Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors, T790M, and Clinical Trials

Abstract

Tumours with sensitizing mutations in the EGFR gene constitute a distinct molecular subgroup of non-small-cell lung cancers (NSCLCS) that benefit from precision medicine. First- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIS) are recommended as upfront therapy for EGFR-mutated advanced NSCLC and, compared with chemotherapy, have resulted in superior progression-free survival, improved tumour response rates, and improved quality of life. However, resistance inevitably develops, and the third-generation tki osimertinib has been approved to target the gatekeeper EGFR mutation T790M, which is responsible for resistance in 60% of cases. Multiple drivers of tki resistance have now been identified, and many new drugs are in development. With respect to this rapidly evolving field, our review highlights the current status of treatment options for patients with EGFR-mutated advanced nsclc, focusing especially on identified causes of resistance, challenges, and clinical trials aiming to improve outcomes in this patient population.