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Seiki Hasegawa

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    MA05 - Update on Clinical Trials and Treatments (ID 123)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 11
    • Now Available
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      MA05.01 - Second or Third Line Anti-PD-1 Therapy After Multimodality Therapy Including Total Pleurectomy in Malignant Pleural Mesothelioma (Now Available) (ID 1955)

      13:30 - 15:00  |  Presenting Author(s): loic Lang-Lazdunski  |  Author(s): Yu Zhi Zhang, Sanjay Popat, Mary O'Brien, Jeremy Steele, Tom Newsom-Davis, Arnaud Scherpereel, Hasna Bouchaab, Alexandra Rice, Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Background

      Surgical resection plays an important role in the management of selected patients with malignant pleural mesothelioma (MPM). Early experience with anti-PD-1 immunotherapy showed promise in MPM, but it is yet uncertain if it can improve outcomes when tumour relapses following surgical resection, radiotherapy and chemotherapy. We reviewed our experience in patients who received Pembrolizumab or Nivolumab following multimodality therapy.

      Method

      Retrospective study including patients with histologically-proven MPM having completed multimodality therapy and received anti-PD-1 immunotherapy as 2nd or 3rd line treatment. Data were retrieved from a prospective mesothelioma database. Histopathology, BAP1, MTAP and PD-L1 (22C3) immunohistochemistry were performed on surgical specimens and reported by a senior pathologist. All patients had chest computed tomography and positron emission tomography (PET-CT) as part of their normal follow-up. Response evaluation was determined using RECIST 1.1 criteria.

      Result

      16 patients received anti-PD-1 immunotherapy between August 2015 and March 2019. All patients had total pleurectomy/decortication, prophylactic radiotherapy (21Gy/3) and systemic chemotherapy based on pemetrexed and platinum. Median age was 68.5 years, with male predominance (13/16). 56% had epithelioid type, 44% had biphasic type. Median time to starting immunotherapy was 20 months (range 11-42) following surgery. Median ECOG performance status was 0. Twelve patients received Pembrolizumab and 4 received Nivolumab. Median number of cycles of anti-PD-1 therapy received was 5 (range 1-33). Disease control rate at 12 weeks was 56.2% and 7 (43.7%) patients had disease progression. Adverse events were observed in 6 patients (one Grade 3). Eight patients were alive by 1st April 2019. Median OS from starting immunotherapy was 13.5 months. Three patients received treatment for 14 months or more. Five patients started further therapy after discontinuing immunotherapy.

      Conclusion

      In our cohort, second or third-line anti-PD-1 immunotherapy showed efficacy with DCR comparable to non-surgical setting. Further studies are warranted to validate our preliminary findings.

      wclc 2019 figure 1anti pd1.jpg

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      MA05.02 - Log Odds of Positive Lymph Nodes Predicts Overall Survival and the Benefit of Postoperative Radiotherapy in Malignant Pleural Mesothelioma (Now Available) (ID 1059)

      13:30 - 15:00  |  Presenting Author(s): Yang Wo  |  Author(s): Yuanyong Wang, Tong Lu, Wenjie Jiao

      • Abstract
      • Presentation
      • Slides

      Background

      Nodal categories of malignant pleural mesothelioma (MPM) are mostly adopted from lung cancer staging criteria and the N descriptors in the eighth edition of TNM staging system have not been fully verified. We aimed to evaluate the effectiveness of the current N descriptors and a novel prognosticator—the log odds of positive lymph nodes (LODDS)—in predicting overall survival (OS) and postoperative radiotherapy (PORT) benefit in MPM.

      Method

      Patients in the Surveillance, Epidemiology, and End Results (SEER) database with MPM undergoing surgery and lymph nodes examination were extracted and restaged according to the 8th edition TNM staging system. LODDS was calculated as loge[(positive nodes count+0.5)/(negative nodes count+0.5)]. X-tile software determined the optimal cut-point for LODDS. Log-rank tests along with Cox regression analyses were adopted for survival analyses. Harrell's C-index statistic measured discriminatory ability and prognostic performance.

