title: Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial.
abstract: BACKGROUND
  Mammalian target of rapamycin (mTOR) inhibitors are recommended as first-line treatment of renal angiomyolipoma associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sporadic LAM), but follow-up is limited. Longer term efficacy and tolerability data from a Phase 3, double-blind, placebo-controlled trial are presented.
  
  
  METHODS
  Following favorable results from the primary analysis (data cutoff 30 June 2011) of the EXIST-2 trial, patients still receiving study treatment were allowed to enter an open-label extension. Everolimus was initiated at 10 mg once daily and titrated based on tolerability. The primary outcome was angiomyolipoma response rate (≥ 50% reduction from baseline in target lesion volumes). Safety was a secondary endpoint.
  
  
  RESULTS
  As of the cutoff date (1 May 2013), 112 patients had received everolimus, and the response rate in 107 patients with angiomyolipoma (median duration of medication exposure of 28.9 months) was 54%. The proportion of patients achieving angiomyolipoma reductions of ≥ 30% and ≥ 50% increased over time, reaching 81.6% (62/76) and 64.5% (49/76), respectively, by Week 96. No everolimus-treated patients experienced renal bleeding. The long-term safety profile was consistent with previous reports; adverse events (AEs) were mostly Grade 1/2, and there were no new safety issues. The frequency of emerging AEs and severe AEs lessened over time.
  
  
  CONCLUSIONS
  Longer term everolimus treatment appeared safe and effective in patients with TSC- or sporadic LAM-associated renal angiomyolipoma not requiring surgical intervention. Continued reduction in angiomyolipoma volume was demonstrated, and there was no angiomyolipoma-related bleeding; AEs were predictable and generally manageable.
  
  
  BACKGROUND
  clinicaltrialsgov identifier: NCT00790400 (http://clinicaltrials.gov/ct2/show/NCT00790400).
authors.affiliation: St. Jude Children's Research Hospital and Le Bonheur Children's Hospital, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Bissler
authors.affiliation: Royal Sussex County Hospital, Brighton, UK.
authors.forename: John Christopher
authors.initials: JC
authors.lastname: Kingswood
authors.affiliation: National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Radzikowska
authors.affiliation: Universitair Medisch Centrum, Utrecht, The Netherlands.
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Zonnenberg
authors.affiliation: Minnesota Epilepsy Group, St Paul, MN, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Frost
authors.affiliation: Moscow Research Institute of Pediatrics and Pediatric Surgery, Moscow, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Belousova
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der Universität MüNchen, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Sauter
authors.affiliation: Osaka University Hospital, Osaka, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Nonomura
authors.affiliation: Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Brakemeier
authors.affiliation: Division of Child and Adolescent Psychiatry, University of Cape Town, Cape Town, South Africa.
authors.forename: Petrus J
authors.initials: PJ
authors.lastname: de Vries
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Berkowitz
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Miao
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Segal
authors.affiliation: Novartis Pharmaceuticals S.A.S., Rueil-Malmaison, France.
authors.forename: Severine
authors.initials: S
authors.lastname: Peyrard
authors.affiliation: Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
mesh_terms: D000293:Adolescent; D000328:Adult; D018207:Angiomyolipoma / Q000188:drug therapy* / Q000473:pathology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D000068338:Everolimus / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000473:pathology; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018192:Lymphangioleiomyomatosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014402:Tuberous Sclerosis / Q000188:drug therapy*; D047368:Tumor Burden / Q000187:drug effects; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus
keywords: everolimus; mTOR inhibitors; renal angiomyolipoma; sporadic lymphangioleiomyomatosis; tuberous sclerosis complex