Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study

Abstract

Objectives: We examined the long-term effects of everolimus in patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.

Methods: 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.

Results: 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.

Conclusions: 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.

Trial registration: ClinicalTrials.gov NCT00790400.

Fig 1. CONSORT flow diagram of patient disposition in the double-blind followed by open-label periods.

^aPatients with angiomyolipoma progression were unblinded at the end of the double-blind phase, and patients who were on placebo were allowed to cross over to open-label everolimus.

Fig 2. Best percentage reduction in the sum volume of target renal angiomyolipomas each individual patient reported at any time point in the study in 101 evaluable patients.^a

^a11 patients were considered “non-evaluable” due to missing overall angiomyolipoma response status at each radiological assessment. Among the 12 patients with a best overall response with the status “not evaluable”, only one patient reported at least one radiological assessment with a non-missing overall angiomyolipoma response status.

Fig 3. Renal angiomyolipoma response rate with everolimus over time.

Fig 4. Time to renal angiomyolipoma progression.

Fig 5. Reduction in SEGA volume with everolimus over time in patients with renal angiomyolipomas.

Fig 6. Median GFR (A) and creatinine (B) over time.

Medians are connected by lines, means are displayed as dots. Boxes are drawn from P25 to P75. Whiskers extend from P10 to P90. # indicates values that lie outside [P10, P90]. *Baseline assessment is the last performed before start of everolimus. Post-baseline laboratory assessments performed at unplanned schedule or more than 28 days after discontinuation of everolimus are not presented. Only results from central laboratory are included. Abbreviations: BL = baseline; GFR = glomerular filtration rate; P = percentile.