title: Everolimus for angiomyolipoma associated with tuberous  sclerosis complex or sporadic lymphangioleiomyomatosis  (EXIST-2): a multicentre, randomised, double-blind,  placebo-controlled trial.
abstract: BACKGROUND
  Angiomyolipomas are slow-growing tumours associated with constitutive activation of mammalian target of rapamycin (mTOR), and are common in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis. The insidious growth of these tumours predisposes patients to serious complications including retroperitoneal haemorrhage and impaired renal function. Everolimus, a rapamycin derivative, inhibits the mTOR pathway by acting on the mTOR complex 1. We compared the angiomyolipoma response rate on everolimus with placebo in patients with tuberous sclerosis or sporadic lymphanioleiomyomatosis-associated angiomyolipomata.
  
  
  METHODS
  In this double-blind, placebo-controlled, phase 3 trial, patients aged 18 years or older with at least one angiomyolipoma 3 cm or larger in its longest diameter (defined by radiological assessment) and a definite diagnosis of tuberous sclerosis or sporadic lymphangioleiomyomatosis were randomly assigned, in a 2:1 fashion with the use of an interactive web response system, to receive oral everolimus 10 mg per day or placebo. The primary efficacy endpoint was the proportion of patients with confirmed angiomyolipoma response of at least a 50% reduction in total volume of target angiomyolipomas relative to baseline. This study is registered with ClinicalTrials.gov number NCT00790400.
  
  
  RESULTS
  118 patients (median age 31·0 years; IQR 18·0–61·0) from 24 centres in 11 countries were randomly assigned to receive everolimus (n=79) or placebo (n=39). At the data cutoff, double-blind treatment was ongoing for 98 patients; two main reasons for discontination were disease progression (nine placebo patients) followed by adverse events (two everolimus patients; four placebo patients). The angiomyolipoma response rate was 42% (33 of 79 [95% CI 31–53%]) for everolimus and 0% (0 of 39 [0–9%]) for placebo (response rate difference 42% [24–58%]; one-sided Cochran-Mantel-Haenszel test p<0·0001). The most common adverse events in the everolimus and placebo groups were stomatitis (48% [38 of 79], 8% [3 of 39], respectively), nasopharyngitis (24% [19 of 79] and 31% [12 of 39]), and acne-like skin lesions (22% [17 of 79] and 5% [2 of 39]).
  
  
  CONCLUSIONS
  Everolimus reduced angiomyolipoma volume with an acceptable safety profile, suggesting it could be a potential treatment for angiomyolipomas associated with tuberous sclerosis.
  
  
  BACKGROUND
  Novartis Pharmaceuticals.
authors: Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3039, USA. john.bissler@cchmc.org
authors: John J
authors: JJ
authors: Bissler
authors: J Christopher
authors: JC
authors: Kingswood
authors: Elżbieta
authors: E
authors: Radzikowska
authors: Bernard A
authors: BA
authors: Zonnenberg
authors: Michael
authors: M
authors: Frost
authors: Elena
authors: E
authors: Belousova
authors: Matthias
authors: M
authors: Sauter
authors: Norio
authors: N
authors: Nonomura
authors: Susanne
authors: S
authors: Brakemeier
authors: Petrus J
authors: PJ
authors: de Vries
authors: Vicky H
authors: VH
authors: Whittemore
authors: David
authors: D
authors: Chen
authors: Tarek
authors: T
authors: Sahmoud
authors: Gaurav
authors: G
authors: Shah
authors: Jeremie
authors: J
authors: Lincy
authors: David
authors: D
authors: Lebwohl
authors: Klemens
authors: K
authors: Budde
mesh_terms: D000328:Adult; D018207:Angiomyolipoma / Q000150:complications / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004311:Double-Blind Method; D000068338:Everolimus; D005260:Female; D006801:Humans; D018192:Lymphangioleiomyomatosis / Q000150:complications; D008297:Male; D011446:Prospective Studies; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014402:Tuberous Sclerosis / Q000150:complications
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; D020123:Sirolimus