IRESSA (gefitinib) was the first in a new class of anti-cancer drugs, known as epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors, to gain market approval and is currently licensed for the treatment of advanced non-small-cell lung cancer (NSCLC) in 36 countries worldwide. Approvals were based on two phase II trials, IDEAL 1 and 2, which showed IRESSA to be an effective treatment for many patients with previously-treated advanced NSCLC. Approximately 50% of patients in the IDEAL trials achieved tumour shrinkage or stabilisation of their tumour and the drug was found to be generally well tolerated with the most commonly reported adverse drug reactions being mild-to-moderate skin rash and diarrhoea [1,2].

In December 2004, AstraZeneca announced the results of the phase III ISEL (IRESSA Survival Evaluation in Lung Cancer) study which compared IRESSA with placebo in patients with advanced NSCLC who had failed one or two prior chemotherapy regimens. ISEL showed some improvement in survival with IRESSA but this failed to reach statistical significance, compared with placebo, in the overall population or in patients with adenocarcinoma . Pre-planned subgroup analyses showed a statistically significant increase in survival with IRESSA, compared with placebo, in patients of Asian origin and in patients who had never smoked [3]. In addition, exploratory analyses of biomarker data from ISEL have suggested that high EGFR gene copy number is a strong predictor of benefit with IRESSA in pre-treated advanced NSCLC.

Following the announcement of the ISEL data, AstraZeneca voluntarily withdrew the European submission for IRESSA and regulatory authorities in the USA and Canada limited the use of IRESSA to those patients already experiencing benefit from the drug. In the Asia Pacific region, due to the molecular differences in lung cancer, IRESSA has become an established therapy for pre-treated advanced NSCLC and use of the drug in the first-line advanced setting is now being studied in a large phase III pan-Asian trial known as the IPASS study.

From the ISEL results, and broad clinical experience, it is clear that IRESSA is an effective treatment for some advanced NSCLC patients. AstraZeneca is now focussed on identifying those NSCLC patients who are most likely to benefit from the drug.

IRESSA targets signalling pathways that appear to play a major role in the growth of many solid tumours and therefore may have a therapeutic potential in a broad range of cancers. Ongoing investigation of this potential includes clinical trials in head and neck cancer and breast cancer.


References

1. Fukuoka M et al. J Clin Oncol 2003; 21: 2237-2246
2. Kris M et al. J Am Med Assoc 2003; 290: 2149-2158.
3. Thatcher N et al. Lancet 2005; 366: 1527-1537.