Molecular markers predictive of response to EGFR inhibitors
Authors: Bruce Johnson, Pasi Janne
Journal: Clinical Cancer Research (2008)

PL04-01  Four years have passed since mutations of the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) were discovered in patients with lung cancer who had dramatic clinical responses to treatment with the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib. Additional laboratory and clinical studies have provided further insights into the biological impact of EGFR mutations. The other common genomic changes that arise in lung cancer that have an impact on EGFR-TKI sensitivity include KRAS and PTEN mutations, secondary T790M mutations in EGFR, and MET amplification. The retrospective and prospective studies have shown that EGFR mutations are closely associated with an increased response rate, prolongation in time to progression and survival compared to those with a wild type EGFR. Patients with EGFR mutations treated with gefitinib or erlotinib have a response rate of approximately 80%, a median time to progression in excess of approximately one year, and a median survival in excess of two years. The prospective randomized studies of patients with non-small cell lung cancer and sensitizing mutations of EGFR treated with chemotherapy versus erlotinib or gefitinib are ongoing outside of the United States in Europe and Japan.  The genomic changes associated with resistance to treatment with gefitinib and erlotinib are a DNA mutation which changes the threonine to methionine at the 790th amino acid of EGFR known as the (T790M) mutation as well as amplification of the MET oncogene. The T790M mutation in EGFR is responsible for approximately half of the acquired resistance while MET amplification is responsible for about 30%. Irreversible inhibitors including HKI-272 and PF-299804 can cause growth inhibition in a non-small cell lung cancer with both the resistance and sensitizing mutations, while gefitinib and erlotinib do not. HKI-272 has been tested in a randomized Phase II trial and PF-299804 has completed Phase I testing and the Phase II trials have started. The Phase II trial of HKI-272 enrolled patients previously treated with gefitinib and erlotinib and EGFR mutation testing was prospectively incorporated into the trials. The results of these trials will be reported in 2009. The Phase I trial of PF-299804 has been completed and the Phase II trials are beginning. Patients with non-small cell lung cancer treated with chemotherapy plus either erlotinib or gefitinib have had partial responses to subsequent treatment with PF-299804. Preclinical work has documented the non-small cell lung cancer cell line, HCC827, can be made to be resistant to gefitinib and is referred to as HCC827 GR. The mechanism of resistance is caused MET amplification. The in vitro and in vivo experiment have shown that joint inhibition of MET and EGFR with gefitinib plus a MET inhibitor can slow the growth of the HCC827 GR, the lung cancer cell line that developed resistance to gefitinib. Clinical trials with an EGFR inhibitor, erlotinib, with MET inhibitors are to be undertaken.