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Joachim Aerts



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    FP12 - Tumor Biology and Systems Biology - Basic and Translational Science (ID 188)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP12.06 - GRIm-Score Variations Predict Outcome in Metastatic NSCLC Patients Treated with First-Line Pembrolizumab (ID 3363)

      00:00 - 00:00  |  Author(s): Joachim Aerts

      • Abstract
      • Slides

      Introduction

      Prompt identification of metastatic non-small cell lung cancer patients (NSCLC) who benefit from first-line pembrolizumab is crucial in clinical practice. The Gustave Roussy Immune Score (GRIm-score) takes into account neutrophil-to-lymphocyte ratio (NLR), serum albumin concentration and lactate dehydrogenase (LDH) and its prognostic score has been investigated in patients treated with immune check-point inhibitors (ICIs). To further assess the predictive value of baseline GRIm-score (GRImT0), we separately investigated two cohorts of metastatic NSCLC patients treated with first-line pembrolizumab immunotherapy or chemotherapy (CHT). We also investigated whether GRIm-score at 45 days since treatment initiation (GRImT1) and GRIm-score deterioration between the two time points may better predict clinical outcomes.

      Methods

      We retrospectively evaluated 222 metastatic NSCLC patients: 135 treated with pembrolizumab and 87 treated with chemotherapy. NLR, serum albumin and LDH concentrations were assessed at T0 and at T1. According to the GRIm-score, patients were assigned 1 point if they had NLR > 6, LDH > upper limit normal or albumin < 3.5 g/dl, for a total of 3 points. Patients with a GRIm-score <2 were considered as having a low Score. Chi-squared test was used to evaluate the association between variables. Median overall survival (OS) and progression free survival (PFS) were estimated by Kaplan-Meier method and log-rank test was used to assess differences by subgroups. The independent prognostic and predictive role of the scores was further analysed by multivariate logistic regression and Cox proportional hazard analyses.

      Results

      Median follow up of the whole population was 24.0 months, median OS and PFS were 12.0 months and 6.5 months, respectively. In both cohorts, no difference in terms of OS between patients with low and high GRImT0 was found. Otherwise, median OS and PFS of the low GRImT1 group were significantly longer than those of the high GRImT1 group in pembrolizumab-treated patients, but not in the CHT cohort (pembrolizumab cohort: low vs. high; median OS not reached vs. 9.2 months, p = 0.004 and median PFS 10.8 vs. 2.3 months, p = 0.002). The outcome of patients receiving pembrolizumab with no GRIm deterioration was better compared to patients with GRIm deterioration in terms of OS (median OS not reached vs. 12.0 months, p < 0.001), PFS (median PFS 20.6 vs. 2.6 months, p < 0.001) and objective response rate (58.2% vs 7.6%, p = 0.003). The prognostic and predictive role of GRImT1 and of GRIm deterioration in the pembrolizumab-cohort was also confirmed at multivariate analyses, after adjusting for performance status (PS), smoking and disease burden (high GRImT1 HR for death: 2.63, 95% CI 1.18-5.86, p = 0.01, GRIm deterioration HR for death: 3.28, 95% CI 1.39-7.74, p = 0.006).

      Conclusion

      Our data shown that GRImT1 and GRIm deterioration are more reliable predictors of outcome compared to GRImT0 in NSCLC patients treated with pembrolizumab. Their prognostic and predictive value was independent of PS, smoking and disease burden. Both GRImT1 and GRIm deterioration represent useful and easy-to-access early indicators of treatment response in metastatic NSCLC patients treated with first-line pembrolizumab and might help guiding clinicians’ choices in this setting.

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    MA06 - Molecular Developments and Novel Treatments in Mesothelioma and Thymoma (ID 134)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
    • Presentations: 2
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      MA06.02 - Chair (ID 4235)

      14:15 - 15:15  |  Presenting Author(s): Joachim Aerts

      • Abstract

      Abstract not provided

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      MA06.03 - Phosphorylated Ribosomal Protein S6, Correlation With Characteristics and Clinical Outcome in Patients With MPM: Results from ETOP Mesoscape (ID 2260)

