Long-Term Use of Everolimus in Patients with Tuberous Sclerosis Complex: Final Results from the EXIST-1 Study

Abstract

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.

Conflict of interest statement

Competing Interests: Dr. Franz received support from Novartis for other research at his institution, was consultant to Novartis (payments to employer CCHMC), received honoraria from Novartis and Lundbeck Pharmaceuticals, has been reimbursed by Novartis and Lundbeck Pharmaceuticals for travel costs for lectures, and performed legal work in reviewing medical malpractice cases, occasionally in giving expert testimony for various attorneys. Dr. Belousova received honoraria as speaker from Novartis and served as principal investigator on 2 research studies funded by Novartis Oncology. Dr. Sparagana received honoraria as a speaker for Novartis, served as site principal investigator on this and another research study funded by Novartis Oncology, serves on professional advisory board of Tuberous Sclerosis Alliance (TSA), and has received travel funds from the TSA related to role on the TSC Natural History Database Steering Committee. Drs. Bebin, Kuperman, Witt, and Flamini served as principal investigators on a research study funded by Novartis Oncology. Dr. Frost served as a consultant and participated in Advisory Boards for Novartis. Dr. Wu serves on the professional advisory board for the Tuberous Sclerosis Alliance, received honoraria from, serves on the scientific advisory board and the speakers’ bureau for Novartis and Lundbeck, and received research support from the Tuberous Sclerosis Alliance, Novartis, Today’s and Tomorrow’s Children Fund, Department of Defense/Congressionally Directed Medical Research Program, and the National Institutes of Health. Dr. Curatolo received honoraria for serving on advisory boards and providing lectures on behalf of Novartis Oncology. Dr. de Vries served as a consultant and participated in Advisory Boards for Novartis and received travel honoraria from Novartis (donated to charity). Dr. Berkowitz and Ms. Niolat are employees of Novartis. Dr. Jóźwiak received honoraria for serving on advisory boards and providing lectures on behalf of Novartis Oncology. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. CONSORT diagram.

*Administrative problems defined as non-compliant with study visit or non-compliant with study drug.

Fig 2. Median percentage reduction in SEGA and renal angiomyolipoma volume over time.

Fig 3. Proportion of patients with ≥50% reduction/improvement in SEGA, renal angiomyolipoma, or skin lesions.

* *Skin lesion response determined as partial or complete by Physician’s Global Assessment.