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J.F. Kurland



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    Best of Posters - IASLC Selection - Part 1 (ID 262)

    • Event: WCLC 2013
    • Type: Exhibit Showcase Session
    • Track:
    • Presentations: 1
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      P2.11-035 - Association of tumor PD-L1 expression and immune biomarkers with clinical activity in patients with non-small cell lung cancer (NSCLC) treated with nivolumab (Anti-PD-1; BMS-936558; ONO-4538) (ID 2372)

      10:05 - 10:10  |  Author(s): J.F. Kurland

      • Abstract
      • Slides

      Background
      The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation upon interaction with its ligands, PD-L1 and PD-L2. In a Phase 1 dose-escalation/cohort expansion study (CA209-003; NCT00730639), nivolumab, a fully human PD-1 receptor blocking antibody, delivered durable responses in patients with solid tumors, including advanced NSCLC. Immunohistochemistry (IHC) analysis of tumor samples from this study suggested an association between pre-treatment tumor PD-L1 expression and clinical response to nivolumab in patients with melanoma (Grosso JF J Clin Oncol. 2013;31(suppl):abs 3016; Topalian SL NEJM 2012;366:2443-54). Here we investigate the association between PD-L1 expression by IHC and response to nivolumab in patients with NSCLC, and patient response with pre-/post-dose absolute lymphocyte counts (ALC) and selected lymphocyte cell subsets.

      Methods
      129 patients with NSCLC from the CA209-003 trial received nivolumab between 2008 and 2012 (1–10 mg/kg IV every 2 weeks) during dose escalation and/or cohort expansion. Archived formalin-fixed paraffin-embedded pre-treatment tumor tissue and pre-treatment and on-treatment peripheral whole blood samples were analyzed to explore potential pharmacodynamic/predictive biomarkers associated with nivolumab therapy. Pre-treatment tumor PD-L1 expression was evaluated by IHC using an automated assay developed by Dako based on a sensitive and specific anti-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. Lymphocyte subsets in the periphery were measured using flow cytometry.

      Results
      Tumor membrane PD-L1 expression was measured in 63 patients with NSCLC (29 squamous; 34 non-squamous). 31/63 (49%) NSCLC biopsies were PD-L1+. There was no apparent association between PD-L1 protein expression and NSCLC histology: for squamous and non-squamous tumors, 52% (15/29) and 47% (16/34) were PD-L1+, respective. Objective response rates for PD-L1+ and PD-L1- NSCLC patients with non-squamous and squamous histology are shown in the Table. Objective responses were observed in patients with squamous and non-squamous NSCLC who were negative for PD-L1 expression. Since increases in on-treatment ALC and activated T-cell phenotypes have been shown to positively associate with favorable clinical outcomes in ipilimumab monotherapy (Ku GY Cancer 2010;116:1767-75; Carthon BC Clin Cancer Res 2010;16:2861-71), results from an analysis correlating patient response with pre-/post-dose ALC and T-cell populations in patients with NSCLC receiving nivolumab will be presented.

      Table. Patient response according to PD-L1 expression status in patients with NSCLC
      Tumor type PD-L1 expression status Objective response rate, n/N (%)
      NSCLC (all patients) + 5/31 (16.1)
      – 4/32 (12.5)
      NSCLC (squamous) + 2/15 (13.3)
      – 3/14 (21.4)
      NSCLC (non-squamous) + 3/16 (18.8)
      – 1/18 (5.6)

      Conclusion
      Further evaluation of PD-L1 as a molecular marker of nivolumab therapy is required. Association of PD-L1 protein expression with clinical outcome is currently being prospectively assessed in ongoing Phase 3 trials. Clinical Trial Registration Number: NCT00730639

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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
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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. Kurland

      • 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.