The team, led by co-first authors Judith Verdonk and Leila-Sophie Otten under the supervision of pharmacist Rob ter Heine, focused on non-small cell lung cancer, the setting in which pembrolizumab is most commonly used. Three approved dosing regimens were compared in silico: 2 milligrams per kilogram every three weeks, a flat 200 milligrams every three weeks, and a flat 400 milligrams every six weeks. These regimens were established through modelling and simulation during drug development, but the authors argue that the pharmacodynamic surrogate underpinning them, peripheral receptor occupancy, has never been rigorously validated as a predictor of clinical benefit.

To build their model, the researchers started from a physiological pharmacokinetic framework describing how pembrolizumab moves through plasma and penetrates tumour tissue. Antibody tumour penetration is a notoriously inefficient process, governed by convective transport, diffusion and antigen-mediated binding that can slow or even reverse the movement of drug into tumour interstitium. The model accounted for these dynamics, extending earlier work on antibody tumour transport, and then added two crucial layers: receptor occupancy kinetics and the induction of interleukin-2, a cytokine whose production reflects genuine T cell activation rather than mere receptor blockade.

The interleukin-2 parameters were not invented from thin air. They were derived from ex vivo experiments in which patient T cells were exposed to pembrolizumab and their functional responses measured. This experimental grounding matters, because an earlier study by the same group had already revealed a critical gap between receptor occupancy and T cell functionality: cells whose PD-1 receptors were fully occupied by the drug did not necessarily show the downstream signalling and cytokine production that clinicians would want to see. The new study translates that laboratory observation into a quantitative, patient-scale simulation framework.

The simulations produced a striking and, for the field, uncomfortable result. All three approved regimens achieved near-complete PD-1 receptor occupancy, both in the circulation and within the tumour microenvironment. On the traditional view, this means all three doses should be pharmacodynamically equivalent, and indeed this saturation logic is precisely why regulators and developers accepted the regimens as interchangeable. Yet when the researchers looked at predicted interleukin-2 concentrations, a very different picture emerged. The cytokine levels were predicted to rise and fall throughout the dosing interval, tracking the concentration of pembrolizumab itself rather than the occupancy of its receptor.

Even more provocatively, the 400 milligram every-six-weeks regimen, the highest total dose per interval, produced the highest predicted interleukin-2 levels. If immune activation rather than receptor saturation is what drives anti-tumour efficacy, then the longest-interval regimen may not be a mere convenience option but potentially the most immunologically active of the three. The authors are careful to note that interleukin-2 is a marker, not a proven mediator of clinical response, and that more activation is not automatically better; excessive immune stimulation can contribute to toxicity. But the finding decisively breaks the assumed link between occupancy and pharmacodynamic effect.

A second important nuance concerned the tumour itself. Changes in intratumoural interleukin-2 concentrations were predicted to be considerably less pronounced than those in plasma. In other words, even if systemic immune activation fluctuates substantially between doses, the immune microenvironment inside the tumour may experience a more buffered response. This has implications for how biomarkers are interpreted: a blood sample showing robust cytokine swings may not faithfully represent what is happening at the site where the immune system meets the cancer. It also raises the possibility that intratumoural pharmacodynamics, not plasma pharmacokinetics, should be the target of future dose optimisation efforts.

The broader context makes these findings timely. Pembrolizumab is expensive, and health systems worldwide have scrutinised whether lower doses or longer intervals could deliver the same benefit at reduced cost. Pharmacokinetic simulation studies and even randomised trials of low-dose immunotherapy in head and neck cancer have suggested that less drug may suffice. Meanwhile, other lines of research have explored whether the timing of infusion within the day, circadian chronotherapy, influences survival. What has been missing from all these debates is a validated pharmacodynamic marker that actually reflects the biological effect the drugs are meant to produce. This study argues that receptor occupancy, the marker the field has relied upon, fails that test.

The authors conclude that receptor occupancy is an inadequate pharmacodynamic surrogate for pembrolizumab and, by extension, for the broader class of PD-1 inhibitors. They call for the development of robust pharmacodynamic markers and, crucially, a clearer definition of the level and pattern of immune activation required for optimal efficacy. Until such markers exist, dose selection for checkpoint inhibitors will remain guided by surrogates that may bear little relationship to the biology that matters. The study, funded by Stichting Treatmeds as part of the NVALT30/DEDICATION-1 trial programme, was approved by the ethics committee METC Oost-Nederland and conducted according to the Declaration of Helsinki. Its message is likely to resonate far beyond lung cancer: for a drug class that has transformed oncology, the question of how much drug patients really need may have been asking the wrong question all along.

Subject of Research: Translational pharmacokinetic-pharmacodynamic modelling of pembrolizumab dosing, receptor occupancy and immune activation in non-small cell lung cancer

Article Title: Translational modelling challenges receptor‑occupancy‑based dosing of PD‑1 inhibitors like pembrolizumab

Article References: Verdonk, J. D. J., Otten, L.-S., Montaseri, G., van den Heuvel, M. M., Smeets, R. L., Koenen, H. J. P. M., & ter Heine, R. (2026). Translational modelling challenges receptor‑occupancy‑based dosing of PD‑1 inhibitors like pembrolizumab. British Journal of Cancer. https://doi.org/10.1038/s41416-026-03612-w

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03612-w

Keywords: pembrolizumab, PD-1 inhibitors, receptor occupancy, cancer immunotherapy, pharmacokinetic modelling, interleukin-2, non-small cell lung cancer, dose optimisation, pharmacodynamics, immune checkpoint inhibitors, tumour penetration, drug dosing