The effect of everolimus on renal angiomyolipoma in pediatric patients with tuberous sclerosis being treated for subependymal giant cell astrocytoma

Abstract

Background: Patients with tuberous sclerosis complex (TSC) often have multiple TSC-associated hamartomas, particularly in the brain and kidney.

Methods: This was a post hoc analysis of pediatric patients being treated for subependymal giant cell astrocytomas (SEGAs) during the phase 3, randomized, double-blind, placebo-controlled EXIST-1 trial. Patients were initially randomly assigned to receive everolimus 4.5 mg/m²/day (target blood trough 5-15 mg/dl) or placebo and could continue in an open-label extension phase. Angiomyolipoma response rates were analyzed in patients aged <18 years with ≥1 target angiomyolipoma lesion at baseline. Response was defined as the proportion of patients with a ≥50% reduction in the sum volume of target renal angiomyolipomata from baseline, in the absence of new target angiomyolipomata, a >20% increase in kidney volume from nadir, and angiomyolipoma-related bleeding ≥ grade 2. Tolerability was also assessed.

Results: Overall, this analysis included 33 patients. Renal angiomyolipoma response was achieved by 75.8% of patients (95% confidence interval, 57.7-88.9%), with sustained mean reductions in renal angiomyolipoma volume over nearly 4 years of treatment. In addition, most (≥80%) achieved clinically relevant reductions in angiomyolipoma volume (≥50%), beginning at week 24 and continuing for the remainder of the study. Everolimus was generally well tolerated in this subgroup, with most adverse events being grade 1 or 2 in severity.

Conclusions: Although everolimus is currently not indicated for this use, this analysis from EXIST-1 demonstrates its long-term efficacy and safety for the treatment of renal angiomyolipoma in pediatric patients undergoing treatment for TSC-associated SEGA.

Keywords: Angiomyolipoma; Everolimus; Pediatrics; Subependymal giant cell astrocytoma; Tuberous sclerosis complex.

Fig. 1

Best percentage change in renal angiomyolipoma volume on treatment. *Percentage change in sum of volumes of target angiomyolipoma lesion available for one subject, but contradicted by overall angiomyolipoma response = progressive disease. ^aPatients for whom best percentage change in target angiomyolipoma lesion volume was not available or with overall response of “not evaluable” were excluded from the graph

Fig. 2

a Mean (standard deviation) reductions in the sum of volume of target angiomyolipoma lesions over time and b the proportions of patients achieving an angiomyolipoma volume reduction of ≥50% or ≥30% over time

Fig. 3

Angiomyolipoma volume over time in patients switching from placebo to everolimus, as measured by a the sum of volumes of the target angiomyolipoma and b the percentage change from baseline