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T. John



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    OA22 - Novel Trials and Biomarkers in Malignant Pleural Mesothelioma (ID 403)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      OA22.02 - Nintedanib plus Pemetrexed/Cisplatin in Patients with MPM: Phase II Findings from the Placebo-Controlled LUME-Meso Trial (ID 4191)

      14:20 - 15:50  |  Author(s): T. John

      • Abstract
      • Presentation
      • Slides

      Background:
      Standard first-line treatment for patients with unresectable malignant pleural mesothelioma (MPM) is pemetrexed/cisplatin, yielding a median overall survival (OS) of only ~1 year, thus new approaches are required. As demonstrated by the bevacizumab MAPS study, inhibition of the VEGF pathway is of interest as a treatment approach for MPM. Nintedanib is an oral, triple angiokinase inhibitor of VEGFR, PDGFR and FGFR. This study will evaluate the efficacy and safety of nintedanib plus pemetrexed/cisplatin in patients with advanced MPM.

      Methods:
      Patients with unresectable MPM (chemo-naïve, ECOG PS 0–1) were stratified by histology (epithelioid/biphasic) and randomised (1:1) to receive up to 6 cycles of pemetrexed (500 mg/m[2])/cisplatin (75 mg/m[2]) on Day 1 plus nintedanib (200 mg bid)/placebo on Days 2–21. Patients without disease progression received maintenance treatment with nintedanib/placebo. The primary endpoint was progression-free survival (PFS).

      Results:
      87 patients were randomised to receive pemetrexed/cisplatin, plus nintedanib/placebo. Patient characteristics were comparable between the groups. PFS was longer in the nintedanib vs the placebo arm, in both the overall study population and in epithelioid patients (Table 1). Preliminary OS data also favour nintedanib. All patients experienced at least one adverse event (AE, any grade), with 7% of patients in the nintedanib arm discontinuing due to AEs, vs 15% with placebo. Serious AEs occurred in 36% vs 42% of patients in the nintedanib and placebo arms, respectively. The most common ≥grade 3 AEs occurring in nintedanib vs placebo patients were neutropenia (34% vs 10%), ALT increase (14% vs 2%) and gamma glutamyltransferase increase (14% vs 0%).

      Conclusion:
      Nintedanib plus pemetrexed/cisplatin demonstrated clinical efficacy with improved PFS and a tolerable safety profile in patients with unresectable MPM. Based on these promising findings, this Phase II study was extended to a confirmatory Phase III trial, which is currently enrolling patients. Clinical trial identifier: NCT01907100.

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    P1.08 - Poster Session with Presenters Present (ID 460)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Surgery
    • Presentations: 1
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      P1.08-038 - VATS Sub-Lobar Anatomical Pulmonary Resections: Indications and Outcomes in Thoracic Oncological Practice (ID 5815)

      14:30 - 15:45  |  Author(s): T. John

      • Abstract
      • Slides

      Background:
      In patients with limited pulmonary reserve, sub-lobar anatomic pulmonary resection (SLAPR) may have reduced perioperative morbidity and mortality and additionally may better preserve long-term pulmonary function compared to lobectomy. SLAPR may also mitigate the oncological deficiencies of wedge resection. However, the safety and oncological efficacy of video assisted thoracoscopic surgical (VATS) SLAPR has not been well described. We therefore audited our recent experience of VATS SLAPR to evaluate: indications, safety, and oncological outcomes.

      Methods:
      We retrospectively reviewed a prospectively maintained database to identify all consecutive patients who underwent planned VATS SLAPR with curative intent. Demographics, co-morbidities, indications and treatment outcomes were retrieved, with supplemental chart review where necessary.

      Results:
      Seventy seven VATS SLAPRs were performed between December 2010 and May 2016. Median age of patients was 67 (44-83) years and 57% (44/77) were male. The majority (47/77; 61%) of SLAPRs were undertaken for resection of NSCLC. Indications for SLAPR in NSCLC patients included: inadequate pulmonary reserve (DLCO <60% or predicted post-operative DLCO <40%) in 21/47 (44%), excessive (≥2 major) comorbidities in 18/47 (38%), advanced age (≥75 years) in 13/47 (27%) or a combination of these factors precluding lobectomy. In patients with metastatic 22(28%) and benign 8(10%) nodules, indications included proximity to vascular structures or inability to palpate lesion precluding simple wedge resections. Superior segmentectomy (22/77; 28%) and lingula sparing left upper lobectomy (17/77; 22%) were the commonest SLAPRs performed. Seventy one (92%) were completed via VATS. Emergency conversion occurred in one case. Morbidity rate was 30% (23/77) and 30 day mortality rate was 2.5% (2/77). Pre-operative DLCO was not associated with post-operative pulmonary complication (P=0.7) or length of hospital stay (P=0.20). In the NSCLC sub group, all patients were clinically stage I; R0 resection was achieved in 100%. Median of 12(4-27) nodes were excised with a nodal upstaging rate of 25% (12/47) and pathological stage was I in 65%. Median disease free survival (DFS) was 40 months and median overall survival (OS) was not reached. Loco regional recurrence rate was zero. Pre-operative DLCO dichotomised using median did not correlate with OS (P=0.8) or DFS (P=0.29).

      Conclusion:
      A variety of VATS SLAPRs may be performed safely with acceptable morbidity and mortality in high risk patients. Complete microscopic resection and adequate nodal dissection can be achieved. Although larger studies and longer follow is needed, our findings suggest that VATS SLAPR achieves comparable oncological outcomes in high risk patients to formal lobectomy.