      14:15 - 15:15  |  Author(s): Joachim Aerts

      • Abstract
      • Presentation
      • Slides

      Introduction

      Malignant pleural mesothelioma (MPM) is an aggressive malignancy with increasing prevalence and poor prognosis. The European Thoracic Oncology Platform (ETOP) Mesoscape project was designed to address clinical, pathological, and molecular characteristics of MPM patients and their impact on outcome, along with having formalin-fixed paraffin embedded tumour tissue available for central analysis. In previous studies the phosphorylated ribosomal protein S6 (pS6), which is a downstream target of PI3K /mTORC1 signaling, was associated with clinical outcome, and low pS6 immunoreactivity was significantly correlated with longer progression free survival in other MPM patients. Correlating pS6 with the clinical as well as pathological information in Mesoscape allows researchers to improve the knowledge and facilitate decision-making in patients with MPM.

      Methods

      A biobank with fully annotated tissue samples was established for ETOP Mesoscape, and Tissue Micro Arrays (TMAs) were constructed. Expression of phospho-S6 (p-S6, Ser240/244, Cell Signaling Technology, 1:50 dilution) was explored in the ETOP Mesoscape cohort. Immunohistochemical evaluation of the TMAs was conducted by two independent observers in a blinded manner. The staining intensity was semi-quantitatively scored 0 (negative), 1 (weak), 2 (moderate), or 3 (strong). Furthermore, the percentage of cells with any positivity was proportionally scored 0 (0%), 0.1 (1%–9%), 0.5 (10%–49%), or 1.0 (50% and more). An aggregate H-score was obtained by multiplication of intensity with percentage staining (final range: 0-3 per core). The final H-score was determined by averaging the H-scores of all the cores from the same patient. Patients’ classification as pS6-high/low, was based on median H-score.

      Results

      Up to 14 July 2020, the ETOP Mesoscape included pS6 IHC results on 269 of the 499 patients from 10 centers, diagnosed between 1999-2018. The remaining cases are currently undergoing pS6 scoring.

      Overall, patients in the Mesoscape database are primarily men (84%), of 0/1 ECOG Performance status (46/46%), with known previous exposure to asbestos (75%) and a median age of 64 years. The primary histology of included tumours is epithelioid (72%), followed by biphasic (22%) and sarcomatoid (6%). Clinical staging is available for 77%. The stage distribution (I/II/III/IV) is 14/29/42/15%.

      Calretinin and WT1 are detected in the vast majority of patients tested (Calretinin: 97%; WT1: 89%). Also, 90% (of those tested) are CK5/6 positive, 91% D2-40 positive and 97% Pan-CK positive. Palliative treatment has been administered in 41%.

      PS6-high patients (128 patients with H-score>1.375) are significantly associated with higher age, more T-stage of 3/4, and higher percentage of right localization compared to pS6-low patients (141 patients with H-score≤1.375). Overall survival (OS) is non-significantly different between pS6-low and pS6-high patients (medians: 21.4 months; 95%CI:[15.3-23.4] and 17.8 months; 95%CI:[15.1-20.7], respectively; log-rank p=0.61]. In the multivariate Cox model, pS6 is also non-significant (p=0.31), while gender, histology, and treatment strategy are the only significant survival predictors.

      Conclusion

      Based on preliminary data, high pS6 expression is associated with higher age and T-stage; effect in survival is non-significant. Updated and additional results on the expression and clinical significance of pS6 from the full ETOP Mesoscape cohort will be presented at the conference.

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    OA09 - Mesothelioma from Pathogenesis to Therapy (ID 132)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
    • Presentations: 1
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      OA09.06 - Nivolumab in Recurrent Malignant Pleural Mesothelioma: Real-World Data From Expanded Access Program In The Netherlands (ID 1757)

      15:30 - 16:30  |  Author(s): Joachim Aerts

      • Abstract
      • Presentation
      • Slides

      Introduction

      Second-line treatment options for patients with recurrent malignant pleural mesothelioma (MPM) after first line chemotherapy are lacking. Nivolumab, an anti-PD-1 monoclonal antibody, showed promising results in phase II trials in pre-treated MPM patients. Data from the PROMISE-meso randomized phase III trial (NCT02991482), however, failed to show superiority of pembrolizumab (anti-PD-1) over chemotherapy in second line treatment. The aim of our study was to describe the clinical outcome of pre-treated MPM patients receiving nivolumab in a real-world setting and potentially identify a subgroup of patients that do benefit from anti-PD-1 treatment through extensive analysis of clinical and peripheral blood parameters.

