Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study.
<h4>Objectives</h4>We examined the long-term effects of everolimus in patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.<h4>Methods</h4>Following favorable results from the double-blind core phase of EXIST-2 (NC...
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Public Library of Science (PLoS)
2017-01-01
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| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180939&type=printable |
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| author | John J Bissler J Chris Kingswood Elzbieta Radzikowska Bernard A Zonnenberg Elena Belousova Michael D Frost Matthias Sauter Susanne Brakemeier Petrus J de Vries Noah Berkowitz Maurizio Voi Severine Peyrard Klemens Budde |
| author_facet | John J Bissler J Chris Kingswood Elzbieta Radzikowska Bernard A Zonnenberg Elena Belousova Michael D Frost Matthias Sauter Susanne Brakemeier Petrus J de Vries Noah Berkowitz Maurizio Voi Severine Peyrard Klemens Budde |
| author_sort | John J Bissler |
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| description | <h4>Objectives</h4>We examined the long-term effects of everolimus in patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.<h4>Methods</h4>Following favorable results from the double-blind core phase of EXIST-2 (NCT00790400), patients were allowed to receive open-label everolimus (extension phase). Patients initially randomly assigned to everolimus continued on the same dose; those who were receiving placebo crossed over to everolimus 10 mg/day. Dose modifications were based on tolerability. The primary end point was angiomyolipoma response rate, defined as a ≥50% reduction from baseline in the sum volume of target renal angiomyolipomas in the absence of new target angiomyolipomas, kidney volume increase of >20% from nadir, and angiomyolipoma-related bleeding grade ≥2. The key secondary end point was safety.<h4>Results</h4>Of the 112 patients who received ≥1 dose of everolimus, 58% (95% CI, 48.3% to 67.3%) achieved angiomyolipoma response. Almost all patients (97%) experienced reduction in renal lesion volumes at some point during the study period. Median duration of everolimus exposure was 46.9 months. Sixteen (14.3%) patients experienced angiomyolipoma progression at some point in the study. No angiomyolipoma-related bleeding or nephrectomies were reported. One patient on everolimus underwent embolization for worsening right flank pain. Subependymal giant cell astrocytoma lesion response was achieved in 48% of patients and skin lesion response in 68% of patients. The most common adverse events suspected to be treatment-related were stomatitis (42%), hypercholesterolemia (30.4%), acne (25.9%), aphthous stomatitis and nasopharyngitis (each 21.4%). Ten (8.9%) patients withdrew because of an adverse event. Renal function remained stable, and the frequency of emergent adverse events generally decreased over time.<h4>Conclusions</h4>Everolimus treatment remained safe and effective over approximately 4 years. The overall risk/benefit assessment supports the use of everolimus as a viable treatment option for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.<h4>Trial registration</h4>ClinicalTrials.gov NCT00790400. |
| format | Article |
| id | doaj-art-adb7a1c8a2244a96b11096a9f9d07b28 |
| institution | DOAJ |
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| language | English |
| publishDate | 2017-01-01 |
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| spelling | doaj-art-adb7a1c8a2244a96b11096a9f9d07b282025-08-20T02:45:57ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01128e018093910.1371/journal.pone.0180939Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study.John J BisslerJ Chris KingswoodElzbieta RadzikowskaBernard A ZonnenbergElena BelousovaMichael D FrostMatthias SauterSusanne BrakemeierPetrus J de VriesNoah BerkowitzMaurizio VoiSeverine PeyrardKlemens Budde<h4>Objectives</h4>We examined the long-term effects of everolimus in patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.<h4>Methods</h4>Following favorable results from the double-blind core phase of EXIST-2 (NCT00790400), patients were allowed to receive open-label everolimus (extension phase). Patients initially randomly assigned to everolimus continued on the same dose; those who were receiving placebo crossed over to everolimus 10 mg/day. Dose modifications were based on tolerability. The primary end point was angiomyolipoma response rate, defined as a ≥50% reduction from baseline in the sum volume of target renal angiomyolipomas in the absence of new target angiomyolipomas, kidney volume increase of >20% from nadir, and angiomyolipoma-related bleeding grade ≥2. The key secondary end point was safety.<h4>Results</h4>Of the 112 patients who received ≥1 dose of everolimus, 58% (95% CI, 48.3% to 67.3%) achieved angiomyolipoma response. Almost all patients (97%) experienced reduction in renal lesion volumes at some point during the study period. Median duration of everolimus exposure was 46.9 months. Sixteen (14.3%) patients experienced angiomyolipoma progression at some point in the study. No angiomyolipoma-related bleeding or nephrectomies were reported. One patient on everolimus underwent embolization for worsening right flank pain. Subependymal giant cell astrocytoma lesion response was achieved in 48% of patients and skin lesion response in 68% of patients. The most common adverse events suspected to be treatment-related were stomatitis (42%), hypercholesterolemia (30.4%), acne (25.9%), aphthous stomatitis and nasopharyngitis (each 21.4%). Ten (8.9%) patients withdrew because of an adverse event. Renal function remained stable, and the frequency of emergent adverse events generally decreased over time.<h4>Conclusions</h4>Everolimus treatment remained safe and effective over approximately 4 years. The overall risk/benefit assessment supports the use of everolimus as a viable treatment option for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.<h4>Trial registration</h4>ClinicalTrials.gov NCT00790400.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180939&type=printable |
| spellingShingle | John J Bissler J Chris Kingswood Elzbieta Radzikowska Bernard A Zonnenberg Elena Belousova Michael D Frost Matthias Sauter Susanne Brakemeier Petrus J de Vries Noah Berkowitz Maurizio Voi Severine Peyrard Klemens Budde Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study. PLoS ONE |
| title | Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study. |
| title_full | Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study. |
| title_fullStr | Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study. |
| title_full_unstemmed | Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study. |
| title_short | Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study. |
| title_sort | everolimus long term use in patients with tuberous sclerosis complex four year update of the exist 2 study |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180939&type=printable |
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