A PK-PD model linking biomarker dynamics to progression-free survival in patients treated with everolimus and sorafenib combination therapy, EVESOR phase I trial.

Autor: Puszkiel, Alicja, You, Benoit, Payen, Léa, Lopez, Jonathan, Guitton, Jérôme, Rousset, Pascal, Fontaine, Juliette, Péron, Julien, Maillet, Denis, Tartas, Sophie, Bonnin, Nathalie, Trillet-Lenoir, Veronique, Colomban, Olivier, Augu-Denechere, Diane, Freyer, Gilles, Tod, Michel
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Zdroj: Cancer Chemotherapy & Pharmacology; May2023, Vol. 91 Issue 5, p413-425, 13p
Abstrakt: 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® 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. Trial registration: ClinicalTrials.gov Identifier: NCT01932177. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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