Everolimus for subependymal giant cell astrocytoma: 5-year final analysis

Abstract

Objective: To analyze the cumulative efficacy and safety of everolimus in treating subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis complex (TSC) from an open-label phase II study (NCT00411619). Updated data became available from the conclusion of the extension phase and are presented in this ≥5-year analysis.

Methods: Patients aged ≥ 3 years with a definite diagnosis of TSC and increasing SEGA lesion size (≥2 magnetic resonance imaging scans) received everolimus starting at 3mg/m(2) /day (titrated to target blood trough levels of 5-15ng/ml). The primary efficacy endpoint was reduction from baseline in primary SEGA volume.

Results: As of the study completion date (January 28, 2014), 22 of 28 (78.6%) initially enrolled patients finished the study per protocol. Median (range) duration of exposure to everolimus was 67.8 (4.7-83.2) months; 12 (52.2%) and 14 (60.9%) of 23 patients experienced SEGA volume reductions of ≥50% and ≥30% relative to baseline, respectively, after 60 months of treatment. The proportion of patients experiencing daily seizures was reduced from 7 of 26 (26.9%) patients at baseline to 2 of 18 (11.1%) patients at month 60. Most commonly reported adverse events (AEs) were upper respiratory tract infection and stomatitis of mostly grade 1 or 2 severity. No patient discontinued treatment due to AEs. The frequency of emergence of most AEs decreased over the course of the study.

Interpretation: Everolimus continues to demonstrate a sustained effect on SEGA tumor reduction over ≥5 years of treatment. Everolimus remained well-tolerated, and no new safety concerns were noted.

© 2015 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

Figures

Figure 1

Patient flow diagram. aWithdrew consent due to noncompliance with antiepileptic medication and worsening hyperkinesis after 4.7 months of treatment in the core phase. bLost to follow‐up after 31.8 months of treatment. cDiscontinued treatment due to inconvenience and cost after 60 months of treatment. dDied due to seizure in her sleep (ie, sudden unexplained death in epilepsy). eNoncompliance and inability to keep up with the study visits after 17.5 months of treatment (n = 1) and withdrawal of parental consent after 21.5 months (n = 1).

Figure 2

Effect of long‐term everolimus treatment on subependymal giant cell astrocytoma (SEGA) volume. Postcontrast T1 magnetic resonance images from 4 patients (rows) illustrate SEGA response at 6 months (B, F, J, N) and long‐term (C, G, K, O) with everolimus. D, H, L, and P show volumetric measurements for the same patients throughout the entire duration of the study. The arrows point to SEGAs. The red line indicates response in contralateral SEGA in a patient with bilateral lesions. All 4 patients were on active treatment at the time of study completion.

Figure 3

Reduction in primary subependymal giant cell astrocytoma (SEGA) volume from baseline over time. Only data for yearly time points after month 12 are presented; however, radiological assessments were performed every 6 months after month 12.

Figure 4

Comparison of primary subependymal giant cell astrocytoma (SEGA) response in individual patients by independent central radiology review at 6 months and 60 months, and the best response at any time point. The dotted lines denote clinically relevant cutoffs of ≥30% and ≥50% reductions from baseline in primary SEGA volume. Data are arranged by decreasing response at 6 months. Best response and 6‐month data are shown for all 28 patients; 60‐month data are shown for the 23 patients with centrally reviewed SEGA scans at that time point.

Figure 5

Patient‐reported seizure frequency (full analysis set). aMore than 6 months since last seizure before baseline or no seizure since last visit. BL = baseline.