Reasons for response differences seen in the V15-32, INTEREST and IPASS trials

The first phase III study to assess the effect of gefitinib and docetaxel on the survival of Japanese patients with non-small-cell lung cancer who received previous treatment with platinum doublets, the V15-32 trial, did not establish noninferiority of gefitinib over docetaxel in terms of the effect on overall survival, despite the results showing a twofold higher response rate to gefitinib. The overall survival favored docetaxel for the first 18 months and gefitinib thereafter. The INTEREST trial, which compared docetaxel and gefitinib, demonstrated noninferiority of gefitinib, and the survival curves were completely superimposed. In this trial, patients had been recruited from 24 countries from Europe, Asia, and North and South America. Results of the IPASS trial showed superior progression-free survival for gefitinib compared with the combination of carboplatin and paclitaxel as first-line treatment in Asian patients who were nonsmokers and had adenocarcinoma histology. In this Review, we discuss the reasons for the differences in the effects of molecular-targeted drugs and cytotoxic antineoplastic agents observed in these trials. We also highlight the magnitude of the antitumor activity of these two different categories of drugs, and discuss how this could affect future clinical trial design and analysis.