Combination effects of gefitinib plus cisplatin in non-small cell lung cancer (NSCLC): Why have phase III trials failed?

Abstract

11022 Background: Four phase III large scale randomized controlled trials combining standard chemotherapeutics and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced NSCLC have failed to show benefit. The mechanism for the failure is still yet not clear. Methods: Seventeen NSCLC cell lines were tested; two had induced P-glycoprotein (Pgp) over-expression. Three of the 4 EGFR mutants exhibited activating mutations. All lines were simultaneously treated with gefitinib plus cisplatin (GC). Selected 4 lines were tested with paclitaxel plus cisplatin (PC) or gefitinib (PG) and three-drug combination (PCG). The MTT assay with application of classical isobole method and statistical analysis was used and dose-log response curves (DRCs) were examined for evaluating the possible resistance mechanisms. Results: We found that combined GC regimen had significant antagonism at the IC50 level (13/15 lines; mean CI=1.184±0.037, P=0.001). The mean CI values of PCG were higher than or comparable with those of PC or PG in either EGFR wild type or mutant cells. DRC analysis mainly showed non-saturable passive resistance, suggesting that gefitinib 0.001–0.3 μM could interfere with cisplatin cell entry in a dose dependent fashion when cisplatin concentrations over 1–3μM, thus leaded to antagonism. Giving gefitinib 24 hours after administration of cisplatin could abolish the antagonism. Conclusions: In NSCLC cells, combination of GC showed antagonistic interaction likely because gefitinib interfered with cisplatin cell entry. Three-drug combination PCG was not better than two-drug combination PC or PG in either EGFR wild type or mutant cells. Clinically, simultaneously combined EGFR TKI with platinum in NSCLC should be avoided regardless of EGFR mutation status. [Table: see text]