Prospective real-world study on the pharmacokinetics of pembrolizumab in patients with solid tumors

Publikation

Prospective real-world study on the pharmacokinetics of pembrolizumab in patients with solid tumors

Wissenschaftlicher Artikel/Review - 01.01.2021

Hurkmans Daan P, Mathijssen Ron H J, Aerts Joachim G J V, van der Veldt Astrid A M, Schreurs Marco W J, van der Leest Cor H, Koch Birgit C P, Debets Reno, Jörger Markus, Wijkhuijs Annemarie J M, Basak Edwin A, Putter Lisanne, de Joode Karlijn, Sassen Sebastiaan D T, Koolen Stijn L W

Zitation

Hurkmans D, Mathijssen R, Aerts J, van der Veldt A, Schreurs M, van der Leest C, Koch B, Debets R, Jörger M, Wijkhuijs A, Basak E, Putter L, de Joode K, Sassen S, Koolen S. Prospective real-world study on the pharmacokinetics of pembrolizumab in patients with solid tumors. J Immunother Cancer 2021; 9

Art

Wissenschaftlicher Artikel/Review (Englisch)

Zeitschrift

J Immunother Cancer 2021; 9

Veröffentlichungsdatum

01.01.2021

eISSN (Online)

2051-1426

Kurzbeschreibung/Zielsetzung

BACKGROUND
Dosing schemes of pembrolizumab (anti-programmed cell death protein 1 monoclonal antibody) are solely based on pharmacokinetic (PK) modelling derived from phase I-III trials. The current study aimed to determine factors affecting PK and its relationship with clinical outcome in the real-world setting.

METHODS
Advanced-stage cancer patients, who were treated with pembrolizumab monotherapy (2 mg/kg Q3W or 200 mg flat Q3W), were prospectively included for serial sampling to obtain trough concentrations. A PK model was generated, covariate effects assessed and internally validated by a bootstrap procedure. PK parameters were related to overall survival (OS) and the occurrence of immune-related adverse events (irAEs).

RESULTS
588 serum samples derived from 122 patients with (non-)small-cell lung cancer ([N]SCLC), malignant pleural mesothelioma (MPM), melanoma and urothelial cell cancer (UCC) were analyzed. Median follow-up was 2.2 years. A one-compartment PK model was generated: body surface area (BSA) and serum albumin had a significant effect on drug clearance (CL; covariate estimate 1.46 and -1.43, respectively), and serum lactate dehydrogenase (LDH) on the distribution volume(V; 0.34). A significant inverse CL-OS relationship was determined for NSCLC (HR:1.69; 95%CI1.07-2.68; p=0.024) and MPM (HR: 3.29; 95% CI 1.08 to 10.09; p=0.037), after correction for prognostic factors, which could not confirmed for melanoma (p=0.22) or UCC (p=0.34). No relationship could be determined between CL and grade 3 irAEs (p=0.70).

CONCLUSIONS
High interpatient variability of pembrolizumab PK is determined by BSA and serum albumin (on CL) and LDH (on V). A strong inverse CL-OS relationship was demonstrated for NSCLC and MPM, which could not be observed for melanoma and UCC. The findings suggest that personalized dosing should be prospectively explored.