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