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.

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.