The Discovery of Osimertinib (TAGRISSO™): An Irreversible Inhibitor of Activating and T790M Resistant Forms of the Epidermal Growth Factor Receptor Tyrosine Kinase for the Treatment of Non‐Small Cell Lung Cancer

Michael J. Waring

Successful Drug Discovery, 2018
doi: 10.1002/9783527808694.ch12

Non‐small cell lung cancer (NSCLC) consists of a group of diseases that account for 80‐85% of lung cancer cases. Signaling through epidermal growth factor receptor (EGFR) is important for the maintenance of healthy tissue in particular epithelial cells, but it is also highly expressed in a number of cancers and in particular NSCLC. Despite initial encouraging responses to treatment in EGFR activating mutant tumors, it has been observed that resistance to tyrosine kinase inhibitor (TKI) therapy develops fairly rapidly. Pioneering work at Zeneca Pharmaceuticals in the 1990s led to the discovery of the anilinoquinazoline class of EGFR inhibitors. An analysis of responses to therapy led to the discovery of activating mutations in the EGFR kinase domain. This mutation is a point mutation at threonine 790, which becomes methionine (T790M). This chapter shows tumor responses in T790M‐positive patients in response to osimertinib treatment.