PURPOSE: Agents inhibiting the epidermal growth factor receptor (EGFR) have 
shown clinical benefit in a subset of non-small cell lung cancer patients 
expressing amplified or mutationally activated EGFR. However, responsive 
patients can relapse as a result of selection for EGFR gene mutations that 
confer resistance to ATP competitive EGFR inhibitors, such as erlotinib and 
gefitinib. We describe here the activity of EXEL-7647 (XL647), a novel 
spectrum-selective kinase inhibitor with potent activity against the EGF and 
vascular endothelial growth factor receptor tyrosine kinase families, against 
both wild-type (WT) and mutant EGFR in vitro and in vivo.
EXPERIMENTAL DESIGN: The activity of EGFR inhibitors against WT and mutant EGFRs 
and their effect on downstream signal transduction was examined in cellular 
assays and in vivo using A431 and MDA-MB-231 (WT EGFR) and H1975 (L858R and 
T790M mutant EGFR) xenograft tumors.
RESULTS: EXEL-7647 shows potent and long-lived inhibition of the WT EGFR in 
vivo. In addition, EXEL-7647 inhibits cellular proliferation and EGFR pathway 
activation in the erlotinib-resistant H1975 cell line that harbors a double 
mutation (L858R and T790M) in the EGFR gene. In vivo efficacy studies show that 
EXEL-7647 substantially inhibited the growth of H1975 xenograft tumors and 
reduced both tumor EGFR signaling and tumor vessel density. Additionally, 
EXEL-7647, in contrast to erlotinib, substantially inhibited the growth and 
vascularization of MDA-MB-231 xenografts, a model which is more reliant on 
signaling through vascular endothelial growth factor receptors.
CONCLUSIONS: These studies provide a preclinical basis for clinical trials of 
XL647 in solid tumors and in patients bearing tumors that are resistant to 
existing EGFR-targeted therapies.