      Methods

      Since October 2017, patients with MPM received nivolumab in the BMS-sponsored Expanded Access Program (EAP). Patients were eligible if they had progressive disease after at least one line of chemotherapy; a good clinical performance score at time of screening (ECOG 0-1); adequate lab values; no autoimmune disease and no treatment with systemic steroids (>10 mg/day prednisone equivalents). In the Erasmus Medical Center and The Netherlands Cancer Institute, patients were treated biweekly with nivolumab 3mg/kg independent of PD-L1 expression. CT scan evaluation was performed every 6-12 weeks, using modified RECIST for malignant mesothelioma supplemented with the immune RECIST criteria regarding pseudoprogression and confirmation of response.

      Results

      At the WCLC 2020, data of the Erasmus cohort with addition of the NCI cohort, accounting for 107 patients will be presented. This will include the results of 59 patients treated with nivolumab at the Erasmus MC that were presented at the WCLC 2019 (MA05.09). In the full cohort, the median progression-free survival (mPFS) was 2.3 months (95% CI: 1.6-2.9) and the median overall survival (mOS) was 6.7 (95% CI: 6.2-10.0) months. After 12 weeks, the disease control rate (DCR) was 37% and the objective response rate (ORR) was 10%. PD-L1 status was determined in 33 patients (30%) and PD-L1 positivity (≥1%) was associated with an improved ORR (36% vs 9%, p-value 0.05), but not with PFS or OS. Low albumin was associated with worse OS (p-value 0.002). Median OS was significantly longer for patients who had partial response to treatment (p-value 0.0002). Remarkably, with a median follow up of 14.1 months in the group of patients with PR (n=10), no deaths were reported and only 2 patients progressed.

      Conclusion

      In this real-world analysis, ORR and mOS were lower compared to those obtained in phase II and III trials with checkpoint inhibitors. However, exceptional survival rates were observed in patients who had a radiological response. PD-L1 expression and albumin were associated with greater response rate and may represent useful biomarkers for nivolumab treatment in MPM.

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    P24 - Mesothelioma, Thymoma and Other Thoracic Malignancies - Mesothelioma Clinical and Trials in Progress (ID 138)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 01:00, ePoster Hall
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      P24.03 - A Multicenter Randomized Phase III Trial of Dendritic Cell Maintenance Therapy After Chemotherapy in Mesothelioma; Denim Trial (ID 1784)

      00:00 - 01:00  |  Author(s): Joachim Aerts

      • Abstract
      • Slides

      Introduction

      Malignant Pleural Mesothelioma (MPM) is an aggressive, and lethal cancer. Current treatment first line treatment, consisting of a combination of antifolate and platinum-based chemotherapy, results in an overall survival of 9-15 months. There are no approved maintenance therapies and no treatment has yet shown improved survival in the relapsed setting. Immune checkpoint inhibition exhibits some clinical activity suggesting that adaptive immunity may be harnessed for effective therapy. However mesotheliomas exhibit low numbers of tumor-infiltrating CD8+ T-cells. Dendritic cell (DC) therapy can be therapeutically harnessed to instigate an immune response and activate tumor-specific CD8+ T-cells. Allogenic tumor-lysate loaded DC therapy has proven to be effective in mice and is both safe and feasible in patients. We have therefore initiated a European multicenter, open label randomized, phase 2/3 trial to examine the efficacy of DC therapy in patients with histologically proven MPM.

      Methods

      In this open-label, multicenter phase III trial patients are randomized after first line chemotherapy treatment to receive either DC therapy plus Best Supportive Care (BSC) or BSC only according to the discretion of the local investigator after first line chemotherapy treatment. The primary end point is overall survival. The secondary endpoints will be safety and tolerability, progression-free survival , overall response rate and quality of life. Immunomonitoring will be done as part of the exploratory analysis. 230 patients are planned to be enrolled in the trial. Study enrollment started in May 2018 and inclusion is expected to be completed in the last quartile of 2020. The independent data safety monitoring board last reviewed the trial in September 2019 and suggested that the trial continues as planned. A new futility analysis is planned in the spring of 2020.

      Conclusion

      This Phase III trial will determine whether DC therapy in patients with MPM can improve clinical outcomes as a maintenance treatment after chemotherapy to provide a new treatment option for MPM.

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