Plasma cell free PD-L1 RNA expression correlated with tissue PD-L1 immunohistochemical staining and tumor mutation burden in non-small cell lung cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15049-e15049
Author(s):  
Paul R. Walker ◽  
Mark Bowling ◽  
Nitika Sharma ◽  
Praveen Namireddy ◽  
Teresa Parent ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Protein Expression ◽  
Immune Checkpoint ◽  
Immunohistochemical Staining ◽  
Immune Checkpoint Inhibitor ◽  
Advanced Nsclc ◽  
Checkpoint Inhibitor ◽  
Small Cell ◽  
Small Cell Lung ◽  
L1 Protein

e15049 Background: Programmed death ligand-1 (PD-L1) protein expression by immunohistochemical staining (IHC) correlates with response to immune checkpoint inhibitor (ICI) therapies in non-small cell lung cancer (NSCLC). Tumor mutational burden (TMB) is another immune biomarker of ICI response in NSCLC. Clinical studies indicate tissue PD-L1 protein expression and TMB are independent yet complementary. Both are limited by tissue acquisition and potential heterogeneity. Plasma cell free PD-L1 RNA (cfRNA) levels and tissue protein PD-L1 expression and TMB was analyzed and correlated in patients with advanced NSCLC. Methods: Patients with advanced NSCLC underwent complementary plasma and tissue next generation sequencing (NGS) with immune biomarkers prior to treatment. Plasma PD-L1 cfRNA was assessed by the Circulogene proprietary direct-on-specimen enrichment technology NGS platform. Correlating tissue testing was performed by the Caris Molecular Intelligence platform with the anti-PD-L1 22C3 IHC antibody and TMB measuring the total number of non-synonymous somatic mutations per megabase. Results: 107 patients with advanced NSCLC were evaluated with simultaneous plasma and tissue NGS testing. 17% (95% confidence interval [CI] 10-24%) patients plasma PD-L1 positive. 48.5% (CI 38-57%) tissue IHC PD-L1 positive. 7 of 18 plasma PD-L1 positive patients were tissue PD-L1 negative. 48% (CI 39-58%) total patients TMB ≥ 10 mutations per megabase (TMB high). Correlating TMB high in 72% (CI 50-94%) of plasma PD-L1 positive and 56% (CI 42-69%) of tissue PD-L1 positive patients. TMB high in 49% (CI 37-59%) plasma PD-L1 negative and 50% (CI 35-65%) tissue PD-L1 negative patients. Conclusions: Although less frequent than tissue PD-L1 protein expression, plasma PD-L1 cfRNA expression correlated with a higher association of tissue TMB high findings than tissue PD-L1 positive patients. There was not any TMB high difference between plasma PD-L1 negative and tissue PD-L1 negative patients. Over one-third of plasma PD-L1 positive patients were tissue PD-L1 negative. Clinical correlation with immune checkpoint inhibitor therapies is ongoing.

scholarly journals Identification of NOTCH4 mutation as a response biomarker for immune checkpoint inhibitor therapy

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Junyu Long ◽  
Dongxu Wang ◽  
Xu Yang ◽  
Anqiang Wang ◽  
Yu Lin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Bladder Cancer ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Esophagogastric Cancer ◽  
Clinical Benefits

Abstract Background Immune checkpoint inhibitor (ICI) therapy elicits durable antitumor responses in patients with many types of cancer. Genomic mutations may be used to predict the clinical benefits of ICI therapy. NOTCH homolog-4 (NOTCH4) is frequently mutated in several cancer types, but its role in immunotherapy is still unclear. Our study is the first to study the association between NOTCH4 mutation and the response to ICI therapy. Methods We tested the predictive value of NOTCH4 mutation in the discovery cohort, which included non-small cell lung cancer, melanoma, head and neck squamous cell carcinoma, esophagogastric cancer, and bladder cancer patients, and validated it in the validation cohort, which included non-small cell lung cancer, melanoma, renal cell carcinoma, colorectal cancer, esophagogastric cancer, glioma, bladder cancer, head and neck cancer, cancer of unknown primary, and breast cancer patients. Then, the relationships between NOTCH4 mutation and intrinsic and extrinsic immune response mechanisms were studied with multiomics data. Results We collected an ICI-treated cohort (n = 662) and found that patients with NOTCH4 mutation had better clinical benefits in terms of objective response rate (ORR: 42.9% vs 25.9%, P = 0.007), durable clinical benefit (DCB: 54.0% vs 38.1%, P = 0.021), progression-free survival (PFS, hazard ratio [HR] = 0.558, P < 0.001), and overall survival (OS, HR = 0.568, P = 0.006). In addition, we validated the prognostic value of NOTCH4 mutation in an independent ICI-treated cohort (n = 1423). Based on multiomics data, we found that NOTCH4 mutation is significantly associated with enhanced immunogenicity, including a high tumor mutational burden, the expression of costimulatory molecules, and activation of the antigen-processing machinery, and NOTCH4 mutation positively correlates activated antitumor immunity, including infiltration of diverse immune cells and various immune marker sets. Conclusions Our findings indicated that NOTCH4 mutation serves as a novel biomarker correlated with a better response to ICI therapy.

scholarly journals Soluble PD-L1 is a predictive and prognostic biomarker in advanced cancer patients who receive immune checkpoint blockade treatment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
So Yeon Oh ◽  
Soyeon Kim ◽  
Bhumsuk Keam ◽  
Tae Min Kim ◽  
Dong-Wan Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Prognostic Factor ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Progressive Disease ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Checkpoint Inhibitor Therapy

AbstractCirculating soluble programmed death-1 ligand (sPD-L1) is measurable in the serum of cancer patients. This study aimed to investigate the significance of sPD-L1 in cancer patients receiving immune checkpoint inhibitor therapy. Blood samples were obtained before and after immune checkpoint inhibitor therapy (January 2015 to January 2019). The study cohort consisted of 128 patients who were diagnosed with non-small cell lung cancer (n = 50), melanoma (n = 31), small cell lung cancer (n = 14), urothelial carcinoma (n = 13), and other cancers (n = 20). Patients with a high level (> 11.0 pg/μL) of sPD-L1 were more likely to exhibit progressive disease compared with those with a low level (41.8% versus 20.7%, p = 0.013). High sPD-L1 was also associated with worse prognosis; the median PFS was 2.9 (95% confidence interval [CI] 2.1–3.7) months versus 6.3 (95% CI 3.0–9.6) months (p = 0.023), and the median OS was 7.4 (95% CI 6.3–8.5) months versus 13.3 (95% CI 9.2–17.4) months (p = 0.005). In the multivariate analyses, high sPD-L1 was an independent prognostic factor for both decreased PFS (HR 1.928, p = 0.038) and OS (HR 1.788, p = 0.004). sPD-L1 levels did not correlate with tissue PD-L1 expression. However, sPD-L1 levels were positively correlated with neutrophil to lymphocyte ratios and negatively correlated with both the proportion and the total number of lymphocytes. We found that high pretreatment sPD-L1 levels were associated with progressive disease and were an independent prognostic factor predicting lower PFS and OS in these patients.

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