Effects of Bevacizumab and Everolimus for the treatment of Vestibular Schwannomas in patients with Neurofibromatosis Type 2
Aziz Ouerdani (1,4), Stéphane Goutagny (2), Michel Kalamarides (3), and Iñaki F. Trocóniz (4)
(1) NUMED Team, INRIA Rhône-Alpes, Grenoble, France, (2) Neurosurgery, Beaujon Hospital, Assistance Publique Hôpitaux de Paris, Clichy, France, (3) Neurosurgery, Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France, (4) Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy; University of Navarra, Pamplona, Spain
Objectives: To develop a mechanism-based mixed-effects model to evaluate and compare the efficiency of bevacizumab and everolimus for the treatment of vestibular schwannomas (VS) in patients with neurofibromatosis type 2 (NF2).
Methods: Data analysis included 22 patients with NF2. 13 patients received bevacizumab at 5 mg/kg every 2 weeks (reduced at every 3 or 4 weeks for some patients), 7 patients received everolimus at 10 mg once daily (reduced to 5 mg once daily for some patients), and the 2 last patients received both treatments at distinct periods. VS were classified into 4 stages (from I to IV) according to their tumor size that display a high variability (Initial VS size: median = 1.51 cm3; range = 0.03 – 14 cm3). Data were log transformed and analyzed in NONMEM 7.2 with the SAEM algorithm. We then used the model to simulate different protocols of bevacizumab only and everolimus only.
Results: VS growth was described by a Simeoni growth model  where the proliferation and the cell death were depending on the VEGF levels. Bevacizumab and VEGF concentrations in nM are simulated from a published Target Mediated Drug Disposition (TMDD) model . Everolimus reduces VEGF synthesis through mTORC1 inhibition. Cell death is 4 times higher with bevacizumab than everolimus. Tumor smaller than 7.5 cm3 grow exponentially. After 7.5 cm3 VS grow linearly at a rate of 0.3 cm3 per month. Everolimus efficiency was decreased because of the deactivation of a negative feedback loop that increases tumor growth. Our model confirms the roles of the VEGF on the proliferation and survival of Schwann cells. Tumor shrinkage in patients treated by bevacizumab is more important than in everolimus treated patients. Simulations suggest that bevacizumab effect on VS might be dose-dependent. Moreover higher dose of everolimus does not improve tumor shrinkage and worsen the regrowth after the end of the treatment.
Conclusions: We developed a mechanism-based model to compare bevacizumab and everolimus efficacy. Our model confirms the roles of the VEGF on VS growth and the better tumor shrinkage induced by bevacizumab treatment.
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 Panoilia E; Schindler E, Samantas E, et al. A pharmacokinetic binding model for bevacizumab and VEGF165 in colorectal cancer patients. Cancer Chemother Pharmacol. 2015; DOI 10.1007/s00280-015-2701-3