      Result

      A total of 534 patients were enrolled in this study. N descriptors were unevenly distributed. Most cases were staged as N0 (51.9%) and N1 (47.0%), with only 1.1% staged as N2. The eighth edition N descriptors failed to clarify the survival difference between adjacent categories and were incapable of predicting PORT benefit. The cut-points for LODDS were classified as follows: LODDS1 (≤-2.61), LODDS2 (-2.56≤LODDS≤0.62), and LODDS3 (≥0.87). The median survival of LODDS1 was 23.1 months compared with 17.9 months (HR=1.397, P=0.005) and 13.0 months (HR=2.317, P<0.001) for LODDS2 and LODDS3, respectively. The survival curves stratified by LODDS separated nicely without overlapping and the benefit of PORT was limited to cases with LODDS3 (≥0.87). LODDS also provided better C-index than the conventional N descriptors.

      layout 1.jpg

      Conclusion

      LODDS performs better than N descriptors for predicting survival and benefits of PORT in resected MPM, and it could be considered as a potential parameter to compensate for defects in the 8th AJCC TNM staging for MPM.

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      MA05.03 - Impact of Time to Surgery on Outcomes in Patients Undergoing Outright Resection for Malignant Pleural Mesothelioma (Now Available) (ID 648)

      13:30 - 15:00  |  Presenting Author(s): Chi-Fu Jeffrey Jeffrey Yang  |  Author(s): Soraya Voigt, Vignesh Raman, Oliver K Jawitz, Thomas A D’amico, David Harpole

      • Abstract
      • Presentation
      • Slides

      Background

      We hypothesized that a longer interval to surgery would be associated with worse overall survival for patients with malignant pleural mesothelioma (MPM).

      Method

      The National Cancer Database (NCDB) for patients with cT1-3N0-1M0 MPM who underwent surgery without induction therapy. Patients with interval of <1 or >180 days were excluded. Patients were grouped into quartiles based on distribution of time intervals to surgery: Q1 (1-30 days), Q2 (31-50 days), Q3 (51-80 days), and Q4 (>80 days). The primary outcome was overall survival. Secondary outcomes were upstaging to pN2 and margin-positive (>R0) resection rate. Survival was estimated using the Kaplan-Meier and Cox Proportional Hazards methods. Nodal upstaging and >R0 resection rates were modeled with multivariable logistic regression.

      Result

      A total of 812 patients met study criteria. The median interval from diagnosis to surgery was 52 days. The unadjusted median survival for Q1, 2, 3, and 4 was 16, 19, 20, and 27 months, respectively (log-rank p=0.004). In multivariable analysis, increased time to surgery was not associated with worse overall survival (Table 1), and Q4 (>80 days) was independently associated with improved survival compared to Q1. When modeled as a continuous variable, an increased time to surgery was associated with a small but clinically insignificant increase in survival (AHR 0.997; 95%CI 0.995-0.999; p=0.005). In a multivariable regression of factors predicting pathologic upstaging to N2, increased time to surgery was significantly associated with upstaging (adjusted odds ratio [AOR] for Q4 compared to Q1: 2.26; 95%CI 1.04-5.28). In a separate regression of >R0 resection, an increased interval to surgery was not associated with margin-positive resection (AOR 0.70; 95%CI 0.41-1.21).

      Conclusion

      An increasing interval from diagnosis to definitive surgery for MPM was not associated with worse overall survival or margin-positive resection, but was associated with higher likelihood of pathologic nodal upstaging in this analysis.

