inhibiting the oncogene-addicted state 0, . Among patients with NSCLC, the presence of EGFR mutations correlates with certain clinical characteristics (female gender, nonsmoking status, Asian ethnicity, and adenocarcinoma histology) , several of which had been previously The diverse HER signaling network. Receptor-specific ligands for HER-/EGFR, HER-, and HER-4 have been identified, but not for HER-. Receptor engagement leads to tyrosine phosphorylation and activation of signaling pathways (boxes) depending upon the arrangements of ligand–ErbB engagement (thick arrows denote homodimerization and thin arrows denote heterodimerization; “X” represents the absence of intrinsic TK activity). Abbreviations: Afatinib

EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; HB, heparin-binding; HER, human epidermal growth factor receptor; MAPK, mitogen-activated protein kinase; NRG, neuregulin; PIK, phosphatidyl inositol -kinase; PLC, phospholipase C; STAT, signal transducers and activators of transcription; TGF, transforming growth factor; TK, tyrosine kinase. overexpression has been detected in a variety of epithelial malignancies, including NSCLC 0. This observation spurred the study of EGFR inhibitors, such as gefitinib (Iressa ; AstraZeneca, Wilmington, DE) and erlotinib (Tarceva ; Genentech, South San Francisco, CA), in patients with NSCLC. Both agents are orally available, reversible, smallmolecule inhibitors of the TK portion of the receptor. They inhibit ATP binding and subsequent signal transduction and downstream effector functions . In phase II trials, activity was observed with gefitinib in patients with advanced NSCLC and prior Afatinib BIBW2992 chemotherapy. Gefitinib dosed at 50 mg and 500 mg daily yielded response rates (RRs) of 8% and 9%, respectively, in a multicenter trial conducted in the European Union and Japan (Iressa Dose Evaluation in Advanced Lung Cancer IDEAL ) , and 9% and % in a multicenter trial conducted in the U.S. (IDEAL ) .

A multicenter phase II trial studying erlotinib in previously treated patients with advanced NSCLC reported an RR of .% sociated with greater clinical benefit with EGFR TKIs , , . Prospective clinical trials of patients with tumors harboring activating EGFR mutations have been performed, reporting RRs55% and indicating first-line activity of EGFR TKIs in genetically selected tumors –5. Despite these impressive RRs in mutant EGFR NSCLCs, in a randomized phase III trial (Iressa Non-small-cell lung cancer Trial Evaluating REsponse and Survival against Taxotere) of previously treated patients with NSCLC that demonstrated the noninferiority of gefitinib compared with docetaxel with respect to the OS time (median, 7.6 months versus 8.0 months; HR, .00; 96% CI, 0.905–.50), there was no difference in the OS times noted in subgroups with a higher Afatinib EGFR inhibitor EGFR gene copy number or EGFR mutation 6. These results called into question the role of patient selection by EGFR mutation status prior to initiation of gefitinib therapy. The rationale of prospective genotyping and patient selection was subsequently supported by the results of the phase III Iressa Pan-Asia Study (IPASS) trial 7, which included ,00 genetically unselected patients with advanced lung adenocarcinoma who received first-line gefitinib or carboplatin plus paclitaxel. The progression-free survival (PFS) interval was significantly longer with gefitinib than with chemotherapy in the overall population (HR, 0.74; 95% CI, 0.65– 0.85; p  .00).

Notably, in a preplanned exploratory subgroup analysis of 6 patients whose tumors possessed EGFR mutations, the PFS duration was significantly longer for patients receiving gefitinib than for those receiving carboplatin plus paclitaxel (HR, 0.48; 95% CI, 0.6–0.64; p  .00), whereas in patients whose tumors did not have an EGFR mutation (n 76), the PFS interval was significantly shorter with gefitinib than with chemotherapy (HR, .85;