Epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase protein. EGFR plays an important role in controlling cell division and survival. Osimertinib (AZD9291) is a mutant-selective, irreversible inhibitor of EGFR kinase activity in non-small-cell lung cancer (NSCLC).

Osimertinib is an orally active, potent, and selective third-generation irreversible inhibitor of both EGFR mutant (EGFRm+) sensitizing and T790M resistance mutants that spare wild-type EGFR. Particularly, Osimertinib shows an apparent IC₅₀ of 12 nM against L858R and 1 nM against L858R/T790M. Consistently, treatment of cells with Osimertinib inhibits phosphorylation of HER2 at moderate potency levels.

Osimertinib is a potent and selective EGFR inhibitor. Non-small-cell lung cancer (NSCLC). It possesses antitumor activity in NSCLC.

Osimertinib potently and selectively targets mutant EGFR cell lines in vitro. Osimertinib also potently inhibits phosphorylation of EGFR in T790M mutant cell lines, PC-9VanR (ex19del/T790M), with mean IC₅₀ potency less than 15 nM. In addition, Osimertinib potently inhibits p-EGFR and downstream signaling substrates (p-AKT, p-ERK) in cells. Osimertinib shows high levels of phenotype potency in both sensitizing-mutant (mean IC₅₀ of 8 nM in PC-9) and T790M (mean IC₅₀ of 11 and 40 nM in H1975 and PC-9VanR respectively) EGFR cell lines. Besides, Osimertinib causes profound and sustained regression in mutant EGFR in vivo xenograft models.

Osimertinib demonstrates good bioavailability and has moderate clearance resulting in a half-life of around 3 hours after oral dosing in the mouse. Moreover, Osimertinib causes profound and sustained regression in mutant EGFR in vivo transgenic tumor models. Osimertinib induces significant and sustained tumor regression in transgenic models of EGFR-TKI sensitizing and T790M resistant NSCLC. Furthermore, Osimertinib strongly inhibits both p-EGFR and downstream signaling pathways in the H1975 model.

All in all, Osimertinib is an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in NSCLC.

Reference:
Darren A E Cross, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014 Sep;4(9):1046-61.