XL647—A Multitargeted Tyrosine Kinase Inhibitor: Results of a Phase II Study in Subjects with Non-small Cell Lung Cancer Who Have Progressed after Responding to Treatment with Either Gefitinib or Erlotinib
2012
Introduction Although patients with non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor ( EGFR ) activating mutations commonly experience significant regressions when treated with
erlotinibor
gefitinib, they uniformly develop resistance to these agents. The secondary EGFR
T790Mmutation is found in 50% of patients with acquired resistance. Herein, we studied XL647, an oral small molecule inhibitor of multiple receptor tyrosine kinases, including EGFR, VEGFR2, HER2, and EphB4, in NSCLC patients known or suspected of having tumors harboring
T790M. Methods Eligible patients included those with relapsed or recurrent advanced NSCLC who progressed after ≥12 weeks of stable disease or response to
erlotinibor
gefitiniband/or those patients with a documented EGFR
T790M. XL647 300 mg was administered once daily. The primary end point was objective
response rate. Pretreatment plasma samples were collected for
mutation testingof
circulating tumor DNA. Results Forty-one patients were enrolled; 33 were evaluable for efficacy. One partial response was observed (
response rate3% and 90% confidence interval, 0% to 14%). Of patients whose tumors harbored
T790M, 67% (8/12) had progression of disease as
best responsecompared with 14% (3/21) of those without this mutation. Plasma samples from 40 patients were available for
mutation testing, 14 (35%) of which were found to have EGFR mutations. Conclusions The 3%
response rateobserved did not meet the prespecified threshold to recommend further study of XL647 in patients who develop acquired resistance to
erlotinibor
gefitinib. Patients with
T790Mhad a significantly worse progression-free survival.
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