Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2)

A multicentre, randomised, double-blind, placebo-controlled trial

John Bissler, J. Christopher Kingswood, Elzbieta 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

Research output: Contribution to journalArticle

418 Citations (Scopus)

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]). 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.

Original languageEnglish (US)
Pages (from-to)817-824
Number of pages8
JournalThe Lancet
Volume381
Issue number9869
DOIs
StatePublished - Jan 1 2013

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Lymphangioleiomyomatosis
Angiomyolipoma
Tuberous Sclerosis
Placebos
Sirolimus
Nasopharyngitis
Everolimus
Stomatitis
Acne Vulgaris
Double-Blind Method
Disease Progression
Neoplasms

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2) : A multicentre, randomised, double-blind, placebo-controlled trial. / Bissler, John; Kingswood, J. Christopher; Radzikowska, Elzbieta; Zonnenberg, Bernard A.; Frost, Michael; Belousova, Elena; Sauter, Matthias; Nonomura, Norio; Brakemeier, Susanne; De Vries, Petrus J.; Whittemore, Vicky H.; Chen, David; Sahmoud, Tarek; Shah, Gaurav; Lincy, Jeremie; Lebwohl, David; Budde, Klemens.

In: The Lancet, Vol. 381, No. 9869, 01.01.2013, p. 817-824.

Research output: Contribution to journalArticle

Bissler, J, Kingswood, JC, Radzikowska, E, Zonnenberg, BA, Frost, M, Belousova, E, Sauter, M, Nonomura, N, Brakemeier, S, De Vries, PJ, Whittemore, VH, Chen, D, Sahmoud, T, Shah, G, Lincy, J, Lebwohl, D & Budde, K 2013, 'Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): A multicentre, randomised, double-blind, placebo-controlled trial', The Lancet, vol. 381, no. 9869, pp. 817-824. https://doi.org/10.1016/S0140-6736(12)61767-X
Bissler, John ; Kingswood, J. Christopher ; Radzikowska, Elzbieta ; Zonnenberg, Bernard A. ; Frost, Michael ; Belousova, Elena ; Sauter, Matthias ; Nonomura, Norio ; Brakemeier, Susanne ; De Vries, Petrus J. ; Whittemore, Vicky H. ; Chen, David ; Sahmoud, Tarek ; Shah, Gaurav ; Lincy, Jeremie ; Lebwohl, David ; Budde, Klemens. / Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2) : A multicentre, randomised, double-blind, placebo-controlled trial. In: The Lancet. 2013 ; Vol. 381, No. 9869. pp. 817-824.
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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]). 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.",
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T1 - Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2)

T2 - A multicentre, randomised, double-blind, placebo-controlled trial

AU - Bissler, John

AU - Kingswood, J. Christopher

AU - Radzikowska, Elzbieta

AU - Zonnenberg, Bernard A.

AU - Frost, Michael

AU - Belousova, Elena

AU - Sauter, Matthias

AU - Nonomura, Norio

AU - Brakemeier, Susanne

AU - De Vries, Petrus J.

AU - Whittemore, Vicky H.

AU - Chen, David

AU - Sahmoud, Tarek

AU - Shah, Gaurav

AU - Lincy, Jeremie

AU - Lebwohl, David

AU - Budde, Klemens

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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]). 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.

AB - 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]). 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.

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