Effect of everolimus on angiogenic biomarkers in patients with tuberous sclerosis complex (TSC): Results from EXIST-1 and EXIST-2.

Tumor Biology
Session Type and Session Title: 
General Poster Session, Tumor Biology
Abstract Number: 


J Clin Oncol 30, 2012 (suppl; abstr 10619)
David Neal Franz, Christopher Kingswood, Sergiusz Jozwiak, Klemens Budde, Elena Belousova, Steven Sparagana, B. A. Zonnenberg, Michael Frost, Gaurav D. Shah, Jeremie Lebrec, James Ford, Creton Kalfoglou, David Chen, John Bissler; Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Royal Sussex County Hospital, Brighton, United Kingdom; The Children's Memorial Health Institute of Warsaw, Warsaw, Poland; Charite-Universitätsmedizin Berlin, Berlin, Germany; Moscow Research Institute of Pediatrics and Pediatric Surgery, Moscow, Russia; Texas Scottish Rite Hospital for Children, Dallas, TX; Universitair Medisch Centrum, Utrecht, Netherlands; Minnesota Epilepsy Group, St. Paul, MN; Novartis Pharmaceuticals, Florham Park, NJ; SDE Services AG, Pratteln, Switzerland; Novartis Pharmaceuticals, East Hanover, NJ

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Abstract Disclosures


Background: The efficacy and safety of everolimus, an oral mTOR inhibitor, was assessed in two randomized, double-blind, placebo-controlled, phase 3 trials: EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400). EXIST-1 examined everolimus for the treatment of subependymal giant cell astrocytoma (SEGA) associated with TSC and EXIST-2 for the treatment of renal angiomyolipoma (AML) associated with either TSC or sporadic lymphangioleiomyomatosis. In each instance, everolimus was superior to placebo for the primary endpoints, SEGA and renal AML response rates. Inhibitors of mTOR have antiangiogenic effects on tumor growth in vitro and in vivo. Methods: Patients were randomized to receive everolimus (n=78) starting at 4.5 mg/m2/day (target trough, 5-15 ng/mL) or placebo (n=39) in EXIST-1 and 10 mg/day everolimus (n=79) or placebo (n=39) in EXIST-2. Plasma samples were taken at baseline and pre-dosing on day 1 of weeks 4, 12, 24, 36, and 48 of treatment. Angiogenic markers of interest were vascular endothelial growth factor (VEGF)-A and -D, placental growth factor (PlGF), soluble VEGF receptor-1 (sVEGFR1), soluble VEGF receptor 2 (sVEGFR2), c-Kit, and collagen type IV. Results: Compared with placebo, a sustained ~30% and ~60% increase in VEGF-A was observed in the everolimus arm of EXIST-1 and EXIST-2, respectively. A concomitant decrease in collagen type IV (~25% EXIST-1; ~45% EXIST-2) and sVEGFR2 (~25% both trials) was also observed in the everolimus arm. A sustained decrease (~60%) in VEGF-D was observed in the everolimus arm of EXIST-2, but not EXIST-1. In both studies, no change was observed in PlGF, sVEGFR1, or c-Kit plasma concentrations in the everolimus arm or any biomarkers evaluated in the placebo arm. Baseline sVEGFR2 and VEGF-D were ~40% and ~4-fold higher, respectively, while VEGF-A was ~50% lower in EXIST-2 compared with EXIST-1. A similar baseline plasma concentration for the other biomarkers was noted in both studies. Conclusions: Patients presenting with SEGA or renal AML associated with TSC had a reduction in plasma concentrations of sVEGFR2, collagen type IV, and VEGF-D (AML only) and an increase in VEGF-A. Everolimus may have antiangiogenic properties in TSC patients.