Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

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.

Fig. 1

Resistance mechanisms reported for osimertinib according to the line of treatment. The two pie charts depict resistance mechanisms that have been identified in tissue and/or in plasma after resistance to second-line and first-line osimertinib, respectively. Only studies that enrolled more than 15 patients have been taken into account for the ranges of the percentages. In some cases, different molecular aberrations might co-exist in the same patient

Fig. 2

Schematic representation of the known mechanisms of resistance to osimertinib Resistance mechanisms to osimertinib can consist of EGFR modifications (mutation/amplification), bypass pathway activation, downstream pathway activation, epithelial-to-mesenchymal transition (EMT), histologic transformation, oncogenic gene fusions and cell-cycle gene aberrations. Abbreviations: act, activation; amp, amplification; del, deletion; mut, mutation

Fig. 3

Potential treatment algorithm of T790M EGFR-mutated NSCLC. The present figure depicts the most common molecular events within EGFR that can occur after the onset of osimertinib resistance. (1) T790M loss/C797S: in this scenario, NSCLC cells re-acquire sensitivity to first-generation and second-generation EGFR-TKIs; (2) T790M/C797S in cis: NSCLC cells are amenable to novel fourth-generation EGFR-TKIs which are currently in development and (3) T790M/C797S in trans: NSCLC cells become sensitive to combination therapy with osimertinib and first-generation EGFR-TKIs