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T. Phillips

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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)

      09:55 - 10:25  |  Author(s): T. Phillips

      • Abstract
      • Slides

      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.

      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.

      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)

      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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