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T. Meniawy



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    MO19 - Lung Cancer Immunobiology (ID 91)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO19.03 - The effects of epidermal growth factor (EGFR) receptor inhibitors on the immune system in patients with advanced non-small cell lung cancer (NSCLC) (ID 3152)

      10:30 - 12:00  |  Author(s): T. Meniawy

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR tyrosine kinase inhibitors (TKIs) have an important role in the treatment of NSCLC, particularly in the context of activating mutations, but resistance invariably develops. Recently, the immune checkpoint blockers anti-PD1 and anti-PDL1 were the first immunotherapies to demonstrate activity in advanced lung cancer. As immunotherapies such as anti-CTLA4, anti-PD1 and anti-PD-L1 antibodies enter clinical practice, there is potential to combine immunotherapies with TKIs to improve patient outcomes. The immune effects of EGFR-TKIs have not been elucidated, and the aim of this study is to examine the effect of TKIs on the immune response in patients with NSCLC, to provide a rationale and pilot data to underpin future clinical development of combinations of TKIs and immunotherapy.

      Methods
      Patients with advanced NSCLC who were commencing an EGFR-TKI were included in this prospective study. Eligible patients had a confirmed diagnosis of NSCLC, were treated with a single-agent EGFR-TKI , had no concurrent autoimmune disease and received no chemotherapy within 21 days, or corticosteroid therapy within 3 days of study entry. Peripheral blood samples were collected before commencing a TKI and 7 days, 21 days and 8 weeks after start of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and immediately frozen for subsequent analysis by 8-colour flow cytometry for relevant surface and intracellular marker expression. 4 panels were developed to examine the activation and proliferation status of effector CD8[+] T and CD4[+] T-regulatory cells (Tregs), enumeration of dendritic cells and B-cells, as well as the inhibitory pathway programmed death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2 on T cells and antigen-presenting cells. Changes in immune parameters will be correlated with overall survival (OS) and radiological response (RECIST 1.1 criteria) at 8 weeks post-treatment.

      Results
      33 eligible patients were prospectively enrolled. Histopathology was adenocarcinoma (n=23), squamous cell carcinoma (n=7) and NSCLC not otherwise specified (NOS, n=3)). 12 patients had an activating EGFR mutation, 11 were EGFR wild type, and mutation-status was unknown in 10. 6 patients received the TKI gefitinib and 4 received erlotinib as first-line treatment for EGFR-mutation positive disease. 22 patients received erlotinib and 1 patient received afatinib as second or subsequent line therapy. At time of this report, 22/33 patients were deceased. Median OS from study entry was: all patients (7.7 months); mutation-positive (11.1 months); and mutation negative (4.4 months). Samples for 13 patients (2 were mutation-positive) have been analysed for effector T cell and Treg panels and no significant changes were seen between baseline and subsequent time points. Data will be presented for all samples.

      Conclusion
      This is the first study to explore to the immune effects of EGFR-TKIs. Initial results have not revealed a significant effect on peripheral T-cells, and analysis of remaining patient samples and other panels is in progress. An understanding of the immune effects of targeted therapies will be crucial in the rational development of strategies for incorporating immunotherapy into the anti-EGFR treatment paradigm, in an era of promising immunotherapy and checkpoint blockade approaches.

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    P2.14 - Poster Session 2 - Mesothelioma (ID 196)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P2.14-004 - EORTC and CALGB prognostic models, but not neutrophil-to-lymphocyte ratio, are prognostic in unselected patients with newly diagnosed malignant mesothelioma (ID 1259)

      09:30 - 16:30  |  Author(s): T. Meniawy

      • Abstract

      Background
      Neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation, was proposed as a prognostic biomarker in a number of malignancies, including malignant pleural mesothelioma (MPM). We examined baseline variables predictive of overall survival (OS) in patients with newly diagnosed MPM, including NLR and the established EORTC and CALGB prognostic models.

