The C-Met Inhibitors Emd 1214063 And Emd 1204831 Are Effective In Combination With Egfr And Vegf Inhibitors In Nsclc Models

c-Met is a receptor tyrosine kinase that has hepatocyte growth factor as its ligand. Evidence from biochemical and human genetic studies indicate that c-Met is one of the most frequently activated tyrosine kinases in human cancer. Dysregulated c-Met signaling can result in the development of tumors highly dependent on c-Met. Furthermore, enhanced c-Met signaling is likely involved in conferring resistance to epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors. The orally available EMD 1214063 and EMD 1204831 inhibit c-Met activity in a potent and highly selective fashion, and are currently being evaluated in cancer patients. Here we report the activity of these compounds in combination with inhibitors of EGFR and VEGF in various tumor xenograft models. EMD 1214063 was tested alone and in combination with EGFR inhibitors (erlotinib and cetuximab) in xenografts of erlotinib-resistant tumor cells, namely the lung cancer H1975 and the NCI-H441 non-small-cell lung cancer (NSCLC) cell lines. The H1975 cell line expresses moderate amounts of c-Met, and EMD 1214063 was inactive as a single agent (treatment group/control group [T/C] 78%; tumor growth delay [TGD] 2 days). Cetuximab was active with a T/C of 13% inducing a TGD of 21 days. The combination of EMD 1214063 and cetuximab was active with a T/C of α1% and a TGD of 42 days. The NCI-H441 cell line is characterized by constitutive c-Met overexpression and is sensitive to c-Met inhibitors in vivo. EMD 1214063 (100 mg/kg) was active inducing a T/C of 20%, while erlotinib alone (30 mg/kg) was not efficacious. However, the combination of EMD 1214063 with erlotinib enhanced tumor growth inhibition, induced partial tumor regression in 2/9 mice, and delayed tumor re-growth. These data are compatible with the hypothesis that cMet pathway activation confers resistance to EGFR inhibitors. We additionally investigated the combination of either EMD 1214063 or EMD 1204831 with VEGF inhibitors in NSCLC models. In NCI-H441 xenografts, EMD 1204831 produced a modest T/C (66%) at the suboptimal dose of 25 mg/kg/bid, similarly to aflibercept at 40 mg/kg (T/C 55%). In contrast, the combination of both compounds yielded a T/C of 1% with partial responses in 2/10 mice. In the EBC-1 model, treatment with EMD 1214063 (10 mg/kg) or with the antiVEGF antibody B20-4.1 (20 mg/kg) as single agents resulted in a T/C of β21% (with partial regression in 1/10 mice) and 19%, respectively. In contrast, the combination of EMD 1214063 and B20-4.1 exhibited enhanced anti-tumor activity with a T/C of −72% and partial regressions in 10/10 mice. These data support the hypothesis that EMD 1214063 or EMD 1204831 may be effective in NSCLC patients in combination with VEGF-targeting agents. In conclusion, our findings provide a rationale to evaluate the efficacy of the combination of EMD 1214063 or EMD 1204831 with EGFR and VEGF inhibitors in NSCLC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1787. doi:1538-7445.AM2012-1787