The effect of everolimus on renal angiomyolipoma in patients with tuberous sclerosis complex being treated for subependymal giant cell astrocytoma: subgroup results from the randomized, placebo-controlled, Phase 3 trial EXIST-1

Abstract

Background: Tuberous sclerosis complex (TSC) is characterized by benign tumours in multiple organs, including the brain, kidneys, skin, lungs and heart. Our objective was to evaluate everolimus, an mTOR inhibitor, in the treatment of angiomyolipoma in patients with subependymal giant cell astrocytoma (SEGA) associated with TSC.

Methods: EXamining everolimus In a Study of Tuberous Sclerosis Complex-1 (NCT00789828), a prospective, double-blind, randomized, placebo-controlled, Phase 3 study, examined everolimus in treating SEGA associated with TSC. Patients with serial SEGA growth from pre-baseline to baseline scans were randomly assigned (2:1) to receive 4.5 mg/m(2)/day everolimus (target blood trough: 5-15 ng/mL; n = 78) or placebo (n = 39). Angiomyolipoma response rates were analysed in patients (n = 44) with target baseline angiomyolipoma lesions (≥1 angiomyolipoma; longest diameter ≥1.0 cm). An angiomyolipoma response rate, defined as the proportion of patients with confirmed angiomyolipoma response, was assessed by kidney CT or MRI screening at baseline, at 12, 24 and 48 weeks and annually.

Results: Angiomyolipoma response rates were 53.3% (16/30) and 0% (0/14) for everolimus- and placebo-treated patients, respectively. Angiomyolipoma reductions ≥50% in the sum of volumes of all target lesions were seen only in everolimus-treated patients (56.5, 78.3 and 80.0%) compared with placebo-treated patients (0% at each time point) at Weeks 12, 24 and 48, respectively. Greater percentages of everolimus-treated patients had angiomyolipoma reductions ≥30% at these same time points (82.6, 100 and 100% versus 8.3, 18.2 and 16.7% for everolimus versus placebo, respectively).

Conclusions: Everolimus showed efficacy in reducing angiomyolipoma lesion volume in patients with SEGA associated with TSC.The trial is registered with ClinicalTrials.gov, number NCT00789828; https://ichgcp.net/clinical-trials-registry/NCT00789828?term=EXIST-1&rank=1.

Keywords: everolimus; renal angiomyolipoma; tuberous sclerosis complex.

© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Figures

FIGURE 1:

CONSORT flow diagram of patient disposition in the double-blind period up to the cut-off date (2 March 2011).

FIGURE 2:

Percentage change from baseline of sum of volumes (cm3) of target angiomyolipoma lesions by time window.

FIGURE 3:

Box plot of percentage change from baseline in sum of volumes of target angiomyolipoma lesions by time window. Fifth percentile, first quartile, median, third quartile, 95th percentile and mean (•) are displayed in the box plot, as are extreme values (*).

FIGURE 4:

Box plot of change from baseline in sum of volumes of target angiomyolipoma lesions by time window. Fifth percentile, first quartile, median, third quartile, 95th percentile and mean (•) are displayed in the box plot, as are extreme values (*). #Values that lie outside the range of the y-axis.

FIGURE 5:

Box plot of concentration–time profiles for everolimus at pre-dose (trough) by time window. Median is displayed as (−), mean as (•), boxes are drawn from 25th percentiles to 75th percentiles and whiskers extend from 10th percentiles to 90th percentiles. #Values that lie outside the range of 10th percentiles and 90th percentiles.

FIGURE 6:

Box plot of concentration–time profiles for everolimus at 2 h post-dose by time window. Medians are displayed as (−) and means as (•), boxes are drawn from 25th percentiles to 75th percentiles and whiskers extend from 10th percentiles to 90th percentiles. #Values that lie outside the range of 10th percentiles and 90th percentiles.