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C. Genova



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    MA 13 - New Insights of Diagnosis and Update of Treatment (ID 674)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Early Stage NSCLC
    • Presentations: 1
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      MA 13.02 - Comprehensive Genetic Analysis Related to  PD-L1 Expression in Early-stage Lung Squamous Cell Carcinoma (ID 9077)

      15:45 - 17:30  |  Author(s): C. Genova

      • Abstract
      • Presentation
      • Slides

      Background:
      Recently, anti PD-1/PD-L1 immunotherapies have yielded promising outcomes in advanced squamous NSCLC. Several studies have suggested that tumor PD-L1 protein expression status might correlate with outcome and response to treatment. The aim of this study is to identify mRNA gene signatures and microRNAs associated with tumor PD-L1 expression in early-stage lung squamous cell carcinoma (SCC).

      Method:
      Early stage (I-II) SCC resected patient tumors were collected from 6 cancer centers as part of the SPECS II program. Gene expression profiling was performed on the specimens. PD-L1 protein expression was evaluated by immunohistochemistry on SCC FFPE tissue using the Dako 22C3 PD-L1 antibody. The tumor proportion score (TPS) for PD-L1 protein expression was compared with comprehensive clinicopathological, mRNA and miRNA data.

      Result:
      The prevalence of PD-L1 expression in this cohort of 255 Stage I-II SCC patients was 46.7% with a TPS cutoff of ≥ 1%, and 9.8% with a cutoff of ≥ 50%. Among 202 cases with available clinical and expression data, no significant association was observed between PD-L1 expression and clinical outcome. We identified a 12-gene signature from mRNA microarray using the Minimax Concave Penalty (MCP) regression method with an AUC of 0.92 at ≥ 5% TPS cutoff. A subset of 138 miRNAs was shown to be significantly differentially expressed between PD-L1 positive and PD-L1 negative groups at false discovery rate (FDR) of 0.05 with TPS cutoffs of ≥ 1%, ≥ 5% and ≥ 10%. No miRNAs were found to be significantly differentially expressed between the groups using a TPS cutoff of ≥ 50%. Gene Set Enrichment Analysis (GSEA) identified two pathways with gene sets that were significantly enriched (FDR < 0.05) in the PD-L1 negative group. No significant association was found between tumor mutation burden and PD-L1 expression level.

      Conclusion:
      PD-L1 expression prevalence is lower in early-stage lung SCC than in advanced NSCLC. No significant association was found between PD-L1 expression and prognosis in this cohort. Both mRNA gene signatures and miRNAs were identified to be predictive of PD-L1 expression. Through GSEA, two distinct gene sets were identified with expression correlated to PD-L1, one comprising genes related to ovary and another related to collagens and extracellular matrix (ECM). No significant association was found between tumor mutation burden and PD-L1 expression level. Following validation, these predictive signatures could be used to select patients with positive PD-L1 expression who may benefit from immunotherapy.

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    P1.07 - Immunology and Immunotherapy (ID 693)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P1.07-023 - The Correlation Between B7-H4 Expression and Survival of Non-Small Cell Lung Cancer Patients Treated with Nivolumab (ID 9569)

      09:30 - 16:00  |  Author(s): C. Genova

      • Abstract

      Background:
      In spite of the results achieved by nivolumab in advanced non-small cell lung cancer (NSCLC), reliable predictive factors are still needed, and even the expression of the programmed death protein 1 ligand (PD-L1) has a limited role in predicting benefit from this agent. Our aim was to determine whether the expression of other molecules involved in immune response might be associated with outcomes of NSCLC patients receiving nivolumab.

      Method:
      This retrospective study included patients treated with nivolumab for advanced NSCLC (Nivolumab Cohort). Response rate (RR) and progression-free survival (PFS) were assessed by response evaluation criteria in solid tumors (RECIST) v 1.1 and immune-related response criteria (irRC). Available tumor specimens were analyzed by immunohistochemistry (IHC) in order to determine the expression of PD-L1, PD-1 ligand 2 (PD-L2), PD-1, B7-H3, and B7-H4. The possible correlations between IHC findings and clinical outcomes were explored. Additionally, the meaningful biomarkers observed in the Nivolumab Cohort were assessed in a population of NSCLC patients treated with platinum-based chemotherapy (Chemotherapy Cohort) and the results from the two cohorts were compared in order to determine whether the administered treatment played a role in our observations.

      Result:
      The Nivolumab Cohort included 46 evaluable patients. The following proportions of positive IHC samples were observed: PD-L1=15.22%; PD-L2= 17.39; PD-1= 67.39%; B7-H3= 13.04%; B7-H4= 36.96%. At univariate analysis, patients expressing B7-H4 ≥1% had significantly lower PFS compared to those patients with B7-H4 <1% according to RECIST (1.67 vs. 2.00 months; p= 0.026) and irRC (1.73 vs. 2.17 months; p= 0.039), as well as a numerically lower overall survival (OS; 4.37 vs. 9.83 months; p= 0.064). At multivariate analysis for OS, PD-L1 ≥1% had favorable effect (HR= 0.29; p= 0.027), while B7-H4 ≥1% had unfavorable effect (HR= 2.98; p= 0.006). No other correlation was observed in this cohort. Within the Chemotherapy Cohort (n=27), no significant correlation between IHC findings and response or survival was observed. At the multivariate analysis including both cohorts, a statistically significant interaction was observed between OS and the combined effect of B7-H4 expression and treatment (p= 0.048), favoring nivolumab in B7-H4 <1% patients (HR= 0.60) and chemotherapy in B7-H4 ≥1% patients (HR= 0.67).

      Conclusion:
      A meaningful negative correlation between B7-H4 expression and outcomes was observed with nivolumab, but not with chemotherapy. In spite of a relatively small patient population, our results strongly encourage further studies exploring the potential role of B7-H4 as predictor of outcomes during treatment with nivolumab.