[Efficacy of PD-1/PD-L1 immune checkpoint inhibitors and PD-L1 testing in thoracic cancers]. / Efficacité des inhibiteurs du checkpoint immunitaire PD-1/PD-L1 et testing PD-L1 dans les cancers thoraciques.

Tumoral immune environment is a major component of cancer. Its composition and its organization represent a reproducible characteristic of tumors and a validated prognostic factor. In non-small cell lung cancer (NSCLC), cytotoxic T CD8+ lymphocyte density, associated with a Th1 environment and tertiary lymphoid structures impacts survival. Tumor cell-immune cell interaction is targeted by PD1/PD-L1 inhibitors. In advanced NSCLC, PD1/PD-L1 inhibitors are more effective than second-line chemotherapy. Pembrolizumab outperforms first-line chemotherapy in NSCLC strongly positive for PD-L1. PD1/PD-L1 inhibitors are currently tested in mesothelioma and thymic tumors. PD-L1 expression evaluated with immunochemistry is the most studied predictive biomarker of PD1/PD-L1 inhibitor efficacy. Tumor and immune cell expression of PD-L1 is still difficult to evaluate because of intra-tumoral heterogeneity and expression modulation by the microenvironment. Four commercial diagnostic antibodies are in development, with differences concerning recognized epitopes, methodology of evaluation of PD-L1 expression, positivity threshold, kit and platforms used. Clinical trials in NSCLC have shown that patients with tumors strongly positive for PD-L1 derived the best clinical benefit with PD1/PD-L1 inhibitors whereas clinical benefit is less common in tumors negative for PD-L1. PD-L1 expression is not a perfect biomarker since some PD-L1 negative NSCLC respond to PD1/PD-L1 inhibitors and some PD-L1 positive NSCLC do not. PD-L1 testing is likely to be implemented in daily practice for selection of advanced NSCLC that will be treated with pembrolizumab, underscoring the relevance of ongoing harmonization studies of the use of the different antibodies available for PD-L1 testing.

[German expert consensus on programmed cell death ligand 1 (PD-L1) testing in perioperative systemic therapy of muscle invasive bladder cancer]. / Deutscher Expertenkonsens zur PD-L1-Testung ("programmed cell death ligand 1") in der perioperativen Systemtherapie des muskelinvasiven Blasenkarzinoms.

The risk of recurrence in patients with muscle invasive bladder cancer (MIBC) after radical cystectomy depends on the pathological tumor stage. In particular, patients with lymph node metastasis (pN+), locally advanced (≥pT3), or residual muscle invasive tumor despite neoadjuvant chemotherapy are at high risk. Currently, the importance of adjuvant therapy with immune checkpoint inhibitors is increasing in the context of perioperative systemic therapeutic concepts. The indication for the PD­1 inhibitor nivolumab currently approved in the European Union requires testing of PD-L1 (programmed cell death ligand 1) protein expression by immunochemistry in tumor tissue. Focusing on MIBC patients at high risk of recurrence, new questions arise regarding the implementation and interpretation of PD-L1 testing. An interdisciplinary group of experts from Germany has discussed relevant issues from a clinicopathological point of view and developed practical recommendations to facilitate the implementation of validated and quality-assured PD-L1 testing for the approved indications in daily clinical practice.

[Standardized and quality-assured predictive PD-L1 testing in the upper gastrointestinal tract. German version]. / Standardisierte und qualitätsgesicherte prädiktive PD-L1-Testung im oberen Gastrointestinaltrakt.

As a result of the high approval dynamics and the growing number of immuno-oncological therapy concepts, the complexity of therapy decisions and control in the area of carcinomas of the esophagus, gastroesophageal junction and stomach is constantly increasing. Since the treatment indication for PD­1 inhibitors that are currently approved in the European Union is often linked to the expression of PD-L1 (programmed cell death-ligand 1), the evaluation of tissue-based predictive markers by the pathologist is of crucial importance for treatment stratification. Even though the immunohistochemical analysis of the PD-L1 expression status is one of the best studied, therapy-relevant biomarkers for an immuno-oncological treatment, due to the high heterogeneity of carcinomas of the upper gastrointestinal tract, there are challenges in daily clinical diagnostic work with regard to implementation, standardization and interpretation of testing. An interdisciplinary group of experts from Germany has taken a position on relevant questions from daily pathological and clinical practice, which concern the starting material, quality-assured testing and the interpretation of pathological findings, and has developed recommendations for structured reporting.

Programmed Death Ligand-1 Testing in Adenocarcinoma Lung: A Comparative Study of Cell Block versus Biopsy.

