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Y. Xiao



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    MO19 - Lung Cancer Immunobiology (ID 91)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 2
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      MO19.09 - Molecular correlates of PD-L1 status and predictive biomarkers in patients with non-small cell lung cancer (NSCLC) treated with the anti-PDL1 antibody MPDL3280A (ID 1653)

      11:20 - 11:25  |  Author(s): Y. Xiao

      • Abstract
      • Presentation
      • Slides

      Background
      In NSCLC, antitumor immune response may be inhibited by PD-L1 expression. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, aims to restore tumor-specific T-cell immunity by blocking PD-L1 binding to its receptors, PD-1 and B7.1.

      Methods
      Patients with squamous or nonsquamous NSCLC received MPDL3280A IV q3w up to 1 year as part of a phase I dose escalation/expansion study. Objective response rate (ORR) was assessed by RECIST v1.1 and included unconfirmed/confirmed responses. EGFR and KRAS status was initially assessed locally by investigators. Archival tumor tissues were evaluated centrally by IHC for PD-L1 and CD8. A qPCR-based gene expression panel measuring ≈90 immune-related genes was used to characterize the tumor immune microenvironment at baseline and during MPDL3280A treatment.

      Results
      41 NSCLC patients first dosed at 1-20 mg/kg prior to Aug 1, 2012, were evaluable for efficacy with an ORR of 22%. Baseline tumor samples were available for IHC (n=33) and for gene expression analysis (n=29). Of patients with available tissue, 5 were PD-L1 tumor status positive and 28 were PD-L1 tumor status negative. Relationship between PD-L1 status and EGFR/KRAS status is described below (table). Elevated baseline PD-L1 expression was associated with response to MPDL3280A (80% ORR vs 14% ORR for PD-L1negative patients), and PD-L1 expression coordinated with CD8+ T cells. A Th1-type T-cell gene signature (including CD8, Granzyme-B and EOMES) was associated with treatment response. Non-responders exhibited at least a 2-fold higher ratio over CD8 of genes associated with immunosuppression, including RORC, FOXP3, TGFb1 and IL10 compared with responders. On treatment, responding tumors across indications showed increasing PD-L1 expression and a Th1-dominant immune infiltrate, providing evidence for adaptive PD-L1 up-regulation.

      Conclusion
      PD-L1 expression and a Th1 driven T-cell gene signature correlated with response to MPDL3280A in NSCLC, and MPDL3280A therapy led to T-cell reactivation and restored antitumor immunity. Additionally, expression of immune suppressive factors in NSCLC tumors is associated with a lack of benefit from MPDL3280A. These data provide mechanistic insights into immunotherapy and patient selection for MPDL3280A monotherapy. Preliminary observations suggest clinical activity and molecular characteristics may be associated with PD-L1 tumor expression. Updated data will be presented. Table: Relationship between PD-L1 status and EGFR/KRAS mutational status

      PD-L1-Positive (n = 5) PD-L1-Negative (n = 28) PD-L1 Unknown (n = 7) Overall (n = 40)*
      EGFRm, n 1 2 1 4
      EGFR WT, n 2 20 4 26
      EGFR Unknown, n 2 6 2 10
      KRASm, n 1 4 1 6
      KRAS WT, n 2 8 3 13
      KRAS Unknown, n 2 16 3 21
      * 1 patient had missing data.

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      MO19.10 - Prevalence and prognostic association of PD-L1 protein and immune gene expression in NSCLC (ID 2437)

      11:25 - 11:30  |  Author(s): Y. Xiao

      • Abstract
      • Presentation
      • Slides

      Background
      Programmed Death Ligand 1 (PD-L1, CD274, B7-H1) is an immune checkpoint molecule that binds to the receptors PD-1 and B7.1 on activated T cells. Binding negatively regulates T-cell function in both physiological and pathological conditions. Recent clinical studies have suggested that numerous cancers, including NSCLC, may utilize PD-L1 expression to escape T-cell mediated cytotoxic activity. Inhibition of PD-L1 can restore anti-tumor immunity, leading to clinical responses. A better understanding of PD-L1 expression patterns, co-expression with other immune markers and actionable disease associated biomarkers may provide insight into the future design of cancer immunotherapy trials in NSCLC.

