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Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex : 2-year open-label extension of the randomised EXIST-1 study . BACKGROUND In the EXIST-1 trial , initiated on Aug 10 , 2009 , more than 35 % of patients with subependymal giant cell astrocytoma ( SEGA ) associated with tuberous sclerosis complex had at least 50 % reduction in SEGA volume after 9·6 months of treatment with everolimus . In this Article , we report interim data ( up to Jan 11 , 2013 ) to support longer-term tolerability and efficacy of everolimus from the continuing 4-year extension phase of EXIST-1 . METHODS We assessed data from a prospective , open-label extension of a multicentre , phase 3 , randomised , double-blind , placebo-controlled study in patients with tuberous sclerosis complex who had SEGA that was growing and needed treatment . In this extension study , we included all patients who had been assigned everolimus during the double-blind , randomised phase of the trial and those patients who crossed over from the placebo group to receive everolimus during the randomised phase or at the start of the extension phase . All patients received oral everolimus at a starting dose of 4·5 mg/m ( 2 ) per day . Everolimus dose was subsequently adjusted subject to tolerability to attain blood trough concentrations of 5-15 ng/mL . An independent central radiology review team assessed SEGA response ( at least a 50 % reduction from baseline in total volume of all target SEGAs ; the primary endpoint ) by MRI at 12 , 24 , and 48 weeks , then every year thereafter in all patients who received at least one dose of everolimus . This study was registered with ClinicalTrials.gov , number NCT00789828 . FINDINGS Of the original 117 randomly assigned patients , 111 were given everolimus between Aug 20 , 2009 , and Jan 11 , 2013 ( date of data cutoff ) ; we included these patients in our longer-term analysis . Median duration of everolimus exposure was 29·3 months ( IQR 19·4-33·8 ) . Median follow-up was 28·3 months ( IQR 19·3-33·0 ) . 54 ( 49 % ) patients had a response of 50 % or greater reduction in SEGA volume ( 95 % CI 39·0-58·3 ) , and duration of response was between 2·1 and 31·1 months ( median not reached ) . SEGA volume was reduced by 50 % or more in 39 ( 37 % ) of 105 patients at 24 weeks , 48 ( 46 % ) of 104 patients at 48 weeks , 36 ( 47 % ) of 76 patients at 96 weeks , and 11 ( 38 % ) of 29 patients at 144 weeks . Stomatitis ( 48 [ 43 % ] patients ) and mouth ulceration ( 33 [ 30 % ] patients ) were the most frequent treatment-related adverse events ; infections were the most commonly reported treatment-related serious adverse event , occurring in 15 ( 14 % ) patients . 35 ( 32 % ) patients reported treatment-related grade 3 or 4 adverse events , the most common of which were stomatitis ( nine [ 8 % ] ) and pneumonia ( nine [ 8 % ] ) . 18 ( 16 % ) patients had treatment-related serious adverse events . Six ( 5 % ) patients withdrew because of adverse events . INTERPRETATION These results support the longer-term use of everolimus in patients who have few treatment options and who need continued treatment for tuberous sclerosis complex and its varied manifestations . Reduction or stabilisation of tumour volume with everolimus will hopefully provide long-term clinical benefit in patients with SEGA . FUNDING Novartis Pharmaceuticals .
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Intervention_Pharmacological
Everolimus
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Outcome_Physical
attain blood trough concentrations
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Outcome_Other
reduction in SEGA
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Outcome_Other
39·0-58·3 ) , and duration of
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Outcome_Other
at 144 weeks
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Outcome_Other
patients ) and mouth
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Outcome_Adverse-effects
adverse events ;
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Outcome_Adverse-effects
grade 3 or 4 adverse
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Outcome_Adverse-effects
patients had treatment-related serious adverse
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Outcome_Adverse-effects
withdrew because of adverse
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Outcome_Other
Reduction or stabilisation of tumour
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Participant_Condition
patients with tuberous sclerosis complex
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Participant_Condition
subependymal giant cell astrocytoma ( SEGA )
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Participant_Condition
tuberous sclerosis complex
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Participant_Condition
tuberous sclerosis complex who had SEGA that was growing and needed treatment
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Participant_Sample-size
117
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Participant_Sample-size
111
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Participant_Condition
tuberous sclerosis