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      Maintenance Therapy With Everolimus for Subependymal Giant Cell Astrocytoma in Patients With Tuberous Sclerosis – Final Results From the EMINENTS Study

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          Abstract

          The aim of this EMINENTS prospective, single-center, open-label, single-arm study was to evaluate the cumulative efficacy and safety of reduced doses of everolimus (maintenance therapy) in patients with tuberous sclerosis and subependymal giant cell astrocytoma (SEGA).

          Methods: The trial included 15 patients who had undergone at least 12 months of treatment with a standard everolimus dose. The dose of everolimus was reduced to three times a week, with a daily dose as in standard regimen. Data of 14 patients were analyzed. SEGA volume (SV) was evaluated at study entry and subsequent time points by an experienced radiologist. Adverse events (AEs) noted during maintenance therapy were compared to the AEs of standard dose period.

          Results: Patients were followed over a mean duration 58.37 months (95%CI: 45.95–70.78). The differences in SEGA volume between subsequent time points (0, 3, 6,12, 18, 24, 36, 48, and 60 months) were not statistically significant ( p = 0.16). At the end of the study, 7 out of 10 patients had stable SEGA volume. No clinical symptoms of progression were observed in any patients. No patient or tumor-related risk factors of progression were identified. Regarding AEs, infections (stomatitis, bronchitis, diarrhea) and laboratory abnormalities (neutropenia, anemia, hyperglycemia) occurred less frequently during maintenance therapy compared to the standard dose regimen.

          Conclusions: Final results from EMINENTS study confirm that maintenance therapy with everolimus might represent a rational therapeutic option for patients TSC and SEGA after effective full dose treatment. It could be an option for patients who experienced everolimus-related AEs, instead of discontinuation of therapy. Careful evaluation of possible progression, especially concerning first six months of maintenance therapy should be advised.

          Clinical Trial Registration: www.drks.de, identifier DRKS00005584.

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          Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis.

          Neurosurgical resection is the standard treatment for subependymal giant-cell astrocytomas in patients with the tuberous sclerosis complex. An alternative may be the use of everolimus, which inhibits the mammalian target of rapamycin, a protein regulated by gene products involved in the tuberous sclerosis complex. Patients 3 years of age or older with serial growth of subependymal giant-cell astrocytomas were eligible for this open-label study. The primary efficacy end point was the change in volume of subependymal giant-cell astrocytomas between baseline and 6 months. We gave everolimus orally, at a dose of 3.0 mg per square meter of body-surface area, to achieve a trough concentration of 5 to 15 ng per milliliter. We enrolled 28 patients. Everolimus therapy was associated with a clinically meaningful reduction in volume of the primary subependymal giant-cell astrocytoma, as assessed on independent central review (P<0.001 for baseline vs. 6 months), with a reduction of at least 30% in 21 patients (75%) and at least 50% in 9 patients (32%). Marked reductions were seen within 3 months and were sustained. There were no new lesions, worsening hydrocephalus, evidence of increased intracranial pressure, or necessity for surgical resection or other therapy for subependymal giant-cell astrocytoma. Of the 16 patients for whom 24-hour video electroencephalography data were available, seizure frequency for the 6-month study period (vs. the previous 6-month period) decreased in 9, did not change in 6, and increased in 1 (median change, -1 seizure; P=0.02). The mean (±SD) score on the validated Quality-of-Life in Childhood Epilepsy questionnaire (on which scores can range from 0 to 100, with higher scores indicating a better quality of life) was improved at 3 months (63.4±12.4) and 6 months (62.1±14.2) over the baseline score (57.8±14.0). Single cases of grade 3 treatment-related sinusitis, pneumonia, viral bronchitis, tooth infection, stomatitis, and leukopenia were reported. Everolimus therapy was associated with marked reduction in the volume of subependymal giant-cell astrocytomas and seizure frequency and may be a potential alternative to neurosurgical resection in some cases, though long-term studies are needed. (Funded by Novartis; ClinicalTrials.gov number, NCT00411619.).
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            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.

