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Rolf Stahel



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    IBS06 - Multimodality Treatment - Realtime Data from National Registries (Ticketed Session) (ID 37)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      IBS06.01 - Realtime Data from Europe ETOP / ESTS Database (Now Available) (ID 3331)

      07:00 - 08:00  |  Author(s): Rolf Stahel

      • Abstract
      • Presentation
      • Slides

      Abstract

      Title: Mesothelioma Realtime Data from Europe - ETOP Mesoscape / ESTS Database

      Introduction:

      Malignant pleural mesothelioma (MPM) is an aggressive malignancy with increasing prevalence and poor prognosis. Despite a still increase in incidence, it remains an orphan disease and studying limited numbers of MPM cases hampers the derivation of solid conclusions.

      The combination of two databases including clinical as well as pathological information will allow researchers to improve the knowledge and facilitate decision-making in patients with MPM.

      The European Thoracic Oncology Platform (ETOP) Mesoscape project and the European Society of Thoracic Surgeons’ (ESTS) database are designed to address clinical, pathological, and molecular characteristics of mesothelioma patients and their impact on outcome. The joined analysis of both databases is a unique approach to real-time data reflecting the reality of mesothelioma characteristics, treatment and prognosis in Europe.

      Materials and Methods:

      A decentralized biobank with fully annotated tissue samples is established for ETOP Mesoscape. Selection criteria for participating centers included sufficient number of cases, and documented ethical approval. Patient selection is based on availability of comprehensive clinical data with adequate follow-up, and adequate quantity and quality of formalin-fixed tissue.
      The ESTS database is a clinical database with pre-operative, intra-operative and post-operative data. A minimum set of data is captured, including demographic, histology, treatment, staging and follow up data.

      The characteristics between the two databases are compared using the Fisher’s exact test (for categorical variables) and Mann-Whitney test (for continuous variables), while Kaplan-Meier method (with log-rank test).

      Results:

      Up to 29 May 2019, the ETOP Mesoscape included information on 497 patients from 10 centers, diagnosed between 1999-2018. In the ESTS database, as of April 2019, 2269 patients are included, diagnosed between 1989-2019.

      Patients in both databases are primarily men (84% in the ETOP, 71% in the ESTS), of 0/1 ECOG Performance status (46/46% and 59/29% in ETOP and ESTS respectively), with known previous exposure to asbestos (75% and 93%) and median ages 64 and 67 years old.

      Significant differences are detected between the two data sources with respect to gender, exposure to asbestos and age (p-value <0.001).

      The primary histology of patients is epithelioid (72% in ETOP and 70% in ESTS), followed by biphasic (22%; 17%) and sarcomatoid (6%; 9%) (not significantly different between the two databases).

      Clinical staging is available for 77% of the patients in ETOP, but only for the 28% in the ESTS database. The stage distribution (I/II/III/IV) is 14/29/42/15% in the ETOP and 23/21/41/16% in the ESTS (significantly difference p<0.001).

      Among the biomarkers common in both data sources, Calretinin and WT1 are detected in the vast majority of patients tested (Calretinin: 97% in both cases; WT1: 89% and 87% in the ETOP and ESTS database respectively).

      For the ETOP cases 90% (of those tested) are CK5/6 positive, 91% D2-40 positive and 97% Pan-CK positive.

      Palliative treatment has been administered in 41% of the ETOP cases. Among them, 84% received palliative chemotherapy (with the vast majority 92%, using multiple agents). Palliative surgery was undertaken in 32% (62 of 194 patients with available information) and palliative radiotherapy for 13% of the patients.

      Complete resection has been performed in 59% of the ETOP Mesoscape patients. This was combined with induction chemotherapy (81%), while adjuvant chemotherapy and radiotherapy was administered in 4% and 37% respectively.

      The surgical approach adopted for the ESTS patients was either video-assisted thoracoscopic surgery (VATS) (59%) or thoracotomy (41%) based on a subset of 887 patients with available information. Post-operation treatment information is available for 620 ESTS patients. Among them, 71% received chemotherapy, 54% underwent surgery and 15% radiotherapy.

      Conclusion:

      We present the combined results from the ETOP Mesoscape and the ESTS database, one of the largest databases. These two series allow us to report on mesothelioma epidemiology and treatment.

      Up to now, the comparison of the baseline characteristics of the patients of the two data sources revealed some statistically significant differences with respect to gender, age, exposure to asbestos and clinical stage.

      As tissue from all ETOP Mesoscape patients is preserved locally and is available for detailed molecular investigations, Mesoscape provides an excellent basis to evaluate the influence of molecular parameters on the disease outcome, besides providing an overview of the molecular landscape.

