Abstract B212: Integrating the pre-clinical pharmacokinetic, pharmacodynamics, and efficacy data for AZD9291, an oral, irreversible inhibitor of EGFR activating (EGFRm+) and resistant (EGFRm+/T790M) mutations and an active metabolite to predict the human pharmacokinetics and potential efficacious dose in patients.

Abstract

Abstract Small molecule tyrosine kinase inhibitors gefitinib and erlotinib have demonstrated clinical benefit in advanced NSCLC patients with the EGFR activating mutation but ultimately disease progression develops due to resistant mutations. The most common resistant mutation is EGFR T790M and remains a key area of unmet need. AZD9291 is an irreversible inhibitor of both the EGFR activating mutant (EGFRm+) and resistance mutation (EGFRm+/T790M), while maintaining a margin to wild type EGFR. AZD9291 has demonstrated impressive efficacy and regressions at low doses in mouse xenograft models for both activating (EGFRm+) and resistant (EGFRm+/T790M) mutant forms of EGFR (PC9 and H1975 cell lines). Analysis of plasma samples from these xenograft studies identified a des-methylated metabolite circulating in addition to AZD9291 with subsequent in vitro studies indicating the metabolite was around five fold more potent than AZD9291. A program of mouse xenograft studies was undertaken to determine the tumor pEGFR pharmacodynamics (PD) and tumor growth inhibition (TGI) of AZD9291 and metabolite. Mathematical models incorporating an irreversible binding component have been developed to describe the contribution of AZD9291 and metabolite exposure to the pEGFR PD and TGI in the mouse (a PK/PD-TGI model). Pre-clinical drug metabolism and pharmacokinetic data were used to predict the human pharmacokinetics of AZD9291 and formation of the active metabolite. The predicted human exposures of both AZD9291 and metabolite were then used to drive the PK/PD-TGI model to simulate inhibition of pEGFR and inhibition of tumor growth. Assuming that human tumours and biomarkers behave in a similar way to those in mouse xenografts, these simulations suggest that a dose of 7-17 mg of AZD9291 once a day would be efficacious in patients with advanced NSCLC harboring the EGFR activating and T790M resistant mutations. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B212. Citation Format: Peter Ballard, Susan Ashton, Darren Cross, Richard Dimelow, James Yates. Integrating the pre-clinical pharmacokinetic, pharmacodynamics, and efficacy data for AZD9291, an oral, irreversible inhibitor of EGFR activating (EGFRm+) and resistant (EGFRm+/T790M) mutations and an active metabolite to predict the human pharmacokinetics and potential efficacious dose in patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B212.