Reversible ATP-competitive inhibitors targeting the epidermal growth factor 
receptor (EGFR) have been established as the most effective treatment of 
patients with advanced non-small cell lung cancer (NSCLC) harboring "activating" 
mutations in exons 19 and 21 of the EGFR gene. However, clinical activity is 
limited by acquired resistance which on average develops within 10 months of 
continued treatment. The mechanisms for acquired resistance include selection of 
the EGFR T790M mutation in approximately 50% of cases, and MET gene 
amplification, PIK3CA gene mutation, transdifferentiation into small-cell lung 
cancer and additional rare or unkown mechanisms. Afatinib is a small molecule 
covalently binding and inhibiting the EGFR, HER2 and HER4 receptor tyrosine 
kinases. In preclinical studies, afatinib not only inhibited the growth of 
models with common activating EGFR mutations, but was also active in lung cancer 
models harboring wild-type EGFR or the EGFR L858R/T790M double mutant. Clinical 
efficacy of afatinib has been extensively studied in the LUX-Lung study program. 
These trials showed promising efficacy in patients with EGFR-mutant NSCLC or 
enriched for clinical benefit from EGFR tyrosine kinase inhibitors gefitinib or 
erlotinib. Here we review the current status of clinical application of afatinib 
in NSCLC. We also discuss clinical aspects of resistance to afatinib and 
strategies for its circumvention.