      Variable

      Adjusted HR

      95% CI

      P value

      Interval (ref:Q1)

      Q2

      Q3

      Q4

      1.07

      0.96

      0.74

      0.84-1.36

      0.76-1.22

      0.58-0.95

      0.61

      0.75

      0.02

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      MA05.04 - Discussant - MA05.01, MA05.02, MA05.03 (Now Available) (ID 3733)

      13:30 - 15:00  |  Presenting Author(s): Clarissa Baldotto  |  Author(s):

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA05.05 - Post-Discontinuation Treatments in IFCT-GFPC-0701 MAPS Trial: Real-World Effectiveness of 2nd-Line (2L) Treatments for Mesothelioma (Now Available) (ID 815)

      13:30 - 15:00  |  Presenting Author(s): Gerard Zalcman  |  Author(s): Solene Brosseau, Julien Mazieres, Jacques Margery, Laurent Greillier, Clarisse Audigier-Valette, Denis Moro-Sibilot, Olivier Molinier, Romain Corre, Isabelle Monnet, Valérie Gounant, Frédéric Rivière, Radj Gervais, Henri Janicot, Chrystele Locher, Alexandra Langlais, Jean-Jacques Parienti, Franck Morin, Arnaud Scherpereel

      • Abstract
      • Presentation
      • Slides

      Background

      MAPS phase 3 trial assessing the addition of bevacizumab to pemetrexed-cisplatin doublet set a new standard of care in malignant pleural mesothelioma (MPM) patients, showing 18.8 months median overall survival (OS) with triplet combo. While both arms were well balanced in terms of 2L treatments, the size of the OS benefit from second-line treatments remains controversial.

      Method

      Long-term survival data were collected in the 342 MAPS patients alive at the end of the first-line (1L) treatments, in both arms. Median OS and 2-year survivals were calculated from the initiation of 2L. Multivariate analysis using Cox model included the stratification variables of the MAPS trial, along with the treatment arm (with or without bevacizumab).

      Result

      342/442(77.4%) patients received 2L treatment for disease progression after MAPS trial, of which 324 received chemotherapy (CT), 18 palliative radiotherapy (RT), while 100/442 (22.6%) remained untreated. 160/342 patients (46.8%) had a platinum-based doublet CT. 163 patients (47.7%) received a single-drug CT. 172/324 (53.1%) received a pemetrexed-containing regimen (alone or with platinum), 84 (25.9%) a gemcitabine-based CT, 16 (4.9%) vinorelbin alone, 48 (14.8%) gemcitabine alone, while in 12 (3.7%) single-agent bevacizumab was resumed. Median age was lower in patients with doublet CT (64.4 years, IQR 60.2-68.9) vs. single-drug CT patients (66.3 years, IQR 61.5-70.3), patients receiving RT (68.5 years, IQR 63.3-70.5) or untreated patients (67.8 years, IQR 63.4-71) (p=0.007). There were more PS=2 patients (10%) in the untreated group, compared with 0.6%, 1.8% and 5.6% in those receiving doublet, monotherapy or radiotherapy, respectively (p<0.001). A lower proportion of patients receiving 2L doublet CT had sarcomatoid/biphasic MPM (11.2%) compared with 21.5%, 38.9% and 25% in those with single-arm agent, RT or untreated, respectively (p=0.002). When compared with those treated with 2L single-agent, patients with 2L doublet had more frequently objective response (11.9 vs. 3.1%, p=0.005) and disease control (60.3 vs. 34.6%, p<0.0001). From the date of 2L therapy initiation, median OS was 3.2 months, 95%CI [1.7-5.0] for RT vs. 7.0 months 95%CI[5.6-7.8] for single-agent CT, or 12.2 months 95%CI [9.5-14.1] for doublet CT. HRs were adjusted for 1L treatment type (bevacizumab-containing or not), PS, smoking, and histology. Adj.HR (single-agent vs. doublet) was 1.21, 95% CI(0.96-1.53), p=0.11. Adj.HR (monotherapy vs. RT) was 0.39, 95%CI[0.24-0.65], p=0.0003. Adj.HR (combination CT vs. RT) was 0.32 95%CI[0.19-0.54], p<0.0001. 1-year OS was 11.8%, 95%CI [0.0-27.1], 48.7%, 95%CI [39.9-57.5], and 32.9%, 95%CI [25.1-40.6], in patients with RT alone, single agent CT or combination CT, while 2-year OS was 0%, 14.2%, and 20.0% respectively.

