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 singleinstitution 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 C20 % 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.To the memory of Beatrice Larroque, who died accidentally as this paper was written.Electronic supplementary material The online version of this article

A phase 1 trial of everolimus and bevacizumab in children with recurrent solid tumors

“…Fouladi et al reported what to our knowledge is the only previous single‐agent everolimus trial for pediatric patients with solid tumors, in which everolimus administered daily demonstrated tolerability and mTOR pathway signaling inhibition in PBMCs . Sporadic case reports have described everolimus use for patients with pediatric central nervous system tumors, acute lymphoblastic leukemia, kaposiform hemangioendothelioma, and vestibular schwannomas …”

“…23 Sporadic case reports have described everolimus use for patients with pediatric central nervous system tumors, acute lymphoblastic leukemia, kaposiform hemangioendothelioma, and vestibular schwannomas. [26][27][28][29] The COG performed a randomized study of temsirolimus as an mTOR inhibitor or bevacizumab combined with cyclophosphamide and vinorelbine (ARST0921; ClinicalTrials.gov identifier NCT01222715), 15 whereas the ADVL0918 trial (ClinicalTrials.gov identifier NCT01141244) 16 added temsirolimus to a regimen of irinotecan and temozolomide. Despite widespread interest in bevacizumab for adult cancers, to the best of our knowledge its development and indications for pediatric oncology remain uncertain, reflecting its somewhat disappointing responses in children.…”

A prolonged response to platinum‐based therapy in a patient with metastatic urothelial carcinoma harboring a single rearranged and truncated NF2 gene

“…As a result of the genetic finding of truncation of the one NF2 allele remaining in his tumor, the patient was subsequently started on the mTOR inhibitor, everolimus (10 mg daily). Tumors with defective NF2 function are characterized by constitutive activation of the mTOR pathway and appear to respond to targeted inhibition of the mTOR pathway . Unfortunately, our patient was unable to tolerate everolimus, and developed fatigue with generalized pain, which affected his activities of daily living.…”

2016 Children's Tumor Foundation conference on neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis

“…Earlier work by Dr. Vijaya Ramesh’s (Harvard University, MA) laboratory established aberrant activation of mTORC1 signaling in NF2-deficient meningiomas (James et al, 2009; James et al, 2012), which led to clinical trials with the rapamycin analog everolimus for NF2-associated tumors (Goutagny, Giovannini, & Kalamarides, 2017; Goutagny et al, 2015). Further, they showed that the dual mTORC1/mTORC2 inhibitor AZD2014 was more effective than rapamycin in blocking proliferation of meningioma cells.…”

“…Kalamarides, 2017; Goutagny et al, 2015). Further, they showed that the dual mTORC1/mTORC2 inhibitor AZD2014 was more effective than rapamycin in blocking proliferation of meningioma cells.…”