Effect of everolimus on skin lesions in patients treated for subependymal giant cell astrocytoma and renal angiomyolipoma: final 4-year results from the randomized EXIST-1 and EXIST-2 studies

D. N. Franz, K. Budde, J. C. Kingswood, E. Belousova, S. Sparagana, P. J. de Vries, N. Berkowitz, A. Ridolfi, John Bissler

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: Tuberous sclerosis complex (TSC) is a genetic disorder associated with tumour growth in various organs, including the brain, kidneys, heart and skin. Cutaneous lesions are prevalent manifestations of TSC, occurring in up to 90% of patients. Oral mammalian target of rapamycin inhibitors, such as everolimus, is believed to be effective for treatment of TSC-associated lesions because they act on the underlying disease pathophysiology. Objective: We evaluated the long-term effect of oral everolimus on TSC-associated skin lesions as a secondary objective in the phase III studies EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400) after approximately 4 years of treatment. Materials and methods: Everolimus was dosed 4.5 mg/m2/day (titrated to trough 5–15 ng/mL) in patients with TSC-associated subependymal giant cell astrocytoma in EXIST-1, and 10 mg/day initially in adult patients with TSC- or sporadic lymphangioleiomyomatosis–associated renal angiomyolipoma in EXIST-2. Following positive results from the core phase, remaining patients were offered open-label everolimus in an extension. Skin lesion response rate was the proportion of patients achieving complete or partial clinical response. Results: A total of 105 patients in EXIST-1 and 107 in EXIST-2 received everolimus and had ≥1 skin lesion at baseline. Skin lesion response rate (95% confidence interval) was 58.1% (48.1–67.7%) in EXIST-1 and 68.2% (58.5–76.9%) in EXIST-2; most were partial responses. At week 192 (EXIST-1: n = 55; EXIST-2: n = 56), 69% and 66% had a response. Most common drug-related adverse event was stomatitis (41–45%). Conclusion: Oral everolimus improved TSC-related skin lesions, with responses sustained over 4 years of treatment in EXIST-1 and EXIST-2.

Original languageEnglish (US)
Pages (from-to)1796-1803
Number of pages8
JournalJournal of the European Academy of Dermatology and Venereology
Volume32
Issue number10
DOIs
StatePublished - Oct 1 2018

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Angiomyolipoma
Tuberous Sclerosis
Astrocytoma
Kidney
Skin
Stomatitis
Inborn Genetic Diseases
Sirolimus
Everolimus
Drug-Related Side Effects and Adverse Reactions
Therapeutics
Confidence Intervals
Brain
Growth

All Science Journal Classification (ASJC) codes

  • Dermatology
  • Infectious Diseases

Cite this

Effect of everolimus on skin lesions in patients treated for subependymal giant cell astrocytoma and renal angiomyolipoma : final 4-year results from the randomized EXIST-1 and EXIST-2 studies. / Franz, D. N.; Budde, K.; Kingswood, J. C.; Belousova, E.; Sparagana, S.; de Vries, P. J.; Berkowitz, N.; Ridolfi, A.; Bissler, John.

In: Journal of the European Academy of Dermatology and Venereology, Vol. 32, No. 10, 01.10.2018, p. 1796-1803.

Research output: Contribution to journalArticle

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title = "Effect of everolimus on skin lesions in patients treated for subependymal giant cell astrocytoma and renal angiomyolipoma: final 4-year results from the randomized EXIST-1 and EXIST-2 studies",
abstract = "Background: Tuberous sclerosis complex (TSC) is a genetic disorder associated with tumour growth in various organs, including the brain, kidneys, heart and skin. Cutaneous lesions are prevalent manifestations of TSC, occurring in up to 90{\%} of patients. Oral mammalian target of rapamycin inhibitors, such as everolimus, is believed to be effective for treatment of TSC-associated lesions because they act on the underlying disease pathophysiology. Objective: We evaluated the long-term effect of oral everolimus on TSC-associated skin lesions as a secondary objective in the phase III studies EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400) after approximately 4 years of treatment. Materials and methods: Everolimus was dosed 4.5 mg/m2/day (titrated to trough 5–15 ng/mL) in patients with TSC-associated subependymal giant cell astrocytoma in EXIST-1, and 10 mg/day initially in adult patients with TSC- or sporadic lymphangioleiomyomatosis–associated renal angiomyolipoma in EXIST-2. Following positive results from the core phase, remaining patients were offered open-label everolimus in an extension. Skin lesion response rate was the proportion of patients achieving complete or partial clinical response. Results: A total of 105 patients in EXIST-1 and 107 in EXIST-2 received everolimus and had ≥1 skin lesion at baseline. Skin lesion response rate (95{\%} confidence interval) was 58.1{\%} (48.1–67.7{\%}) in EXIST-1 and 68.2{\%} (58.5–76.9{\%}) in EXIST-2; most were partial responses. At week 192 (EXIST-1: n = 55; EXIST-2: n = 56), 69{\%} and 66{\%} had a response. Most common drug-related adverse event was stomatitis (41–45{\%}). Conclusion: Oral everolimus improved TSC-related skin lesions, with responses sustained over 4 years of treatment in EXIST-1 and EXIST-2.",
author = "Franz, {D. N.} and K. Budde and Kingswood, {J. C.} and E. Belousova and S. Sparagana and {de Vries}, {P. J.} and N. Berkowitz and A. Ridolfi and John Bissler",
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T2 - final 4-year results from the randomized EXIST-1 and EXIST-2 studies

