Early clinical development of ARQ 197, a selective, Non-ATP-competitive inhibitor targeting MET tyrosine kinase for the treatment of advanced cancers

Alex Adjei, Brian Schwartz, Edward Garmey

Research output: Contribution to journalArticle

55 Citations (Scopus)

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 gemcit-abine), and colorectal (in combination with cetuximab and irinotecan) cancers further highlight the potential role of ARQ 197 in existing and emerging anticancer therapeutic regimens.

Original languageEnglish (US)
Pages (from-to)788-799
Number of pages12
JournalOncologist
Volume16
Issue number6
DOIs
StatePublished - Jun 1 2011
Externally publishedYes

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Epithelial-Mesenchymal Transition
Protein-Tyrosine Kinases
irinotecan
Neoplasms
Therapeutics
Vascular Endothelial Growth Factor Receptor
Receptor Protein-Tyrosine Kinases
Germ Cells
Non-Small Cell Lung Carcinoma
Antineoplastic Agents
Disease-Free Survival
Signal Transduction
Lung Neoplasms
Histology
Pharmacokinetics
Placebos
ARQ 197
Clinical Trials
Safety
Drug Therapy

Keywords

  • C-MET
  • EGFR
  • Epithelial growth factor inhibitor
  • Hepatocyte growth factor
  • Kinase receptor inhibitor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Early clinical development of ARQ 197, a selective, Non-ATP-competitive inhibitor targeting MET tyrosine kinase for the treatment of advanced cancers. / Adjei, Alex; Schwartz, Brian; Garmey, Edward.

In: Oncologist, Vol. 16, No. 6, 01.06.2011, p. 788-799.

Research output: Contribution to journalArticle

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