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Anne Madroszyk



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    OA15 - Targeted Agents and Immunotherapy for Small Cell Lung Cancer (ID 152)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
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      OA15.02 - Carboplatin-Etoposide Versus Topotecan as Second-Line Treatment for Sensitive Relapsed Small-Cell Lung Cancer: Phase 3 Trial (Now Available) (ID 546)

      14:30 - 16:00  |  Author(s): Anne Madroszyk

      • Abstract
      • Presentation
      • Slides

      Background

      Topotecan is currently the only drug approved in Europe in second line setting for small-cell lung cancer (SCLC). This study investigates whether the doublet carboplatin-Etoposide was superior to topotecan monotherapy as second-line treatment in patients with sensitive relapsed SCLC.

      Method

      this open-label, multicenter, phase 3 trial randomized patients with SCLC that responded to first-line platin etoposide doublet treatment but showed evidence of disease relapse or progression at least 90 days after completion of the first-line treatment. Enrolled patients were randomly assigned (1:1) to receive combination chemotherapy (Six cycles of 3-weeks Carboplatin, AUC 5, day 1 and Etoposide 100 mg/Sqm/d 1-3, intra-venous) or oral Topotecan (2.3 mg/Sqm/d 1-5, every 3 weeks). Primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), quality of life and tolerance in the intention-to-treat population, (clinical trialgouv: NCT02738346)

      Result

      178 patients were screened and 164 randomized in 36 centers, with 82 assigned to each treatment group (age: 64.5 ± 7.2 years, men: 72.8%, PS 0/1/>1: 34.7%/56.3%/ 9%. Median PFS was significantly longer in combination chemotherapy group (4.7 months, 95% CI: 3.9-5.5) compare to topotecan group (2.7 months, 95% CI: 2.3-3.2), HR: 0.6, 95% CI 0.4-0.8, p < 0.002. The ORR were significantly more important in the combination chemotherapy than in topotecan arm (ORR 49 % vs 25 %, p < 0,002), but without difference in term of median OS, 7.5 months (95% CI: 5.4-8.7) in combination chemotherapy group versus 7.4 months (95% CI.6.0-9.3) in topotecan arm. Grade 3/4 neutropenia were significantly more common in the topotecan group than in the combination chemotherapy group (35.8% vs 19.7 %, p < 0.001. There is a non-significant trend for more febrile neutropenia in topotecan arm compare to combination arm (13.6 % 6.2 %, p = 0.19, and no difference for grade 3/4 thrombopenia, 35.8 % vs 30.9 %, and anemia, 24.6 % vs 21 %, for topotecan and combination arms, respectively. Two treatment-related deaths occurred in the topotecan arm (febrile neutropenia with sepsis), none in the combination arm. Results of quality of life outcomes will be presented at the meeting.

      Conclusion

      platin - etoposide re-challenge can be considered as a standard second-line chemotherapy for sensitive relapsed SCLC.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-33 - Deep Phenotyping of Immune Populations Reveals Baseline Predictors of Pembrolizumab Efficacy in NSCLC on KEYNOTE-001 (Now Available) (ID 2292)

      09:45 - 18:00  |  Author(s): Anne Madroszyk

      • Abstract
      • Slides

      Background

      Medical treatment of lung cancer has irreversibly changed since the development of immune checkpoint inhibitors like pembrolizumab. However, immune biomarkers of efficacy are still lacking. Preliminary data in melanoma showed that a high baseline blood level of classical monocytes was associated with improved outcome in patients treated with programmed cell death-1 (PD-1) inhibitors. This led us to explore the immune landscape of non-small cell lung cancer (NSCLC) patients treated with pembrolizumab on KEYNOTE-001 using high-dimensional mass cytometry.

      Method

      We analyzed 38 advanced NSCLC patients treated with pembrolizumab on KEYNOTE-001 at UCLA. Mass cytometry (CyTOF) was performed on baseline peripheral blood mononuclear cells (PMBC). We used a panel of 31 antibodies defining major immune populations of myeloid cells (plasmacytoid and myeloid dendritic cells, myeloid-derived suppressor cells, classical and CD16+ monocytes), lymphoid cells (B cells, NK cells, TReg, γδ T-cells, sub-populations of CD4+ and CD8+ T-cells), selected co-stimulatory (CD28, ICOS, 41BB), co-inhibitory molecules (PD-1, PD-L1, TIM3, LAG3, CTLA-4) and cytotoxicity molecules (perforin, granzymeB). Unsupervised clustering combined with predictive regression model (Citrus algorithm, false discovery rate = 1%) was used to detect immune populations differing between patients that experienced an objective response on trial, as assessed by immune-related response criteria (responders) vs those that did not (non-responders). Classical manual gating (FlowJo software) was used to confirm the Citrus results.

      Result

      Among the 38 patients analyzed via CyTOF, 27 patients had sufficient viable cells for analysis. Citrus algorithm comparing responders (n=7) and non-responders (n=20) revealed significant frequency differences in specific subtypes of three immune populations: monocytes, CD4+ and CD8+ T-cells. Manual gating confirmed that responders (vs non-responders) had increased frequency (%CD45+) of classical monocytes perforin+ granzymeB+ (5.54% vs 2.55%, p=0.029), central memory CD4+ T-cells ICOS+ CD28+ PD1+ (1.29% vs 0.83%, p=0.06) and over-expression of 41BB (mean metal intensity (MMI)=0.15 vs MMI=0.09, p=0.006) and perforin (MMI=108.4 vs MMI=70.7, p=0.004) in effector memory CD8+ T-cells.

      Conclusion

      Mass cytometry in the blood reveals that a high baseline frequency of activated and cytotoxic monocytes, CD4+ and CD8+ T-cells predicted for pembrolizumab efficacy in advanced NSCLC. Preliminary analyses correlating immune cell populations and overall survival are ongoing and suggest a similar increase in the three immune cell populations found to be higher in responders vs non-responders.

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