Abstract
Osimertinib is an irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that is highly selective for EGFR-activating mutations as well as the EGFR T790M mutation in patients with advanced non-small cell lung cancer (NSCLC) with EGFR oncogene addiction. Despite the documented efficacy of osimertinib in first- and second-line settings, patients inevitably develop resistance, with no further clear-cut therapeutic options to date other than chemotherapy and locally ablative therapy for selected individuals. On account of the high degree of tumour heterogeneity and adaptive cellular signalling pathways in NSCLC, the acquired osimertinib resistance is highly heterogeneous, encompassing EGFR-dependent as well as EGFR-independent mechanisms. Furthermore, data from repeat plasma genotyping analyses have highlighted differences in the frequency and preponderance of resistance mechanisms when osimertinib is administered in a front-line versus second-line setting, underlying the discrepancies in selection pressure and clonal evolution. This review summarises the molecular mechanisms of resistance to osimertinib in patients with advanced EGFR-mutated NSCLC, including MET/HER2 amplification, activation of the RAS–mitogen-activated protein kinase (MAPK) or RAS–phosphatidylinositol 3-kinase (PI3K) pathways, novel fusion events and histological/phenotypic transformation, as well as discussing the current evidence regarding potential new approaches to counteract osimertinib resistance.
Highlights
The identification of activating mutations in the gene encoding the epidermal growth factor receptor (EGFR) tyrosine kinase in patients with non-small cell lung cancer (NSCLC) and the subsequent development of targeted therapy with smallmolecule EGFR tyrosine kinase inhibitors (TKIs) has dramatically revolutionised the treatment landscape of these tumours
Taking into account the positive overall survival (OS) results derived from the addition of chemotherapy to first-generation TKIs for the first-line treatment of patients with EGFR-mutated NSCLC,[99] randomised trials exploring osimertinib combined with chemotherapy in the same clinical setting are needed
PERSPECTIVES The remarkable success of osimertinib for the treatment of patients with advanced EGFR-mutated NSCLC has been mitigated by the development of acquired resistance to this agent
Summary
Alessandro Leonetti[1,2], Sugandhi Sharma[2], Roberta Minari[1], Paola Perego[3], Elisa Giovannetti[2,4] and Marcello Tiseo 1,5. Osimertinib is an irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that is highly selective for EGFR-activating mutations as well as the EGFR T790M mutation in patients with advanced non-small cell lung cancer (NSCLC) with EGFR oncogene addiction. Despite the documented efficacy of osimertinib in first- and second-line settings, patients inevitably develop resistance, with no further clear-cut therapeutic options to date other than chemotherapy and locally ablative therapy for selected individuals. On account of the high degree of tumour heterogeneity and adaptive cellular signalling pathways in NSCLC, the acquired osimertinib resistance is highly heterogeneous, encompassing EGFR-dependent as well as EGFRindependent mechanisms. Data from repeat plasma genotyping analyses have highlighted differences in the frequency and preponderance of resistance mechanisms when osimertinib is administered in a front-line versus second-line setting, underlying the discrepancies in selection pressure and clonal evolution.
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