Revisiting bevacizumab + cytotoxics scheduling using mathematical modeling: proof of concept study in experimental non-small cell lung carcinoma

Diane-Charlotte Imbs 1, 2 Raouf El Cheikh 1, 2 Arnaud Boyer 3, 1 Joseph Ciccolini 1 Celine Mascaux 3 Bruno Lacarelle 1 Fabrice Barlesi 3 Dominique Barbolosi 1 Sébastien Benzekry 4, 5, *
* Corresponding author
1 SMARTc unit - Simulation & Modelling : Adaptive Response for Therapeutics in Cancer
2 OMIT - Oncologie multidisciplinaire et innovations thérapeutiques
3 Oncologie multidisciplinaire et innovations thérapeutiques [Hôpital Nord - APHM]
4 IMB - Institut de Mathématiques de Bordeaux
5 MONC - Modélisation Mathématique pour l'Oncologie
IMB - Institut de Mathématiques de Bordeaux, Inria Bordeaux - Sud-Ouest, Institut Bergonié - CRLCC Bordeaux
Abstract : Concomitant administration of bevacizumab and pemetrexed-cisplatin is a common treatment for advanced non-squamous non-small cell lung cancer (NSCLC). Vascular normalization following bevacizumab administration may transiently enhance drug delivery, suggesting improved efficacy with sequential administration. To investigate optimal scheduling, we conducted a study in NSCLC-bearing mice using. First, experiments demonstrated improved efficacy when using sequential versus concomitant scheduling of bevacizumab and chemotherapy. Using a mathematical model of tumor growth under therapy accounting for the normalization effect, we predicted an optimal delay of 2.8 days between bevacizumab and chemotherapy. This prediction was confirmed experimentally, with reduced tumor growth of 38% as compared to concomitant scheduling, and prolonged survival (70 vs. 74 days). Alternate sequencing of 8 days failed in achieving similar increase in efficacy, thus emphasizing the utility of modeling support to identify optimal scheduling. The model could also be a useful tool in the clinic to personally tailor regimen sequences.
Keywords : Population pharmacokinetics-pharmacodynamics Drug-drug interactions Pharmacokinetics-pharmacodynamics Combination therapy Oncology Mixed effect models Computational biology Personalized Therapy Systems biology
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Diane-Charlotte Imbs, Raouf El Cheikh, Arnaud Boyer, Joseph Ciccolini, Celine Mascaux, et al.. Revisiting bevacizumab + cytotoxics scheduling using mathematical modeling: proof of concept study in experimental non-small cell lung carcinoma. CPT: Pharmacometrics and Systems Pharmacology, American Society for Clinical Pharmacology and Therapeutics ; International Society of Pharmacometrics, 2018, pp.1-9. ⟨10.1002/psp4.12265⟩. ⟨hal-01624423v2⟩

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