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S. Burgers



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    OA 02 - Mesothelioma: Challenges For New Treatment (ID 653)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Mesothelioma
    • Presentations: 2
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      OA 02.01 - Randomized Phase II Study of Anetumab Ravtansine or Vinorelbine in Patients with Malignant Pleural Mesothelioma (ID 9377)

      11:00 - 11:10  |  Author(s): S. Burgers

      • Abstract
      • Presentation
      • Slides

      Background:
      Anetumab ravtansine (BAY 94-9343) is a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DM4. We report the results of a randomized phase II trial of anetumab ravtansine compared to vinorelbine in patients with advanced malignant pleural mesothelioma (MPM) who have high mesothelin expression and have progressed on platinum/pemetrexed-based first-line chemotherapy (NCT02610140).

      Method:
      Patients (≥18 years) with locally advanced or metastatic MPM with progressive disease following first-line treatment with pemetrexed-based chemotherapy, with or without bevacizumab, were eligible. Patients were pre-screened based on obligatory tumor staining for mesothelin as determined by the Ventana MSLN (SP74) immunohistochemistry assay. The primary efficacy endpoint was progression-free survival (PFS) per central radiologic review using modified RECIST criteria for MPM. Secondary objectives included overall survival, tumor response, and safety. Patients were randomized in a 2:1 ratio to anetumab ravtansine 6.5 mg/kg Q3W IV or vinorelbine 30 mg/m[2] QW IV.

      Result:
      A total of 166 patients were randomized to anetumab ravtansine and 82 to vinorelbine; 3 and 10 patients, respectively, not receiving treatment were included for efficacy but not safety assessments. The treatment arms were evenly balanced, with 73% male, 64% ECOG performance status 1, 96% epithelioid histology, and a mean 2.5 (±2.4) months since last progression. The median duration of treatment (anetumab vs vinorelbine) was 12.6 weeks (range 3-61) vs 13.0 weeks (range 1-43). Treatment-emergent grade (G) ≥3 adverse events (AEs) were seen in 85 (52.1%) and 53 (73.6%) of patients, respectively. G3/G4 neutropenia (22.2%/16.7%) occurred in the vinorelbine arm whereas corneal epitheliopathy (39.3% all grade, 1.8% G3) was distinct for the anetumab ravtansine arm. Serious AEs (any grade) were similar; 52 (31.9%) vs 25 (34.7%). Treatment-emergent AEs leading to dose modification were 42.9% in the anetumab ravtansine arm and 80.6% in the vinorelbine arm. There was one treatment-related G5 event in each arm. Median PFS was 4.3 months (95% CI:4.1, 5.2) for anetumab ravtansine vs 4.5 months (4.1, 5.8) for vinorelbine; hazard ratio 1.22 (0.85, 1.74), p=0.859. Fourteen (8.4%) patients in the anetumab ravtansine arm had an objective response vs 5 (6.1%) in the vinorelbine arm, with no complete responses. Interim median overall survival was 10.1 mo (7.6, -) vs 11.6 mo (7.7, 12.5), respectively, p-value 0.721.

      Conclusion:
      In relapsed MPM, anetumab ravtansine was not superior to vinorelbine with respect to PFS.

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      OA 02.02 - Ipilimumab and Nivolumab in the Treatment of Recurrent Malignant Pleural Mesothelioma: A Phase II Study (ID 9389)

      11:10 - 11:20  |  Author(s): S. Burgers

      • Abstract
      • Presentation
      • Slides

      Background:
      There is an increasing interest in the use of IO therapy in Mesothelioma (MPM). We previously reported on the effect of nivolumab (s.a) in patients with recurrent MPM with a disease control rate of 50% at 12 weeks. We therefore decided to test the effect of the combination of nivolumab and ipilimumab in recurrent MPM.

      Method:
      Patients with previously treated MPM and a PS of 0-1 are consented in this single arm prospective study. Pleural lesions must be available for biopsy before and after 6 weeks of treatment.Nivolumab is administered at a fixed dose of 240 mg (q2w) until progression and combined with ipilimumab (1mg/kg) on week 1, 7, 13 and 19. CT scans are performed every 6 weeks for analysis and duration of response. The primary endpoint is disease controle rate at 12 weeks. Translational research is performed on paired biopsies. A Simon’s minimax two-stage design is used to identify a DCR of >50%. Therefore 33 patients will be included.

      Result:
      From October 2016 until August 2017 38 patients gave informed consent. Three patients did not start due to progression or impossibility to biopsy. Two stopped after 1 cycle (due to progression or withdrawn consent). At time of analysis (August 29) 25 patients could be evaluated for response. At 12 weeks a DCR of 72% (18/25) and ORR of 28% (7/25) is observed. Two patients continued treatment after progression at 6 weeks; 1 achieved a PR after 4 months , and the other one is stable. Of the first 11 patients that have been in study for 6 months, 5 have PR, 1 SD and 4 PD. Toxicity is mild. SAE’s reported in the 38 patients occurred in 11 patients with grade 3 or 4 toxicity. No grade 5 toxicity was observed.

