event ATP binding and autophosphorylation of the EGFR tyrosine kinase [20, 21]. Phase I studies in patients with solid malignancies showed both agents to be well tolerated and associated with meaningful antitumor activity or disease stabilization [22, 23]. Phase II studies investigating gefitinib and erlotinib for the treatment of NSCLC have produced similar responses. Trials with gefitinib showed response rates of 10–19%, with approximately 40% of patients experiencing an improvement in symptoms [24– 26]. Similarly, treatment with erlotinib produced a response rate of 12.3% and was also well tolerated [26]. A significant improvement in overall survival was observed in the BR.21 study investigating erlotinib versus placebo (6.7 vs 4.7 months, respectively [HR, 0.70; p<0.001]) [27]. Conversely, treatment with gefitinib was not associated with significant improvement in overall survival over placebo in the ISEL trial (5.6 vs 5.1 months, respectively [HR, 0.89, p=0.087]), despite a higher response rate and longer time to progression for gefitinib-treated patients [28]. Although these trials showed different results, further analyses from both studies reported variations in efficacy according to clinical characteristics and molecular biomarkers.

Therefore, these clinical characteristics and, more recently, molecular analysis may have the potential to predict response to the first-generation TKIs. Increasingly, physicians are making treatment decisions based on a patient’s clinical characteristics. Improved response to TKIs has been observed in different patient subgroups, according to gender, ethnicity, smoking status and histopathology [29, 30]. Specifically, patients of female gender, East Asian ethnicity, no history of smoking, or those with adenocarcinoma, are relatively more likely to respond [27, 28, 31]. However, the value of the clinical criteria in the prediction of survival is lower. For example, although never-smoking status remained significant, other patient characteristics were not significant after tests for interaction in the BR.21 randomized phase III study [27]. Furthermore, patients with squamous histology, as well as adenocarcinomas, experienced a survival benefit in this trialSensitivity to TKI therapy is associated with particular EGFR mutations—“activating” mutations [32–34]. EGFR kinase domain mutations are found in four exons (18–21), which are in close proximity to the ATP-binding pocket of the enzyme [35]. In-frame deletions in exon 19 and an exon 21 substitution (L858R) are the most common mutations, together representing 85–90% of all EGFR mutations in NSCLC [36]. These mutations are associated with improved outcomes following treatment with EGFR TKIs because the location of the mutations leads to an alteration in the catalytic domain resulting in enhanced binding of the TKI [37]. Retrospective analyses show response rates of up to 75% and better outcomes in patients with “activating” mutations [38, 39].

Analyses also suggest differences in outcomes between different “activating” mutations [38, 40]. Studies exploring the relationship between exon 19 deletions and the L858R point mutation, and patient outcome following erlotinib or gefitinib treatment MK-8669 demonstrate that patients with NSCLC and EGFR exon 19 deletions have a longer survival following treatment with gefitinib or erlotinib compared with those with the L858R mutation [38, 40]. However, prospective analyses have shown that the presence of less common EGFR mutations (other than exon 19 deletions and the L858R mutation) is also associated with poor response to reversible EGFR TKIs, such as gefitinib [41, 42]. The value of screening for EGFR mutations in lung cancer patients has recently been MK-8669 572924-54-0 investigated by the Spanish Lung Cancer group, in which 16.6% of 2,105 patients newly diagnosed with NSCLC were found to have an EGFR mutation and were subsequently treated with erlotinib. This cohort experienced an impressive median progression-free survival of 14 months and an overall survival of 27 months. This important study suggests that large scale screening for EGFR mutations in lung cancer patients is feasible and worthwhile [43]. Prospective studies are important for further characterizing the impact of EGFR mutations on outcomes because these mutations are prognostic as well as potentially predictive markers [38, 44, 45].

The Spanish Lung Cancer group is currently randomizing patients with EGFR mutations to first-line treatment with either erlotinib or chemotherapy (the conventional standard of care) [46]. The phase III IPASS study was the first trial to select patients based on clinical criteria [31]. Never-/lightsmokers with adenocarcinoma in this East Asian MK-8669 AP23573 population demonstrated a superior progression-free survival rate for first-line gefitinib when compared with carboplatin/ paclitaxel. In a subgroup-analysis, significantly longer progression free survival was seen for first-line gefitinib when compared with carboplatin/pa