Osimertinib (AZD9291) is a potent, selective, irreversible inhibitor of EGFR sensitising (Exon 19 and L858R) and T790M resistant mutation. In vivo, in the mouse, it is metabolised to an active des-methyl metabolite AZ5104. In order to understand the therapeutic potential in patients, this study aimed to assess the relationship between osimertinib pharmacokinetics (PK), the PK of the active metabolite, the pharmacodynamics (PD) of phosphorylated EGFR reduction and efficacy in mouse xenograft models of EGFR driven cancers including two NSCLC lines. Osimertinib was dosed in xenografted models of EGFR driven cancers. In one set of experiments changes in phosphorylated EGFR were measured in order to confirm target engagement. In a second set of efficacy studies the resulting changes in tumor volume over time after repeat dosing of osimertinib were observed. To account for the contributions of both molecules a mathematical modelling approach was taken to integrate the resulting data sets. The model was able to describe the PK, PD and efficacy in A431, PC9 and H1975 xenografts with the differences in sensitivity described by the varying potency against wild-type, sensitising and T790M mutant EGFR and the phosphorylated EGFR reduction required to reduce tumor volume. It was found based upon the in vivo PD. It was inferred that recovery of pEGFR is slower after chronic dosing due to reduced re-synthesis. It was predicted and further demonstrated that although inhibition is irreversible the re-synthesis of EGFR is such that infrequent intermittent dosing is not as efficacious as once daily dosing.
- Received March 17, 2016.
- Revision received July 11, 2016.
- Accepted July 12, 2016.
- Copyright ©2016, American Association for Cancer Research.