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Everolimus therapy for angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: Results from EXIST-2.

356 Background: We evaluated everolimus, an oral mTOR inhibitor, for treating angiomyolipoma (AML) in patients with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM).


METHODS
EXIST-2 ( NCT00790400 ) is a prospective, international, randomized, double-blind, placebo-controlled, phase III study. Patients (≥1 AML with longest diameter ≥3 cm) were stratified by (i) TSC and enzyme-inducing anti-epileptic drug (EIAED) use, (ii) TSC and EIAED non-use, (iii) sLAM and randomized 2:1 to receive everolimus 10 mg daily (n=79) or placebo (n=39). Kidney CT/MRI was performed at baseline, at 12, 24, and 48 weeks, and then annually. Primary efficacy endpoint was the proportion of patients with AML response (best overall confirmed ≥50% reduction in sum of volumes of all target AML relative to baseline). Secondary efficacy endpoints included time to AML progression and skin lesion response rate in patients with >1 skin lesion at baseline (n=114). Adverse events (AE) were monitored every visit. Core phase results (6 months from last patient randomized) are presented.


RESULTS
Patient characteristics were balanced across the 2 groups; median patient age was 31 years. Median treatment duration was 38.1 weeks (everolimus) and 34.0 weeks (placebo). Everolimus best overall response rate (41.8%) was superior to placebo (0%) for the primary efficacy endpoint (p<0.0001). Median time to AML progression was 11.4 months for placebo and was not reached for everolimus. The everolimus group had a significantly higher best overall skin lesion response rate (complete or partial response) than placebo (26% vs. 0%; p=0.0002). Everolimus was associated with an acceptable safety profile consistent with previous reports in TSC, with most AEs being grade 1 or 2. Serious AE incidence was similar in the treatment arms (everolimus 19.0% vs. placebo 17.9%).


CONCLUSIONS
Everolimus treatment produced a clinically and statistically significant reduction in AML volume compared with placebo and showed a safety profile consistent with previous reports. Everolimus represents the first potential pharmacologic treatment option for patients with AML.