Somatic mutations in the
kinase domain of the
epidermal growth factor receptor (EGFR) gene are found in approximately 10% of
lung adenocarcinomas sequenced in the United States and in approximately 30% sequenced in Asia. These mutations are associated with sensitivity to the EGFR inhibitors
gefitinib and
erlotinib. Many patients who initially respond to
erlotinib or
gefitinib subsequently relapse. Studies have identified EGFR T790M mutations in
tumors from patients who initially responded and then relapsed. The T790M mutation, when combined in vitro with treatment-sensitizing EGFR mutations, permits the continued growth of
tumor cells in the presence of
erlotinib and
gefitinib.
HKI-272 is an irreversible EGFR/HER/ErbB inhibitor that has been shown to inhibit the growth of T790M mutant cells in vitro in human
lung cancer cell lines and in murine cells transfected with sensitizing EGFR mutations. A phase I
HKI-272 monotherapy trial in patients with solid
tumors is close to completion. Preliminary analyses of the trial, presented at the 2006 annual meeting of American Society of Clinical Oncology, showed that
HKI-272 can achieve stable disease control for over 6 months in some patients with
non-small cell lung cancer that has progressed
after treatment with
gefitinib or
erlotinib. A phase II trial of
HKI-272 in
non-small cell lung cancer patients has been initiated.
HKI-272 might offer benefits to
non-small cell lung cancer patients who have relapsed after an initial response to
erlotinib.