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 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.

Therapeutic drug monitoring guidelines in oncology: what do we know and how to move forward? Insights from a systematic review

“…On the basis of a defined exposure–response relationship, it is suggested that PopPK models be developed to support dose individualization. Up to now, studies on PopPK have been conducted for a variety of antineoplastic drugs, including atezolizumab, 53 brentuximab vedotin, 54 busulfan, 9 , 11 , 55 dasatinib, 56 methotrexate, 7 , 57 , 58 sunitinib, 59 and vincristine 60 , 61 in pediatric patients and acalabrutinib, 62 afatinib, 63 atezolizumab, 53 brentuximab vedotin, 54 dostarlimab, 64 erlotinib, 65 necitumumab, 66 nivolumab, 67 pembrolizumab, 68 savolitinib plus osimertinib, 69 siltuximab, 70 and trastuzumab 71 in adults. Based on heterogeneous data, the quantification, and identification of variability and simulations, PopPK is an essential tool to individualize drug doses to reduce toxicity and improve patients’ outcomes.…”