The approval of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) 15 years ago allowed a dramatic leap in the clinical outcome of patients with EGFR-mutated non-small cell lung cancer (NSCLC). The hope that this treatment generated for a cure was slightly diminished by the realization that resistance to TKIs is inevitable. Nevertheless, important insights into the mechanisms of resistance were gained by characterization of the drug-resistant tumor cells. These studies provided critical information about on- and off-target mechanisms of resistance and ultimately led to the development of treatments such as osimertinib. This drug was first approved in patients with EGFR-activating mutations with concurrent T790M mutations. In this setting, the objective response rate (ORR) was 71% versus 31% for second-line chemotherapy (p<0.001), and progression free survival (PFS) was 8.5 months compared with 4.2 months for chemotherapy . Other targetable bypass pathways, such as activation of the MET signaling pathway, have also been identified [2–4]. However, the magnitude of the challenge of resistance has become abundantly clear, particularly the fact that, as the number of lines of targeted therapy patients receive increases, the length of time on subsequent treatments decreases, while the molecular complexity of the tumors increase . This process is known to occur in other molecular subtypes of lung cancer as well as other cancers [6–12].
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