Correlation Of PD-L1 Expression Research Articles

Abstract 1566: Establishment of analytical performance features of two immunohistochemistry assays for PD-L1 expression in lung cancer

Abstract Therapies that target PD-1/PD-L1 and overcome checkpoint inhibition have shown great promise in the treatment of a variety of cancers, with PD-L1 expression demonstrated as a biomarker of therapy response in a variety of tumor types. There are multiple IHC assays that are used to measure PD-L1 expression in formalin-fixed, paraffin-embedded tissues (FFPE) with significant variability in primary antibody, assay platform, scoring criteria, and assay cut-offs. This situation creates potential confusion in applications of PD-L1 immunohistochemistry (IHC) assays for the appropriate intended use. In this study we evaluated two assays (Dako pharmDx PD-L1 28-8 assay and Ventana PD-L1 SP263) in 45 non-small cell lung cancer samples encompassing predominately squamous cell carcinomas (35) and adenocarcinomas (10). PD-L1 protein expression, measured by the percentage of tumor cell showing positivity for PD-L1 staining, has been compared between two assays. PD-L1 results were interpreted by using various assay cutoffs. Correlation of PD-L1 expression measured by positivity in percentage of tumor cell staining with each of the two assays achieved a significant concordance (r2 = 0.91). Similar trends in percentage of positive of tumor cells were demonstrated across a broad dynamic range of staining. Cutoffs that have been established in clinical studies and referenced in the respective assay package inserts (>1% positivity percentage of tumor cells for 28-8 assay and >25% positivity percentage of tumor cells for the SP263 assay) were used as the reference, for interpreting the test results as positive or negative. When these established cutoffs were applied, a low-to-medium concordance between two assays has been demonstrated (r2 = 0.58). When the same cutoff (1% or 25%) was applied, the correlation has been improved markedly (r2 = 0.73 or 0.95 respectively). In this sample set the 25% cutoff produced the more consistent data when comparing the two methods. Changes in the classification of PD-L1 status was also observed for both Dako pharmDx PD-L1 28-8 assay (29%, 13/45) and Ventana PD-L1 SP263 (22%, 10/45) assays when the established cutoff was replaced. The findings of this study are consistent with others such as those from Blueprint phase I study. This comparison study showed that the two assays (Dako pharmDx PD-L1 28-8 assay and Ventana PD-L1 SP263) were analytically comparable. Further investigation is warranted to explore both the analytical and clinical performance of the various PD-L1 assays across multiple assay cut-points. Citation Format: Lei Zhang, Claire Begot, Robert McGee, Steven M. Anderson. Establishment of analytical performance features of two immunohistochemistry assays for PD-L1 expression in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1566.

Discordance rate of PD-L1 expression between primary and metastatic lesions in urothelial carcinoma (UC).

493 Background: Immune checkpoint inhibitors (ICI) targeting PD-1 or PD-L1 are effective in select patients with advanced UC. High PD-L1 expression enriches for response to ICIs; however, the predictive value of PD-L1 expression is limited, which may be due in part to dynamic expression of PD-L1 in the tumor environment. We sought to characterize PD-L1 expression in primary UC and paired metastatic lesions to gain insight into the potential temporal discordance of tumor PD-L1 expression during the metastatic process. Methods: Immunohistochemical (IHC) staining for PD-L1 using the SP-142 antibody was performed on primary tumors and matched metastatic specimens in 83 patients with advanced UC. IHC staining was scored for the percentage of cells positive ( < 5%, ≥5%) in tumor cell (TC) and immune cell (IC) compartments. Correlation of PD-L1 expression in TCs and ICs was estimated using Spearman’s correlation coefficients (ρ). Cohen’s kappa statistics (κ) were utilized to assess the agreement in PD-L1 expression between groups. Results: High (≥5%) PD-L1 expression in primary and metastatic biopsies, respectively, was observed in 6.1% and 14.6% of TCs and in 7.8% and 11.7% of ICs. High co-expression of PD-L1 in both TC and IC compartments was infrequent in primary and metastatic lesions (3.6% and 2.6%, respectively). PD-L1 expression in TCs was positively correlated with PD-L1 expression in ICs in primary tumors (ρ = 0.47) and in metastatic lesions (ρ = 0.27). TC PD-L1 expression in primary tumors was correlated with TC PD-L1 expression in paired metastatic lesions (ρ = 0.44) but there was minimal agreement in high expression rates between primary and metastatic lesions in the TC compartment (κ = 0.147). IC PD-L1 expression in primary tumors was not correlated with IC PD-L1 expression in paired metastatic lesions (ρ = 0.05) and there was poor agreement in high expression rates between primary and metastatic lesions in the IC compartment (κ = 0.086). Conclusions: High PD-L1 IC expression is temporally discordant between primary and metastatic UC lesions. Future studies of PD-1/PD-L1 targeted therapies in patients with metastatic UC should utilize recent biopsies of metastatic lesions to define PD-L1 expression when feasible.