      Methods
      Expression of PD-L1 was measured by immunohistochemistry (IHC) in archival tumors and, in some cases, in paired metastases in 2 FFPE NSCLC tumor tissue collections. Set 1 (N=561) was collected from patients who were eligible for surgery with curative intent from 2003 to 2005 at MD Anderson Cancer Center. The samples from Set 2 (N=300) contained surgically resected NSCLC tissue collected between 2006 and 2011 (UCCC and Norwegian Radium Hospital). PD-L1 expression was analyzed in both malignant and non-malignant cells (e.g., infiltrating immune cells). In addition, a multiplex qPCR assay that measures ≈90 immune-related genes was used to characterize the tumor immune microenvironment in the NSCLC tumor samples. Disease associated biomarkers, including the mutation status of EGFR and KRAS, as well as expression of MET (by IHC) were also evaluated.

      Results
      Prevalence of PD-L1 was comparable between adenocarcinoma and squamous cell carcinoma (≈30% in tumor cells; ≈45% and ≈50%, respectively, in immune cells). PD-L1 prevalence varied depending on the pathological stage, and was higher in Stages I-IIIA than in Stages IIIB-IV. Similarly, the prognostic value of PD-L1 varied by both stage and histology. In adenocarcinoma, tumors with PD-L1–positive tumor cells had a higher frequency of KRAS mutation and high Met expression, and a lower frequency of EGFR mutation compared with PD-L1–negative tumors. In contrast, tumors with PD-L1–positive and PD-L1–negative immune cells had a comparable frequency of high Met expression. Expression of PD-L1 was frequently co-localized with CD8+ T-cell infiltrates. Gene expression profiling revealed differences in the tumor immune environment, including genes associated with cytotoxic T-cells, between adenocarcinomas and squamous cell carcinomas. PD-L1 protein and immune gene expression associations with patient characteristics will be described in further detail.

      Conclusion
      These data provide a comprehensive description of PD-L1 expression in the context of disease biology utilizing large independent cohorts of well-characterized lung cancer tissues. The results highlight the complexity of the tumor immune environment in NSCLC with particular emphasis on the association with factors such as pathological stage, histology and oncogenic mutational status. These analyses may help guide future development of immunotherapy trials in NSCLC.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-005 - The High Incidence of Overlap between Actionable Biomarkers in NSCLC: Potential Impact on Future Clinical Trial Design (ID 360)

      09:30 - 09:30  |  Author(s): Y. Xiao

      • Abstract

      Background
      Recent advances in molecular profiling of non-small cell lung cancer (NSCLC) have led to the replacement of platinum-based chemotherapy with targeted therapies for certain genetic subsets of NSCLC (ALK rearrangements, some EGFR activating mutations). It is also known that myriad pathways can drive resistance, the unfortunate norm for most patients. A greater understanding of the overlap across multiple biomarker subsets, including activating mutations, signal transduction pathways, and immune system markers, might aid in prognostic assessment, predictive biomarker development and the design of combination or sequential treatment regimens.

      Methods
      The prevalence and prognostic significance of nine biomarkers (TTF1, p63, EGFR mutation, KRAS mutation, MET immunohistochemistry [IHC], PDL1 IHC, PTEN IHC, NaPi2B IHC, ECDH IHC) across two independent sample sets (Set 1, n=561; Set 2, n=300) were tested. With the exception of ECDH, all assays were IVD or companion diagnostics. Set 1 was collected from patients who were eligible for surgery with curative intent from 2003–2005 at MD Anderson Cancer Center in the USA. Samples from Set 2 were part of a collaboration between the University of Colorado Cancer Center, USA and The Norwegian Radium Hospital, and contained surgically-resected NSCLC tissues collected from 2006–2011.

      Results
      The prevalence of each biomarker varied significantly by histology. For adenocarcinoma samples, the prevalence of each biomarker was: EGFR mutation (13%), KRAS mutation (29%), TTF1 IHC (83%), p63 IHC (7%), MET IHC (50%), PDL1 IHC (45%), PTEN loss IHC (11%), NaPi2B IHC (76%), EGFR IHC (FLEX cut-off, 11%). In squamous-cell carcinoma, the prevalence of each biomarker was: TTF1 IHC (2%), p63 IHC (87%), MET IHC (13%), PDL1 IHC (50%), PTEN loss IHC (13%), NaPi2B IHC (3%), EGFR IHC (FLEX cut-off, 40%). In addition, more than 67% of patients were positive for more than one biomarker and >33% were positive for at least three biomarkers. The diagnostic criteria for each biomarker and correlations with patient characteristics will be described in further detail. Figure 1. Biomarker Overlap in Adenocarcinoma in Set 1 (n=337) Figure 1

      Conclusion
      Collectively, these data suggest that the biomarker landscape in NSCLC is complex and will be increasingly dynamic as more experimental agents approach pivotal testing. Grant support: this study was partially funded by UT Lung Specialized Programs of Research Excellence grant (P50CA70907; IIW)