Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer.
Approximately 10 to 15% of patients with non-small cell lung cancer have tumors that depend on activation of the epidermal growth factor receptor (EGFR), as evidenced by mutations in EGFR. In these patients, there is often an initial dramatic response to treatment with the first-generation EGFR tyrosine kinase inhibitors (TKIs) erlotinib or gefitinib. A small number of patients with EGFR mutations have primary resistance to erlotinib and gefitinib, and most patients who initially respond to treatment with erlotinib or gefitinib will develop resistance to first-generation EGFR TKIs. The problems with both primary and acquired resistance to erlotinib and gefitinib support the need for development of additional agents that inhibit EGFR signaling in such patients. This is an overview of three representative second-generation EGFR TKIs. HKI-272, a second-generation irreversible EGFR TKI that also inhibits HER2, has completed accrual of a phase II trial in both untreated patients and patients with acquired resistance to erlotinib or gefitinib. XL647 is a reversible inhibitor of EGFR, HER2, and vascular epidermal growth factor receptor. Preclinical work shows that XL647 can inhibit cell lines bearing mutated forms of EGFR that have been associated with acquired resistance. BIBW2992 is an irreversible EGFR TKI that also inhibits HER2 and vascular epidermal growth factor receptors. In vitro work shows that this compound inhibits wild-type EGFR, EGFR exon 19 deletion, EGFR L858R, and EGFR T790M, the mutation associated with acquired resistance. The preliminary results from phase I and phase II trials for BIBW-2992 and XL647 are discussed.
Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. rielyg@mskcc.org
Gregory J
GJ
Riely
D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000556:secondary; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D019008:Drug Resistance, Neoplasm; D015507:Drugs, Investigational / Q000008:administration & dosage*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage*; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome
D015507:Drugs, Investigational; D011799:Quinazolines; D011804:Quinolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C487932:neratinib; D000077156:Gefitinib