Abstract 3612: Potent preclinical anti-tumor activity of MGCD265, an orally active Met/VEGFR multitargeted kinase inhibitor in Phase II clinical development, in combination with an EGFR inhibitor

MGCD265 is an oral multitargeted receptor tyrosine kinase inhibitor in Phase II clinical development. MGCD265 targets the Met receptor tyrosine kinase and blocks Met activities which contribute to cancer development and progression such as cell proliferation, motility/invasion, angiogenesis and tumor cell survival. Although there is a large body of literature supporting Met activities as key to epithelial-mesenchymal transition and tumorigenesis, it is now accepted that the coordination of Met signaling with other regulators is central to oncogenesis. Met engages in cross-talks with several membrane proteins including the EGFR. Met and EGFR are coexpressed on tumor cells and functionally cooperate to amplify activating signals. Moreover, in NSCLC, Met gene amplification or overexpression of HGF, has been identified as a major molecular mechanism through which tumors evade EGFR inhibition by specific inhibitors such as gefitinib and erlotinib. Taken together, these studies provide a compelling rationale for concomitantly inhibiting Met and EGFR. In the present study, we have analyzed the in vivo anti-tumor activity of MGCD265 in combination with an EGFR-specific inhibitor, erlotinib. We demonstrate that this combination achieves greater antitumor responses than treatment with either agent alone, in multiple xenografts including NSCLC models. This is observed in the absence of overt toxicity. Furthermore, the PK of MGCD265 and erlotinib was analyzed when the two agents were co-administered, and indicated that there are no drug-drug interactions. In addition, in a NSCLC xenograft model that expresses an EGFR mutant resistant to erlotinib (T790M), MGCD265 significantly improved the anti-tumor activity when combined with erlotinib. The mechanisms underlying efficient tumor growth inhibition by this combination are presently under investigation. Preliminary results suggest that in addition to downregulating Met activation, MGCD265 may modulate EGFR activation by inhibiting the expression of the EGFR ligands TGFα and EREG. These preclinical studies provide support for the clinical development of MGCD265 in combination with erlotinib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3612.