Two phase II trials (IDEAL-1 and IDEAL-2) showed that gefitinib produced a response rate of 9%C18% and overall disease control rate of 43%C50% in patients with relapsed NSCLC.46,47 However the phase III ISEL trial that randomized nearly 1700 patients with advanced NSCLC to gefitinib or placebo, failed to reveal an overall survival benefit.48 A recent phase III trial (INTEREST) showed that gefitinib was noninferior to Dibutyl phthalate docetaxel in terms of overall survival (OS) in patients with relapsed NSCLC; it was also better tolerated and correlated with better quality of life.49 Similarly, another randomized phase II study comparing gefitinib with vinorelbine in chemo-na?ve elderly patients with advanced non-small-cell lung cancer found that gefitinib had similar response rates and progression-free (PFS) and overall survival to vinorelbine.50 Two trials (INTACT-1 and INTACT-2) trials that combined gefitinib with chemotherapy in the first-line setting,34,35 did not show any survival benefit from the addition of gefitinib. intracellular tyrosine kinase activity of the receptor, and monoclonal antibodies that target the extracellular domain in the ligand-binding region. Gefitinib (Iressa?; AstraZeneca) and Erlotinib (Tarceva?; OSI Pharmaceuticals, Inc. Melville, NY) are the two most studied drugs in the EGFR-tyrosine kinase inhibitor class. Canertinib (“type”:”entrez-nucleotide”,”attrs”:”text”:”C11033″,”term_id”:”1536104″,”term_text”:”C11033″C11033), lapatinib (“type”:”entrez-nucleotide”,”attrs”:”text”:”GW572016″,”term_id”:”289151303″,”term_text”:”GW572016″GW572016, Tykerb?; GlaxoSmithKline, Research Triangle Park, NC), PKI166, and EKB569 are examples of other drugs in this class currently in development. The most well known EGFR monoclonal antibody is cetuximab (Erbitux?; Bristol-Myers Squibb Company, Princeton, NJ). Panitumumab (AMG706, Vectibix?; Amgen Inc., Thousand Oaks, CA), matuzumab (EMD7000), and nimotuzumab (h-R3) Dibutyl phthalate are EGFR monoclonal antibodies currently being developed. Clinical trials of tyrosine kinase inhibitors Gefitinib Gefitinib was the first EGFR-TKI tested in clinical trials. Two phase II trials (IDEAL-1 and IDEAL-2) showed that gefitinib produced a response rate of 9%C18% and overall disease control rate of 43%C50% in patients with relapsed NSCLC.46,47 However the phase III ISEL trial that randomized nearly 1700 patients with advanced NSCLC to gefitinib or placebo, failed to reveal an overall survival benefit.48 A recent phase III trial (INTEREST) showed that gefitinib was noninferior to docetaxel in terms of overall survival (OS) in patients with relapsed NSCLC; it was also better tolerated and correlated with better quality of life.49 Similarly, another randomized phase II study comparing gefitinib with vinorelbine in chemo-na?ve elderly patients with advanced non-small-cell lung cancer found that gefitinib had similar response rates and progression-free (PFS) and overall survival to vinorelbine.50 Two trials (INTACT-1 and INTACT-2) trials that combined gefitinib with chemotherapy in the first-line setting,34,35 did not show any survival benefit from the addition of gefitinib. On the other hand, although the IPASS (Iressa Pan-Asia Study) comparing gefitinib with carboplatin/paclitaxel for previously untreated Asian never- or light-smokers with advanced adenocarcinoma found no difference in overall survival,51 patients who had gene mutations had a greater response rate (71.2% vs 41.3%) and improved overall survival (HR, 0.48; 95% CI: 0.36C0.64; p 0.0001) with gefitinib. Erlotinib Unlike gefitinib, erlotinib has shown clinical efficacy that has resulted in its unrestricted US Food and Drug Administration (FDA) approval in NSCLC. BR21, a randomized phase III Dibutyl phthalate trial of Dibutyl phthalate 731 patients with stage IIIB or IV NSCLC showed that patients Has1 randomized to erlotinib had a statistically significant increase in overall survival, PFS, and overall response rate.15 However, similar to the results seen with gefitinib, phase III trials evaluating the combination of a platinum-based doublet alone or with erlotinib, gemcitabine C cisplatin (TALENT)52 and carboplatin C paclitaxel (TRIBUTE)53 did not show any advantage to the addition of erlotinib. Cetuximab Introduction Cetuximab is a human-mouse chimeric immunoglobulin G1 (IgG1) class monoclonal antibody directed against the EGFR with proven second- or third-line efficacy in colorectal54 and head and neck cancers.55,56 This monoclonal antibody binds to the extracellular ligand-binding domain with affinity five times greater than natural ligands like TGF- and EGF.57 Binding of cetuximab prevents dimerization and subsequent activation by auto-phosphorylation of the receptor in the intracellular kinase domain.58 The receptor-antibody complex is internalized and degraded, thereby decreasing EGFR availability.59 studies show the antibody also mediates antibody-dependent cellular cytotoxicity (ADCC) against the receptor.60 Preclinical studies with cetuximab suggested that there was inhibition of growth of human NSCLC cell lines and other EGFR-expressing cell lines = 0.0441). One-year survival also was higher in the cetuximab group (47% vs 42%). Interestingly however there was no difference in PFS between the two groups. Though the benefit with the addition of cetuximab was modest, the results of this trial led to cetuximab being incorporated into the National Comprehensive Cancer Network (USA) guidelines for use in the first-line setting in combination with cisplatin and vinorelbine (see http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf). Preliminary results of pre-specified subgroup analyses suggest a greater benefit with the addition of cetuximab in Caucasians. Caucasian patients who received cetuximab had a median survival of 10.5 months as opposed to 9.1 months in those who did.