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    SH02 - Highlight of the Previous Day (ID 99)

    • Event: WCLC 2019
    • Type: Highlight of the Previous Day Session
    • Track:
    • Presentations: 1
    • Now Available
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      SH02.01 - Locally Advanced (Now Available) (ID 3667)

      11:30 - 13:00  |  Presenting Author(s): Rolf Stahel

      • Abstract
      • Presentation
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      Abstract not provided

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    YI04 - Basics of Immunology (ID 110)

    • Event: WCLC 2019
    • Type: Young Investigator Session
    • Track: Young Investigators
    • Presentations: 1
    • Now Available
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      YI04.03 - The Place of Immunotherapy in NSCLC Therapeutic Algorythm (Now Available) (ID 3710)

      13:30 - 15:00  |  Presenting Author(s): Rolf Stahel

      • Abstract
      • Presentation
      • Slides

      Abstract

      Place of immunotherapy in the NSCLC treatment algorithm

      Therapy with immune checkpoint inhibitors has entered standard of care for patients with metastatic NSCLC. Data from extended phase I studies are available on the long-term effect of single agent immune checkpoint inhibition in later line. These studies demonstrate a 16% 5-year survival for nivolumab and pembrolizumab in pretreated patients (1), the impact of PD-L1 expression on long term outcome (2) and the importance of obtaining an objective response (3). Nivolumab and pembrolizumab, both PD-1 directed antibodies and atezolizumab, a PD-L1 directed antibody all have been approved for second or later line therapy based on comparative studies with docetaxel monotherapy demonstrating superior survival and an improved toxicity profile. However, results of recent studies in first line treatment have led to a rapid adoption of immune checkpoint inhibition upfront. This started with the results of the KEYNOTE-024 study demonstrating survival benefit of single agent pembrolizumab over platin-based combination therapy for patients with advanced NSCLC with a tumor proportion score of 50% or higher (4). With these results, PD-L1 testing has entered clinical routine. A series of clinical trials examined the survival impact of adding immune checkpoint inhibition to standard platin-based chemotherapy. Based on these results pembrolizumab added to platin-based chemotherapy, carboplatin and pemetrexed in non-squamous NSCLC (KEYNOTE,-189), carboplatin-paclitaxel or nab-paclitaxel in squamous NSCLC (KEYNOTE-407) (5,6), or alternatively atezolizumab combined with bevacizumab, carboplatin and paclitaxel (IMpower150) or with carboplatin and nab-paclitaxel (Impower130) for non-squamous NSCLC (7,8) have become standard of care, independent of the expression of PD-L1 in tumor tissues. The results of these t and additional trials in first line metastatic NSCLC have been summarized recently (9). Obviously, important questions remain to be answered. One open question regards the upfront treatment of patients with tumors having a strong PD-L1 expression. Lacking randomized data the debate remains open whether pembrolizumab alone or its combination with platin-based chemotherapy would ultimately be the best option. The KEYNOTE-042 trial compared pembrolizumab with platin-based chemotherapy in patients with tumors with at least 1% PD-L1 expression. The trial was positive for pembrolizumab, however the analysis of patient subgroups according to PD-L1 expression suggests the benefit to be mostly derived from patients with strongly expressing tumors and thus these results might only marginally impact clinical practice. A second open question regards the optimal selection of patients which could be spared from upfront treatment with chemotherapy and could benefit from single agent immune checkpoint or combined PD-+/PD-L1 and CTLA4 inhibition. Two trials examining the role of nivolumab in first line treatment (CHECKMATE-026 and CHECKMATE-227) demonstrated that a high tumor mutation burden is predictive for a better response to immune checkpoint inhibition. The later trial (10) and the analysis subgroups of the MYSTIC trial are in support of the hypothesis of potential superior effects of combining PD-1/PD-L1 inhibition with CTLA4 inhibition for patients with a high tumor mutation burden, measured directly in tumor tissue or indirectly on circulating tumor DNA, however, formal prove from prospective trials is pending. It is important to note that with the exception of IMpower150 and Impower130, all other trials excluded patients with known EGFR and ALK mutations, the main reason being the relative lack of efficacy of second line immune checkpoint inhibition in these patients. The benefit in progression-free survival and overall survival seen in patients with EGFR mutated tumors when treated with the atezolizumab bevacizumab quadruplicate, but not with the atezolizumab triplicate lends support for the use of the quadruplicate regimen for patients with EGFR mutated tumors failing tyrosine kinases.

      Gettinger, et al. Five-Year Follow-Up of Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer: Results From the CA209-003 Study. J Clin Oncol 2018 Jun 10;36(17):1675-1684

      Garon E, et al. Five-Year Overall Survival for Patients With Advanced Non‒Small-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study. J Clin Oncol 2019 Jun 2:JCO1900934

      Horn, L, et al. Safety and clinical activity of atezolizumab monotherapy in metastatic non-small-cell lung cancer: final results from a phase I study. Eur J Cancer 2018 Sep;101:201-209.

      Reck M, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. NEJM 2016 Nov 10;375(19):1823-1833

      Ghandi L, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. NEJM 2018 May 31;378(22):2078-2092.

      Pas-Arez L, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. 2018 Nov 22;379(21):2040-2051.

      Sozinski MA, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. NEJM 2018 Jun 14;378(24):2288-2301.

      West H, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2019 May 20. pii: S1470-2045(19)30167-6.

      Peters S, et al. How to Make the Best Use of Immunotherapy as First-Line Treatment for Advanced/Metastatic Non-Small-Cell Lung Cancer. Ann Oncol 2019 Mar 26. pii: mdz109. doi: 10.1093/annonc/mdz109

      Hellman MD, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. NEJM 2018 May 31;378(22):2093-2104.

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