Abstracts

Rationale: TSC is characterized by tumors in multiple organ systems and disabling neurological disorders. Currently the standard of care for SEGA associated with TSC is watchful waiting unless the disease progresses to symptoms. Symptomatic SEGAs, a surgical emergency, are managed with neurosurgical resection, but may not be possible in select patients due to location or size of the tumor or other underlying health issues. A prospective, open-label, phase I/II trial (NCT00411619) of everolimus, an oral, selective mTOR inhibitor, demonstrated a significant reduction in asymptomatic SEGA tumor volume and patient-reported seizure frequency. The extension phase of this trial was undertaken to monitor the long-term safety and efficacy of ongoing everolimus treatment in patients with SEGA associated with TSC. Methods: Patients ≥3 years of age with a definitive TSC diagnosis and serial increase in SEGA lesion size on ≥2 MRI scans received everolimus starting at 3 mg/m²/day orally, titrated to achieve blood trough concentration of 5-15 ng/mL, subject to tolerability. In the initial study, the primary endpoint was to evaluate the safety and potential side effects of everolimus. Measures of efficacy were reduction from baseline in primary SEGA volume and corresponding ≥30% or ≥50% response rate. Results: At analysis cut-off date (14 Dec 2011), 24 of the 28 patients initially enrolled in the study remained on everolimus treatment (median dose, 5.22 mg/m²/day [range, 2.0-11.8]). Median treatment duration was 45.7 months (range, 4.7-58.5). After 36 (n=23), 42 (n=16), and 48 (n=10) months of everolimus treatment, there was a ≥30% reduction from baseline of the primary SEGA volume in 78.3%, 75.0%, and 90% of patients, respectively, and a ≥50% reduction of the primary SEGA volume from baseline in 43.5%, 37.5%, and 50.0% of patients at the same time points. Seizure frequency (patient reported) generally decreased over time (Table 1). At 36 months (n=22), 72.7% patients reported no seizure since their last visit compared with 38.5% at baseline, and only 4.5% had ≥1 seizure per day compared with 26.9% at baseline. Adverse events (AEs) remained similar to those previously reported for everolimus, mostly grade 1/2 (Table 2). There were no drug-related grade 4 AEs and there were 6 drug-related grade 3 AEs. No patient discontinued treatment due to an AE. Conclusions: The results of the 3-year analysis report the latest follow-up data for these patients and confirm maintenance of reductions in SEGA volume. No new safety concerns were identified, and everolimus was well tolerated with prolonged use, which becomes important as other uses of everolimus are investigated, including epilepsy. Longer term everolimus therapy continues to be safe and effective for treatment of SEGA in patients with TSC.