l cell lung cancer (NSCLC). NSCLC is a major cause of cancer mortality accounting for ~80% of all cases, the remaining 20% being attributable to the small-cell lung cancer type (SCLC). As of 2009, gefitinib was reported to be approved for use in more than 60 countries worldwide that included the US, Japan and countries in the European Union (EU). Mutations in Egfr are among several well documented contributors to non-small cell lung cancer (NSCLC). They remove an autoinhibitory effect and lead to increase activity even in the absence of ligand binding. Mutations that render the receptor constitutively active also confer higher affinity for the TKI drugs. Gefitinib is primarily metabolized by CYP3A4 and also by CYP3A5, CYP2D6 and the extrahepatic CYP1A1. The drug has been shown to inhibit the activity of CYP2C19 as well as CYP2D6 but the clinical relevance of these findings is however questioned. The efficiency of gefitinib and other TKI is unfortunately lost within one year of treatment due to acquired resistance. Secondary mutations in Egfr interfere with TKI binding and promote constitutive activation. In addition, amplification of Met oncogene which normally does not engage Egfr members, also leads to increased activation of the receptor and appears to involve Erbb3. Met amplification can lead to increased activation of downstream signaling pathways independent of Egfr; Egfr and Met mediated signaling impinge upon the same intracellular cascades. These intracellular cascades have been shown to be altered in NSCLC. Gefitinib is less expensive and its association with rash incidence lower than erlotinib. Other side effects of gefitinib and erlotinib include GI disturbances. It is to be mentioned here that interstitial lung disease (ILD) is a rare, but potentially life-threatening side effect of TKI with overall reported incidence of 1% but higher, 3-5%, in Asian patients. The eventually acquired resistance to TKI and the involvement of other altered pathways in NSCLC, has prompted the development of other drugs for the treatment of the disease, including second generation TKI. [To access a related diagram page at PharmGKB, click here]...(less)