      Conclusion

      Second-line monotherapy only gave a 7-months median OS in MPM patients, comparing unfavorably to 11.9 and 15.9-months median OS with 2nd/3rd-line nivolumab or nivolumab+ipilimumab respectively, in the IFCT-1501 MAPS-2 randomized phase 2 trial. Conversely, 2L platinum-based chemo, in younger fit patients, still gave a 12.2-months median OS, not statistically different from monotherapy in the multivariate analysis, as a consequence of PS influence, although clinically meaningful. Based on these results, immunotherapy might be preferred for 2L/3L MPM patients, while monotherapy CT shows limited survival benefit.

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      MA05.07 - Efficacy and Safety of Re-Treatment with Tremelimumab and Durvalumab Within the NIBIT-MESO-1 Study (Now Available) (ID 1867)

      13:30 - 15:00  |  Presenting Author(s): Luana Calabro'  |  Author(s): Giulia Rossi, ALDO Morra, Anna Maria Di Giacomo, Giovanni Amato, Claudio Rosati, Ornella Cutaia, Maria Grazia Daffinà, Diana Giannarelli, MICHELE Maio

      • Abstract
      • Presentation
      • Slides

      Background

      Targeting immune-checkpoint inhibitors (ICI) had proven effective in a variety of tumor types. However, primary and secondary resistance to treatment is emerging as a major limitation of ICI therapy, and scattered information is available on the therapeutic efficacy of re-treatment in ICI-resistant subjects. Here we investigated the efficacy and safety of re-treatment with tremelimumab and durvalumab in malignant mesothelioma (MM) patients who developed resistance to these agents in the phase II NIBIT-MESO-1 study (Calabrò L et al, Lancet Resp Med 2018).

      Method

      Patients eligible for re-treatment per the NIBIT-MESO-1 protocol were those who completed 4 dosing cycles of tremelimumab combined with durvalumab, and achieved partial response (PR) or stable disease (SD), followed by progressive disease (PD) during the maintenance with durvalumab or the follow-up phase. Subjects who met the re-treatment criteria received tremelimumab (1 mg/Kg, i.v.) and durvalumab (20 mg/Kg, i.v.) every 4 weeks (Q4W) for 4 doses (re-induction phase), followed by durvalumab (20 mg/Kg, i.v.) Q4W for additional 9 doses (maintenance phase). Objective response rate (ORR), disease control rate (DCR), per immune-related (ir)-modified RECIST criteria, overall survival (OS), and safety were evaluated. Adverse events (AEs) were recorded according to CTC v4.0.

      Result

      Seventeen (42.5%) of the 40 MM patients enrolled in the NIBIT-MESO-1 study met the criteria for re-treatment and received therapy. Among them 8 (47%) completed the re-induction phase, 7 (41.2.%) went on maintenance phase, and 1 (5%) entered the follow-up phase. As of April 1st 2019, 16/17 patients were discontinued during re-treatment because of PD, and 7 received additional lines of therapy. Seven out of the 17 (41.2%) re-treated subjects had an irSD, while no ir-ORR were observed. At a median follow-up of 35.8 months, median OS of re-treated patients was significantly (p=0.005) higher (25.6 months, 95% CI: 6.1-45.1) as compared to the 23 subjects who were not re-treated (9.9 months, 95% CI: 7.7-12.1). Grade 1-2 irAEs occurred in 6/17 (35%) re-treated patients, were most frequently dermatological and reversible per protocol guideline; no grade 3-4 irAEs were observed.

      Conclusion

      Re-treatment with tremelimumab and durvalumab of MM patients who developed resistance to therapy in the course of the NIBIT-MESO-1 study is clinically effective and safe in a sizeable proportion of re-treated subjects.

