EGFR tyrosine kinase inhibitors: difference in efficacy and resistance

Lung cancer will be diagnosed in 230,000 patients in the U.S. in 2013. Adenocarcinoma will be the most common histology, and 10 % of lung cancers will be diagnosed in never or former light smokers. These patients will be those most likely to harbor targetable mutations, in particular, mutations in epidermal growth factor (EGFR). Preclinical work beginning in the 1980s led to the development of EGFR-targeted therapy in lung cancer patients. Analysis of the responders to gefitinib and erlotinib led to the discovery of activating mutations underlying sensitivity to EGFR-directed treatment. Although EGFR-mutant patients have higher response rates, better quality of life, and longer progression free survival, all patients eventually develop resistance. Mutations in the tyrosine kinase domain that render tumors resistant to erlotinib and gefitinib are the most common mechanism of resistance. A second generation of EGFR inhibitors are now making their way to the clinic, with hopes of thwarting these resistance mechanisms or providing more durable responses via irreversible inhibition, as well as targeting of additional HER receptors. Here we review the evolution of EGFR as a target in lung cancer, and the second generation of EGFR inhibitors in development.