EGFR MUTATIONS PREDICT FOR RESPONSE FROM EGFR TKI THERAPY, BUT HAVE NOT BEEN ASSOCIATED WITH PROLONGED SURVIVAL Somatic mutations in the tyrosine kinase domain of EGFR

ceptor tyrosine kinase expressed in the majority of nonsmall-cell lung cancers (NSCLC) (Dazzi et al. 1989; Kaseda et al. 1989). The efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs) in preclinical tumor models, together with their favorable toxicity profiles, led to their clinical development in NSCLC and other solid tumors (Higgins et al. 2004). Erlotinib and gefitinib are smallmolecule inhibitors of the EGFR tyrosine kinase, which showed evidence of antitumor activity in patients with NSCLC as single agents (Lynch et al. 2004b). This activity was recently shown to translate to a significant survival benefit in a randomized phase III trial of erlotinib versus placebo (hazard ratio [HR] = 0.73) in second-/third-line NSCLC (Shepherd et al. 2005), whereas gefitinib failed to demonstrate a significant survival advantage in a trial of similar design (HR = 0.89) (Tamura and Fukuoka 2005). Erlotinib’s survival advantage in second-/third-line lung cancer was observed in an unselected patient population. However, it is possible that some patient subpopulations might derive greater benefit than others. Indeed, one hypothesis would be that patients whose tumors are most dependent on EGFR signaling for growth and survival would derive greatest therapeutic benefit, whereas patients with tumors that are functionally independent of EGFR would not derive benefit. In this review, we examine the molecular and clinical markers that have been shown to be associated with outcome in NSCLC patients treated with EGFR TKIs and we discuss how these are related to tumor dependence on signaling through EGFR.