      Clinical trial infomation: NCT02588131

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      MA05.08 - Discussant - MA05.05, MA05.06, MA05.07 (Now Available) (ID 3734)

      13:30 - 15:00  |  Presenting Author(s): James Spicer

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA05.09 - Real-World Data of Nivolumab and Pembrolizumab in Chemotherapy Pre-Treated Mesothelioma Patients (Now Available) (ID 1918)

      13:30 - 15:00  |  Presenting Author(s): Daphne Dumoulin  |  Author(s): Luca Cantini, Robert anton Belderbos, Darlene Mercieca, Robin Cornelissen, Joachim G.J.V. Aerts

      • Abstract
      • Presentation
      • Slides

      Background

      Both nivolumab and pembrolizumab have shown positive results in phase II studies in patients following chemotherapy in mesothelioma patients. However, these studies were done in a limited number of patients with strict inclusion criteria, while reports show a difference between real life and study setting.

      Method

      In our mesothelioma center, we treated patients that progressed during or after chemotherapy treatment with nivolumab 3mg/kg once every 2 weeks independent of PD-L1 expression or with pembrolizumab 200mg once every 3 weeks when PD-L1 expression was ³1%, both in Early Patient Access programs. All patients were pre-treated with at least one cycle of platinum/folate treatment. CT scan evaluation was done using modified RECIST every 6 weeks.

      Result

      In total, we treated 78 patients with nivolumab and 13 patients with pembrolizumab. Median age of the patients was 71 years (29-85) at start of the checkpoint inhibitor treatment, 80 (88%) were male. Performance status was ECOG 0 in 19 patients, ECOG 1 in 57 patients, ECOG 2 in 9 patients. Data analysis thus far showed 9 partial responses (10%) and 31 patients with stable disease (29%) and therefore a disease control rate of 39% at twelve weeks of treatment. Median progression free survival is 2.4 months and median overall survival 6,3 months. Median duration of response had not been reached yet. These data will be updated for the meeting. Two cases of pseudoprogression were seen on checkpoint inhibition therapy where progression according to modified RECIST was followed by response during continuation of PD-1 therapy. Toxicity was in line with historical data.

      Conclusion

      We believe that this large dataset, using real-world data, can truly give an insight in the clinical benefit of these immune checkpoint inhibitors. In comparison with the published phase I and II trials on nivolumab and pembrolizumab, the response rates appear to be lower in a real-life setting. However, clinically meaningful and durable responses are seen in a population that has no other proven therapy options.

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      MA05.10 - Pembrolizumab in the Treatment of Patients with Malignant Pleural Mesothelioma Following Progression After Initial Chemotherapy (Now Available) (ID 2788)

      13:30 - 15:00  |  Presenting Author(s): Keith Cengel  |  Author(s): Sharyn I Katz, Leonid Roshkovan, Sally McNulty, Jinjiang Lian, Daniel Aleynick, Melissa Jane Culligan, Joseph Friedberg, Sunil Singhal, Charles B. Simone, Li, Christine Ciunci, Melina E Marmarelis, Evan Alley, Corey Jay Langer

      • Abstract
      • Presentation
      • Slides

      Background

      Checkpoint inhibitor (CPI) therapies have demonstrated clinical benefit in patients (pts) with malignant pleural mesothelioma (MPM) and are now included in the NCCN guidelines as an acceptable treatment option. Herein, we report our initial experience treating pts with MPM in the palliative second line or greater setting.

      Method

      Between January 2016 and November 2018, 74 pts with biopsy proven MPM were treated with pembrolizumab every three weeks until confirmed disease progression or unacceptable toxicity. Progression-free survival (PFS) and OS were defined as the time from first pembrolizumab dose to recurrence and death, respectively, or to last contact. Response rates (RR) were measured by a dedicated thoracic radiologist using modified RECIST 1.1 criteria. Adverse events were routinely recorded/scored at each follow up visit. according to CTCAE 4.0 with level of attribution to pembrolizumab.

