzikansky  3 , Anat Stemmer-Rachamimov  4 , Marco Giovannini  5 , Michel Kalamarides  6 , Fred G Barker 2nd  7 , Vijaya Ramesh  1   2 , Scott R Plotkin  1
Affiliations

Prospective phase II trial of the dual mTORC1/2 inhibitor vistusertib for progressive or symptomatic meningiomas in persons with neurofibromatosis 2

Justin T Jordan et al. Neurooncol Adv. .

Abstract

Background: Meningiomas occur in 80% of persons with neurofibromatosis 2 (NF2) and cause significant mortality and morbidity, yet there are no effective medical treatments. NF2-deficient tumors have constitutive activation of mammalian/mechanistic target of rapamycin (mTOR), and treatment with mTORC1 inhibitors results in growth arrest in a minority of tumors, with paradoxical activation of the mTORC2/AKT pathway. We studied the effect of vistusertib, a dual mTORC1/mTORC2 inhibitor, in NF2 patients with progressive or symptomatic meningiomas.

Methods: Vistusertib was administered orally at 125 mg twice daily for 2 consecutive days each week. The primary endpoint was the imaging response in the target meningioma, defined as a volume decrease of 20% compared with the baseline. Secondary endpoints included toxicity, imaging response of nontarget tumors, quality of life, and genetic biomarkers.

Results: Eighteen participants (13 female), median age of 41 (range, 18-61) years, were enrolled. In target meningiomas, the best response was partial response (PR) in 1/18 tumors (6%) and stable disease (SD) in 17/18 tumors (94%). For all measured intracranial meningiomas and vestibular schwannomas, the best imaging response was PR in 6/59 tumors (10%) and SD in 53 (90%). Treatment-related grade 3/4 adverse events occurred in 14 (78%) participants, and 9 participants discontinued treatment due to side effects.

Conclusions: Although the study did not meet the primary endpoint, vistusertib treatment was associated with high rates of SD in progressive NF2-related tumors. However, this dosing regimen for vistusertib was poorly tolerated. Future studies of dual mTORC inhibitors for NF2 should focus on optimizing tolerability and evaluating the relevance of tumor stability in participants.

Keywords: NF2; mTOR; mTORC1; mTORC2; meningioma; neurofibromatosis 2; vistusertib.

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Conflict of interest statement

J.T.J.—Paid consulting for NF Network, Recursion Pharmaceuticals, CereXis, Health2047, and Navio Theragnostics. Royalties from Elsevier Publishing. C.C.O.—Paid consulting for AstraZeneca. R.D.T.—No disclosures. J.V.C.—No disclosures. R.L.B.—No disclosures. G.S.—No disclosures. A.M.—No disclosures. A.S.-R.—No disclosures. M.G.—Consults for NF2 Therapeutics and Puma Biotechnology. M.K.—Paid consulting for Recursion Pharmaceuticals. F.G.B.— No disclosures. V.R.—No disclosures. S.R.P.—Dr. Plotkin is co-founder of NFlection Therapeutics and NF2 Therapeutics and consults for AstraZeneca, SonalaSense, and Akouos.

Figures

Figure 1.
Figure 1.
(A) Duration of study treatment with reasons for treatment discontinuation and (B) best percentage change from baseline in meningiomas and schwannomas (n = 59).
Figure 1.
Figure 1.
(A) Duration of study treatment with reasons for treatment discontinuation and (B) best percentage change from baseline in meningiomas and schwannomas (n = 59).
Figure 2.
Figure 2.
Genetic severity, activity of mTORC1 and mTORC2 pathways in archival tumors, and best clinical response in participants treated with vistusertib. Genetic severity was classified as severe (severity score = 3), moderate (severity score = 2), or tissue mosaics (severity score = 1) according to the NF2 Genetic Severity Scoring System.
See this image and copyright information in PMC

References

    1. Evans DG, Moran A, King A, et al. . Incidence of vestibular schwannoma and neurofibromatosis 2 in the North West of England over a 10-year period: higher incidence than previously thought. Otol Neurotol. 2005; 26(1):93–97. - PubMed
    1. Mautner VF, Lindenau M, Baser ME, et al. . The neuroimaging and clinical spectrum of neurofibromatosis 2. Neurosurgery. 1996; 38(5):880–885; discussion 885–6. - PubMed
    1. Smith MJ, Higgs JE, Bowers NL, et al. . Cranial meningiomas in 411 neurofibromatosis type 2 (NF2) patients with proven gene mutations: clear positional effect of mutations, but absence of female severity effect on age at onset. J Med Genet. 2011; 48(4):261–265. - PubMed
    1. Goutagny S, Bah AB, Henin D, et al. . Long-term follow-up of 287 meningiomas in neurofibromatosis type 2 patients: clinical, radiological, and molecular features. Neuro-Oncology. 2012; 14(8):1090–1096. - PMC - PubMed
    1. Betz C, Hall MN.. Where is mTOR and what is it doing there? J Cell Biol. 2013; 203(4):563–574. - PMC - PubMed