PD-L1 diagnostic tests: a systematic literature review of scoring algorithms and test-validation metrics

Abstract

BackgroundThe programmed death receptor 1 (PD-1) protein is a cell-surface receptor on certain lymphocytes that, with its ligand programmed death ligand 1 (PD-L1), helps to down-regulate immune responses. Many cancer types express PD-L1 and evade immune recognition via the PD-1/PD-L1 interaction. Precision therapies targeting the PD-1/PD-L1 pathway have the potential to improve response and thereby offer a novel treatment avenue to some patients with cancer. However, this new therapeutic approach requires reliable methods for identifying patients whose cancers are particularly likely to respond. Therefore, we conducted a systematic literature review assessing evidence on test validation and scoring algorithms for PD-L1 immunohistochemistry (IHC) tests that might be used to select potentially responsive patients with bladder/urothelial cell, lung, gastric, or ovarian cancers for immunotherapy treatment.Methods and resultsTo identify evidence on commercially available PD-L1 IHC assays, we systematically searched MEDLINE and Embase for relevant studies published between January 2010 and September 2016 and appraised abstracts from recent oncology conferences (January 2013 to November 2016). Publications that met the predefined inclusion criteria were extracted and key trends summarized.In total, 26 eligible primary studies were identified, all of which reported on the test validation metrics associated with PD-L1 IHC tests in lung cancer, most using immunohistochemistry testing. There was significant heterogeneity among the available tests for PD-L1. Specifically, no definitive cutoff for PD-L1 positivity was identifiable, with more than one threshold being reported for most antibodies. Studies also differed as to whether they evaluated tumor cells only or tumor cells and tumor-infiltrating immune cells. However, all of the tests developed and validated to support a therapeutic drug in the context of phase 2–3 clinical trials reported more than 90% inter-reader concordance. In contrast, other PD-L1 antibodies identified in the literature reported poorer concordance.ConclusionsPublished validation metric data for PD-L1 tests are mainly focused on immunohistochemistry tests from studies in lung cancer. The variability in test cutoffs and standards for PD-L1 testing suggests that there is presently no standardized approach. This current variability may have implications for the uptake of precision treatments.

Programmed death–ligand 1 expression on direct Pap‐stained cytology smears from non–small cell lung cancer: Comparison with cell blocks and surgical resection specimens

“…Quantification of PD‐L1 expression in patients with advanced NSCLC is useful for predicting the response to immunotherapy with checkpoint inhibitors that disrupt the PD‐1/PD‐L1 interaction . Two commercially available PD‐L1 IHC assays, the PD‐L1 IHC 22C3 pharmDx and the Ventana PD‐L1 SP263 assays, have been shown to be highly concordant in quantifying PD‐L1 expression regardless of the TPS cutoff levels or sample type (surgical resections/biopsies vs cytological specimens) …”

“…The Dako platform (Agilent Technologies/Dako, Carpinteria, CA, USA) has developed the 22C3 and 28‐8 antibodies in conjunction with pembrolizumab and nivolumab. The Ventana platform (Ventana Medical Systems Inc, Tucson, Arizona) has developed the SP142 and SP263 antibodies in conjunction with atezolizumab and durvalumab . Several clinical trials have demonstrated great heterogeneity in the cutoff levels and methods used for PD‐L1 testing and the assessment of PD‐L1 positivity based on the various assays …”

Profiles of immune infiltration in colorectal cancer and their clinical significant: A gene expression‐based study

“…Tumor‐infiltrating immune cells (TIICs), whose function and composition subtly altered according to the immune status of the host, have been reported to be effectively targeted by drugs and to correlate with the clinical outcome . Mechanism studies confirmed that between TIICs and malignant cells in the tumor stroma, there is in fact a complex interaction which has significant prognostic relevance as the immune system has a dual role by supporting both host defense and tumor progression .…”

The evolving role of immuno‐oncology for the treatment of head and neck cancer

“…63 Furthermore, multiple different assays and different staining protocols may yield different outcomes, particularly with regard to the percentage of tumor cells expressing PD-L1 and whether PD-L1 expression in the microenvironment is taken into consideration. 64,65 Moreover, because PD-L1 can induce early T cell proliferation, it is possible that in certain instances, PD-L1 expression will actually be beneficial. 62 Finally, based on recent data in NSCLC, it is likely that some mAbs targeting the PD-1 pathway are dependent on PD-L1 expression while other are not.…”

“…Additionally, core/fine needle aspiration biopsies used for analysis may not be representative of PD‐L1 expression levels in the tumor as a whole . Furthermore, multiple different assays and different staining protocols may yield different outcomes, particularly with regard to the percentage of tumor cells expressing PD‐L1 and whether PD‐L1 expression in the microenvironment is taken into consideration . Moreover, because PD‐L1 can induce early T cell proliferation, it is possible that in certain instances, PD‐L1 expression will actually be beneficial .…”