      Conclusion:
      In this interim analysis nivolumab plus ipilimumab meets the primary endpoint for patients with recurrent malignant mesothelioma. Toxicity is mild. The full data set will be presented at the WCLC.

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    P1.09 - Mesothelioma (ID 695)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Mesothelioma
    • Presentations: 1
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      P1.09-008 - A 4-microRNA Signature in Serum Can Discriminate Between Non-Small-Cell Lung Cancer and Malignant Pleural Mesothelioma (ID 9956)

      09:30 - 09:30  |  Author(s): S. Burgers

      • Abstract
      • Slides

      Background:
      Differential diagnosis of malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC) can be difficult. For both malignancies various studies have in recent years investigated circulating cell-free microRNAs (miRs) as potential diagnostic markers, with most of these focusing on NSCLC. One of the most recent studies has suggested a 4-miR signature consisting of miR-141, miR-200b, miR-193b and miR-301 in serum to be specific for NSCLC patients. Here, we investigated the value of this 4-miR signature in discriminating serum samples from NSCLC and MPM patients.

      Method:
      RNA was extracted from a series of serum samples from 98 NSCLC, 98 MPM and 96 healthy controls collected at the Netherlands Cancer Institute between 1995 and 2011. MicroRNA-specific TaqMan assays were used to quantify serum microRNA levels in the t groups which after initial quality control consisted of 65, 68 and 58 samples in the NSCLC, MPM and control groups, respectively. Expression levels of individual microRNAs between the different groups were analysed using one-way ANOVA with Tukey-Kramer Posthoc Test. Binary logistic regression modelling was used to generate the 4-miR-signature, for which accuracy in discriminating NSCLC from MPM or healthy was analysed by ROC curve analysis.

      Result:
      Analysis of the signature microRNAs showed for all 4 miRs trends towards higher abundance in serum from NSCLC patients. Statistical significance was however only reached for miR-141, which was found to be increased by 4.4-fold in NSCLC compared to healthy controls (p=0.014) and by 5.6-fold in NSCLC vs MPM (p=0.004). Although we did not observe significant differences in abundance for all microRNAs, ROC curve analysis of the 4-miR signature confirmed the discriminatory potential with an AUC 0.73 (95% CI: 0.62-0.85) for NSCLC vs healthy controls. When applying the best achievable Youden Index as cut-off point, the signature showed a sensitivity of 91.4% and a specificity of 44.4%. In addition to being able to discriminate NSCLC from healthy controls, the 4-miR-signature also proved to be valuable for discriminating NSCLC from MPM, where an AUC of 0.77 (95% CI: 0.66-0.89), a sensitivity of 74.3% and a specificity of 80.4% could be observed.

      Conclusion:
      Initial analyses have confirmed the diagnostic potential of the previously described NSCLC-specific serum-based microRNA signature for distinguishing NSCLC from healthy controls. In addition, we have shown that the same signature can also discriminate between NSCLC and MPM.

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    P3.14 - Radiotherapy (ID 730)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Radiotherapy
    • Presentations: 1
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      P3.14-005 - Treatment Response Measured on Conebeam-CT During Concurrent Chemoradiation for NSCLC Patients (ID 9814)

      09:30 - 09:30  |  Author(s): S. Burgers

      • Abstract
      • Slides

      Background:
      The management of NSCLC-patients has evolved towards a more personalized care approach. Currently, the outcomes of concurrent chemoradiation (CCRT) in NSCLC patients are evaluated after the end of treatment, while individual treatment response during treatment is not taken into account. To pursue adaptive radiotherapy, it is important to distinguish responses during treatment and correlate this with outcome. Therefore, the aim was to identify subgroups that show a distinct treatment response during CCRT and correlate this with treatment outcome.

      Method:
      NSCLC-patients treated with CCRT between 2007-2013 were included. Treatment consisted of 66Gy/24 fractions with concurrent daily Cisplatin. Deformable image registration of the planning-CT to all Conebeam-CTs acquired during treatment was performed, and the gross tumor volumes on the ConeBeam-CTs were measured. Latent Class Growth Modeling was used to identify subgroups showing a distinct treatment response of the primary tumor during CCRT. Cox survival analysis was performed to assess the association of subgroup ‘membership’ with overall survival (OS) and progression free survival (PFS).

      Result:
      402 patients were included. Median follow-up was 63 months and median OS was 23 months (95%CI 20-26 months) and median PFS was 18 months (95%CI 15–21 month). Six different patterns of treatment response were identified (Figure1). Group 1&2 showed a relatively stable pattern during treatment. Group 5 showed tumor progression in the first week followed by sharp decrease in tumor volume. All other groups showed a decrease in tumor volume from start of treatment. Remarkably, the groups 1&5, that didn’t show a decrease in tumor volume from the beginning of treatment, had a significantly improved OS and PFS. Figure 1



      Conclusion:
      Six groups showing a distinct treatment response during CCRT were identified. This is an important finding to be able to pursue adaptive radiotherapy. First analyses revealed an association between tumor response during treatment and OS and PFS. In-depth analyses are warranted.

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