Background: Immunotherapy currently stands as a novel treatment option, specifically in cases of advanced non-small cell lung carcinoma (NSCLC). Expression of programmed death ligand-1 (PD-L1) in tumor cells forms the mainstay for the use of anti-PD-L1 monoclonal antibodies in the treatment of NSCLC. Aims: The objectives of the study were to assess utility of cell blocks for testing of PD-L1 in adenocarcinoma lung and to compare the expression of PD-L1 in cell blocks and the corresponding biopsy specimens. Materials and Methods: The current study was a prospective case series that included 20 cases of NSCLC-adenocarcinoma lung. Cases included in the study had biopsies performed from lung masses, along with which cell blocks were prepared from fine needle aspiration cytology (FNAC) samples. Testing for PD-L1 was done using the monoclonal PD-L1 antibody, SP-263 clone on the Ventana Benchmark XT system. PD-L1 expression was assessed only in the tumor cells, and cases with >1% expression, cytoplasmic or membranous, in tumor cells were categorized as positive. Results: PD-L1 expression was identified in the biopsy samples of tumor cells of 20% of cases (n = 4/20). In the corresponding cell blocks, PD-L1 expression was identified in the tumor cells of 15% of cases (n = 3/20). Sensitivity and specificity of cell blocks were 75% and 100%, respectively. Positive and negative predictive values were 100% and 94.12%, respectively. Conclusion: PD-L1 testing has both predictive and prognostic implications. PD-L1 testing in cell block samples is a potential alternative, specifically in cases where biopsy tissue is minimal or unavailable.

Standardized and quality-assured predictive PD-L1 testing in the upper gastrointestinal tract.

As a result of the high approval dynamics and the growing number of immuno-oncological concepts, the complexity of treatment decisions and control in the area of cancers of the esophagus, gastroesophageal junction and stomach is constantly increasing. Since the treatment indication for PD-1 inhibitors that are currently approved in the European Union is often linked to the expression of PD-L1 (programmed cell death-ligand 1), the evaluation of tissue-based predictive markers by the pathologist is of crucial importance for treatment stratification. Even though the immunohistochemical analysis of the PD-L1 expression status is one of the best studied, therapy-relevant biomarkers for an immuno-oncological treatment, due to the high heterogeneity of carcinomas of the upper gastrointestinal tract, there are challenges in daily clinical diagnostic work with regard to implementation, standardization and interpretation of testing. An interdisciplinary group of experts from Germany has taken a position on relevant questions from daily pathological and clinical practice, which concern the starting material, quality-assured testing and the interpretation of pathological findings, and has developed recommendations for structured reporting.

PD-L1 assessment in cytology samples predicts treatment response to checkpoint inhibitors in NSCLC.

BACKGROUND: Testing for tumor programmed death ligand-1 (PD-L1) expression was initially developed with histology specimens in non-small cell lung cancer (NSCLC). However, cytology specimens are widely used for primary diagnosis and biomarker studies in clinical practice. Limited clinical data exist on the predictiveness of cytology-derived PD-L1 scores for response to immune checkpoint inhibitor (ICI) therapy. METHODS: We reviewed all NSCLC specimens clinically tested at the University Health Network (UHN) for PD-L1 with 22C3pharmDx, from 01/2013 to 04/2021. Treatment outcomes in patients treated with single agent ICI therapy were reviewed and compared according to cytology- and histology-derived PD-L1 scores. RESULTS: We identified 494 and 1942 unique patients with cytology- and histology-derived tumor proportion scores, respectively, during the study period. Informative testing rates were 95 % vs 98 % for cytology and histology, respectively. Clinical data were available for 152 patients treated with single agent ICI: 61 cytology and 91 histology. Overall response rates (ORR) were similar for cytology and histology (36 % vs 34 %; p = 0.23), as well as median progression free survival (PFS) (4.9 vs 4.2 months; p = 0.99) and overall survival (23.4 vs 19.7 months; p = 0.99). The results remained similar even after adjusting for PD-L1 expression levels and line of ICI treatment (PFS HR 1.15; 95 %CI 0.78-1.70; p = 0.47). CONCLUSIONS: Treatment outcomes to single agent ICI based on cytology-derived PD-L1 scores were comparable to histology controls. Our results support PD-L1 biomarker testing on both cytology and histology specimens.

Real-world study of PD-L1 testing patterns and treatment distribution in patients with metastatic non-small-cell lung cancer in Israel.

