Pharmacokinetic/Pharmacodynamic Analysis of Savolitinib Plus Osimertinib in an EGFR-Mutation Positive, MET-Amplified Non-Small Cell Lung Cancer Model.

Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), recommended as first-line treatment for patients with locally advanced/metastatic EGFR-mutation positive (EGFRm) non-small cell lung cancer (NSCLC). However, MET-amplification/overexpression is a common acquired osimertinib resistance mechanism. Savolitinib is an oral, potent, and highly selective MET-TKI; preliminary data suggest that combining osimertinib with savolitinib may overcome MET-driven resistance. A patient-derived xenograft (PDX) mouse model with EGFRm, MET-amplified NSCLC was tested with a fixed osimertinib dose (10 mg/kg, for exposures equivalent to [≈] 80 mg), combined with doses of savolitinib (0-15 mg/kg, ≈0-600 mg once-daily), both with 1-aminobenzotriazole (to better match clinical half-life). After 20 days of oral dosing, samples were taken at various timepoints to follow the time-course of drug exposure in addition to phosphorylated MET and EGFR (pMET; pEGFR) change. Population pharmacokinetics, savolitinib concentration versus percentage inhibition from baseline in pMET, and the relationship between pMET and tumor growth inhibition (TGI) were also modeled. As single agents, savolitinib (15 mg/kg) showed significant anti-tumor activity, reaching ~84% TGI and osimertinib (10 mg/kg) showed no significant anti-tumor activity (34% TGI, P>0.05 vs. vehicle). Upon combination, at a fixed dose of osimertinib, significant savolitinib dose-related anti-tumor activity was shown, ranging from 81% TGI (0.3 mg/kg) to 84% tumor regression (15 mg/kg). Pharmacokinetic-pharmacodynamic modeling showed that the maximum inhibition of both pEGFR and pMET increased with increasing savolitinib doses. Savolitinib demonstrated exposure-related combination anti-tumor activity when combined with osimertinib in the EGFRm MET-amplified NSCLC PDX model.