Long-term efficacy and safety of everolimus for the treatment of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) in EXIST-1: approximately 3.5 years of exposure (P2.235)

OBJECTIVE: To examine the efficacy and safety of the oral mTOR inhibitor everolimus for the treatment of SEGA associated with TSC using data from the open-label extension phase of the EXIST-1 trial (data cutoff, January 17, 2014). BACKGROUND: TSC, an autosomal dominant genetic disorder, results in nonmalignant hamartomas in several organs. In the brain, growing SEGAs may obstruct cerebrospinal fluid flow, causing life-threatening hydrocephalus. The randomized, double-blind, phase 3 EXIST-1 trial (NCT00789828) demonstrated superiority of everolimus over placebo in reducing SEGA volume in patients with TSC. DESIGN/METHODS: Patients (median age, 9.5 years [range, 0.8-26.6 years]) received 4.5 mg/m2/day oral everolimus (n=78; titrated to target trough 5-15 ng/mL) or placebo (n=39). The primary endpoint, SEGA response rate, was defined as proportion of patients with 蠅50[percnt] 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[percnt] vs 0.0[percnt]; P˂0.0001) at the original cutoff (March 2, 2011). Following these positive results, open-label everolimus was offered to all patients (including those on placebo) in an extension phase. As of January 17, 2014, 111 patients received 蠅1 dose of everolimus and were included in this extension analysis. Median duration of exposure to everolimus was 41.1 months. Best overall SEGA response rate was 53.2[percnt] (95[percnt] confidence interval [CI], 43.4-62.7[percnt]). SEGA progressions were observed in 11 (9.9[percnt]) patients. AEs were similar to previous reports. Incidences of emerging AEs decreased over time. Most frequent serious AEs reported in ˃3[percnt] of patients were pneumonia (12.6[percnt]), convulsion, (4.5[percnt]), pyrexia (4.5[percnt]), and gastroenteritis (3.6[percnt]). No significant impact on growth or sexual maturation was observed. CONCLUSIONS: Everolimus continued to show reduction in SEGA volume with no new safety concerns. Study Supported by: Pharmaceuticals Corporation Disclosure: Dr. Franz has received personal compensation for activities with Novartis and Lundbeck Research USA, Inc. Dr. Belousova has nothing to disclose. Dr. Sparagana has received personal compensation for activities with Lapharcon LLC, CTS, Novartis, and Upsher-Smith Laboratories. Dr. Bebin has received personal compensation for activities with Medscape. Dr. Frost has received personal compensation for activities with Lundbeck Research USA, Inc., Novartis, UCB Pharma, and Questcor as a speaker and/or advisory board member. Dr. Kuperman has nothing to disclose. Dr. Witt has received personal compensation for activities with AstraZeneca as an advisory board member. Dr. Kohrman has received personal compensation for activities with Novartis as a consultant. Dr. Flamini has nothing to disclose. Dr. Wu has received personal compensation for activities with Tuberous Sclerosis Alliance, Novartis, Lundbeck Research USA, Inc., the Department of Defense, and the National Institutes of Health. Dr. Curatolo has received personal compensation for activities with Shire Pharmaceuticals Group, and Novartis as an advisory board member. Dr. de Vries has received personal compensation for activities with Novartis. Dr. Berkowitz has received personal compensation for activities with Novartis. 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 and/or advisor.