Abstract PL2-1: The impact of genomic changes on the treatment of lung cancer
Authors: Bruce E. Johnson, Pasi Jänne
Journal: Clinical Cancer Research (2010)

Abstract The discovery of mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) 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, paved the way to personalized medicine in lung cancer (1–3). Other common genomic changes that arise in lung cancers with an impact on EGFR-TKI sensitivity include KRAS and PTEN mutations, secondary T790M mutations in EGFR, and MET amplification (4–8). The retrospective and prospective studies have shown that EGFR mutations are closely associated with response, prolongation in time to progression and survival. Patients with EGFR mutations treated with gefitinib or erlotinib have a response rate of approximately 60–80%, a median time to progression in excess of nine months to one year, and a median survival in excess of two years. The prospective single arm and randomized studies of patients with previously untreated advanced non-small cell lung cancer were treated with erlotinib or either combination platinum-based combination chemotherapy versus gefitinib (9–12). The patients with EGFR mutations treated with gefitinib had a 1.5 to 2 fold longer time to progression compared to those treated with platinum-based doublet chemotherapy. 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 (5, 7, 8, 13). The T790M mutation in EGFR is responsible for approximately half of the acquired resistance while MET amplification is responsible for about 20%. 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. The phase I dose of HKI-272 has been completed and the recommended phase II dose has been tested in a randomized phase II (14). 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. PF-299804 has completed phase I testing and the phase II trials are being completed. A few 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. A novel covalent pyrimidine EGFR inhibitor has been identified by screening an irreversible kinase inhibitor library specifically against EGFR T790M. The agents with the lead compound (referred to as WZ 4002) are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors, gefitinib and erlotinib in vitro (15). The agent(s) are being studied and developed as potential therapeutic agents. 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 (16). 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 being undertaken. Investigators from Japan discovered a gene that arose from a translocation in adenocarcinomas of the lung which could transform NIH 3T3 cells (17). They discovered the transforming gene was a fusion of the ALK gene with echinoderm microtubule-associated protein-like 4 (EML4) in Japanese non-small cell lung cancers. The ALK and EML4 genes are both located in the short arm of chromosome 2 separated by 12 Mb and are oriented in opposite 5′ to 3′ directions. The translocation gives rise to a fusion gene in which the ALK tyrosine kinase is constituatively activated. Further studies have shown the translocation is present non-small cell lung cancers arising in patients from the United States and Europe. The translocated gene can now be detected by using fluorescence in situ hybridization (FSIH) in histologic sections of the tumor (18–20). There are drugs which are directed against the ALK tyrosine kinase including TAE684 and PF2341066. PF-02341066 has been tested in patients with EML4-ALK translocations in an expansion cohort of the phase I trials and has shown evidence of antitumor activity with response rates of approximately 70% in patients with this translocation (21). PF-02341066 is being tested in patients with relapsed NSCLC and EML4-ALK translocations randomized to either conventional therapy with pemetrexed or docetaxel versus PF-02341066 (ClinicalTrials.gov NCT01000025). Citation Information: Clin Cancer Res 2010;16(7 Suppl):PL2-1