338 Clinicopathological Correlation of PD-L1 Expression in Primary and Metastatic Breast Cancer and Infiltrating Immune Cells

338 Clinicopathological Correlation of PD-L1 Expression in Primary and Metastatic Breast Cancer and Infiltrating Immune Cells

Correlation of PD-L1 expression with p16INK4A expression in nonoropharyngeal head and neck squamous cell carcinoma.

39 Background: The expression of PD-L1 expression is important for tumor cells to evade the immune system. The level of its expression and its correlation to disease prognosis is unclear in non-oropharyngeal head and neck squamous cell carcinoma (non-OPHNSCC). Methods: A retrospective clinicopathologic analysis was performed for 106 non-OPHNSCC patients diagnosed during the period from 2007 to 2014. We made tissue arrays from the paraffin-embedded non-OPHNSCC samples obtained from the patients, and studied PD-L1 and p16INK4A expression by immunohistochemistry. Systemic inflammatory factors including C-reactive protein, serum white blood cell, neutrophil, monocyte, and lymphocyte count were also analyzed to study the correlation. Results: We found that PD-L1 was overexpressed in 32.1% (34/106) and p16INK4A in 20.8% (22/106) of the patients who were studied. The expression of PD-L1 was associated with p16INK4A expression ( p < 0.01), but was not associated with the level of systemic inflammatory factors. No significant prognostic values of PD-L1, p16INK4A, or other clinicopathologic factors were found except tumor stage (stage I/II vs. III/IV, p=0.03). Conclusions: This study demonstrates the correlation between PD-L1 and p16INK4A in non-OPHNSCC, which may provide important information for designing the clinical trials of anti-PD1/PDL1 treatment in head and neck cancer patients. [Table: see text]

Abstract 477: Correlation of PD-L1 expression and HPV status among primary and metastasized HNSCC tumors

Abstract Dysregulation of the immune checkpoints has been identified as one of the mechanisms tumor cells employ for immune escape. Human papillomavirus (HPV) plays an important role in the etiology of one subset of Head and Neck Squamous Cell Carcinomas (HNSCC). Recent studies reported that PD-1/PD-L1 pathway may be correlated with HPV-associated HNSCC. The degree of PD-L1 expression has been reported to be increased in those patients with HPV-positive disease. Also, PD-L1 expression in HNSCC was observed in the primary, recurrent, and metastatic disease setting. However, the clinicopathological implications associated with PD-L1 in HNSCC, as well as in disease metastasis, remain largely unclear. Using immunohistochemistry (IHC) and In situ hybridization (ISH) on VENTANA BenchMark ULTRA automated stainers, 40 cases of HNSCC, with matching primary and metastatic cancer stages, were evaluated for expression of PD-L1, p16, a surrogate marker of transforming HPV infections, and presence of HPV. Formalin-fixed paraffin-embedded tumor samples were subjected to PD-L1- and p16-IHC as well as HPV-ISH. A potential association between PD-L1 expression and HPV status among primary tumors and matched metastases was analyzed. Our data show that expression of PD-L1 or p16 is concordant in the majority of HNSCC primary vs metastatic tumor cases tested. Agreement rate of p16 expression among 40 case pairs of primary vs metastatic tumor was 88.2% with a 95% Confidence Interval (CI) of (73.4-95.3). PD-L1 expression was 76.9% (61.7-87.4) concordant among the 40 case pairs. Agreement rate between PD-L1 and p16 was 77.1% (61.0-87.9) in primary cases and 51.3% (35.9-66.6) in metastatic cases. No obvious association between PD-L1 and p16 expression was observed. Citation Format: Chenglu C. Quon, Xiaoling Xia, Lupe Manriquez, Crystal Schemp, Dawn Sloane, Shahad Alabagi, Mohammed G. Abdelwahab, Pengfei Gu, Lizhen Pang, Khalid Hanif, Nicole Schechter. Correlation of PD-L1 expression and HPV status among primary and metastasized HNSCC tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 477.

Correlation of PD-L1 expression with immune cell infiltrates, genome-wide copy number aberrations and survival in mesothelioma.

8518Background: Recent clinical studies using immune checkpoint inhibitors in mesothelioma (MM) have shown promise in shifting treatment paradigms. However, the immune environment and targets of th...

