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.