title: Early clinical development of ARQ 197, a selective, non-ATP-competitive inhibitor targeting MET tyrosine kinase for the treatment of advanced cancers.
abstract: 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.
authors.affiliation: Roswell Park Cancer Institute, Buffalo, New York, USA. alex.adjei@roswellpark.org
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Brian
authors.initials: B
authors.lastname: Schwartz
authors.forename: Edward
authors.initials: E
authors.lastname: Garmey
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D000068818:Cetuximab; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use; D011804:Quinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: C551661:ARQ 197; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011760:Pyrrolidinones; D011799:Quinazolines; D011804:Quinolines; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; D000077146:Irinotecan; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D000068818:Cetuximab; D002166:Camptothecin