Correlation of PD-L1 expression with EGFR, KRAS, or ALK alterations and with survival of non-small cell lung cancer (NSCLC) treated with EGFR-TKIs: A meta-analysis of published trials.

e20576Background: Pre-clinical data demonstrate that PD-L1 expression could be modulated by some driven genes. However, these associations and the utility of PD-L1 in advanced NSCLC patients underg...

Development of an immunohistochemistry assay for PD-L1 for using the 22C3 antibody in melanoma.

e14503Background: The expression of PD-L1 has been reported in a number of human malignancies. Studies showed the correlation of PD-L1 expression in tumor or inflammatory cells, with clinical outco...

Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma

Immune checkpoint inhibitors targeting programmed cell death 1 (PD1) or its ligand (PD-L1) showed activity in several cancer types. We performed immunohistochemistry for CD3, CD8, CD20, HLA-DR, phosphatase and tensin homolog (PTEN), PD-1, and PD-L1 and pyrosequencing for assessment of the O6-methylguanine-methyltransferase (MGMT) promoter methylation status in 135 glioblastoma specimens (117 initial resection, 18 first local recurrence). PD-L1 gene expression was analyzed in 446 cases from The Cancer Genome Atlas. Diffuse/fibrillary PD-L1 expression of variable extent, with or without interspersed epithelioid tumor cells with membranous PD-L1 expression, was observed in 103 of 117 (88.0%) newly diagnosed and 13 of 18 (72.2%) recurrent glioblastoma specimens. Sparse-to-moderate density of tumor-infiltrating lymphocytes (TILs) was found in 85 of 117 (72.6%) specimens (CD3+ 78/117, 66.7%; CD8+ 52/117, 44.4%; CD20+ 27/117, 23.1%; PD1+ 34/117, 29.1%). PD1+ TIL density correlated positively with CD3+ (P < .001), CD8+ (P < .001), CD20+ TIL density (P < .001), and PTEN expression (P = .035). Enrichment of specimens with low PD-L1 gene expression levels was observed in the proneural and G-CIMP glioblastoma subtypes and in specimens with high PD-L1 gene expression in the mesenchymal subtype (P = 5.966e-10). No significant differences in PD-L1 expression or TIL density between initial and recurrent glioblastoma specimens or correlation of PD-L1 expression or TIL density with patient age or outcome were evident. TILs and PD-L1 expression are detectable in the majority of glioblastoma samples but are not related to outcome. Because the target is present, a clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastoma.

A phase III open-label study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus investigator’s choice in advanced melanoma patients progressing post anti-CTLA-4 therapy.

TPS9105^ Background: Despite the recent approval of ipilimumab and vemurafenib for advanced melanoma, there is still a large unmet need for patients (pts) who have progressed on anti-CTLA-4 therapy and a BRAF inhibitor (depending on BRAF status). Programmed death-1 (PD-1) is a co-stimulation inhibitory receptor that negatively regulates T-cell activation and is upregulated in tumor-infiltrating lymphocytes. Upregulation of PD-1 is also associated with advanced disease in melanoma. Nivolumab, an anti-PD-1 receptor blocking monoclonal antibody, demonstrated durable antitumor activity in a phase 1 study in 106 pts with advanced melanoma with objective responses (OR) observed in 31% and stable disease ≥24 weeks in 6% with a manageable safety profile (Topalian SL et al; ESMO 2012 [Abstr 453P]). Here we describe a phase III study designed to compare the clinical benefit of nivolumab to chemotherapy of investigator’s choice in previously treated pts with unresectable or metastatic melanoma. Methods: In this two arm open-label study, approximately 390 pts will be randomized 2:1 to receive either nivolumab 3 mg/kg IV every two weeks (Arm A) or either dacarbazine 1000 mg/m2 IV or carboplatin AUC6/paclitaxel 175 mg/m2 IV every 3 weeks (Arm B) until disease progression or treatment discontinuation. Pts included are those with ≤2 regimens for advanced melanoma who have progressed on anti-CTLA-4 therapy as well as a BRAF inhibitor if BRAF V600-mutation positive. Pts without active brain metastases are eligible. All pts require baseline fresh biopsy to determine PD-L1 expression. Pts will be stratified by tumor PD-L1 expression, BRAF status, and prior anti-CTLA-4 best response. Tumor response per RECIST 1.1 will be assessed 9 weeks following randomization and every 6 weeks thereafter for the first year. After the first year, response will be assessed every 12 weeks until disease progression or treatment discontinuation. The co-primary endpoints are overall survival (OS) and OR rate. Secondary endpoints include progression-free survival, correlation of PD-L1 expression with clinical outcome, and health-related quality of life. Clinical trial information: NCT01721746.