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 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 ac-quired 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 (x)80 mg], combined with doses of savolitinib (0-15 mg/kg, R-.: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 time points to follow the time course of drug exposure in addition to phos- phorylated MET and EGFR (pMET and pEGFR) change. Popula-tion 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 antitumor activity, reaching 84% TGI, and osimertinib (10 mg/kg) showed no significant antitumor activity (34% TGI, P > 0.05 vs. vehicle). Upon combination, at a fixed dose of osimertinib, signif-icant savolitinib dose-related antitumor 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 antitumor activity when combined with osimertinib in the EGFRm MET-amplified NSCLC PDX model.