Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial

Summary

Background

Tuberous sclerosis complex is a genetic disorder leading to constitutive activation of mammalian target of rapamycin (mTOR) and growth of benign tumours in several organs. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms—eg, hydrocephalus, requiring surgery. In an open-label, phase 1/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. We assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex.

Methods

In this double-blind, placebo-controlled, phase 3 trial, patients (aged 0–65 years) in 24 centres in Australia, Belgium, Canada, Germany, the UK, Italy, the Netherlands, Poland, Russian Federation, and the USA were randomly assigned, with an interactive internet-response system, in a 2:1 ratio to oral everolimus 4·5 mg/m² per day (titrated to achieve blood trough concentrations of 5–15 ng/mL) or placebo. Eligible patients had a definite diagnosis of tuberous sclerosis complex and at least one lesion with a diameter of 1 cm or greater, and either serial growth of a subependymal giant cell astrocytoma, a new lesion of 1 cm or greater, or new or worsening hydrocephalus. The primary endpoint was the proportion of patients with confirmed response—ie, reduction in target volume of 50% or greater relative to baseline in subependymal giant cell astrocytomas. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00789828.

Findings

117 patients were randomly assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI 15–52; one-sided exact Cochran-Mantel-Haenszel test, p<0·0001). Adverse events were mostly grade 1 or 2; no patients discontinued treatment because of adverse events. The most common adverse events were mouth ulceration (25 [32%] in the everolimus group vs two [5%] in the placebo group), stomatitis (24 [31%] vs eight [21%]), convulsion (18 [23%] vs ten [26%]), and pyrexia (17 [22%] vs six [15%]).

Interpretation

These results support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis. Additionally, everolimus might represent a disease-modifying treatment for other aspects of tuberous sclerosis.

Funding

Novartis Pharmaceuticals.

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.