Potent preclinical antitumor activity of MGCD265, an oral Met/VEGFR kinase inhibitor in phase II clinical development, in combination with taxanes or erlotinib.

Abstract

e13595 Background: Therapeutics used to treat patients with NSCLC include cytotoxic agents such as taxanes, and targeted agents such as EGFR inhibitors. Although these treatments provide some clinical benefit, there is a need for improved therapies in advanced NSCLC. MGCD265 targets Met, VEGFR1/2/3, Tie-2 and Ron. Met is overexpressed and phosphorylated in NSCLC, and Met activation is identified as a molecular mechanism through which tumors evade specific inhibition of EGFR. In support of the clinical development of MGCD265, the studies described here provide a rationale for combining MGCD265 with a taxane or an EGFR inhibitor. Methods: The in vivo anti-tumor activity of MGCD265 (10 or 20mg/kg orally, daily) in combination with either docetaxel (5 or 10mg/kg, iv weekly), paclitaxel (30mg/kg iv, on days 0, 1, 13, 14),or an EGFR inhibitor, erlotinib (25 or 50 mg/kg orally, daily), was analyzed in multiple xenograft models including NSCLC models. The anti-angiogenic activity of MGCD265 with docetaxel was evaluated by immunohistochemistry following CD31 labeling of tumor sections from treated animals. Results: We demonstrate that the combination of MGCD265 with docetaxel or paclitaxel achieves greater anti-tumor responses than treating with either agent alone and this occurs in the absence of overt toxicity. The combination of MGCD265 with docetaxel also results in greater reduction of tumor vasculature. Good anti-tumor activity in the absence of overt toxicity is also demonstrated when MGCD265 is combined with erlotinib in NSCLC xenografts including a model that expresses an EGFR mutant resistant to erlotinib (T790M). PK analyses demonstrate that the combination of MGCD265 with either docetaxel, paclitaxel or erlotinib does not result in drug-drug interactions. Conclusions: The combination of MGCD265 with either a taxane or erlotinib results in improved antitumor activities when compared to treatments with either agent alone. In addition, these combinations are well tolerated and do not show drug-drug interactions. These preclinical studies support the clinical development of MGCD265 in combination with docetaxel or erlotinib in patients with NSCLC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MethylGene MethylGene