Journal
CANCER CHEMOTHERAPY AND PHARMACOLOGY
Volume 91, Issue 5, Pages 413-425Publisher
SPRINGER
DOI: 10.1007/s00280-023-04520-z
Keywords
Everolimus; Sorafenib; Biomarkers; PKPD modeling and simulation
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The objective of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model linking everolimus and sorafenib exposure with biomarker dynamics and progression-free survival (PFS). The study found a correlation between sorafenib plasma exposure and soluble vascular endothelial growth factor receptor 2 (sVEGFR2) dynamics. The simulated dosing schedule of sorafenib 200 mg bid 5 days-on/2 days-off + continuous everolimus 5 mg qd showed a higher median PFS compared to the EVESOR trial.
Purpose The objective was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model linking everolimus and sorafenib exposure with biomarker dynamics and progression-free survival (PFS) based on data from EVESOR trial in patients with solid tumors treated with everolimus and sorafenib combination therapy and to simulate alternative dosing schedules for sorafenib. Patients and methods Everolimus (5-10 mg once daily, qd) and sorafenib (200-400 mg twice daily, bid) were administered according to four different dosing schedules in 43 solid tumor patients. Rich PK and PD sampling for serum angiogenesis biomarkers was performed. Baseline activation of RAS/RAF/ERK (MAPK) pathway was assessed by quantification of mRNA specific gene panel in tumor biopsies. The PK-PD modeling was performed using NONMEM (R) software. Results An indirect response PK-PD model linking sorafenib plasma exposure with soluble vascular endothelial growth factor receptor 2 (sVEGFR2) dynamics was developed. Progression-free survival (PFS) was described by a parametric time-to-event model. Higher decreases in sVEGFR2 at day 21 and higher baseline activation of MAPK pathway were associated with longer PFS (p = 0.002 and p = 0.007, respectively). The simulated schedule sorafenib 200 mg bid 5 days-on/2 days-off + continuous everolimus 5 mg qd was associated with median PFS of 4.3 months (95% CI 1.6-14.4), whereas the median PFS in the EVESOR trial was 3.6 months (95% CI 2.7-4.2, n = 43). Conclusion Sorafenib 200 mg bid 5 days-on/2 days-off + everolimus 5 mg qd continuous was selected for an additional arm of EVESOR trial to evaluate whether this simulated schedule is associated with higher clinical benefit.
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