Elsevier

The Lancet

Volume 381, Issue 9869, 9–15 March 2013, Pages 817-824
The Lancet

Articles
Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(12)61767-XGet rights and content

Summary

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.

Introduction

Tuberous sclerosis complex is caused by decreased or absent expression of the genes TSC1 (hamartin) or TSC2 (tuberin), and is characterised by the growth of hamartomas in the kidney, brain, heart, liver, and skin.1, 2, 3 These hamartomas predispose patients to organ system dysfunction, including autism spectrum disorder, intellectual disability, and epilepsy.1, 2, 3 Angiomyolipomas are associated with loss of heterozygosity at the TSC1 or TSC2 gene locus, occur in roughly 80% of patients with tuberous sclerosis, and cause the largest proportion of adult deaths from the disease.3, 4, 5 As angiomyolipomas enlarge, aneurysm and haemorrhage risk increases.6 Enlarging renal angiomyolipomas can cause chronic kidney disease needing dialysis or eventual renal transplantation.7 Patients with angiomyolipomas often develop new lesions and recurrence of treated lesions.8 Lymphangioleiomyomatosis occurs in around 30% of women with tuberous sclerosis, and also rarely occurs in patients without tuberous sclerosis complex (sporadic lymphangioleiomyomatosis).3, 8, 9, 10, 11

Hamartin and tuberin form a complex with Tre2-Bub2-Cdc16 (TBC) 1 domain family, member 7 (TBC1D7), which is required for the proper regulation of Rheb and mammalian target of rapamycin complex 1 (mTORC1) by cellular growth conditions.12 The hamartin-tuberin complex inhibits mTORC1, and loss of the complex leads to constitutive mTORC1 activation, aberrant signalling, and tumour growth.13 The ability of sirolimus, an mTOR inhibitor, to improve manifestations of tuberous sclerosis, including angiomyolipoma, subependymal giant-cell astrocytoma, and lymphangioleiomyomatosis, has been shown in a small number of studies that were reported after the initiation of our trial.14, 15, 16 Furthermore, angiomyolipomas are thought to arise from one progenitor cell called the perivascular epithelioid cell (PEC).8 The PEC gives rise to a family of neoplasms termed perivascular epithelioid cell neoplasms or PEComas.5, 8 Since angiomyolipomas are an example of a PEComa, they have the potential to produce vascular collagen (ie, collagen type IV).

Everolimus is a rapamycin derivative that inhibits the mTOR pathway by acting on mTORC1. A phase 1–2 clinical trial with everolimus was done in a small population of patients (n=38, median age 32 years, 28 were men) with tuberous sclerosis, lymphangioleiomyomatosis, or both (ClinicalTrials.gov identifier NCT00457964) at doses of 5 mg or 10 mg once daily, or 30 mg, 50 mg, or 70 mg once weekly. A mean reduction in the sum of the volumes of target angiomyolipoma lesions (defined as lesions with a maximum diameter of at least 1 cm) at 12 months of 47% was reported (p<0·0001). The response was similar between daily and weekly dosing arms. Adverse events were primarily characterised by mouth ulcers and infections, and were manageable and consistent with the known safety profile of everolimus in patients with tuberous sclerosis.

Here we report the first prospective, international, randomised, double-blind, placebo-controlled, phase 3 study to assess everolimus efficacy and safety in patients with angiomyolipoma associated with tuberous sclerosis or sporadic lymphangioleiomyomatosis. Additionally, the effect of everolimus on mediators of tumour vascularisation, vascular endothelial growth factor D (VEGF-D), and collagen type IV, are presented.

Section snippets

Patients

Eligible patients aged 18 years or older had at least one angiomyolipoma 3 cm or larger in its longest diameter, and a definite diagnosis of tuberous sclerosis per consensus criteria17, 18 or sporadic lymphangioleiomyomatosis (biopsy-proven or chest CT scan).19 Patients were excluded if their angiomyolipoma required surgery at randomisation, or if they had angiomyolipoma-related bleeding or embolisation during the 6 months before randomisation. Patients with lymphangioleiomyomatosis were

Results

Between May 8, 2009, and Dec 30, 2010, 118 patients across 24 centres in 11 countries were randomly assigned to receive everolimus (n=79) or placebo (n=39). At data cutoff (June 30, 2011), 83% (98 of 118) of patients were receiving double-blind study treatment, whereas 17% (20 of 118) had discontinued, mainly because of disease progression (placebo group only; figure 1). Median dose intensity was 10 mg per day for both treatment groups; mean dose intensity was 8·6 mg per day in the everolimus

Discussion

The results of this trial show the benefit of everolimus for treating angiomyolipomas associated with tuberous sclerosis complex. The best overall response rate was significantly higher for everolimus than for placebo and comparable with the response to embolisation.23 Everolimus had a homogeneous and consistent effect across all subgroups (modified strata, sex, age, or race). Furthermore, reductions in sum of target angiomyolipoma volumes were seen in around 95% of evaluable everolimus

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