Author of

• 12441

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  P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12480

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    P3.06-040 - Characterization of PD-L1 expression and assessment of association with tumor histology and gene expression status in pretreatment non-small cell lung cancer (NSCLC) tumor specimens (ID 2780)

    09:30 - 09:30  |  Author(s): J.F. Novotny
    • Abstract

    Background
    The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation. In a phase 1 study, nivolumab (PD-1 blocking antibody) delivered durable responses in patients with advanced NSCLC, melanoma, and renal cell carcinoma. Immunohistochemistry (IHC) analysis suggested association between pretreatment tumor PD-1 ligand (PD-L1) expression and response to nivolumab in patients with melanoma (Grosso ASCO 2013 abstract 3016; Topalian New Engl J Med. 2012;366:2443). There is little published information associating PD-L1 expression with gene profiles, mutational status, or patient characteristics in NSCLC. Such data may be relevant in understanding which patient subgroups may be more likely to benefit from nivolumab therapy.

    Methods
    60 NSCLC formalin-fixed paraffin-embedded tumor tissue samples (Asterand: 30 squamous; 30 non-squamous) with matching RNA, frozen tissue samples, and patient characteristics/outcomes were utilized. Tumor cell membrane PD-L1 expression was evaluated by IHC using an automated assay based on a sensitive and specific PD-L1 monoclonal antibody (28-8). Tumors were defined as PD-L1 positive (PD-L1+) when ≥5% of the tumor cells had membrane staining at any intensity. PTEN/EGFR expression was analyzed by IHC. Mutations in isolated DNA were analyzed on the AmpliSeq[TM] cancer panel using the Ion Torrent platform. Gene expression was conducted on the Affymetrix platform and association with PD-L1 status analyzed using ANOVA.

    Results
    Of 59 tumor samples with available data assessed by IHC, 42% (25/59) were PD-L1+ and 58% (34/59) were PD-L1 negative (PD-L1-). There was no apparent association between PD-L1 protein expression and NSCLC histology: for squamous and non-squamous tumors, 38% (11/29) and 47% (14/30) were PD-L1+, respectively. No association was observed between PD-L1 status and PTEN or EGFR expression. PD-L1+ tumors, compared with PD-L1- tumors, showed higher expression of several immune-related genes, including interferon-gamma (IFNγ), IFNγ-induced cytokine, and other genes involved in immune-cell regulation. The PD-L1 gene was differentially expressed between IHC PD-L1+ and PD-L1- samples, with no continuous relationship noted. Genes associated with tumor progression and signaling pathways were over-expressed in PD-L1+ versus PD-L1- tumors, including proto-oncogene tyrosine kinase (MET), EGFR ligands, neuropilin-2, and alpha E-catenin. Analysis of key mutations from the Ampliseq panel indicated that rates of detectable mutations in our tumor panel differed from those reported in COSMIC (Catalog of Somatic Mutations in Cancer; http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/), as p14/CDKN2A and CBL mutations were not observed. However, KRAS and TP53 mutation rates were consistent with COSMIC. IHC PD-L1 positivity was observed amongst KRAS mutation-positive (8/10) and KRAS wild-type tumors (15/43), and importantly amongst EGFR mutation-positive and EGFR wild-type tumors.

    Conclusion
    Current data suggest PD-L1 protein expression on NSCLC tumors may be associated with several factors, including expression of immune genes, expression of tumor progression markers, and driver mutations. Ongoing analyses within this tumor panel are exploring putative associations of PD-L1 expression with patient characteristics and outcomes. Findings could help define additional factors that may influence the likelihood of response to nivolumab therapy. Correlates to PD-L1 will be explored in greater detail as part of ongoing phase 3 trials of nivolumab in NSCLC.