Premier Lecture Series

Lung cancer is the most common cause of cancer death worldwide, and the majority of cases are associated with cigarette smoking. Non-small cell lung cancer (NSCLC) arising in smokers has a different spectrum of molecular abnormalities than does NSCLC arising in non-smokers, suggesting differences in molecular etiology, pathogene-sis and possibly prognosis. For example, KRAS mutations occur in 20-40% of NSCLC, are strongly associated with smoking, and have been associated with poor prognosis in some studies but not in others. Molecular abnormalities in NSCLC also represent promising therapeutic targets, since present chemotherapies for advanced or metastatic NSCLC have modest efficacy and considerable side effects. The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is expressed in the majority of NSCLC. The efficacy of EGFR inhibi-tors in preclinical models together with their favorable toxicity profiles, have led to their clinical development in NSCLC and other indications. Erlotinib (Tarceva) and gefitinib (Iressa) are small-molecule inhibitors of the EGFR tyrosine kinase that showed activity in NSCLC as single agents in phase II trials. A US single arm phase II study of erlotinib demonstrated an objective response rate of 12.3%, and gefitinib provided response rates of 10.4% in non-Japanese patients and 27.5% in Japanese patients. Non-smokers have a markedly higher response rate than smokers. However, randomized phase III studies of gefitinib or erlotinib in combination with chemotherapy failed to demonstrate an increase in efficacy for EGFR inhibitors over chemotherapy alone. One suggested explanation for this may be that cytostatic agents could cause a schedule-dependent antagonism of cytotoxic drugs by inhibiting progression through the cell cycle and apoptosis. Alternatively, patients were not selected to enrich for likelihood of response to an EGFR inhibitor in these trials. In contrast to HER2 testing for trastuzumab therapy, EGFR expression does not predict for sensitivity to inhibitors in preclinical models or in tumors from treated patients, and hence there is no molecular method for patient selection. Recent reports have associated somatic mutations in the tyrosine kinase domain of EGFR in a subset of NSCLC with sensitivity of the tumors to gefitinib (Lynch et al., 2004; Paez et al., 2004). Paez et al. found tyrosine kinase domain mutations were restricted to EGFR (out of the 47 tyrosine kinases tested) in a panel of 119 lung cancers. The frequency of heterozygous mutations (amino acid substitutions and deletions) was found to be 2% in the American population and 26% in …