ArticlesEfficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial
Introduction
Tuberous sclerosis complex is estimated to affect more than 1 million people worldwide.1 It is an autosomal dominant genetic disorder characterised by benign tumours (hamartomas) that arise in many organs, including the brain, kidneys, skin, eyes, lungs, heart, and liver.2 The most common manifestations of tuberous sclerosis are neurological (eg, epilepsy, intellectual disability, and neurobehavioural and psychiatric problems, including autism spectrum disorder) followed by renal and pulmonary symptoms.1, 3 Subependymal giant cell astrocytomas are slow-growing tumours, usually located near the foramen of Monro,1 that develop in up to 20% of individuals with tuberous sclerosis.4, 5, 6 They are typically asymptomatic until they reach a size sufficient to cause ventricular obstruction and hydrocephalus. Postoperative morbidity is substantial, although reports vary—about 20% of patients7 and up to 50%.6, 8 Incomplete resection of subependymal giant cell astrocytomas leads to recurrence;1, 9 in a retrospective analysis, recurrence or contralateral occurrence was reported in 34% of patients, with 13% requiring repeat operations.8
The tuberous sclerosis genes TSC1 (hamartin) and TSC2 (tuberin) encode proteins that form the hamartin-tuberin tumour suppressor complex, which restricts the activation of the mammalian target of rapamycin complex 1 (mTORC1), a protein kinase that regulates protein synthesis, and cell growth and proliferation, through Rheb (Ras homologue enriched in brain).10 Most patients with tuberous sclerosis have a mutation in either TSC1 or TSC2,11, 12, 13 resulting in activation of mTORC1. This finding has led to the investigation of mTORC1 blockade as a treatment approach in tuberous sclerosis. The results of case reports and preliminary studies have shown that mTOR inhibition is associated with improvements in the manifestation of tuberous sclerosis including sub-ependymal giant cell astrocytomas, angiomyolipomas (benign renal tumours), and facial angiofibromas.14, 15, 16, 17, 18, 19, 20 In an open-label study of 28 patients with evidence of serial growth of subependymal giant cell astrocytomas, the mTOR inhibitor everolimus (Afinitor, Novartis Pharma Stein AG, Stein, Switzerland) reduced the volume of subependymal giant cell astrocytomas, seizure frequency, and number of facial angiofibromas.21 We assessed the efficacy and safety of everolimus against placebo in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex in the phase 3 EXamining everolimus In a Study of Tuberous sclerosis complex (EXIST-1) trial.
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Patients
Eligible patients (aged 0–65 years) had a definite diagnosis of tuberous sclerosis complex according to consensus criteria,22, 23 at least one target subependymal giant cell astrocytoma with the longest diameter 1 cm or greater as assessed with multiphase MRI, and one or more of the following when the results of an MRI done within 4 weeks of randomisation were compared with an earlier MRI: serial worsening (defined as an increase of at least 25% in volume of subependymal giant cell
Results
Between Aug 20, 2009, and Sept 2, 2010, 117 patients who had subependymal giant cell astrocytomas associated with tuberous sclerosis were randomly assigned to the everolimus (n=78) or placebo group (n=39). Baseline demographics and clinical characteristics were well balanced between the treatment groups, but the everolimus group had a higher proportion of men than did the placebo group and had hydrocephalus (table 1). The median age of patients was 9·5 years (range 0·8–26·6). Skin lesions were
Discussion
We noted a significant reduction in volume of subependymal giant cell astrocytomas associated with tuberous sclerosis complex in the everolimus group relative to the placebo group. Large astrocytomas are associated with increased morbidity and risk of hydocephalus and potential death,29 so stabilisation or even slight reductions in tumour volume translate into clinical benefit, and the reductions noted in this trial are judged clinically significant. This result in a placebo-controlled,
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