Everolimus Long-Term Efficacy and Safety for the Treatment of Subependymal Giant Cell Astrocytoma (SEGA) Associated With Tuberous Sclerosis Complex (TSC) (S42.007)

OBJECTIVE: To examine the long-term efficacy and safety of everolimus, an oral mTOR inhibitor, for the treatment of SEGA associated with TSC using data from the open-label extension phase of the EXIST-1 trial (NCT00789828; data cutoff, 1/11/2013). BACKGROUND: TSC, an autosomal dominant genetic disorder, results in nonmalignant tumor growth in several organs throughout the body. In the brain, growth of SEGA may result in obstruction of cerebrospinal fluid flow, causing life-threatening hydrocephalus. EXIST-1, a randomized, double-blind, phase 3 trial, demonstrated that everolimus was superior to placebo for reducing SEGA volume in patients with TSC. DESIGN/METHODS: Patients (median age, 9.5 years [range, 0.8-26.6years]) received 4.5 mg/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 蠅50% reduction in sum of volumes of all target SEGA (蠅1 SEGA 蠅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 cutoff, 3/2/2011). Following positive results for the original cutoff, placebo patients were offered open-label everolimus in the study extension phase. As of 1/11/2013, 111 patients received 蠅1 dose of everolimus and were included in this extension analysis. Median treatment duration of everolimus was 29.3 months, and SEGA response rate was 48.6% (95% confidence interval [CI], 39.0-58.3%). As of 1/11/2013, median time to SEGA progression was not reached; however, SEGA progressions were observed for 9 (8.1%) patients. Most AEs were grade 1 or 2 and were similar to the original cutoff. The most frequent serious adverse events reported in ˃3% of patients were pneumonia (10.8%), pyrexia (4.5%), gastroenteritis (3.6%), and convulsion (3.6%). CONCLUSIONS: Everolimus continued to reduce SEGA volume with no new safety concerns. Study Supported by: Novartis Pharmaceuticals Corporation Disclosure: Dr. Franz has received personal compensation for activities with Novartis, and Lundbeck Research USA, Inc. Dr. Franz has received research support from Novartis. Dr. Belousova has received personal compensation for activities with UCB Pharma, Sanofi-Aventis Pharmaceuticals Inc., Novartis, Eisai Inc., and GlaxoSmithKlyne, Inc. as a speaker. Dr. Sparagana has received personal compensation for activities with Lapharcon and CTS. Dr. Bebin has received personal compensation for activities with Medscape. Dr. Bebin has received research support from Novartis. Dr. Frost has received personal compensation for activities with Lundbeck, Novartis, UCB Pharma, and Questcor as a speaker and member of advisory boards. Dr. Frost has received research assistance from Novartis and Cyberonics, Inc. Dr. Kuperman has nothing to disclose. Dr. Witt has nothing to disclose. Dr. Kohrman has received personal compensation for activities with Novartis as a consultant. Dr. Kohrman has received research support from UCB Pharma and GlaxoSmithKline Inc. Dr. Flamini has nothing to disclose. Dr. Wu has received personal compensation for activities with Novartis. Dr. Curatolo has received personal compensation for activities with Shire Pharmaceuticals Group, and Novartis. Dr. de Vries has received personal compensation for activities with Novartis. Dr. de Vries has received research support from Novartis. Dr. Berkowitz has received personal compensation for activities with Novartis. Dr. Anak has received personal compensation for activities with Novartis as an employee. Dr. Anak holds stock and/or stock options in Novartis, which sponsored research in which Dr. Anak was involved as an investigator. Dr. Niolat has received personal compensation for activities with Novartis as an employee. Dr. Jozwiak has received personal compensation for activities with Novartis as a consultant.