Last chance for Iressa?

Results from the Phase III INTEREST (IRESSA Non-small-cell lung cancer Trial Evaluating REsponse and Survival against Taxotere) study, published in the 22nd November edition of The Lancet (2008;372:1809-1818), have shown that patients with pretreated advanced non-small cell lung cancer (NSCLC) who received the oral anticancer drug, Iressa (gefitinib), had comparable survival to those treated with intravenous docetaxel. In addition, gefitinib had a more favourable tolerability profile than docetaxel and significantly more gefitinib-treated patients had an improvement in quality of life.

These results follow previous disappointing data for the drug in the ISEL (IRESSA Survival Evaluation in Lung cancer) study, where gefitinib failed to demonstrate a survival advantage versus placebo in NSCLC patients. This led to a severe restriction on the use of the drug in the US and also to AstraZeneca withdrawing its MAA in Europe. As such, gefitinib is not currently licensed in the EU, however on 2nd May, AstraZeneca submitted an MAA to the EMEA seeking approval as a treatment for locally-advanced or metastatic NSCLC patients pretreated with platinum chemotherapy (CT). The application is based on data from the INTEREST study and is the first time a targeted therapy, an EGFr tyrosine kinase inhibitor, has proven non-inferiority for overall survival (OS) relative to CT in patients with pretreated advanced NSCLC.

The INTEREST study was a randomised, open-label, parallel-group trial evaluating survival with gefitinib versus docetaxel in 1,466 patients with locally-advanced or metastatic recurrent NSCLC who had previously received platinum-based CT. Patients were randomly assigned to receive gefitinib (250mg/day; n=733) or docetaxel (75mg/m2; n=733). The primary objective was to compare OS between the groups with co-primary analyses to assess non-inferiority in the overall per-protocol population and superiority in patients with high EGFr-gene-copy number in the intention-to-treat population.

In the study, 1,433 patients were analysed per protocol (723 in the gefitinib group and 710 in the docetaxel group). Non-inferiority of gefitinib compared with docetaxel was confirmed for OS (593 vs 576 events; hazard ratio [HR]=1.02; 96% CI, 0.905 to 1.150, meeting the predefined non-inferiority criterion; median survival 7.6 vs 8.0 months). Superiority of gefitinib in patients with high EGFr-gene-copy number (85 vs 89 patients) was not proven (72 vs 71 events; HR=1.09; 95% CI, 0.78 to 1.51; p=0.62; median survival 8.4 vs 7.5 months).

Will these new data signal a resurrection for the drug? With such mixed results for gefitinib, it is hard to imagine doctors altering their prescribing habits on the basis of the INTEREST data alone, especially when there are many of other options available for treating LC patients. Tarceva (erlotinib), another EGFr inhibitor, is available, as is Avastin (bevacizumab), with more on the horizon, including Erbitux (cetuximab). One thing that could save gefitinb is the use of pharmacogenomics and a test to predict which patients would be suitable for treatment with the drug. However, this is an expensive and time-consuming undertaking, one that AstraZeneca may not see as financially rewarding or competitive as there are already EGFr inhibitors available, such as cetuximab and Vectibix (panitumumab), that are marketed alongside companion diagnostics. As such, INTEREST could be gefitinib’s final chance of success.

Matthew Dennis - Editor, Cancer Drug News