Abstract
BackgroundAntibodies targeting the programmed cell death-1 (PD-1)/PD-ligand 1 (PD-1/PD-L1) checkpoint have shown promising clinical activity in patients with advanced urothelial carcinoma (UC). Expression of PD-L1 in UC tumors has been investigated using different antibody clones, staining protocols, and scoring algorithms. The aim was to establish the extent of concordance among PD-L1 immunohistochemistry (IHC) assays.MethodsTumor biopsy samples (N = 335) were assessed using four commercially available PD-L1 assays: VENTANA SP263, VENTANA SP142, PD-L1 IHC 28–8 pharmDx, and PD-L1 IHC 22C3 pharmDx. PD-L1 analytical staining and classification concordance, including agreement between clinically relevant scoring algorithms, were investigated using overall/positive/negative percentage agreement (OPA/PPA/NPA).ResultsGood analytical correlation was observed among the VENTANA SP263, PD-L1 IHC 22C3 pharmDx, and PD-L1 IHC 28–8 pharmDx assays for tumor cell (TC) and immune cell (IC) PD-L1 staining with Spearman rank coefficients of 0.92–0.93 for TCs and 0.88–0.91 for ICs. However, concordance (preset criterion: ≥85%) between patient PD-L1 status when applying the TC or ICICArea ≥ 25% (VENTANA SP263) cutoff was only achieved for PD-L1 IHC 22C3 pharmDx versus VENTANA SP263 (OPA 92.2%, PPA 86.4%, NPA 95.4%). Differences were observed between patient populations with UC tumors classified as PD-L1 high versus PD-L1 low/negative using combined positive score (CPS) ≥1, CPS ≥10, IC ≥5%, and TC/IC ≥25%.ConclusionsThe VENTANA SP263 and PD-L1 IHC 22C3 pharmDx assays are analytically similar in UC. When the different PD-L1 assays were combined with their specified clinical scoring algorithms, differences were seen in patient classification driven by substantial differences in scoring approaches.
Highlights
Antibodies targeting the programmed cell death-1 (PD-1)/PD-ligand 1 (PD-1/programmed cell death ligand-1 (PD-L1)) checkpoint have shown promising clinical activity in patients with advanced urothelial carcinoma (UC)
Consecutive sections derived from tumor blocks were stained with VENTANA SP263, VENTANA SP142, PDL1 IHC 22C3 pharmDx, and PD-L1 IHC 28–8 pharmDx according to their validated protocols for investigational use, and PD-L1 testing was carried out at Hematogenix (Tinley Park, IL, USA)
A Non-urothelial bladder cancer samples included in the analysis are further defined in Additional file 1 Transurethral resection of bladder tumor (TURBT) transurethral resection of bladder tumor
Summary
Antibodies targeting the programmed cell death-1 (PD-1)/PD-ligand 1 (PD-1/PD-L1) checkpoint have shown promising clinical activity in patients with advanced urothelial carcinoma (UC). Commercially available assays (VENTANA PD-L1 SP263 and VENTANA PD-L1 SP142 [Ventana Medical Systems, Inc., Tucson, Arizona, USA], and PD-L1 immunohistochemistry [IHC] 22C3 pharmDx and PD-L1 IHC 28–8 pharmDx [Agilent Technologies, Santa Clara, California, USA]) have been developed independently in conjunction with immunotherapies targeting the PD-1/PDL1 pathway. These assays use different antibodies, IHC protocols, scoring algorithms, and cutoffs to define high/low PD-L1 expression in UC (Fig. 1) [21,22,23,24,25,26,27,28,29,30]. These differences raise the question of whether the UC patient populations defined as PD-L1 high are the same across clinical trials based on the algorithms (particular combination of scoring method and cutoff) used, and whether results can be compared across trials
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