Rob Ter Heine 1, Judith Verdonk 2, Leila-Sophie Otten 1, Ghazal Montaseri 3, Michel van den Heuvel 4, Ruben Smeets 2, Hans Koenen 2
1 Radboudumc, department of pharmacy, Pharmacology and Toxicology (Nijmegen, The Netherlands), 2 Radboudumc, Laboratory of Medical Immunology (Nijmegen, The Netherlands), 3 Boehringer Ingelheim Pharma GmbH & Co. KG (Biberach an der Riß, Germany), 4 UMCU (Utrecht, The Netherlands)
Background
Optimal dosing of immune checkpoint inhibitors (ICI) like programmed death-1 (PD-1) inhibitors remains uncertain, as dose–response relationships are not well defined. Dosing of the PD-1 inhibitors are often guided by achieving complete peripheral PD-1 receptor occupancy, not necessarily reflecting intratumoral pharmacology or immune activation [1]. Furthermore, the recent finding that timing of drug administration impacts treatment outcomes [2], challenge the paradigm that PD-1 inhibitors are overdosed.
We investigated relationships between pembrolizumab dose, systemic and intratumoral pharmacokinetics, receptor occupancy, and immune activation in non small cell lung cancer (NSCLC) patients.
Methods
A minimal pembrolizumab physiologically based pharmacokinetic model, as previously described by Lindauer et al [3], describing plasma and intratumoral pembrolizumab kinetics was refitted to real world pembrolizumab PK data in non-small cell lung cancer patients. Allometric scaling and time-dependent clearance were added to the pharmacokinetic model. The model was then extended to incorporate receptor occupancy and interleukin 2 (IL 2) induction parameters based on ex vivo dose ranging experiments in peripheral blood mononuclear cells of NSCLC patients[4]. PD-1 receptor occupancy and IL-2 release were described using Emax equations. Simulations were performed for a representative patient receiving three approved regimens: 2 mg/kg Q3W, 200 mg Q3W, and 400 mg Q6W to investigate peripheral and intratumoral receptor occupancy and IL-2 induction for these dosing regimens.
Results
All regimens were predicted to produce near complete PD-1 receptor occupancy in plasma and tumor compartments. Despite this, IL-2 concentrations fluctuated throughout the dosing interval and followed pembrolizumab concentrations rather than receptor occupancy. The 400 mg Q6W regimen yielded the highest IL-2 levels. Intratumoral IL-2 fluctuations were less pronounced than in plasma, but remained clearly concentration dependent.
Conclusions
Receptor occupancy did not predict immune activation as measured by IL-2 concentrations, suggesting receptor occupancy is an inadequate surrogate for pembrolizumab pharmacodynamics. These findings challenge current dose selection strategies and highlight the need for robust pharmacodynamic markers and clearer definition of the immune activation level required for optimal ICI efficacy in NSCLC.
References:
1. Fu et al. Bioanalysis . 2019 Jul;11(14):1347-1358. doi: 10.4155/bio-2019-0090.
2. Landre et al. ESMO Open . 2024 Feb;9(2):102220. doi: 10.1016/j.esmoop.2023.102220.
3. Lindauer et al. CPT Pharmacometrics Syst Pharmacol . 2017 Jan;6(1):11-20. doi: 10.1002/psp4.12130
4. Verdonk et al. https://www.medrxiv.org/content/10.64898/2026.02.04.26345546v1
Reference: PAGE 34 (2026) Abstr 12287 [www.page-meeting.org/?abstract=12287]
Poster: Drug/Disease Modelling - Oncology