Abstract A11: Antitumor activity of targeted and cytotoxic agents in xenograft models correlates with clinical response: A pharmacokinetic-pharmacodynamic analysis.

Abstract

Abstract Immunodeficient mice transplanted subcutaneously with human tumors (xenografts) are a widely used model of preclinical efficacy in the discovery and development of anti-cancer agents. We performed a retrospective population pharmacokinetic-pharmacodynamic (PK-PD) analysis of xenograft efficacy data that accounts for differences in clinical and preclinical drug exposure in order to improve their predictive value. In addition, we investigated the ability of xenograft studies to predict clinical response with newer molecular targeted agents. Data from preclinical and clinical studies with three cytotoxic chemotherapeutic agents (docetaxel, carboplatin, and 5-fluorouracil) and five molecular targeted agents (erlotinib, sunitnib, dasatinib, trastuzumab, and vismodegib) were included in this analysis. Anti-cancer agents were administered at a range of doses to xenograft mice bearing tumors relevant to the cancer of interest. No correlation was observed when comparing clinical response to % tumor growth inhibition (%TGI) at the maximum tolerated dose (MTD) in mice. PK-PD modeling was used to simulate %TGI in xenografts using human exposures at clinically relevant doses. These simulated %TGI in xenografts driven by human drug exposures were found to correlate (r=0.92; p=0.0005) with clinical response, illustrating the importance of taking into account species differences in drug exposure when interpreting xenograft data. Distinct differences were observed in the anti-tumor activity of sunitinib in Colo205 colorectal (simulated %TGI = 64%) and 786-O renal cell adenocarcinoma (simulated %TGI = 81%) xenografts, and vismodegib in medulloblastoma allografts (simulated %TGI =102%) and D5123 colorectal xenografts (simulated %TGI = 33%). These differences were consistent with the underlying biology of these models and demonstrate the importance of understanding tumor biology when selecting relevant xenograft models for molecular targeted agents. Based on these analyzes, agents that lead to greater than 60% tumor growth inhibition in preclinical models at clinically relevant exposures are more likely to lead to responses in the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A11.