      Methods
      Consecutive patients with newly diagnosed MPM between 1[st] January 2005 and 31[st] December 2010 at Sir Charles Gairdner Hospital, Western Australia were included in this retrospective study. Eligible patients had a confirmed diagnosis of MPM, neutrophil and lymphocyte count within 90 days of diagnosis, no concurrent haematological malignancy, and follow-up more than 90 days from diagnosis. Any subsequent treatment, including supportive care alone, was allowed. Variables to be analysed and cut-off determination was predetermined according to previous reports. Multiple imputation was performed for missing values, and univariate analyses and multivariate Cox models were calculated for OS.

      Results
      274 of 369 patients screened met the eligibility criteria and were included in this retrospective study. 159 received systemic chemotherapy, 10 underwent tri-modality therapy; 2 underwent surgery only, and 103 received supportive care alone. Prognostic factors predictive of shorter survival in univariate analysis were: age ≥ 65 years, non-epithelioid histology, sarcomatous histology, AJCC stage III-IV, ECOG performance status (PS) 2-3, weight loss, chest pain, low haemoglobin and high platelet count. An NLR ≥ 5 at diagnosis did not predict for shorter OS (hazard ratio (HR) 1.25; p=0.122). On multivariate analysis, age, histology, PS, weight loss, chest pain, and platelet count remained significant. The EORTC and CALGB prognostic groups were highly statistically significant as predictors for OS (HR 1.62; p<0.001 and HR 1.65; p<0.001, respectively). On preplanned subgroup analyses, baseline NLR was not prognostic in chemotherapy-treated or non-chemotherapy treated patients.

      Univariate and multivariate analyses of association of prognostic factors with overall survival
      Univariate analysis Multivariate analysis
      Baseline prognostic factor HR (95% CI) P-value HR (95% CI) P-value
      Baseline NLR <5* vs. ≥5 1.25 (0.94-1.66) 0.122 1.02 (0.76-1.37) 0.893
      Age <65* vs. ≥65 years 1.64 (1.24-2.17) <0.001 1.41 (1.05-1.90) 0.023
      Female* vs. Male 1.23 (0.86-1.77) 0.262 1.24 (0.85-1.81) 0.269
      Epithelioid* vs. non-epilthelioid 1.40 (1.08-1.80) 0.009 1.38 (1.05-1.82) 0.023
      Non-sarcomatous* vs. sarc. 2.37 (1.62-3.48) <0.001 1.86 (1.22-2.84) 0.004
      AJCC Stage I-II* vs. III-IV 1.52 (1.17-1.97) 0.002 1.27 (0.97-1.66) 0.087
      ECOG PS 0-1* vs. 2-3 2.35 (1.59-3.46) <0.001 1.81 (1.21-2.70) 0.004
      Weight loss absent* vs. present 2.11 (1.62-2.74) <0.001 1.62 (1.22-2.15) <0.001
      Chest pain absent* vs. present 1.58 (1.21-2.07) <0.001 1.34 (1.02-1.76) 0.038
      Hb difference <10* vs. >10 1.87 (1.41-2.49) <0.001 1.32 (0.96-1.80) 0.087
      WCC (x 10[9]/L) ≤8.30* vs. >8.30 1.22 (0.96-1.57) 0.110 0.95 (0.73-1.25) 0.745
      PLT (x 10[9]/L) ≤400* vs. >400 1.96 (1.49-2.58) <0.001 1.71 (1.26-2.33) <0.001
      Abbreviations: *=referent; AJCC=American Joint Committee on Cancer Staging System; ECOG= Eastern Cooperative Oncology Group, WCC=White cell count; NLR=Neutrophil-to-lymphocyte ratio

      Conclusion
      Our findings validate established baseline prognostic variables as well as the EORTC and CALGB models, but not baseline NLR in unselected patients with newly diagnosed MPM. In guiding treatment decisions for patients at time of diagnosis, multiple variables should be considered that jointly predict survival