Expression of the
receptor tyrosine kinase c-
MET (MET, mesenchymal-epithelial transition factor) in many
cancers, and its participation in multiple signal transduction pathways involved in malignant
tumor growth, suggest a wide therapeutic potential for MET inhibition in human
cancer. Here we describe the discovery and early clinical development of
ARQ 197, a novel, selective, non-
ATP-competitive inhibitor of MET. Phase I studies demonstrate that
ARQ 197 has a predictable pharmacokinetics and favorable safety profile, making it a potentially ideal partner for combination with cytotoxic
chemotherapies and targeted
anticancer agents. Results from phase I and phase II trials demonstrate preliminary evidence of anticancer activity. New data from a global phase II randomized trial comparing a combination of
ARQ 197 plus
erlotinib with
erlotinib/placebo, in
endothelial growth factor receptor inhibitor-naïve patients with locally advanced/metastatic
non-small cell lung cancer, demonstrate improvement in progression-free and overall survival with combined
therapy. Results were especially pronounced for patients with non-squamous
lung cancer histologies, and in particular molecularly defined subgroups including KRAS mutations. These and other data from
ARQ 197 clinical trials in hepatocellular, germ-cell, pancreatic (in combination with
gemcitabine), and colorectal (in combination with
cetuximab and
irinotecan)
cancers further highlight the potential role of
ARQ 197 in existing and emerging anticancer therapeutic regimens.