Aim: We describe PD-L1 testing patterns and first-line treatment for patients with metastatic non-small-cell lung cancer in a 2.3 million-member state-mandated health service in Israel. Materials & methods: Newly diagnosed stage IV non-small-cell lung cancer patients initiating systemic anticancer treatment from 1 January 2017 until 31 December 2018 were identified from the national cancer registry and Maccabi Healthcare Service database and followed until 30 June 2019. Results: The cohort consisted of 410 patients; 58% males, median age 68 years, 70% current/former smokers, 81% adenocarcinoma, 14% had brain metastases, and Eastern Cooperative Oncology Group performance status was 46/17/37% for 0-1/2-4/unknown, respectively. A total of 80% tested for PD-L1 expression, of which 47% had tumor proportion score (TPS) ≥ 50%. A total of 95% with TPS ≥ 50% and no known tumor aberrations (including EGFR mutations, and translocations in ALK and ROS1) received first-line PD-1/PD-L1-inhibitor monotherapy, and 80% of untested/TPS < 50% received platinum doublets. Conclusion: Fast uptake of testing was observed, and treatment patterns showed high adherence to guidelines.

Lay abstract We describe PD-L1 testing patterns in a cohort of 410 patients with stage IV non-small-cell lung cancer. All patients were newly diagnosed and newly treated in the years 2017 and 2018. In this cohort, 58% were males, average age was 68 years and 70% were current or former smokers. In this, 80% were tested for PD-L1 expression and 95% of those with a tumor score of >50% and no other tumor receptor mutations received first-line PD-1/PD-L1-inhibitor monotherapy (most receiving pembrolizumab). Moreover, 80% of those untested for PD-L1 or with a low tumor proportion score (<50%) received chemotherapy. After introduction in 2017, a fast uptake of PD-L1 testing was observed, and treatment patterns showed high adherence to guidelines.

What impacts the cost-effectiveness of PD-L1 testing in non-small cell lung cancer?

Programmed Death Ligand 1(PD-L1) testing is recommended for patients with Non-Small Cell Lung Cancer (NSCLC) at stage IIIB and IV, adenocarcinoma and squamous cell carcinoma. Up to now, no clinical-pathological parameters are perfectly able to select a positive PD-L1-patient. For this reason PD-L1 testing is mandatory for patients with advanced NSCLC for whom an immune checkpoint inhibitor treatment is appropriate. Several studies on the cost-effectiveness of immune checkpoint inhibitors in this subset of patients have been published. Chouaid et al. (Lung Cancer 127, 2019, 44-52) assessed the cost-effectiveness of pembrolizumab versus standard of care platinum-based chemotherapy from the French health care system perspective. The authors did not, however, mention that the type of PD-L1 testing used can impact the cost of therapy, which varies according to methods used and to the country where PD-L1 testing is performed. The lack of specific guidelines can lead to discrepancies in technical and/or clinical validation procedures of PD-L1 testing, and that this also impacts the cost of therapy. In conclusion, the effect of PD-L1 testing on cost-effectiveness of immune checkpoint inhibitors depends on the antibody and platform used for patient selection. The barriers to overcome are the limited quantity of biological material available and lack of standardization of the PD-L1 IHC test methods.

PD-L1 assessment in urothelial carcinoma: a practical approach.

Five programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors are currently approved for treatment of locally advanced or metastatic urothelial carcinoma of the bladder and the upper urinary tract. Due to restrictions by the FDA and EMA first-line treatment with Atezolizumab and Pembrolizumab in platinum-ineligible patients requires immunohistochemical PD-L1 testing. In the second-line setting all drugs are approved without PD-L1 testing. Used PD-L1 assays in clinical trials include the 28-8 pharmDx (Nivolumab), the 22C3 pharmDx (Pembrolizumab), Ventana SP142 (Atezolizumab), and the Ventana PD-L1 SP263 assays (Durvalumab). Differences in antibodies, needed platforms and testing algorithms have raised questions about interchangeability and comparability among these assays and their diagnostic use. We provide a practical review about the current recommendations, used assays and algorithms of PD-L1 testing in urothelial carcinoma to help oncologists, urologists and pathologists to understand analytical features, differences in antibody assays, differences in scoring algorithms and comparability of various PD-L1 assays. We reviewed and summarized published studies from the last four years (2016-2019) on PD-L1 testing in bladder cancer and present a condensed practical guideline including pre-analytical, analytical and test-specific issues.

Circulating tumour cell PD-L1 test for head and neck cancers.

Immune checkpoint inhibitors have gained traction over the last few years in the treatment of metastatic/recurrent head and neck squamous cell carcinoma (HNSCC) patients. Monoclonal antibodies that block the programmed death 1 (PD-1) receptor and its major ligand, PD-L1, have shown durable responses and low toxicity profiles. There are currently no validated predictive biomarkers to select patients likely to respond to anti-PD-1/PD-L1 therapy to avoid unwanted side effects and to reduce healthcare expenditure. A circulating tumour cell (CTC) PD-L1 assay could be developed as a companion diagnostic tool to potentially predict the efficacy of immune checkpoint blockade treatments.