Paper Title
Latest Treatment Options to Overcome Acquired Resistance toOsimertinib for EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) After Prior EGFR-TKI Therapies

Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are common in lung cancers patients who are never-smokers, and many of these EGFR-mutant patients have shown good responses to the 1st-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib in clinical trials since 2003. Unfortunately, almost all patients with advanced NSCLC who responded to either 1st-generation EGFR TKIs (e.g., gefitinib, erlotinib) or the 2nd-generation EGFR TKIs (e.g., afatinib, dacomitinib) will eventually develop acquired resistance, while ~50-60% willdevelop T790M mutation in the EGFR kinase domain.Third-generation EGFR TKIs osimertinib has thus been developed and approved in late 2016 as the treatment choice for patients with the T790M mutation who have had disease progression following prior EGFR TKI therapies. However, acquired resistance to osimertinibwill also develop and canbe complex to overcome. Progression on osimertinib after prior EGFR-TKI treatment (i.e., after 1st-/2nd line EGFR TKIs) revealed that the biology of patients who retain T790M and those who lose T790M can bevery different. For those who retain T790M, about ~50% develop C797S mutation as well, which prevents osimertinib from binding at the ATP cleft. However, those who lost T790M may have a broad range of non-EGFR resistance mechanismssuch as MET,mutations in PI3 kinase, HER2 amplification,KRAS, BRAF, etc. Only in cases where C797S mutation is on the trans-site of T790M, dual-EGFR TKIs treatment (e.g., erlotinib combined with osimertinib)can be effective for some time. There is thus an urgent clinical need worldwide to sort out what are the latest and effective treatment options to overcome acquired resistance to osimertinib for EGFR-mutant NSCLC patients after prior EGFR-TKI treatments, as will be discussed in this paper. Keywords - Acquired Resistance, Afatinib, Cetuximab, EGFR (epidermal growth factor receptors), Erlotinib, Gefitinib,Non-Small-Cell Lung Cancer (NSCLC), Never-Smoker’s lung cancer, Osimertinib, Tyrosine Kinase Inhibitor (TKI)