Mechanism-based modeling of the clinical effects of bevacizumab and everolimus on vestibular schwannomas of patients with neurofibromatosis type 2

Abstract

Purpose: To describe the natural growth of vestibular schwannoma in patients with neurofibromatosis type 2 and to predict tumor volume evolution in patients treated with bevacizumab and everolimus.

Methods: Clinical data, including longitudinal tumor volumes in patients treated by bevacizumab (n = 13), everolimus (n = 7) or both (n = 2), were analyzed by means of mathematical modeling techniques. Together with clinical data, data from the literature were also integrated to account for drugs mechanisms of action.

Results: We developed a model of vestibular schwannoma growth that takes into account the effect of vascular endothelial growth factors and mammalian target of rapamycin complex 1 on tumor growth. Behaviors, such as tumor growth rebound following everolimus treatment stops, was correctly described with the model. Preliminary results indicate that the model can be used to predict, based on early tumor volume dynamic, tumor response to variation in treatment dose and regimen.

Conclusion: The developed model successfully describes tumor volume growth before and during bevacizumab and/or everolimus treatment. It might constitute a rational tool to predict patients' response to these drugs, thus potentially improving management of this disease.

Keywords: Disease progression model; Mechanism-informed models; Mixed-effects models; NF2; Oncology; Population pharmacokinetics–pharmacodynamics; Vestibular schwannoma.