First- and second-generation epidermal growth factor receptor (EGFR) tyrosine 
kinase inhibitors (TKIs) are the evidence-based first-line treatment for 
metastatic non-small-cell lung cancers (NSCLCs) that harbor sensitizing EGFR 
mutations (i.e. exon 19 deletions or L858R). However, acquired resistance to 
EGFR TKI monotherapy occurs invariably within a median time frame of one year. 
The most common form of biological resistance is through the selection of tumor 
clones harboring the EGFR T790M mutation, present in >50% of repeat biopsies. 
The presence of the EGFR T790M mutation negates the inhibitory activity of 
gefitinib, erlotinib, and afatinib. A novel class of third-generation EGFR TKIs 
has been identified by probing a series of covalent pyrimidine EGFR inhibitors 
that bind to amino-acid residue C797 of EGFR and preferentially inhibit mutant 
forms of EGFR versus the wild-type receptor. We review the rapid clinical 
development and approval of the third-generation EGFR TKI osimertinib for 
treatment of NSCLCs with EGFR-T790M.