Treatments for EGFR-mutant non-small cell lung cancer (NSCLC): The road to a success, paved with failures.
The discovery of epidermal growth factor receptor (EGFR) activating mutations in non-small cell lung cancer (NSCLC) and the success story of EGFR tyrosine kinases inhibitors (TKIs) have changed the paradigm of cancer therapy from empirical cytotoxic chemotherapy to molecular-targeted cancer therapy. As a result, EGFR TKI therapy, including gefitinib, erlotinib and afatinib, has become the standard therapy for NSCLC patients with EGFR activating mutation as first-line therapy. However, most patients inevitably progress despite initial dramatic and rapid response to EGFR TKIs and therefore during the last decade, a lot of efforts have been made to identify and overcome various resistance mechanisms. Fortunately, T790M secondary mutation, the main resistance mechanism, can be overcome by newly developed third-generation EGFR TKIs, such as osimertinib, while most combination trials trying to overcome resistance mechanisms other than T790M mutation have failed so far. To make it worse, spatial and temporal tumor heterogeneity and clonal selection or evolution are also identified in EGFR mutant NSCLC tumors. Nevertheless, advance of comprehensive and more sensitive molecular diagnostics and monitoring technology, such as next-generation sequencing and dynamic monitoring technology using circulating biomarker and development of new cancer medicine with different mechanisms from EGFR TKIs, especially immune checkpoint inhibitors, might affect or change the treatment paradigm of EGFR mutant NSCLC in the near future.
Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul 05505, Republic of Korea. Electronic address: leedaeho@amc.seoul.kr.
Dae Ho
DH
Lee
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
Epidermal growth factor receptor mutation; Non-small cell lung cancer; Resistance mechanism; Tyrosine kinase inhibitor