The oncogenic receptor tyrosine kinases (RTK) AXL and c-Met are over-expressed and constitutively activated in a variety of human cancers. Activation of these receptors contributes to multiple steps in tumor progression, including the epithelial-mesenchymal transition (EMT) by which cancer cells escape to form metastases and frequently develop resistance to a variety of agents, most notably to epidermal growth factor receptor (EGFR) targeted therapies. CEP-40783 is an orally-active, nanomolar potent and highly kinase-selective Type II inhibitor of the AXL and c-Met RTK in drug development. In the current study, five Champions human TumorGraft™ models of NSCLC expressing constitutively activated AXL and/or c-Met were used to determine the anti-tumor efficacy of single agent CEP-40783 compared to paclitaxel and the EGFR inhibitor, erlotinib (Genentech-Roche; OSI Pharmaceuticals). Champions Oncology has developed an innovative platform that utilizes the implantation of primary human tumors in immune-deficient mice in a manner that preserves the biological properties of the original human tumor and results in more rigorous and clinically relevant models for drug discovery. Previous reports have shown the correlation between responsiveness observed in Champions TumorGraft™ models and clinical responses of the patients from which the models were derived. Mice bearing established Champions TumorGrafts™ were treated orally with 10 mg/kg and 30 mg/kg qd of CEP-40783 for 10 to 34 days (until control tumors achieved >1000 mm3 volume) and anti-tumor efficacy and tolerability were evaluated. In 3/5 (60%) of the tumor models, CEP-40783 showed in vivo efficacy, including tumor regressions, significantly superior to that achieved with an optimal regimen of paclitaxel. In 4/4 (100%) of the erlotinib-insensitive tumor models, CEP-40783 demonstrated significant efficacy (66 to 118% TGI) compared to the control group at the 30 mg/kg dose. Additionally, CEP-40783 in combination with erlotinib demonstrated superior anti-tumor efficacy compared to CEP-40783 and erlotinib single agents in the one erlotinib-sensitive model evaluated. CEP-40783 as a single agent and in combination with erlotinib was well tolerated. Retrospective bioinformatics analyses are planned to determine potential signatures of response and resistance to CEP-40783. These results demonstrate that CEP-40783 shows superior efficacy alone and in combination with erlotinib in Champions TumorGraft™ models of NSCLC compared to SOC agents and supports the development of CEP-40783 for the treatment of erlotinib-resistant NSCLC.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C272.
Citation Format: Jay A. Friedman, Rodney Donaldson, Sheila Miknyoczki, Mangeng Cheng, Robert Hudkins, Bruce Dorsey, Mark Ator, Thelma Angeles, Bruce Ruggeri, Elizabeth Bruckheimer. Antitumor activity of the dual AXL/c-Met inhibitor CEP-40783 in Champions primary TumorGraft™ models of human non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C272.