BackgroundThe Combined Positive Score (CPS)1 algorithm includes tumor and immune cells for determination of Programed Death-Ligand 1 (PD-L1) protein expression in tumor tissues and has been analytically and clinically validated for use with PD-L1 IHC 22C3 pharmDx across multiple indications and cutoffs.2 PD-L1 22C3 IHC pharmDx is a qualitative immunohistochemical assay using anti-PD-L1, Clone 22C3 to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) tumor tissues using Autostainer Link 48. PD-L1 IHC 22C3 pharmDx is FDA-approved as an aid in identifying patients for treatment with KEYTRUDA® for six tumor indications at clinically validated CPS diagnostic cutoffs2: gastric or gastroesophageal junction (GC/GEJ) adenocarcinoma (CPS ≥ 1), cervical cancer (CPS ≥ 1), urothelial carcinoma (CPS ≥ 10), head and neck squamous cell carcinoma (HNSCC) (CPS ≥ 1), esophageal squamous cell carcinoma (ESCC) (CPS ≥ 10)3, and triple-negative breast cancer (TNBC) (CPS ≥ 10).MethodsPrecision of PD-L1 IHC 22C3 pharmDx using CPS was assessed for all six indications at the corresponding clinically validated diagnostic cutoffs and at additional exploratory cutoffs under normal, day-to-day testing conditions. Precision testing included Combined Precision (inter-instrument/operator/run (day)), Intra-Run Repeatability, and Observer (inter-/intra-) Scoring Reproducibility studies. FFPE specimens were stained with PD-L1 IHC 22C3 pharmDx and scored using CPS as described in the package insert.2 Four CPS cutoffs were evaluated: CPS ≥ 1 (GC/GEJ, urothelial carcinoma, ESCC, cervical cancer, HNSCC, TNBC), CPS ≥ 10 (GC/GEJ, urothelial carcinoma, ESCC, TNBC), CPS ≥ 20 (HNSCC), and CPS ≥ 50 (HNSCC). Data were analyzed using negative percent agreement (NPA), positive percent agreement (PPA), and overall agreement (OA) with two-sided 95% percentile bootstrap confidence intervals (CIs) based on PD-L1 binary status at the applicable cutoff(s). For each study, data from each CPS cutoff-indication pair were individually analyzed. Meta-analyses were also performed by pooling data from all indications per (i) study and cutoff, and (ii) per study for all tested cutoffs.ResultsNearly all agreement analyses (142/144) for each CPS cutoff-indication pair showed NPA/PPA/OA point estimates (PE) ≥ 90% and CI lower bounds (CILB) ≥ 85%. Meta-analyses showed PE ≥ 90% for NPA/PPA/OA and CILB ≥ 85% per study and cutoff, and per study for all tested cutoffs. Discordant comparisons accounted for <5% of total comparisons performed for each study type.ConclusionsCPS used with PD-L1 IHC 22C3 pharmDx provides precise evaluation of PD-L1 expression across multiple tumor indications and cutoffs under normal, day-to-day testing conditions.AcknowledgementsWe thank the IUSCC Cancer Center at Indiana University School of Medicine, for the use of the Tissue Procurement and Distribution Core, which provided Dako North America, Inc. service.The data and biospecimens used in this project were provided by US Biolab (Gaithersburg, MD, USA), Sofia Bio LLC (New York, NY, USA), Contract Research Ltd (Charlestown, Nevis), and Centre Hospitalier Universitaire (CHU) de Nice (Nice, France) with appropriate ethics approval and through Trans-Hit Biomarkers Inc. Tissue samples were provided by the Cooperative Human Tissue Network which is funded by the National Cancer Institute. Other investigators may have received specimens from the same subjects. Tissue samples supplied by BioIVT (Hicksville, NY, USA).Trial RegistrationN/AReferencesCPS = (# PD-L1 staining cells (tumor cells, lymphotcytes, macrophages))/(Total # viable tumor cells )×100PD-L1 IHC 22C3 pharmDx [Instructions for Use]. Available at: www.agilent.com/library/eifu. Code SK006. Accessed July 2, 2021ESCC was analytically validated as a subtype of esophageal cancer [2].Ethics ApprovalN/AConsentN/A
Background PD-L1 22C3 IHC pharmDx (SK006) is a qualitative immunohistochemical (IHC) assay using anti-PD-L1, Clone 22C3 to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) tumor tissues using the Autostainer Link 48. PD-L1 expression is determined by Combined Positive Score (CPS), which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. 1 SK006 has been analytically validated using CPS across multiple tumor indications and diagnostic cutoffs and is used as an aid in identifying patients for treatment with KEYTRUDA ® . A previous publication presents the analytical performance of the following indications: gastric or gastroesophageal junction (GC/GEJ) adenocarcinoma (CPS ! 1), cervical cancer (CPS ! 1), head and neck squamous cell carcinoma (HNSCC) (CPS ! 1), esophageal cancer (EC/ESCC) (CPS ! 10), and triple-negative breast cancer (TNBC) (CPS ! 10). 2 This study evaluated the analytical performance of the SK006 assay for an additional five individual tumor indications (ovarian carcinoma (OC), prostate cancer (PC), colorectal carcinoma (CRC), renal cell carcinoma (RCC), biliary tract adeno cancer (BTAC)) and a group of 11 rare tumor indications in a basket trial (BT). 3 Two CPS cutoffs were evaluated: CPS ! 1 (OC, PC, CRC, RCC, BTAC and BT [3]) and CPS ! 10 (OC, CRC and BTAC). Methods Combined precision measured inter-instrument, -operator, -day and -lot variation. Intra-run measured repeatability and Inter/Intra-Observer measured scoring reproducibility. Negative percent agreement (NPA), positive percent agreement (PPA), and overall agreement (OA) with two-sided 95% bootstrap confidence intervals (CIs) were used for data analysis, based on the PD-L1 binary status at the evaluated cutoffs.
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