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    P2.02 - Poster Session with Presenters Present (ID 462)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      P2.02-047 - Association of FDG PET, Complete Pathological Response and Overall Survival in Patients with Pancoast Tumours Treated with Trimodality Therapy (ID 5331)

      14:30 - 15:45  |  Author(s): T. John

      • Abstract
      • Slides

      Background:
      Induction chermoradiotherapy (CRT) and surgical resection is considered standard care for treatment of node negative Pancoast tumours. However, not all patients benefit from this approach and there are no well-defined preoperative parameters to identify patients for whom addition of surgery may be unnecessary due to local control with CRT alone. We investigated wether baseline FDG positron emission tomography (PET) scan parameters or changes post induction may predict complete pathological response (pCR) to CRT and hence obviate the need for subsequent resection.

      Methods:
      We conducted a retrospective review of our prospectively maintained single institution database with supplemental chart review to evaluate: PET, histopathological, and clinical outcome parameters in consecutive patients undergoing curative intent trimodality treatment of Pancoast tumours from 2001 to 2015. Metabolic parameters based on the standardized uptake values (SUV) were calculated including SUV~max~ (maximum SUV value), SUV~PTL~ (peak tumour-to-liver ratio)~, ~and TGV (total glycolytic volume, mean SUV x tumour volume). Two pathologists independently reviewed specimens to assess percentage viable tumour in resected tumours.

      Results:
      Nineteen patients (10 Females), median age 61(42-75) yrs completed trimodality treatment with Cisplatin, Etoposide and 45Gy in the majority of cases. Histopathological was data available for all patients. Of the 19 patients baseline PET was available in 15 and post induction PET in 13. Baseline SUVmax < 9.4 was associated with pCR in 4/4 vs. 4/11 patients (p=0.03). A trend towards improved locoregional control with cPR did not reach significance. No PET measured parameter was associated with locoregional control. Baseline TGV > 441 was associated with reduced disease free survival (DFS) 5.7(0.7-10.5) vs. NR months (p=0.002), and overall survival (OS) 15.9(3.1-28.8) vs. NR months (p=0.04). No change in PET parameter measured post induction was associated with cPR, local recurrence, DFS or OS.

      Conclusion:
      In our series, low baseline SUV~max~ was associated with complete pathological response. If confirmed in a larger cohort, including multivariate analysis of other prognostic and predictive factors, this may allow patients at high perioperative risk to be better stratified to either definitive CRT or trimodality therapy. A larger series may be able to identify an association between metabolic response on FDG-PET and CPR, DFS or overall survival.

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    P3.03 - Poster Session with Presenters Present (ID 473)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      P3.03-004 - Genome-Wide Copy Number Aberrations in Mesothelioma and Its Correlation with Tumour Microenvironment including PD-L1 Expression (ID 4506)

      14:30 - 15:45  |  Author(s): T. John

      • Abstract
      • Slides

      Background:
      Recent clinical studies have demonstrated positive correlation between tumour mutational burden and response to immune checkpoint inhibitors (CPI) in several malignancies. Although initial reports of some CPI in Malignant Mesothelioma (MM) have shown promise, the rate of somatic mutations in MM is known to be low and copy number aberrations (CNA) are the prominent genetic alterations. Using a large cohort of MM patients, we investigated CNA, PD-L1 expression and the surrounding immune infiltrates and correlated these parameters to clinicopathological features.

      Methods:
      Tissue microarrays (TMA) were constructed and stained with PD-L1 (E1L3N,CST, Massachusetts), CD4, CD8 and Foxp3 antibodies. PD-L1 positivity (PD-L1+) was defined as >5% membranous staining regardless of intensity and high positive as >50%. Genomic DNA was obtained from tumour cores of a representative subset (100 patients) and used for genome-wide copy number analysis. Percent genome aberrated (PGA) was computed for each sample as the total number of base pairs within altered regions, divided by the total number of base pairs in each region included in the array. Correlations of PGA, CNA profile and individual aberration (loss/gain) frequency with parameters including PD-L1 expression and survival were explored.

      Results:
      Amongst 329 patients evaluated, the median age was 67 years and most were male 274(83.2%). Epithelioid histology (N=203; 62.9%) was the commonest. PD-L1 positivity was seen in 41.7% with high positivity in 9.6%. PD-L1+ correlated with non–epitheloid histology (P=<0.0001) and increased infiltration with CD4, CD8 and FOXP3 lymphocytes. High PD-L1 expression correlated with worse prognosis (HR=2.37; 95%CI: 1.57-3.56; P=<0.0001) on univariate analysis but the effect was found to be time dependent. Neither PGA (P=0.57) nor CNA profile (P=0.76) were found to be associated with PD-L1 expression. After correction for multiple testing, no individual CNA count was significantly associated with PD-L1 status. Although epithelioid histology had higher PGA (P=0.04), high PGA was associated with poorer survival (HR=2.01; 95% CI: 1.24-3.26; P=0.004). This was also true when only epithelioid tumours (n=63) were considered.

      Conclusion:
      Increased genomic alterations in MM did not correlate with PD-L1 expression but was associated with poorer survival. High PD-L1 expression was associated with non-epithelioid MM, poor clinical outcome and increased immunological infiltrates.

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