A blood-based immune marker for resistance to pembrolizumab in patients with metastatic urothelial cancer

Maud Rijnders*, Debbie G. J. Robbrecht, Astrid A. M. Oostvogels, Mandy van Brakel, Joost L. Boormans, Maureen J. B. Aarts, Hayri E. Balcioglu, Paul Hamberg, Jens Voortman, Hans M. Westgeest, Martijn P. Lolkema, Ronald de Wit, Astrid A. M. van der Veldt, Reno Debets

*Corresponding author for this work

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PD1 inhibition is effective in patients with metastatic urothelial cancer (mUC), yet a large fraction of patients does not respond. In this study, we aimed to identify a blood-based immune marker associated with non-response to facilitate patient selection for anti-PD1. To this end, we quantified 18 immune cell populations using multiplex flow cytometry in blood samples from 71 patients with mUC (as part of a biomarker discovery trial; NCT03263039, registration date 28-08-2017). Patients were classified as responder (ongoing complete or partial response, or stable disease; n = 25) or non-responder (progressive disease; n = 46) according to RECIST v1.1 at 6 months of treatment with pembrolizumab. We observed no differences in numbers of lymphocytes, T-cells, granulocytes, monocytes or their subsets between responders and non-responders at baseline. In contrast, analysis of ratios of immune cell populations revealed that a high mature neutrophil-to-T-cell ratio (MNTR) exclusively identified non-responders. In addition, the survival of patients with high versus low MNTR was poor: median overall survival (OS) 2.2 vs 8.9 months (hazard ratio (HR) 6.6; p < 0.00001), and median progression-free survival (PFS) 1.5 vs 5.2 months (HR 5.6; p < 0.0001). The associations with therapy response, OS, and PFS for the MNTR were stronger than for the classical neutrophil-to-lymphocyte ratio (HR for OS 3.5, and PFS 3) and the PD-L1 combined positivity score (HR for OS 1.9, and PFS 2.1). In conclusion, the MNTR distinctly and uniquely identified non-responders to treatment and may represent a novel pre-treatment blood-based immune metric to select patients with mUC for treatment with pembrolizumab.

Original languageEnglish
Pages (from-to)759-767
Number of pages9
JournalCancer Immunology Immunotherapy
Issue number3
Early online date17 Aug 2022
Publication statusPublished - Mar 2023

Bibliographical note

Funding for this research was provided by MSD, The

© 2022. The Author(s).


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