Since the discovery of sensitizing EGFR mutations as a predictive marker of 
sensitivity to EGFR tyrosine kinase inhibitors (TKIs), the field of targeted 
therapy in non-small cell lung cancer (NSCLC) has been revolutionized. Patients 
harbouring these sensitizing mutations treated with EGFR TKI have derived 
significant clinical outcome when compared with standard platinum based 
chemotherapy doublets. However disease progression invariably occurs at a median 
of about 9-13 months from initiation treatment, if acquired resistance commonly 
due to the development of EGFR T790M mutation. A novel class of "third 
generation" EGFR TKIs have been developed that is sensitising and T790M 
mutant-specific whilst sparing WT EGFR, representing a significant breakthrough 
in the treatment in NSCLC patients with acquired resistance harboring these 
genotypes. Early phase clinical data suggest the third generation EGFR TKIs such 
as osimertinib, rociletinib, and HM61713 are highly efficacious and well 
tolerated. Another promising class of EGFR TKI such as AZD3759 has been designed 
to penetrate blood brain barrier to treat brain metastases and leptomeningeal 
disease and has showed promising responses in patients with brain metastases. 
Acquired resistance to third generation EGFR TKIs has been reported including 
EGFR C797S. Given its non-invasive nature, plasma ctDNA is being explored as a 
possible approach to detect T790M mutation and to also inform on novel molecular 
mechansims of tertiary resistance to third generation EGFR TKIs. An 
understanding of the mechanisms of acquired resistance to the third-generation 
EGFR TKIs will greatly aid in the development of the next generation of EGFR 
TKIs.