      Result

      Demographics of the 74 pt cohort are shown in table 1. Twently-nine (39%) of pts experienceda total of 39 grade 1-2 adverse events, possibly or definitely related to therapy (Table 2). There was one grade 4pneumonitis that resulted in new requirement for oxygen, which resolved with steroids; and one patient experienced leukoencephalopathy that resulted in death. The overall response rate (including only partial responses by modified RECIST 1.1) for the entire cohort was 26%. Median progression free survival and overall survival for the entire cohort were 2.8 months and 7.9 months, respectively.

      Table 2: Adverse Events

      CTCAE 4.0 Grade

      AE Description

      1-2

      3-4

      5

      hypothroid

      5

      arthralgias

      8

      colitis

      3

      diarrhea

      2

      lip lesion

      1

      pneumonitis

      2

      1

      SICCA syndrome

      1

      thrombocytopenia

      1

      dermatitis

      1

      hypopigmentation

      1

      nephritis

      1

      fatigue

      1

      abdominal pain

      1

      uveitis

      1

      transaminitis

      1

      elvated alk phos

      1

      leukoencephalopathy

      1

      pruritis

      3

      hypercalcemia

      3

      rash

      2

      Table 1: Demographics

      Age in Years

      median (range)

      Min

      73

      (52-92)

      Gender

      Patients (N=74)

      Female

      29

      39%

      Male

      55

      74%

      Histology

      Epithelial

      58

      78%

      Sarcomatoid

      6

      8%

      Biphasic

      10

      14%

      # of chemotherapy courses

      0

      3

      4%

      1

      42

      57%

      2

      22

      30%

      3-4

      7

      9%

      # of radiotherapy courses

      0

      42

      57%

      1

      30

      41%

      2-3

      6

      8%

      Surgical Resection

      Have EPD

      24

      32%

      Did not have EPD

      50

      68%

      PDL1

      Negative

      21

      28%

      Positive

      12

      16%

      Not Determined

      42

      57%

      Conclusion

      Pembrolizumab in the Tx of MPM was reasonably well tolerated in this large, single institution experience. RR, PFS and OS appear remarkably similar to recent published data from a registry study of off-label use of pembrolizumab in pts with MPM in Switzerland and Australia (include reference). Ongoing studies include analysis of PDL-1 and other potential immunotherapy response biomarkers.

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      MA05.11 - Safety and Efficacy of Nintedanib in Combination with Pembrolizumab in Patients with Refractory/Relapsing Malignant Pleural Mesothelioma (Now Available) (ID 2170)

      13:30 - 15:00  |  Presenting Author(s): Andreea Varga  |  Author(s): Gerard Zalcman, Carlos Gomez-Roca, Samy Ammari, CAROLINE Caramella, Valérie Gounant, Audrey Rabeau, Xavier Paoletti, Capucine Baldini, Patricia Martin-Romano, Stephane Champiat, Perrine Vuagnat, Jean-Marie Michot, Laura Mezquita, Christophe Massard, Benjamin Besse, Jean Charles Soria, Aurelien Marabelle, David Planchard

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is an aggressive disease with no standard of care after progression to first line pemetrexed and platinum-based chemotherapy. Combinations between anti-angiogenic agents and immunotherapy are being developed as angiogenesis and immunosuppression influence each other leading to a more powerful anti-tumor response. Both Nintedanib and Pembrolizumab have been investigated as single agents or in different treatment combinations in MPM patients with interesting activity.

