Abstract 2099: Model-riven optimization of anti-angiogenics combined with chemotherapy: application to bevacizumab + pemetrexed/cisplatin doublet in NSCLC-bearing mice
Authors: Ciccolini Joseph , Benzekry Sebastien , Giacometti Sarah , Barlesi Fabrice , Barbolosi Dominique 
Published: July 2016

Abstract
Bevacizumab-containing protocols are all based upon the concomitant administration of the drugs given in a row. Bevacizumab is expected to induce a transient normalization of the tumor neo-vasculature prior to exert its anti-angiogenic properties. The resulting increase in blood flow could lead to higher drug delivery to the tumors and therefore to higher efficacy, provided that cytotoxics are administered after bevacizumab. Determining this time-window cannot be performed by empirical practice, but mathematical modeling can help to achieve this goal. To this end, we have developed an original mathematical PK/PD model that enables the description of the effect of bevacizumab on the quality of the vasculature and the resulting effects of drugs sequential administration on tumor growth. The model was able to simulate a variety of scheduling and suggested that a 5-days lag between bevacizumab and cytotoxics should achieve higher antiproliferative efficacy as compared with standard administration. To test the predictivity of the model, a comparative study was undertaken in tumor-bearing mice. Human H460 NSCLC cells stably transfected with luciferase were ectotopically implanted in swiss nude mice. Treatment consisted in the combo bevacizumab (20 mg/kg) plus pemetrexed (100 mg/kg) and cisplatin (3 mg/kg) given as 3 cycles administered every 2 weeks following different scheduling. Mice were randomly allocated into 4 groups (n = 12 mice per group): control, concomitant (bevacizumab and chemo given the same day), sequence-1 (chemo followed by bevacizumab 5 days later) and sequence-2 (bevacizumab followed by chemo 5 days later). Tumor growth was monitored twice a week by bioluminescence imaging after i.p. injection of 150 mg/kg luciferine. As predicted by our mathematical model, results showed that the sequential administration of bevacizumab followed 5 days later by the pemetrexed/cisplatin doublet led to a better efficacy (-42% reduction in tumor growth at treatment completion and -35% at study conclusion, p&lt;0.05, One-Way Anova) whereas standard dosing or reverse sequence did not significantly reduce tumor growth. Additionally, this sequential administration of bevacizumab first and cytotoxics next led to a median survival of 75 days, whereas other treatment groups could only achieve 52 days survival and control mice 32 days, respectively. Altogether, our experimental data demonstrate that delaying the administration of the chemotherapy after that of bevacizumab leads to higher efficacy and longer survival as compared with standard dosing. Although preliminary, this study suggests that current administration of bevacizumab could be an underpowered strategy. Besides, this preclinical study confirms the accuracy of our mathematical model to identify the optimal sequencing between anti-angiogenics and cytotoxics.
Citation Format: Joseph Ciccolini, Sebastien Benzekry, Sarah Giacometti, Fabrice Barlesi, Dominique Barbolosi. Model-riven optimization of anti-angiogenics combined with chemotherapy: application to bevacizumab + pemetrexed/cisplatin doublet in NSCLC-bearing mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2099.