            Tuberous sclerosis complex is a genetic disorder leading to constitutive activation of mammalian target of rapamycin (mTOR) and growth of benign tumours in several organs. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms--eg, hydrocephalus, requiring surgery. In an open-label, phase 1/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. We assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex. In this double-blind, placebo-controlled, phase 3 trial, patients (aged 0-65 years) in 24 centres in Australia, Belgium, Canada, Germany, the UK, Italy, the Netherlands, Poland, Russian Federation, and the USA were randomly assigned, with an interactive internet-response system, in a 2:1 ratio to oral everolimus 4·5 mg/m(2) per day (titrated to achieve blood trough concentrations of 5-15 ng/mL) or placebo. Eligible patients had a definite diagnosis of tuberous sclerosis complex and at least one lesion with a diameter of 1 cm or greater, and either serial growth of a subependymal giant cell astrocytoma, a new lesion of 1 cm or greater, or new or worsening hydrocephalus. The primary endpoint was the proportion of patients with confirmed response--ie, reduction in target volume of 50% or greater relative to baseline in subependymal giant cell astrocytomas. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00789828. 117 patients were randomly assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI 15-52; one-sided exact Cochran-Mantel-Haenszel test, p<0·0001). Adverse events were mostly grade 1 or 2; no patients discontinued treatment because of adverse events. The most common adverse events were mouth ulceration (25 [32%] in the everolimus group vs two [5%] in the placebo group), stomatitis (24 [31%] vs eight [21%]), convulsion (18 [23%] vs ten [26%]), and pyrexia (17 [22%] vs six [15%]). These results support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis. Additionally, everolimus might represent a disease-modifying treatment for other aspects of tuberous sclerosis. Novartis Pharmaceuticals. Copyright © 2013 Elsevier Ltd. All rights reserved.
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              Long-Term Use of Everolimus in Patients with Tuberous Sclerosis Complex: Final Results from the EXIST-1 Study

              Background Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has demonstrated efficacy in treating subependymal giant cell astrocytomas (SEGAs) and other manifestations of tuberous sclerosis complex (TSC). However, long-term use of mTOR inhibitors might be necessary. This analysis explored long-term efficacy and safety of everolimus from the conclusion of the EXIST-1 study (NCT00789828). Methods and Findings EXIST-1 was an international, prospective, double-blind, placebo-controlled phase 3 trial examining everolimus in patients with new or growing TSC-related SEGA. After a double-blind core phase, all remaining patients could receive everolimus in a long-term, open-label extension. Everolimus was initiated at a dose (4.5 mg/m2/day) titrated to a target blood trough of 5–15 ng/mL. SEGA response rate (primary end point) was defined as the proportion of patients achieving confirmed ≥50% reduction in the sum volume of target SEGA lesions from baseline in the absence of worsening nontarget SEGA lesions, new target SEGA lesions, and new or worsening hydrocephalus. Of 111 patients (median age, 9.5 years) who received ≥1 dose of everolimus (median duration, 47.1 months), 57.7% (95% confidence interval [CI], 47.9–67.0) achieved SEGA response. Of 41 patients with target renal angiomyolipomas at baseline, 30 (73.2%) achieved renal angiomyolipoma response. In 105 patients with ≥1 skin lesion at baseline, skin lesion response rate was 58.1%. Incidence of adverse events (AEs) was comparable with that of previous reports, and occurrence of emergent AEs generally decreased over time. The most common AEs (≥30% incidence) suspected to be treatment-related were stomatitis (43.2%) and mouth ulceration (32.4%). Conclusions Everolimus use led to sustained reduction in tumor volume, and new responses were observed for SEGA and renal angiomyolipoma from the blinded core phase of the study. These findings support the hypothesis that everolimus can safely reverse multisystem manifestations of TSC in a significant proportion of patients. Trial Registration ClinicalTrials.gov NCT00789828
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                Author and article information

                Contributors
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                09 April 2021
                2021
                : 12
                : 581102
                Affiliations
                [1] 1Department of Pediatrics, Oncology and Hematology, Medical University of Lodz , Lodz, Poland
                [2] 2Department of Pediatric Radiology, Medical University Hospital , Lodz, Poland
                [3] 3Department of Neurology & Epileptology and Pediatric Rehabilitation, The Children's Memorial Health Institute , Warsaw, Poland
                [4] 4Department of Child Neurology, Medical University of Warsaw , Warsaw, Poland
                Author notes

                Edited by: Brahim Tabarki Melaiki, University of Sousse, Tunisia

                Reviewed by: Elena Dmitrievna Belousova, Pirogov Russian National Research Medical University, Russia; Maurizio Elia, Oasi Research Institute (IRCCS), Italy; Emilio Russo, University of Catanzaro, Italy

                *Correspondence: Joanna Trelinska joanna.trelinska@ 123456umed.lodz.pl

                This article was submitted to Pediatric Neurology, a section of the journal Frontiers in Neurology

                †These authors have contributed equally to this work

                Article
                10.3389/fneur.2021.581102
                8062974
                33897576
                45b6e135-e4ed-4c00-8c92-5dc8c7e01550
                Copyright © 2021 Bobeff, Krajewska, Baranska, Kotulska, Jozwiak, Mlynarski and Trelinska.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 17 November 2020
                : 17 March 2021
                Page count
                Figures: 2, Tables: 3, Equations: 0, References: 19, Pages: 10, Words: 5709
                Funding
                Funded by: Narodowe Centrum Nauki 10.13039/501100004281
                Funded by: Uniwersytet Medyczny w Lodzi 10.13039/501100005888
                Categories
                Neurology
                Clinical Trial

                Neurology
                everolimus,mtor inhibitor,maintenance therapy,subependymal giant cell astrocytoma,tuberous sclerosis

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