      Method

      The PEMBIB trial is a multi-centric open-label non-randomized basket phase 1 trial evaluating the combination of nintedanib with pembrolizumab in multiple tumor types. The safety and activity of the dose escalation part of the study were reported at AACR & ASCO meetings in 2018 with an established DLT defined as grade 3 alanine and/or aspartate aminotransferase elevation (ALT/AST). The recommended phase 2 dose is set at 150 mg BID of nintedanib with 200 mg flat dose of pembrolizumab. We would like to report the safety and activity of one of the expansion cohorts of patients with relapsing/refractory MPM which has now been completed. Eligible MPM patients were 18 years or older with an ECOG performance status of 0 or 1, histologically proven MPM that relapsed after at least one line of pemetrexed and platinum-based combination, specific anti-angiogenic eligibility criteria such as no radiographic evidence of cavitary/necrotic or tumors with local invasion of major blood vessels.

      Updated results on the safety profile and efficacy of this anti-angiogenic and anti-PD-1 combination therapy including overall response rate as per RECIST, irRC and mRECIST criteria, disease control rate will be presented at the meeting.

      Result

      The first patient from the MPM cohort was enrolled in July 2017 and the last one in April 2019. Thirty-one eligible MPM patients have been evaluable at the data cut off onJuly 2019, one of them had been enrolled since the dose-escalation part at dose level of 200mg. The age at inclusion was 68 (ranging from 38 to 85), 68% of the patients having an ECOG of 1 and 58% of the histological type was epithelioid. The most frequent adverse events (grades 1, 2 and 3) related to any of the combination drugs were liver enzymes increase, fatigue, decreased appetite, nausea, diarrhea and hypothyroidism. There were two cases of myocarditis, one of grade 3 (pembrolizumab related) and one of grade 5(pembrolizumab and nintedanib related). At the time of the data analysis the efficacy data shows six partial responses (overall response rate of 21%) and seventeen stable disease (disease control rate at 61%.).

      Conclusion

      The combination of Nintedanib with Pembrolizumab shows promising activity in relapsed MPM patients .The toxicity profile appear consistent with previous reports of anti-angiogenic agents and immunotherapy combination.

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      MA05.12 - Discussant - MA05.09, MA05.10, MA05.11 (Now Available) (ID 3735)

      13:30 - 15:00  |  Presenting Author(s): Anna K Nowak

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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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      IBS06.03 - Japanese Data (Now Available) (ID 3333)

      07:00 - 08:00  |  Presenting Author(s): Seiki Hasegawa

      • Abstract
      • Presentation
      • Slides

      Abstract

      Backgrounds

      Annual surveys of cardiothoracic surgery throughout Japan has been conducted by the Japanese Association for Thoracic Surgery (JATS) since 1986 in order to establish the statistics for the number of procedures by operative category1. Regarding malignant pleural mesothelioma (MPM), however, only annual case numbers of both diffuse and localized MPM have been registered since 1996. From 2009 onward, surgical technique, 30-day mortality, and in-hospital mortality have been also described. According to the JATS survey, all-kind of surgery for MPM increased 76% during 1996 and 2016: 164 cases in 1996 and 289 cases in 2016. JATS survey also revealed dramatic increase of pleurectomy/decortication (P/D) cases during 2009 to 2016: proportion of P/D surgery in all curative-intent surgery was 1.4% (2/142) in 2009 and 53.3% (73/137) in 2016.

      Methods

      In 2011, the National Clinical Database (NCD) of Japan adopted an annual web-based nationwide data collection system2. Since NCD is associated with the Japanese Surgical Board Certification System, it contains detailed perioperative clinical information such as preoperative patient characteristics, operation time, blood loss, intraoperative accidents, pathological TNM stages, postoperative adverse events, redo-surgery, 30-day and in-hospital mortality, cause of death, and so on. Approximately 10 million surgical procedures from >5000 hospitals have been collected by 2017.

      An NCD specifically for general thoracic surgery was launched in 20143.

      This time, we conducted an analysis on MPM surgery in Japan using the Japan NCD.

