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

Abstract

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 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 time points to follow the time course of drug exposure in addition to phosphorylated MET and EGFR (pMET and 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 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, significant 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.

Figure 1.

Antitumor activity of savolitinib and osimertinib as single agents and in combination in the EGFRm, MET-amplified, T790M NSCLC NCI-H820 and LG1208 NSCLC PDX models. A, Tumor inhibition time curves with single-agent osimertinib (25 mg/kg) and savolitinib (25 mg/kg), and savolitinib plus osimertinib (treatment once daily for ∼21 days) in the NCI-H820 model. B, Tumor inhibition time curves with single-agent osimertinib (25 mg/kg) and savolitinib (12.5 mg/kg), and savolitinib plus osimertinib in the absence of ABT (treatment once daily for 15 days) in the LG1208 model. C, Tumor inhibition time curves following repeat dosing of single-agent savolitinib, osimertinib, and various doses of savolitinib combined with a fixed dose of osimertinib in the presence of ABT in the LG1208 model. Abbreviations: ABT, 1-aminobenzotriazole; EGFRm, epidermal growth factor receptor mutation positive; NSCLC, non–small cell lung cancer; PDX, patient-derived xenograft; QD, once daily. *Not statistically significant to vehicle (P > 0.05); **Not statistically different to osimertinib alone (P > 0.05).

Figure 2.

Model simulations compared with observed levels of pMET: after a single dose (A), after 3 daily doses (B) and at the end of efficacy study (C); and pEGFR: after a single dose (D), after three daily doses (E); and at end of efficacy study (F). Abbreviations: pEGFR, phosphorylated epidermal growth factor receptor; pMET, phosphorylated MET.

Figure 3.

PK/PD modeling data showing the link between biomarker effects and antitumor activity. A, Comparison of tumor inhibition between observed data (green diamonds) for savolitinib 0 to 15 mg/kg plus osimertinib 10 mg/kg from the EGFRm, MET-amplified, LG1208 NSCLC PDX mouse model and model simulations (solid black line). B, Model simulations for the relationship between the degree of pMET inhibition and effect on the EC₅₀ for the pEGFR inhibition by osimertinib. Abbreviations: BID, twice daily; pEGFR, phosphorylated epidermal growth factor receptor; pMET, phosphorylated MET; QD, once daily.

Figure 4.

Model simulations for the translation to human, exploring the effects on pEGFR and pMET following combination dosing of savolitinib (0 to 600 mg) plus osimertinib (80 mg; N = 10). A, Relationship between dose and the degree of inhibition of pEGFR or pMET at 24 hours after dosing. B, Relationship between dose and the time above 80% inhibition of pEGFR or 95% pMET over a 24-hour interval. C, Relationship between dose and the probability of a single patient achieving adequate exposure to deliver >80% pEGFR and >95% pMET continuously over a 24-hour dosing interval. Abbreviations: BID, twice daily; pEGFR, phosphorylated epidermal growth factor receptor; pMET, phosphorylated MET; QD, once daily.