Update on recent preclinical and clinical studies of T790M mutant-specific irreversible epidermal growth factor receptor tyrosine kinase inhibitors

The first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (1/2g egfr-tkis) gefitinib,erlotinib,and afatinib have all been approved as standard first-line treatments for advanced egfr mutation-positive non-small cell lung cancer. the third-generation (3g) egfr-tkis have been developed to overcome the egfr t790m mutation,which is the most common mechanism of acquired resistance to 1/2g egfr-tki treatment. this resistance mutation develops in half of the patients who respond to 1/2g egfr-tki therapy. the structures of the novel 3g egfr-tkis are different from those of 1/2g egfr-tkis. particularly,3g egfr-tkis have lower affinity to wild-type egfr,and are therefore associated with lower rates of skin and gastrointestinal toxicities. however,many of the adverse events (aes) that are observed in patients receiving 3g egfr-tkis have not been observed in patients receiving 1/2g egfr-tkis. although preclinical studies have revealed many possible mechanisms for these aes,the causes of some aes remain unknown. many mechanisms of resistance to 3g egfr-tki therapy have also been reported. here,we have reviewed the recent clinical and preclinical developments related to novel 3g egfr-tkis,including osimertinib,rociletinib,olmutinib,egf816,and asp8273. © 2016 the author(s).