Document Detail

Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial.
MedLine Citation:
PMID:  23312829     Owner:  NLM     Status:  MEDLINE    
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 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]).
INTERPRETATION: Everolimus reduced angiomyolipoma volume with an acceptable safety profile, suggesting it could be a potential treatment for angiomyolipomas associated with tuberous sclerosis.
FUNDING: Novartis Pharmaceuticals.
John J Bissler; J Christopher Kingswood; Elżbieta Radzikowska; Bernard A Zonnenberg; Michael Frost; Elena Belousova; Matthias Sauter; Norio Nonomura; Susanne Brakemeier; Petrus J de Vries; Vicky H Whittemore; David Chen; Tarek Sahmoud; Gaurav Shah; Jeremie Lincy; David Lebwohl; Klemens Budde
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Publication Detail:
Type:  Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Lancet     Volume:  381     ISSN:  1474-547X     ISO Abbreviation:  Lancet     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-06-17     Completed Date:  2013-07-01     Revised Date:  2014-05-05    
Medline Journal Info:
Nlm Unique ID:  2985213R     Medline TA:  Lancet     Country:  England    
Other Details:
Languages:  eng     Pagination:  817-24     Citation Subset:  AIM; IM    
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MeSH Terms
Angiomyolipoma / complications,  drug therapy*
Antineoplastic Agents / therapeutic use*
Double-Blind Method
Lymphangioleiomyomatosis / complications
Prospective Studies
Sirolimus / analogs & derivatives*,  therapeutic use
Tuberous Sclerosis / complications
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents; 159351-69-6/everolimus; W36ZG6FT64/Sirolimus
Comment In:
Lancet. 2013 Mar 9;381(9869):783-5   [PMID:  23312828 ]
J Urol. 2014 Mar;191(3):626-7   [PMID:  24522027 ]
Urology. 2013 Aug;82(2):278-9   [PMID:  23642941 ]

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