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Anna K. Nowak



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    MS25 - Genetic and Prognostic Markers in Mesothelioma; Going Beyond the Histology Subtypes (ID 803)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 206 AC
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      MS25.01 - Impact of Tumor Volume on Outcome: What Are the Limitations? (ID 11506)

      10:30 - 10:45  |  Presenting Author(s): Anna K. Nowak

      • Abstract
      • Presentation
      • Slides

      Abstract

      A key goal of cancer staging is to stratify patient survival using anatomical tumour characteristics identified on imaging at presentation. The relationship between burden of cancer and patient outcomes is an established tenet of oncology, and most staging and prognostic systems incorporate surrogates or estimates of total tumour burden. Nevertheless, malignant pleural mesothelioma has long posed challenges in quantifying tumour burden for staging and prognostication. Many cancers grow outward from a nidus to form a mass of tumour cells which can be measured in three dimensions and volume of tumour quantified. However, the unique morphology of mesothelioma, growing as a sheet of tumour around the pleural cavity, adds complexity to the routine quantification of tumour burden. Furthermore, CT imaging, at least using human interpretation, may have difficulty distinguishing between pleural tumour and atelectasis, pleural fluid, and pleural scarring or plaques, confounding the accurate measurement of tumour volume.

      The relationship between tumour burden and outcomes in mesothelioma was first reported in 1997, noting that tumour size as measured using 3-D reconstructions of chest CT was prognostic in patients undergoing surgical resection, with a tumour volume <100cc predicting better survival1. These findings have been reproduced in a number of studies, both using CT imaging in the context of extrapleural pneumonectomy2 and using FDG-PET to estimate pleural tumour volume in non-surgically treated patients3. However, the technical challenges of accurately and reproducibly measuring tumour volume have remained barriers to routinely incorporating this metric into clinical practice prognostication, staging systems, and clinical trial stratification.

      In practical terms, what do we need to be able to apply an estimate of tumour volume in everyday clinical practice? Centres of excellence and radiology research laboratories may be able to use computerised estimates of volume as measured by CT scan or FDG-PET scan, however a sound prognostic indicator which can be applied to the population as a whole must also be applicable in a less resource-rich environment. Currently, there are numerous commercial and research tools for measuring tumour volume, however each requires a different level of clinician or radiographer input, and those which require manual oversight or contouring are also prone to inter-observer variability. Furthermore, it is not clear whether there is consistency between platforms.

      The most recent iteration of the IASLC staging database collected information on unidimensional measurements of pleural tumour thickness from 472 patients as a surrogate measure of tumour bulk, attempting to approach the semi-quantification of tumour bulk using a technique which could be rapidly applied in any setting, including community practice or low resource settings. In brief, measurements of pleural tumour were taken perpendicular to the chest wall or mediastinum at the point of maximum tumour thickness, one each in the upper, middle and lower thirds of the thorax4 (Figure 1a and b). As published in the recent update of the AJCC/IUCC staging system for mesothelioma, these measurements could be analysed in a number of ways, but were consistently identified as prognostic indicators and may even provide better discrimination between patient outcomes than existing T stages, which classify by the extent of anatomical organ involvement or invasion, rather than tumour bulk. Whether these measurements were summated, or dichotomised by maximal thickness, or ranked by quartile, these findings were consistent and predicted for overall survival.

      Another recent publication supports the relationship between unidimensional tumour measurements of thickness, and both tumour volume and survival5. Taking three structured measurements from the mediastinum, chest wall, and diaphragm, nine measurements were determined, which correlated significantly (p<0.0001) with total tumour volume as estimated by gross tumour volume from a radiation boost volume calculation. Diaphragmatic tumour thickness was more strongly associated with time to recurrence (p<0.0001) and survival (p=0.001) than mediastinal or chest wall tumour thickness.

