Everolimus long-term safety and efficacy in patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC): final analysis of a phase 2 study (I6-2A)

OBJECTIVE: To assess long-term efficacy and safety of the oral mTOR inhibitor everolimus in the reduction of SEGA tumor volume with data from the conclusion of an open-label, phase II trial (NCT00411619). BACKGROUND: TSC, an autosomal dominant genetic disorder, results in nonmalignant tumors in various organs, including SEGA lesions in the brain. TSC-associated SEGA may cause neurological sequelae such as epilepsy and hydrocephalus. Due to SEGA tumor size or location, surgical resection may not be possible. Everolimus significantly reduced SEGA tumor volume in an open-label, phase I/II trial. Safety and efficacy data for 蠅5 years are presented in this final long-term analysis. DESIGN/METHODS: Patients aged 蠅3 years with a definitive TSC diagnosis and a serial increase in SEGA lesion size (蠅2 MRI scans) received everolimus starting at 3 mg/m²/day (titrated to target blood trough levels of 5-15 ng/mL). The primary efficacy measure was reduction from baseline in primary SEGA volume. RESULTS: At the final analysis cutoff date (January 28, 2014), 22/28 (78.6[percnt]) patients initially enrolled completed the study. Median duration of exposure to everolimus was 67.8 months (range 4.7-83.2 months). After 60 months of treatment, 12/23 (52.2[percnt]) patients experienced SEGA volume reductions 蠅50[percnt] relative to baseline, while 14/23 patients (60.9[percnt]) achieved a reduction 蠅30[percnt]. Patient-reported seizure frequency (ie, proportion of patients experiencing seizures on a daily basis) was reduced from 7/26 (26.9[percnt]) patients at baseline to 2/18 patients (11.1[percnt]) at month 60. Adverse events (AEs) for everolimus remained similar to previous reports. No patient discontinued treatment due to AEs. Most common AEs were upper respiratory tract infection and stomatitis of mostly grade 1 or 2 severity. Incidence of emergent AEs decreased over time. CONCLUSIONS: This analysis confirms the long-term prevention of SEGA growth using everolimus. Safety and tolerability of everolimus improved over 5 years. Study Supported by: Novartis Pharmaceuticals Corporation Disclosure: Dr. Franz has received personal compensation for activities with Novartis and Lundbeck Research USA, Inc. Dr. Care has nothing to disclose. Dr. Holland has nothing to disclose. Dr. Agricola has nothing to disclose. Dr. Tudor has nothing to disclose. Dr. Berkowitz has received personal compensation for activities with Novartis. Dr. Miao has received personal compensation for activities with Novartis as an employee. Dr. Peyrard has received personal compensation for activities with Novartis as an employee. Dr. Krueger has received personal compensation for activities with Novartis and Lundbeck Research USA, Inc. as a consultant, speaker, and/or advisory board participation.