AU - Franz, D. N.

AU - Budde, K.

AU - Kingswood, J. C.

AU - Belousova, E.

AU - Sparagana, S.

AU - de Vries, P. J.

AU - Berkowitz, N.

AU - Ridolfi, A.

AU - Bissler, John

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Background: Tuberous sclerosis complex (TSC) is a genetic disorder associated with tumour growth in various organs, including the brain, kidneys, heart and skin. Cutaneous lesions are prevalent manifestations of TSC, occurring in up to 90% of patients. Oral mammalian target of rapamycin inhibitors, such as everolimus, is believed to be effective for treatment of TSC-associated lesions because they act on the underlying disease pathophysiology. Objective: We evaluated the long-term effect of oral everolimus on TSC-associated skin lesions as a secondary objective in the phase III studies EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400) after approximately 4 years of treatment. Materials and methods: Everolimus was dosed 4.5 mg/m2/day (titrated to trough 5–15 ng/mL) in patients with TSC-associated subependymal giant cell astrocytoma in EXIST-1, and 10 mg/day initially in adult patients with TSC- or sporadic lymphangioleiomyomatosis–associated renal angiomyolipoma in EXIST-2. Following positive results from the core phase, remaining patients were offered open-label everolimus in an extension. Skin lesion response rate was the proportion of patients achieving complete or partial clinical response. Results: A total of 105 patients in EXIST-1 and 107 in EXIST-2 received everolimus and had ≥1 skin lesion at baseline. Skin lesion response rate (95% confidence interval) was 58.1% (48.1–67.7%) in EXIST-1 and 68.2% (58.5–76.9%) in EXIST-2; most were partial responses. At week 192 (EXIST-1: n = 55; EXIST-2: n = 56), 69% and 66% had a response. Most common drug-related adverse event was stomatitis (41–45%). Conclusion: Oral everolimus improved TSC-related skin lesions, with responses sustained over 4 years of treatment in EXIST-1 and EXIST-2.

AB - Background: Tuberous sclerosis complex (TSC) is a genetic disorder associated with tumour growth in various organs, including the brain, kidneys, heart and skin. Cutaneous lesions are prevalent manifestations of TSC, occurring in up to 90% of patients. Oral mammalian target of rapamycin inhibitors, such as everolimus, is believed to be effective for treatment of TSC-associated lesions because they act on the underlying disease pathophysiology. Objective: We evaluated the long-term effect of oral everolimus on TSC-associated skin lesions as a secondary objective in the phase III studies EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400) after approximately 4 years of treatment. Materials and methods: Everolimus was dosed 4.5 mg/m2/day (titrated to trough 5–15 ng/mL) in patients with TSC-associated subependymal giant cell astrocytoma in EXIST-1, and 10 mg/day initially in adult patients with TSC- or sporadic lymphangioleiomyomatosis–associated renal angiomyolipoma in EXIST-2. Following positive results from the core phase, remaining patients were offered open-label everolimus in an extension. Skin lesion response rate was the proportion of patients achieving complete or partial clinical response. Results: A total of 105 patients in EXIST-1 and 107 in EXIST-2 received everolimus and had ≥1 skin lesion at baseline. Skin lesion response rate (95% confidence interval) was 58.1% (48.1–67.7%) in EXIST-1 and 68.2% (58.5–76.9%) in EXIST-2; most were partial responses. At week 192 (EXIST-1: n = 55; EXIST-2: n = 56), 69% and 66% had a response. Most common drug-related adverse event was stomatitis (41–45%). Conclusion: Oral everolimus improved TSC-related skin lesions, with responses sustained over 4 years of treatment in EXIST-1 and EXIST-2.

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