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A. Kotsakis



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    MO13 - SCLC I (ID 118)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO13.04 - <strong>A Phase II Trial of second line Pazopanib in Small Cell Lung Cancer (SCLC) patients: Preliminary results in patients with sensitive disease</strong> (ID 2095)

      10:45 - 10:50  |  Author(s): A. Kotsakis

      • Abstract
      • Presentation
      • Slides

      Background
      Pazopanib, a small molecule competitive inhibitor of the tyrosine kinase of VEGFR‑1, VEGFR‑2, VEGFR‑3, PDGF, and c‑kit has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Microvessel density and VEGF expression in SCLC tumor samples correlate with development of metastases and poor prognosis. A phase II trial of pazopanib in SCLC patients who have relapsed after, or have refractory disease to front-line chemotherapy was conducted.

      Methods
      This is a two-cohort, non-randomized, two-stage phase II study. Patients with sensitive (cohort A) and resistant/refractory (cohort B) histologically confirmed SCLC are enrolled onto the study. An interim analysis has been planned after enrolment of 19 patients in each cohort. Eligible patients have to have measurable disease (RESIST) and ECOG performance status (PS) 0-2. Up to 1 prior regimen (cisplatin/etoposide) for extended disease is allowed. Treatment consists of daily pazopanib 800 mg given p.o.q28 days, until disease progression. The primary endpoint is progression-free rate with a planned sample size of 39 eligible patients per cohort.

      Results
      We present the first interim analysis in cohort A. 19 eligible patients have been enrolled with a median age of 67 years (range 46-77); male 16; PS 0, 10 pts; PS 1, 9 pts. Four patients had only local relapse. Four (21%) partial responses and 8 (42%) stable disease were documented which is translated in a disease control rate (DCR) of 63% (95% CI: 41.5- 85%). The median PFS was 4.3 months and the estimated 1-year survival 58%. Grade 4 neutropenia and diarrhea occurted in 1 patient each; other grade 3 adverse events were fatigue (n=2), nausea (n=1); grade 2 hypertransaminasemia occurred in 2 patients, grade 1 hemorrhage (epistaxis) in 3 and hypertension in 2. No deaths related to the study drug were observed.

      Conclusion
      These preliminary results show that pazopanib is an active and well tolerated drug in patients with sensitive SCLC. Recruitment in both cohorts is ongoing. A biomarker analysis is planned.

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    P3.04 - Poster Session 3 - Tumor Immunology (ID 155)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.04-003 - High levels of circulating immunosuppressive cells predict worst clinical outcome in Non-Small Lung Cancer (NSCLC) patients (ID 2665)

      09:30 - 09:30  |  Author(s): A. Kotsakis

      • Abstract

      Background
      The immune cells can prevent and inhibit tumour development but also may contribute to growth and progression of cancer. Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature cells with immune suppressive properties, have been correlated with worse prognosis in several tumors. In addition, high levels of circulating CD4[+] T regulatory (Tregs) cells exhibit suppressive functional activity against anti-tumour T-cell responses and correlated with worse recurrence-free survival in NSCLC patients. In the present study, we investigated the expression and levels of MDSCs’ subpopulations and CD4[+]Tregs, their correlation to distinct immune cells, as well as to the clinical outcome of patients with advanced NSCLC.

      Methods
      Peripheral blood from 112 chemotherapy-naive patients with stage III/IV NSCLC and 27 healthy donors was analyzed with flow cytometry for the presence of monocytic and granulocytic subpopulations of MDSCs, CD4[+ ]Tregs, as well as the frequencies of distinct immune cells such as CD4[+ ]and CD8[+ ]cells, dendritic cells (DC) and B cells. The frequencies of these cells in the patients were compared to the healthy donors. The patients’ clinical outcome (PFS and OS) was compared according to the frequency of MDSCs and Tregs (high vs low expression as defined by their percentage above healthy donors).

      Results
      Two monocytic (CD14[+]CD15[-]CD11b[+]CD33[+]HLA-DR[-]Lin[-] and CD14[+]CD15[+]CD11b[+]CD33[+]HLA-DR[-]Lin[-]), and a granulocytic (CD14[-]CD15[+]CD11b[+]CD33[+]HLA-DR[-]Lin[-]) subpopulations as well as CD4[+] Tregs (CD3[+]CD4[+]CD25[+high]CD152[+]CD127[-]Foxp3[+]) were increased in patients compared to healthy donors (p<0.001 and p<0.007, respectively). Levels of MDSCs and CD4+ Tregs did not associated with tumor histology or stage of the disease. The levels of both subpopulations of monocytic but not of granulocytic MDSCs were reversely correlated with the levels of dendritic cells (DC) (r[2]=-0.3, p≤0.04) whereas the granulocytic subpopulation of MDSCs was reversely correlated with the levels of CD4[+] T cells (r[2]=-0.3, p=0.006). Increased baseline levels of both monocytic MDSCs’ subpopulations was associated with early relapse despite front-line platinum-based chemotherapy (p=0.05). The detection of baseline CD14[+]CD15[+]CD11b[+]CD33[+]HLA-DR[-]Lin[-] MDSCs within the normal levels was associated with longer OS compared to those with high levels (p=0.0035). Finally, patients with normal CD4[+ ]Tregs frequencies had a higher OS than those with high frequencies (p=0.05).

      Conclusion
      The data show that increased levels of monocytic MDSCs and CD4[+] Tregs in the peripheral blood of NSCLC patients are reversely correlated to the other normal immune cells. These cells could represent potential predictive/prognostic biomarkers since their increased levels were negatively correlated to the treatment outcome.