      In conclusion, whilst tumour volume is clearly a prognostic indicator in mesothelioma, the question of how to best incorporate this metric into routine staging and clinical practice remains open. The IASLC Mesothelioma Staging Database will shortly open to further data collection, and will again incorporate unidimensional measurements of tumour thickness, in an effort to further define a simple and readily applied surrogate of volume. Automated measurement of volume continues to be refined by multiple investigators, and concordance between platforms will be needed to move the field forward.

      1. Pass HI, Temeck BK, Kranda K, Steinberg SM, Feuerstein IR. Preoperative tumor volume is associated with outcome in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1998;115:310-7; discussion 7-8.

      2. Gill RR, Richards WG, Yeap BY, et al. Epithelial malignant pleural mesothelioma after extrapleural pneumonectomy: stratification of survival with CT-derived tumor volume. AJR Am J Roentgenol 2012;198:359-63.

      3. Nowak AK, Francis RJ, Phillips MJ, et al. A Novel Prognostic Model for Malignant Mesothelioma Incorporating Quantitative FDG-PET Imaging with Clinical Parameters. Clin Cancer Res 2010;16:2409-17.

      4. Nowak AK, Chansky K, Rice DC, et al. The IASLC Mesothelioma Staging Project: Proposals for Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Pleural Mesothelioma. J Thorac Oncol 2016;11:2089-99.

      5. de Perrot M, Dong Z, Bradbury P, et al. Impact of tumour thickness on survival after radical radiation and surgery in malignant pleural mesothelioma. The European respiratory journal 2017;49.

      Figure 1: In the IASLC T staging database, tumour bulk was estimated by measuring the thickest tumour at the upper, middle and lower hemithorax bounded by structures shown above and below lines in (a), (b). Tumour is measured perpendicular to the chest wall or mediastinum (c).


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    OA08 - Mesothelioma: Immunotherapy and microRNA for Diagnosis and Treatment (ID 907)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 201 BD
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      OA08.02 - DREAM - A Phase 2 Trial of Durvalumab with First Line Chemotherapy in Mesothelioma: Final Result (ID 12022)

      15:25 - 15:35  |  Presenting Author(s): Anna K. Nowak

      • Abstract
      • Presentation
      • Slides

      Background

      We report here the final results of a single-arm, phase 2 trial designed to determine the activity, safety and tolerability of durvalumab, cisplatin and pemetrexed as first line therapy in MPM. ANZ Clinical trial registry number: ACTRN12616001170415

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Participants were considering first line chemotherapy for MPM, were unsuitable for radical surgery, had an un-irradiated target lesion, and had good performance status (ECOG PS 0-1). Objective tumour response (OTR) and progression free survival (PFS) were assessed primarily according to the modified Response Evaluation Criteria in Solid Tumors for MPM (mRECIST) and as secondary endpoints according to RECIST modified for immunotherapy (iRECIST). Study treatment was durvalumab 1125mg, cisplatin 75mg/m2, and pemetrexed 500mg/m2 all given intravenously on day 1, and repeated every 3 weeks for a maximum of 6 cycles, followed by durvalumab 1125 mg every 3 weeks until progression, unacceptable toxicity, or a maximum total of 12 months. The primary endpoint was PFS at 6 months (PFS6). The sample size of 54 provided 90% power to distinguish the observed proportion PFS6 from a null hypothesis of 45% versus an alternative of 65% with a 1-sided alpha of 5%. Tissue and blood samples were required and collected for translational correlative studies.

