학술논문
Prospective phase II trial of the dual mTORC1/2 inhibitor vistusertib for progressive or symptomatic meningiomas in persons with neurofibromatosis 2.
Document Type
Academic Journal
Author
Jordan JT; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Orr CC; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Thalheimer RD; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Cambillo JV; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Beauchamp RL; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Shaikh G; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Muzikansky A; Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Stemmer-Rachamimov A; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Giovannini M; Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA and Jonsson Comprehensive Cancer Center (JCCC), University of California Los Angeles, Los Angeles, CA, USA.; Kalamarides M; Department of Neurosurgery, Hopital Pitie-Salpetriere, Sorbonne Université, Paris, France.; Barker FG 2nd; Neurosurgical Service, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Ramesh V; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Plotkin SR; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Source
Publisher: Oxford University Press Country of Publication: England NLM ID: 101755003 Publication Model: eCollection Cited Medium: Internet ISSN: 2632-2498 (Electronic) Linking ISSN: 26322498 NLM ISO Abbreviation: Neurooncol Adv Subsets: PubMed not MEDLINE
Subject
Language
English
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.
Competing Interests: 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.
(© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
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.
Competing Interests: 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.
(© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)