ArticlesEverolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study
Introduction
Tuberous sclerosis complex (TSC) is a hereditary disorder that affects about 1 million people worldwide.1 It is caused by autosomal-dominant mutations in TSC1 or TSC2 tumour-suppressor genes, resulting in increased activation of mTOR.1 TSC is characterised by multiple benign hamartomas in various organs, including cortical tubers, subependymal giant cell astrocytomas (SEGAs), and subependymal nodules in the brain. Other organ system manifestations include renal angiomyolipomas in the kidneys and lymphangioleiomyomatosis in the lungs.2, 3
SEGAs are thought to arise from subependymal nodules4, 5 and occur in up to 20% of patients with TSC.6 They are slow-growing tumours, usually located near the foramen of Monro.7 Large astrocytomas are associated with increased morbidity, risk of hydrocephalus, and potential death.8 Reduction or stabilisation of tumour volume, especially long term, might therefore translate into clinical benefit. Before the US Food and Drug Administration approved everolimus in October, 2010, surgery was the only available option for symptomatic or actively growing SEGA;9, 10 however, postoperative complications were common.11 Small studies and case reports have shown efficacy for mTOR inhibitors such as sirolimus12, 13 and everolimus9, 14, 15, 16, 17 in SEGA. Findings from the large, multicentre, randomised controlled trial EXIST-1 confirmed the efficacy of everolimus in patients with SEGA associated with TSC.18 After a median duration of everolimus treatment of 9·6 months, 27 (35%) of 78 patients in the everolimus group had at least a 50% reduction in SEGA volume compared with none in the placebo group (p<0·0001).18
Questions remain about the duration of response to therapy and whether continuous inhibition of mTOR is necessary to maintain response. A case report noted SEGA recurrence after discontinuation of sirolimus in a 21-year-old woman with TSC, followed by further regression after reinstitution of treatment.12 In addition, the long-term effects of everolimus on growth and development in paediatric patients have not been previously examined and might be relevant given reported cases of amenorrhoea and disturbed hormone systems described in adults treated with mTOR inhibitors.19, 20, 21
We report outcomes for all patients enrolled in EXIST-1 who were treated with at least one dose of everolimus (including patients initially randomised to everolimus, and patients randomised to placebo who eventually were given everolimus either due to crossover in the core phase of the study or during the open-label extension phase). We aimed to assess sustained or additional therapeutic effects and the safety profile, including for growth and sexual maturation, of mTOR inhibition in patients with TSC treated with everolimus.
Section snippets
Study design and participants
This is a prospective open-label extension of the international, phase 3, multicentre, randomised, double-blind, placebo-controlled EXIST-1 trial. The extension phase was planned to continue for 4 years after the last patient was randomly assigned to treatment, ensuring follow-up of 4–5 years. Because the results of the core phase of the study favoured everolimus,18 patients initially randomly assigned to the placebo group were given the option to receive open-label everolimus and enter the
Results
117 patients were enrolled in the study between Aug 20, 2009, and Sept 2, 2010; 78 (67%) were randomly assigned to everolimus and 39 (33%) to placebo. 111 patients (33 of whom had originally been assigned to placebo) received at least one dose of everolimus and were included in this analysis (figure 1). The median duration of everolimus exposure was 29·3 months (range 1·9–40·5; IQR 19·4–33·8). Median follow-up was 28·3 months (range 1·9–38·8; IQR 19·3–33·0).
More than half of the enrolled
Discussion
These updated results add to the evidence for the efficacy and safety of everolimus in patients with TSC-associated SEGA (panel). Cumulative experience shows a sustained and more pronounced clinical benefit of everolimus compared with the core study,18 confirming that everolimus maintains efficacy with acceptable tolerability in patients with SEGA associated with TSC. SEGA responses and clinically meaningful reductions in SEGA volume were sustained over time. Only one patient had hydrocephalus
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