Everolimus for subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC): EXIST-1 long-term efficacy and safety results

Introduction EXIST-1 (NCT00789828), a randomized, double-blind, phase 3 trial, demonstrated that everolimus, an mTOR inhibitor, was superior to placebo for reducing SEGA volume in patients with TSC. Long-term safety and efficacy of everolimus were examined using data available 11-January-2013. Methods Patients (median age, 9.5years [range, 0.8-26.6years]) received 4.5mg/m 2 /day oral everolimus (n=78; titrated to a target trough 5-15ng/mL) or placebo (n=39). SEGA response rate (primary endpoint) was defined as proportion of patients with ≥50% reduction in sum of volumes of all target SEGA (≥1 SEGA ≥1 cm in longest diameter) versus baseline. Adverse events (AEs) were monitored at every visit. Results Everolimus was superior to placebo for SEGA response rate (34.6% vs 0.0% P ˂0.0001; original cut-off, 02-March-2011). Following positive results for original cut-off, placebo patients were offered open-label everolimus in the study’s extension phase. As of 11-January-2013, 111 patients received ≥1 dose of everolimus and were included in this extension analysis. Median treatment duration of everolimus was 29.3months and SEGA response rate was 48.6% (95% confidence interval [CI], 39.0-58.3%). As of 11-January-2013, median time to SEGA progression was not reached; however, SEGA progressions were observed for 9 (8.1%) patients. Most AEs continued to be grade 1 or 2. The most frequent serious adverse events occurring in more than 3% of patients were pneumonia (10.8%), pyrexia (4.5%), gastroenteritis (3.6%), and convulsion (3.6%). Conclusion Everolimus continued to reduce SEGA volume with no new safety concerns.