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Long-Term Use of Everolimus in Patients with Tuberous Sclerosis Complex: Final Results from the EXIST-1 Study
David N Franz1, Elena Belousova2, Steven Sparagana3
1Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Background:
Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has demonstrated efficacy in treating subependymal giant cell astrocytomas (SEGAs) and other manifestations of tuberous sclerosis complex (TSC). However, long-term use of mTOR inhibitors might be necessary. This analysis explored long-term efficacy and safety of everolimus from the conclusion of the EXIST-1 study (NCT00789828).
Methods And Findings:
EXIST-1 was an international, prospective, double-blind, placebo-controlled phase 3 trial examining everolimus in patients with new or growing TSC-related SEGA. After a double-blind core phase, all remaining patients could receive everolimus in a long-term, open-label extension. Everolimus was initiated at a dose (4.5 mg/m2/day) titrated to a target blood trough of 5-15 ng/mL. SEGA response rate (primary end point) was defined as the proportion of patients achieving confirmed ≥50% reduction in the sum volume of target SEGA lesions from baseline in the absence of worsening nontarget SEGA lesions, new target SEGA lesions, and new or worsening hydrocephalus. Of 111 patients (median age, 9.5 years) who received ≥1 dose of everolimus (median duration, 47.1 months), 57.7% (95% confidence interval [CI], 47.9-67.0) achieved SEGA response. Of 41 patients with target renal angiomyolipomas at baseline, 30 (73.2%) achieved renal angiomyolipoma response. In 105 patients with ≥1 skin lesion at baseline, skin lesion response rate was 58.1%. Incidence of adverse events (AEs) was comparable with that of previous reports, and occurrence of emergent AEs generally decreased over time. The most common AEs (≥30% incidence) suspected to be treatment-related were stomatitis (43.2%) and mouth ulceration (32.4%).
Conclusions:
Everolimus use led to sustained reduction in tumor volume, and new responses were observed for SEGA and renal angiomyolipoma from the blinded core phase of the study. These findings support the hypothesis that everolimus can safely reverse multisystem manifestations of TSC in a significant proportion of patients.
Trial Registration:
ClinicalTrials.gov NCT00789828.
Insights
Everolimus effectively reduced tumor volume in patients with tuberous sclerosis complex (TSC). Long-term treatment with this mammalian target of rapamycin (mTOR) inhibitor demonstrated sustained efficacy and a manageable safety profile for TSC manifestations.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Tuberous sclerosis complex (TSC) is a genetic disorder characterized by benign tumor growth.
- Subependymal giant cell astrocytomas (SEGAs) are common neurological manifestations of TSC.
- Mammalian target of rapamycin (mTOR) inhibitors, like everolimus, have shown promise in managing TSC.
Purpose of the Study:
- To evaluate the long-term efficacy and safety of everolimus in patients with TSC.
- To assess the sustained reduction in SEGA tumor volume.
- To explore the impact of everolimus on other TSC-related manifestations.
Main Methods:
- Phase 3, international, prospective, double-blind, placebo-controlled trial (EXIST-1).
- Patients received everolimus (4.5 mg/m2/day) with dose titration.
- SEGA response defined as ≥50% reduction in tumor volume; assessment of renal angiomyolipomas and skin lesions.
Main Results:
- 57.7% of 111 patients achieved SEGA response after a median of 47.1 months.
- 73.2% of patients with renal angiomyolipomas and 58.1% with skin lesions responded.
- Adverse events were comparable to previous reports, with stomatitis and mouth ulceration being most common.
Conclusions:
- Everolimus provides sustained tumor volume reduction for TSC-related SEGAs.
- The drug demonstrates efficacy in reversing multisystem manifestations of TSC.
- Long-term everolimus treatment is a safe and effective option for managing TSC.
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