- Combined positive score is a robust, reproducible PD-L1 scoring method that predicts response to pembrolizumab in patients with G/GEJ cancer. This novel scoring method supported US Food and Drug Administration approval of pembrolizumab as third-line therapy for G/GEJ cancer and has facilitated investigation in other indications.
A companion diagnostic assay was codeveloped by Dako for pembrolizumab non–small-cell lung cancer clinical trials to detect PD-L1 expression by immunohistochemistry (IHC). This automated IHC assay has been analytically verified and validated using Dako’s autostainer Link 48 and 22C3 mouse anti-PD-L1 monoclonal antibody to detect the PD-L1 expression in formalin-fixed paraffin-embedded human tumor tissue specimens. The PD-L1 22C3 IHC assay was optimized for high sensitivity and specificity. Repeatability and reproducibility studies were conducted at Dako and at 3 Clinical Laboratory Improvement Amendments certified laboratories during assay development. The studies included: intersite and intrasite, interobserver and intraobserver, interinstrument, interoperator, interday, and interlot, and intraday and intrarun. All precision studies performed at Dako and external laboratories achieved >85% point-estimate agreements for all 3 agreement types (negative, positive, and overall). A clinical cutoff (tumor proportion score ≥50%) of PD-L1 expression was determined and evaluated through a phase 1 clinical trial (KEYNOTE-001) for advanced non–small-cell lung cancer patients treated with pembrolizumab. The treatment effect of pembrolizumab in the 61 subjects who had a tumor PD-L1 of tumor proportion score ≥50% was substantial, with an overall response rate of 41% (95% confidence interval, 28.6-54.3) as compared with 20.6% (95% confidence interval, 15.5-26.5) observed in the 223 subjects irrespective of PD-L1 status. PD-L1 IHC 22C3 pharmDx is a sensitive, precise, and robust companion diagnostic assay, which will facilitate safe and effective use for pembrolizumab in cancer patients.
BackgroundThis analysis evaluates an NY-ESO-1 immunohistochemistry (IHC) clinical trial assay in multiple tumor types for the identification of patients who may be eligible for NY-ESO-1 TCR T-cell targeted therapy. We provide an analysis of NY-ESO-1 expression and prevalence in non-small cell lung carcinoma (NSCLC) tumor samples from a patient cohort of an early Phase I/II clinical trial assessing NY-ESO-1 TCR T-cell therapy. Furthermore, we describe exploratory analyses of NY-ESO-1 prevalence and expression in a preliminary set of multiple tumor types to identify new indications for NY-ESO-1 TCR T-cell therapy.MethodsAn IHC assay was developed to detect NY-ESO-1 expression in formalin-fixed paraffin-embedded (FFPE) specimens utilizing an anti-NY-ESO-1 monoclonal antibody, clone E978. NY-ESO-1 protein expression levels and diagnostic status were determined by pathological evaluation under light microscopy to capture the percentage of tumor cell staining across all tumor cells in specimens at staining intensities 0, 1+, 2+ and 3+. NY-ESO-1 expression data were assessed for: prevalence using a ≥10% cutoff at ≥ 1+ intensity to assign positivity, and prevalence across classification (primary and metastatic) and subtype (adenocarcinoma and squamous cell carcinoma) for the NSCLC specimens.ResultsThe overall prevalence for NSCLC specimens from the Phase I/II trial was 15% (49/325) for NY-ESO-1. A prevalence of 15% (29/191) for primary and 14% (19/132) for metastatic samples, 13% (20/159) for adenocarcinoma, and 14% (5/35) for squamous cell carcinoma was observed. No significant difference was observed between subtype or%Tumor at each intensity. The preliminary set of indications used in exploratory studies had an observed prevalence as follows: gastric adenocarcinoma, 14 (4/28)%; esophageal adenocarcinoma & gastric esophageal junction, 9% (3/35); urothelial, 19% (6/31); head and neck squamous cell carcinoma, 10% (3/30); triple negative breast, 10% (3/30); hepatocellular carcinoma, 3%(1/30); and melanoma, 11% (3/27). NY-ESO-1 protein expression was localized in the cells’ nuclei and surrounding cytoplasm.ConclusionsMultiple indications assessed by the IHC clinical trial assay demonstrated similar NY-ESO-1 expression across the range of staining intensities and percentage of positive tumor observed as that in NSCLC, therefore warranting further development and validation of an IHC assay for NY-ESO-1 detection in these additional tumor types for use in clinical trials. These data support the use of IHC as a tool for the identification of patients whose tumors upregulate NY-ESO-1 in NSCLC and further encourage the investigation of multiple tumor types that may upregulate NY-ESO-1 as potential targets for NY-ESO-1 TCR T-cell therapies.AcknowledgementsThis study (NCT03709706) was funded by GlaxoSmithKline.Trial RegistrationNCT03709706ReferencesThomas R, et al. Front Immunol 2018;9:947Ethics ApprovalThis study was approved by the appropriate institutional review boards and independent ethics committees.
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