High interobserver and intraobserver reproducibility among pathologists assessing PD-L1 CPS across multiple indications.

AIMS: A common concern among pathologists scoring PD-L1 immunohistochemical staining is interobserver and intraobserver variability. We assessed the interobserver and intraobserver reproducibility of PD-L1 scoring among trained pathologists using a combined positive score (CPS; tumour cell and tumour-associated immune cell staining). METHODS AND RESULTS: Data were collected for 2 years (2017-2019) from 456 pathologists worldwide. Digital training encompassed unique, tumour-specific training, and test sets. Samples were stained using PD-L1 IHC 22C3 pharmDx and evaluated at specific CPS cutoffs for gastric cancer (GC), cervical cancer (CC), urothelial cancer (UC), oesophageal cancer (OC), and head and neck squamous cell carcinoma (HNSCC). Pathologists underwent expert-to-peer training and scored 20 blinded samples on day 1 and 25 blinded samples on day 2 (including 15 of the day 1 samples). Interobserver and intraobserver reproducibility were assessed. For GC (120 observers) and CC (32 observers) samples assessed at CPS ≥1, average interobserver agreement was 91.5% and 91.0%, respectively, and average intraobserver agreement was 90.2% and 96.6%, respectively. For UC (139 observers) and OC (52 observers) samples measured at CPS ≥10, average interobserver agreement was 93.4% and 93.7%, respectively, and average intraobserver agreement was 92.0% and 92.5%, respectively. For HNSCC samples (113 observers), average interobserver agreement was 94.1% at CPS ≥1 and 86.5% at CPS ≥20; intraobserver agreement was 94.7% at CPS ≥1 and 90.5% at CPS ≥20. CONCLUSION: The consistently high interobserver and intraobserver concordance rates support the effectiveness of face-to-face training of many global pathologists for scoring PD-L1 CPS across multiple indications at several specific cutoffs.

An update on companion and complementary diagnostic assays for PD-1/PD-L1 checkpoint inhibitors in NSCLC.

Introduction: Development within molecular medicine has given us an increased understanding of the pathophysiology of malignant diseases. This understanding has been the key to a development of a number of new effective target-specific drugs, including the PD-1/PD-L1 checkpoint inhibitors.Areas covered: This review will focus on the clinical validation and utility of the commercially available IHC PD-L1 expression assays linked to the different PD-1/PD-L1 checkpoint inhibitors indicated for treatment of NSCLC. For the discussion of this subject, mainly data from studies where the PD-1/PD-L1 checkpoint inhibitors have been given as monotherapy will be reported.Expert opinion: Although PD-L1 expression is not the perfect biomarker; the different IHC PD-L1 expression assays have had major impact on the clinical development of PD-1/PD-L1 checkpoint inhibitors for treatment of NSCLC. A number of clinical studies in NSCLC have shown that the efficacy of the PD-1/PD-L1 checkpoint inhibitors are positively correlated to the level of PD-L1 expression. Based on studies presented in this review, the recommendation is that monotherapy should mainly be used for treatment of NSCLC patients with a high PD-L1 expression, as defined by the cutoff values for the individual assays linked to the specific PD-1/PD-L1 checkpoint inhibitor.

Programmed death-ligand 1 expression according to epidermal growth factor receptor mutation status in pretreated non-small cell lung cancer.

BACKGROUND: Current clinical trials have suggested poorer efficacies of anti-programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) immunotherapies for non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations, implying lower PD-L1 expression in EGFR-mutant NSCLC than in EGFR-wild type. METHODS: We retrospectively analyzed correlation between PD-L1 expression and EGFR status in clinical samples of pretreated NSCLC. PD-L1 immunohistochemistry was performed using the 28-8 anti-PD-L1 antibody for tumor cell membrane staining. H-score was adopted to evaluate both percentage and intensity. We investigated H-scores ≥1, ≥5, and ≥10 as PD-L1+ cut-offs. H-score ≥10 was defined as strong PD-L1+. RESULTS: We investigated 96 available histologic samples in 77 pretreated patients with NSCLC. Median H-score in EGFR-mutant samples (n=65) was 3 (range, 0-150), whereas EGFR-wild-type (n=31) was 8 (range, 0-134) (p=0.0075). Using H-scores ≥1, ≥5, and ≥10 cut-offs, incidence of PD-L1+ in EGFR-mutant vs. EGFR-wild-type samples were: 85% (55/65) vs. 94% (29/31) (p=0.2159); 42% (27/65) vs. 74% (23/31) (p=0.0027); and 22% (14/65) vs. 48% (15/31) (p=0.0074), respectively. Patient-oriented (n=77) univariate analysis for strong PD-L1+ found age of sample (p=0.0226) and EGFR mutation status (p=0.0490) as significant factors. Multivariate analysis identified EGFR mutation status as the only significant factor (p=0.0121, odds ratio 2.99) for strong PD-L1+. H-scores of PD-L1 expression varied in all 11 cases receiving multiple rebiopsies, and categories of positivity migrated in 10 (91%) of 11 patients. CONCLUSIONS: PD-L1 expression was significantly lower in EGFR-mutant NSCLC samples than in EGFR wild-type samples. Its expression could be dynamic and affected by age of sample.

[Predictive PD-L1 immunohistochemistry for non-small cell lung cancer : Current state of the art and experiences of the first German harmonization study]. / Prädiktive PD-L1-Immunhistochemie beim nichtkleinzelligen Bronchialkarzinom : Aktueller Stand und Erfahrungen der ersten deutschen Harmonisierungsstudie.

BACKGROUND: Antibodies against PD-1 and PD-L1 can cause strong and durable anti-tumor immune responses in non-small cell lung cancer (NSCLC). Immunohistochemistry for PD-L1 (PD-L1 IHC) was tested as a predictive biomarker. Several IHC assays and interpretation criteria were developed in parallel. AIM: The clinical significance of PD-L1 IHC in NSCLC and the optimum method for staining and interpretation of the results are the subject of ongoing studies. The diagnostic application of immunotherapy in NSCLC necessitates harmonization of PD-L1 IHC to obtain evidence for guidelines; therefore, a consensus opinion on a well-founded diagnostic mode of testing should be defined based on published studies and the results of the first German PD-L1 IHC harmonization study. METHODS: 1. Summary of the current data situation. 2. Evaluation of the first German PD-L1 IHC harmonization study (centralized, staining with PD-L1 IHC analogous to studies, 15 cases of NSCLC, 4 IHC study assays [28­8, 22C3, SP142 and SP263] and scoring by 9 pathologists). RESULTS: The use of PD-L1 IHC in NSCLC is suitable for identification of patients with an increased probability of a clinical benefit from immunotherapy. The various proportional cut-offs used to interpret the staining results can be summarized in a total score, which can be reproducibly assessed. The staining patterns of the four assays investigated were, however, not congruent in all situations. DISCUSSION: In principle, the use of PD-L1 IHC for assessment of the expression in tumor cells is a reliably determinable biomarker. Evaluation algorithms should be based on published clinical trials. For NSCLC approvals with obligatory PD-L1 IHC are to be expected but it remains to be seen to what extent PD-L1 IHC will be implemented in the clinical routine.