title: Epidermal growth factor receptor tyrosine kinase inhibitors in late stage clinical trials.
abstract: The epidermal growth factor receptor (EGFR) is a cell membrane receptor that plays a key role in cancer development and progression. Ligand-activated EGFR-dependent signalling is involved in cell proliferation, apoptosis, angiogenesis and metastatic spread. Targeting the EGFR, therefore, represents a promising molecular approach in cancer treatment. Several anti-EGFR agents are in clinical development. Three drugs are currently in Phase II and III development as single agents, or in combination with other anticancer modalities: IMC-225 (cetuximab/Erbitux; ImClone), a chimaeric human-mouse monoclonal IgG(1) antibody, which blocks ligand binding and functional activation of the EGFR; OSI-774 (erlotinib/Tarceva; Genentech/OSI/Roch) and ZD1839 (gefitinib/Iressa; AstraZeneca), two small molecule EGFR-selective inhibitors of tyrosine kinase enzymatic activity, which prevent EGFR autophosphorylation and activation. Iressa is the first EGFR-targeting agent to be registered as an anticancer drug in Japan, in Australia and in the US for the third-line treatment of chemoresistant non-small cell lung cancer (NSCLC) patients. This review will focus on the preclinical background and on the results from the first series of clinical trials with these drugs. Furthermore, continuing clinical trials and a series of open clinical issues for the development of optimal strategies of using EGFR-targeting agents will be discussed.
authors.affiliation: Cattedra di Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale F Magrassi e A Lanzará, Seconda Universitá degli Studi di Napoli, Via S. Pansini 5, 80131 Napoli, Italy. fortunato.ciardiello@unina2.it
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.forename: Ferdinando
authors.initials: F
authors.lastname: De Vita
authors.forename: Michele
authors.initials: M
authors.lastname: Orditura
authors.forename: Sabino
authors.initials: S
authors.lastname: De Placido
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000068818:Cetuximab; D002986:Clinical Trials as Topic; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000068818:Cetuximab; D000077156:Gefitinib