Abstract 4529: Optimization of the sequence for the administration of bevacizumab in combination with pemetrexed and cisplatin in NSCLC : a pharmacology based in vivo study
Authors: boyer arnaud , imbs diane-charlotte , cheikh raouf el , mascaux celine , barlesi fabrice , barbolosi dominique , benzekry sebastien , ciccolini joseph 
Published: July 2017

Abstract
Introduction: Bevacizumab is active in advanced non-small cell lung cancer (NSCLC) and is administred in combination with chemotherapy in first line for non squamous NSCLC. However the best sequence of administration has not been defined. Previously published data suggest that before acting as an antiangiogenic drug, Bevacizumab would initially and transitory normalized the vascularization of the tumor. This initial phase could be thus be optimal to administrate chemotherapy. By using mathematic modeling, we showed that sequential administration of chemotherapy 3 days after Bevacizumab may be more beneficial than concomitant administration. Herein we tested and compared concomitant versus different schema of sequential administration of Bevacizumb with chemotherapy in NSCLC.
Methods: H460 Luc + cells were transfected with dTomato allowing to measure tumor growth by fluorescence. Nude mice were engrafted subcutaneously with around 120,000 cells. Fluorescence was used to monitor tumor growth twice a week and treated with Bevacizumab, Cisplatin and Pemetrexed with various sequences of administration. A total of 15-16 replicates were included in each therapeutic group.
Results Five therapeutic schema were compared : 1) Cisplatine-Pemetrexed only ; 2) concomitant administration of Bevacizumab with Cisplatine-Pemetrexed ; 3) chemotherapy 3 days after Bevacizumab predicted to be the optimal sequence by mathematic modeling; 4) chemotherapy 8 days after Bevacizumab predicted to be the worse sequence by mathematic modeling; 5) control group receiving placebo. Tumor growth was reduced of 38% in group 3 as compared with group 2, but this difference remains non significant (p=0.13), but was significantly reduced compared to groups 1, 4 and 5. The median survival was the longest in group 3 (74 days), as compared with group 2 (70 days), group 4 (67 days), group 1 (54 days) and control group (40 days).
Conclusion: This in vivo study indicate that the sequential administration of Bevacizumab three days before chemotherapy in NSCLC may be the optimal schema as compared with concomitant administration or longer delay as predicted by mathematic modeling. Mechanistic and pharmacokinetic analyses as well as biomarker studies are currently ongoing and should be shortly available.
Citation Format: arnaud boyer, diane-charlotte imbs, raouf el cheikh, celine mascaux, fabrice barlesi, dominique barbolosi, sebastien benzekry, joseph ciccolini. Optimization of the sequence for the administration of bevacizumab in combination with pemetrexed and cisplatin in NSCLC : a pharmacology based in vivo study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4529. doi:10.1158/1538-7445.AM2017-4529