title: Long-Term Use of Everolimus in Patients with Tuberous Sclerosis Complex: Final Results from the EXIST-1 Study.
abstract: 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).
  
  
  RESULTS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00789828.
authors.affiliation: Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: David N
authors.initials: DN
authors.lastname: Franz
authors.affiliation: Department of Pediatrics, Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University, Moscow, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Belousova
authors.affiliation: Department of Neurology, Texas Scottish Rite Hospital for Children, Dallas, Texas, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Sparagana
authors.affiliation: Department of Neurology, University of Alabama School of Medicine, Birmingham, Alabama, United States of America.
authors.forename: E Martina
authors.initials: EM
authors.lastname: Bebin
authors.affiliation: Department of Neurology, Minnesota Epilepsy Group, St. Paul, Minnesota, United States of America.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Frost
authors.affiliation: Department of Neurology, Children's Hospital and Research Center, Oakland, California, United States of America.
authors.forename: Rachel
authors.initials: R
authors.lastname: Kuperman
authors.affiliation: Department of Oncology, University of Heidelberg Medical Center and German Cancer Research Center, Heidelberg, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
authors.affiliation: Department of Neurology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kohrman
authors.affiliation: Department of Neurology, Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: J Robert
authors.initials: JR
authors.lastname: Flamini
authors.affiliation: Department of Neurology, Mattel Children's Hospital at the University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Joyce Y
authors.initials: JY
authors.lastname: Wu
authors.affiliation: Department of Neurology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Curatolo
authors.affiliation: Department of Psychiatry and Mental Health, Division of Child & Adolescent Psychiatry, University of Cape Town, Cape Town, South Africa.
authors.forename: Petrus J
authors.initials: PJ
authors.lastname: de Vries
authors.affiliation: Department of Oncology, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, United States of America.
authors.forename: Noah
authors.initials: N
authors.lastname: Berkowitz
authors.affiliation: Department of Oncology, Novartis Pharmaceuticals S.A.S., Rueil-Malmaison, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Niolat
authors.affiliation: Department of Pediatric Neurology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Sergiusz
authors.initials: S
authors.lastname: Jóźwiak
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D000068338:Everolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014402:Tuberous Sclerosis / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases