Long-term use of everolimus in patients with tuberous sclerosis complex: Final results from the EXIST-1 study

David N. Franz, Elena Belousova, Steven Sparagana, E. Martina Bebin, Michael D. Frost, Rachel Kuperman, Olaf Witt, Michael H. Kohrman, J. Robert Flamini, Joyce Y. Wu, Paolo Curatolo, Petrus J. De Vries, Noah Berkowitz, Julie Niolat, Sergiusz Jóźwiak

Research output: Contribution to journalArticle

56 Citations (Scopus)

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 doubleblind 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.

Original languageEnglish (US)
Article numbere0158476
JournalPLoS One
Volume11
Issue number6
DOIs
StatePublished - Jun 1 2016

Fingerprint

Tuberous Sclerosis
Astrocytoma
sclerosis
giant cells
Angiomyolipoma
lesions (animal)
kidneys
skin lesions
Sirolimus
Kidney
Skin
hydrocephalus
incidence
Stomatitis
Everolimus
Incidence
Hydrocephalus
dosage
Tumor Burden
placebos

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Franz, D. N., Belousova, E., Sparagana, S., Bebin, E. M., Frost, M. D., Kuperman, R., ... Jóźwiak, S. (2016). Long-term use of everolimus in patients with tuberous sclerosis complex: Final results from the EXIST-1 study. PLoS One, 11(6), [e0158476]. https://doi.org/10.1371/journal.pone.0158476

Long-term use of everolimus in patients with tuberous sclerosis complex : Final results from the EXIST-1 study. / Franz, David N.; Belousova, Elena; Sparagana, Steven; Bebin, E. Martina; Frost, Michael D.; Kuperman, Rachel; Witt, Olaf; Kohrman, Michael H.; Flamini, J. Robert; Wu, Joyce Y.; Curatolo, Paolo; De Vries, Petrus J.; Berkowitz, Noah; Niolat, Julie; Jóźwiak, Sergiusz.

In: PLoS One, Vol. 11, No. 6, e0158476, 01.06.2016.

Research output: Contribution to journalArticle

Franz, DN, Belousova, E, Sparagana, S, Bebin, EM, Frost, MD, Kuperman, R, Witt, O, Kohrman, MH, Flamini, JR, Wu, JY, Curatolo, P, De Vries, PJ, Berkowitz, N, Niolat, J & Jóźwiak, S 2016, 'Long-term use of everolimus in patients with tuberous sclerosis complex: Final results from the EXIST-1 study', PLoS One, vol. 11, no. 6, e0158476. https://doi.org/10.1371/journal.pone.0158476
Franz, David N. ; Belousova, Elena ; Sparagana, Steven ; Bebin, E. Martina ; Frost, Michael D. ; Kuperman, Rachel ; Witt, Olaf ; Kohrman, Michael H. ; Flamini, J. Robert ; Wu, Joyce Y. ; Curatolo, Paolo ; De Vries, Petrus J. ; Berkowitz, Noah ; Niolat, Julie ; Jóźwiak, Sergiusz. / Long-term use of everolimus in patients with tuberous sclerosis complex : Final results from the EXIST-1 study. In: PLoS One. 2016 ; Vol. 11, No. 6.
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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 doubleblind 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.",
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T2 - Final results from the EXIST-1 study

AU - Franz, David N.

AU - Belousova, Elena

AU - Sparagana, Steven

AU - Bebin, E. Martina

AU - Frost, Michael D.

AU - Kuperman, Rachel

AU - Witt, Olaf

AU - Kohrman, Michael H.

AU - Flamini, J. Robert

AU - Wu, Joyce Y.

AU - Curatolo, Paolo

AU - De Vries, Petrus J.

AU - Berkowitz, Noah

AU - Niolat, Julie

AU - Jóźwiak, Sergiusz

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N2 - 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 doubleblind 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.

AB - 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 doubleblind 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.

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