Preclinical to clinical translation of pharmacokinetic-pharmacodynamic relationship in EGFR Exon20Ins mutations: a modelling framework for irreversible inhibitors.

EGFR Exon20 insertions (Exon20Ins) constitute the third most common EGFR activating mutation in non-small cell lung cancer. We developed a semi-mechanistic pharmacodynamic (PD) model for irreversible inhibitors of EGFR Exon20Ins mutations by integrating kinetic data of proprietary compounds with a mechanistic description of EGFR turnover and phosphorylation to investigate the preclinical relationship between phosphorylated EGFR (phosEGFR) reduction and efficacy, and its translation to the clinical setting. In engineered NCI-H2073 cells hosting the Exon20 SVDIns mutation, EGFR turnover was studied via SILAC MS and phosEGFR time-course analysed via ELISA. Kinetic parameters were determined from a biochemical binding assay. These data were integrated into the model to describe phosEGFR inhibition in vitro and in vivo. Tumour volume data from xenograft studies were then used to quantify the relationship between phosEGFR inhibition and anti-tumour activity. We found that sustained >84% phosEGFR inhibition is required for tumour regression. Clinical phosEGFR simulations were generated for 2 proprietary inhibitors, providing an early estimation of their active human doses. We also explored clinical phosEGFR reduction induced by the 3rd generation TKI osimertinib, suggesting that limited target engagement may explain modest response achieved in EGFR Exon20Ins at the clinically investigated doses. The developed model is a valuable tool to understand the impact of kinetic characteristics on phosEGFR reduction and related efficacy, select a target engagement-based criterion for therapeutic dose predictions, and provide interpretation and insights on observed clinical efficacy of irreversible inhibitors in EGFR Exon20Ins.