      4c3880bb027f159e801041b1021e88e8 Result

      We recruited 54 participants from Dec 2016 to Sep 2017. Median age was 68 (range 42-82), 82% were male, 60 had ECOG PS 0, and 82% had epithelioid histology. Dose intensities were 97% for cisplatin and 94% for durvalumab. The proportion PFS6 was 57% (31/54, 90% CI 45-68%); median PFS was 6.9 months (95% CI 5.5-9.0). The OTR rate was 48% (95% CI 35-61%) according to mRECIST and 50% (95% CI 37-63) according to iRECIST. The median duration of response was 6.5 months. Grade 3-5 adverse events occurred in 36 participants, including neutropenia in 13%, nausea in 11%, anaemia in 7%, fatigue in 6% and any grade peripheral neuropathy in 35%. There were 4 deaths on study, none attributed to durvalumab. Immune-related adverse events occurred in 17 participants, and were of grade 3 or worse in 8, including increased lipase (1), pancreatitis (1), and renal impairment (1).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The combination of durvalumab, cisplatin, and pemetrexed has demonstrated sufficient activity, safety, and tolerability as first line therapy in MPM to warrant further evaluation in a large-scale, randomised phase 3 trial.

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    PL02 - Presidential Symposium - Top 5 Abstracts (ID 850)

    • Event: WCLC 2018
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 08:15 - 09:45, Plenary Hall
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      PL02.09 - Nintedanib + Pemetrexed/Cisplatin in Patients with Unresectable MPM: Phase III Results from the LUME-Meso Trial (ID 11192)

      09:15 - 09:25  |  Author(s): Anna K. Nowak

      • Abstract
      • Presentation
      • Slides

      Background

      Nintedanib targets VEGFR 1–3, PDGFR α/β, FGFR 1–3, Src and Abl kinases, all implicated in malignant pleural mesothelioma (MPM) pathophysiology. This global Phase II/III, randomised, double-blind study investigated pemetrexed/cisplatin in combination with nintedanib or pemetrexed/cisplatin in combination with placebo, followed by nintedanib or placebo maintenance, in patients with unresectable MPM. In the double-blind, randomised Phase II part, nintedanib plus pemetrexed/cisplatin improved PFS vs placebo (HR=0.56; 95% CI: 0.34–0.91; p=0.017; median 9.4 vs 5.7 months).

      In Phase III, chemotherapy-naïve patients with epithelioid MPM (ECOG PS 0–1) were randomised 1:1 to receive up to six cycles of pemetrexed (500 mg/m2)/cisplatin (75 mg/m2) on Day 1, plus nintedanib (200 mg bid) or matched placebo on Days 2–21. After combination treatment, patients without disease progression received nintedanib or placebo maintenance. The primary endpoint (PFS by investigator assessment) and key secondary endpoint (OS) were planned to be analysed by hierarchical testing, with an interim OS analysis at the time of the primary PFS analysis. PFS was also assessed by independent central review. Based on the assumed treatment effect (HR=0.63), the study had 90% power to detect a statistically significant and clinically meaningful improvement in PFS.

      In total, 458 patients were randomised. Baseline patient characteristics and oncological history were similar between treatment arms. Median duration of nintedanib or placebo administration was 5.3 and 5.1 months, respectively. After 250 events, there was no difference in PFS between nintedanib and placebo arms (HR=1.01; 95% CI: 0.79–1.30; p=0.91; median 6.8 vs 7.0 months, respectively). PFS by central independent review was similar (242 events; HR=0.99; 95% CI: 0.77–1.28; p=0.96; median 6.8 months in each arm). In the interim OS analysis (127 deaths [28% of events]), median OS was 14.4 vs 16.1 months (nintedanib vs placebo; HR=1.12; 95% CI: 0.79–1.58; p=0.54). There were no unexpected safety findings. The proportion of patients with Grade ≥3 AEs was higher with nintedanib than with placebo (72% vs 62%). The most frequently reported Grade ≥3 AE by medical concept in both treatment arms was neutropenia (nintedanib: 32%; placebo: 24%). The proportion of deaths due to serious AEs was 4.0% (nintedanib) and 7.5% (placebo).

      The primary endpoint of the Phase III part of LUME-Meso was not met ‒ Phase II findings were not confirmed. The reported safety profile was consistent with the known safety profiles of nintedanib and pemetrexed/cisplatin.

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