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Everolimus is an orally administered inhibitor of the mammalian target of rapamycin (mTOR).
Everolimus (starting dosage 3.0 mg/m2) was associated with a significant reduction in the volume of the largest subependymal giant cell astrocytoma (SEGA) in 28 patients aged ≥3 years with tuberous sclerosis complex (TSC) in a phase II trial (C2485). At 6 months, 32% of patients treated with everolimus had a ≥50% reduction in the volume of their largest SEGA lesion (assessed via an independent central radiology review); 75% had a ≥30% reduction. No patients developed new lesions. During the extension phase of this trial (median duration 34 months), the reduction in SEGA volume was maintained, with no everolimus recipient requiring surgery or other therapy for SEGA or hydrocephalus.
In a phase III trial (EXIST-1) in 117 patients with SEGA associated with TSC, 35% of everolimus recipients (starting dosage 4.5mg/m2) versus none of the placebo recipients (p< 0.0001) had an overall response (a reduction in the sum of all target SEGA volumes of ≥50% relative to baseline, nonworsening of non-target SEGA lesions, no new SEGA lesions, and no new/worsening hydrocephalus).
Everolimus was generally well tolerated in patients with SEGA associated with TSC; most drug-related adverse reactions were mild to moderate in severity.
Acknowledgments and Disclosures
The manuscript was reviewed by: D.N. Franz: Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA; J. Hauptman: Department of Neurosurgery, Geffen School of Medicine at UCLA, Los Angeles, CA, USA; S. Sparagana: Division of Neurology, Texas Scottish Rite Hospital for Children, Dallas, TX, USA.
The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit.
- 3.National Institute of Neurological Disorders and Stroke. Tuberous sclerosis fact sheet [online]. Available from URL: http://www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosis.htm [Accessed 2011 Aug 20]
- 5.Novartis Pharmaceuticals Corporation. Afinitor® (everolimus) tablets for oral administration: US prescribing information [online]. Available from URL: http://www.pharma.us.novartis.com/product/pi/pdf/afinitor.pdf [Accessed 2011 Aug 20]
- 6.European Medicines Agency. Votubia® (everolimus): summary of product characteristics [online]. Available from URL: http://www.ema.europa.eu [Accessed 2011 Nov 20]
- 7.Novartis Pharmaceuticals Canada, Inc. Afinitor® (everolimus): Canadian prescribing information. Dorval (QC): Novartis Pharmaceuticals, 2011Google Scholar
- 9.Novartis Pharmaceuticals Corporation. Zortress® (everolimus): US prescribing information [online]. Available from URL: http://www.pharma.us.novartis.com/product/pi/pdf/zortress.pdf [Accessed 2011 Sept 1]
- 11.European Medicines Agency. Afinitor® (everolimus): summary of product characteristics [online]. Available from URL: http://www.ema.europa.eu [Accessed 2011 Nov 20]
- 16.Boulay A, Zumstein-Mecker S, Stephan C, et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 2004 Jan 1; 64(1): 252–61PubMedCrossRefGoogle Scholar
- 32.Kovarik JM, Kahan BD, Kaplan B, et al. Longitudinal assessment of everolimus in de novo renal transplant recipients over the first post-transplant year: pharmacokinetics, exposure-response relationships, and influence on cyclosporine. Clin Pharmacol Ther 2001 Jan; 69(1): 48–56PubMedCrossRefGoogle Scholar
- 40.Mehrotra N, Pfuma E, Garnett Q, et al. Exposure-response analysis as evidence for anti-tumour activity of everolimus in the treatment of patients with subependymal giant-cell astrocytoma (SEGA) associated with tuberous scleroisis (TS) [abstract no. 9550]. J Clin Oncol 2011; 29 SupplGoogle Scholar
- 41.Krueger DA, Care MM, Holland K, et al. Long-term safety and efficacy results from an extension phase of an open-label, prospective, phase 1/2 trial of oral everolimus in patients with subependymal giant-cell astrocytomas in tuberous sclerosis complex [abstract plus poster]. Summit on Drug Discovery in TSC and Related Disorders: International TSC Research Conference; 2011 Jul 6–9; Washington, DCGoogle Scholar
- 42.Bebin M, Franz DN, Sahmoud T, et al. Everolimus in subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis complex (TSC): results of EXIST-1, a double-blind placebo-controlled phase 3 trial [abstract]. 2011 European Multidisciplinary Cancer Congress; 2011 Sep 23–27; StockholmGoogle Scholar
- 43.Franz DN, Belousova E, Curatolo P, et al. Results from a double-blind, placebo-controlled, phase 3 trial of everolimus in subependymal giant cell astrocytomas associated with tuberous sclerosis complex [abstract plus poster]. 29th International Epilepsy Congress (IEC); 2011 28 Aug-1 Sep; RomeGoogle Scholar
- 44.Franz D. Clinical trials in the USA for TSC and related disorders [abstract]. Summit on Drug Discovery in TSC and Related Disorders: International TSC Research Conference; 2011 Jul 6–9; Washington, DCGoogle Scholar
- 45.US National Institutes of Health. Efficacy and safety study of RAD001 in patients aged 18 or over with angiomyolipoma associated with tuberous sclerosis complex (TSC) or lymphangioleiomyomatosis (LAM) (EXIST-2) [ClinicalTrials.gov identifier NCT00790400]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2011 Aug 23]