Osimertinib dimesylate is an irreversible and mutant selective EGFR inhibitor (IC50s: 12 and 1 nM against EGFR L858R and EGFR L858R/T790M).

EGFR (L858R/T790M):1 nM, EGFR (L858R):12 nM

Osimertinib (AZD-9291) shows similar potency to early generation tyrosine kinase inhibitor in inhibiting EGFR phosphorylation in EGFR cells harboring sensitizing EGFR mutants including PC-9 (ex19del), H3255 (L858R) and H1650 (ex19del) (mean IC50s: 13 to 54 nM). Osimertinib also potently inhibits phosphorylation of EGFR in T790M mutant cell lines H1975 (L858R/T790M), PC-9VanR (ex19del/T790M), with mean IC50 potency less than 15 nM [1].

The tumor-bearing mice are treated with Osimertinib (5 mg/kg/day) for one to two weeks. Within days of treatment, 5 of 5 C/L858R mice display nearly 80% reduction in tumor volume by magnetic resonance imaging MRI after therapy with Osimertinib, while 5 of 5 mice treated with vehicle shows tumor growth [1]. Upon dosing Osimertinib in three efficacy models, comparable efficacy is observed at relatively low doses (10 mg/kg per day). The excellent efficacy is also observed when Osimertinib is dosed at 5 mg/kg per day [2].