PD-L1 assessment in urothelial carcinoma: a practical approach

Abstract

Five programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors are currently approved for treatment of locally advanced or metastatic urothelial carcinoma of the bladder and the upper urinary tract. Due to restrictions by the FDA and EMA first-line treatment with Atezolizumab and Pembrolizumab in platinum-ineligible patients requires immunohistochemical PD-L1 testing. In the second-line setting all drugs are approved without PD-L1 testing. Used PD-L1 assays in clinical trials include the 28-8 pharmDx (Nivolumab), the 22C3 pharmDx (Pembrolizumab), Ventana SP142 (Atezolizumab), and the Ventana PD-L1 SP263 assays (Durvalumab). Differences in antibodies, needed platforms and testing algorithms have raised questions about interchangeability and comparability among these assays and their diagnostic use. We provide a practical review about the current recommendations, used assays and algorithms of PD-L1 testing in urothelial carcinoma to help oncologists, urologists and pathologists to understand analytical features, differences in antibody assays, differences in scoring algorithms and comparability of various PD-L1 assays. We reviewed and summarized published studies from the last four years (2016-2019) on PD-L1 testing in bladder cancer and present a condensed practical guideline including pre-analytical, analytical and test-specific issues.

Keywords: Bladder cancer; PD-L1 testing; immunohistochemistry; immunotherapy; programmed death-ligand 1 (PD-L1).

Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to declare.

2019 Annals of Translational Medicine. All rights reserved.

Figures

Figure 1

PD-L1 assessment—potential workflow.

Figure 2

PD-L1 assays. (A) Staining characteristics of different Food and Drug Administration and European Medical Agency approved companion diagnostic PD-L1 assays in muscle-invasive bladder cancer (Magnification: 400×). (B) Illustration of heterogeneous PD-L1 expression on tumor and immune cells in a case of muscle-invasive bladder cancer. The staining was performed with the Ventana SP263 assay (Magnification: 20×).

Figure 3

Illustrations of PD-L1 scoring algorithms applied in UC and other cancer types. (A) Ventana immune cell score (IC-Score; %): This score is required to assess first line treatment eligibility with Atezolizumab of platinum-based chemotherapy ineligible patients with metastasized or locally advanced urothelial carcinomas of the bladder and upper urinary tract. Patients are eligible for first-line Atezolizumab treatment if the cut-off of 5%-IC is exceeded. (B) Combined Positive Score (CPS): This score is required to assess first line treatment eligibility with Pembrolizumab of platinum-based chemotherapy ineligible patients with metastasized or locally advanced urothelial carcinomas of the bladder and upper urinary tract. Patients are eligible for first-line Pembrolizumab treatment if the cut-off of 10 is exceeded. Cave: The CPS is capped at 100 (although it could theoretically reach values above 100) and has no dimension. (C) Tumor cell score (TC-Score; %): This score is currently not required for PD-L1 assessment of urothelial carcinomas but it has been explored within the IMvigor trials (Atezolizumab). Furthermore, this score is currently under exploration in the Durvalumab trials. (D) IC-area score (%): This score is currently not required for PD-L1 assessment in urothelial carcinomas, but is currently explored in Durvalumab trials.