      Results (Table 1)

      In the period of 4 years between 2014 and 2017, a total of 622 curative-intent surgery was performed in Japan. Median age was 66 years (IQR, 61-71), and 87.6% were male. A median BMI was 22.6 (20.3-24.8), and 77.3% was ECOG PS0. Induction therapy was given in 40.8% of patients. Extrapleural pneumonectomy was performed in 279 patients (44.9%) and P/D in 343 (55.1%). Blood transfusion was required in 320 (51.4%) patients (Figure 1). Injury of major intrathoracic organ occurred in 22 (3.5%) patients. Morbidity rate was 40.0% (249/622). Thirty-day mortality and in-hospital mortality were 1.1% and 3.2%, respectively (Table 1).

      Conclusion

      In addition to the above JATS survey and Japan NCD, a nationwide, prospective, observational study of patients with MPM has just completed 2-year’s patient accrual4. It is promising that these Japanese data will substantially contribute to understanding MPM in near future.

      1 Thoracic and cardiovascular surgery in Japan in 2016. Committee for Scientific Affairs, The Japanese Association for Thoracic Surgery, Shimizu S, Endo S, Natsugoe S, et al. Gen Thorac Cardiovasc Surg 2019; 67: 377-411.

      2 http://www.ncd.or.jp/

      3 Development of an annually updated Japanese national clinical database for chest surgery in 2014. Endo S, Ikeda N, Kondo T, et al. Gen Thorac Cardiovasc Surg 2016; 64: 569-576.

      4 Shintani Y, Hasegawa S, Takuwa T, et al. Prospective registry database of patients with malignant mesothelioma: Directions for a future Japanese registry-based lung cancer study. J Thorac Dis 2018; 10: 1968-71

      Table 1
      EPP (n=279) P/D (n=343) Total (n=622)
      age (median, IQR) 65 (59-69) 67 (63-73) 66 (61-71)
      male sex 250 (89.6%) 295 (86.0%) 545 (87.6%)
      BMI (median, IQR) 22.3 (20.2-24.2) 23 (20.4-25.1) 22.6 (20.3-24.75)
      PS 0 215 (77.1%) 266 (77.6%) 481 (77.3%)
      1 57 (20.4%) 65 (19.0%) 122 (19.6%)
      2-4 5 ( 1.8%) 10 ( 2.9%) 15 ( 2.4%)
      unknown 2 ( 0.7%) 2 ( 0.6%) 4 ( 0.6%)
      Induction therapy 103 (36.9%) 151 (44.0%) 254 (40.8%)
      Blood transfusion 159 (57.0%) 161 (46.9%) 320 (51.4%)
      Major organ injury 12 ( 4.3%) 10 ( 2.9%) 22 ( 3.5%)
      Morbidity 126 (45.2%) 123 (35.9%) 249 (40.0%)
      30-day mortality 3 ( 1.1%) 4 ( 1.2%) 7 ( 1.1%)
      in-hospital mortality 9 ( 3.2%) 11 ( 3.2%) 20 ( 3.2%)

      figure 1.png

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    P1.06 - Mesothelioma (ID 169)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.06-05 - Clinical Features and Outcomes of Recurrence After Pleurectomy/Decortication for Malignant Pleural Mesothelioma (ID 1182)

      09:45 - 18:00  |  Author(s): Seiki Hasegawa

      • Abstract

      Background

      Malignant pleural mesothelioma (MPM) is an aggressive tumor while most patients experience recurrence after multimodality treatment. However, few clinical studies have been conducted to evaluate the recurrence pattern and survival after Pleurectomy/decortication (P/D) for MPM.

      Method

      We reviewed the patients who registered in the prospective MPM database of our hospital surgery program between September 2012 and December 2017. Eligibility criteria were age ≤80 years, histological subtype on pleural biopsy was epithelioid, clinical stage T1-3N0-1M0 (8th edition), an Eastern Cooperative Oncology Group performance status of 0-1, no major comorbidity. Neoadjuvant chemotherapy (NAC) consisted of pemetrexed followed by cisplatin was performed in all patients who met previously mentioned inclusion criteria. After NAC for three cycles, curative-intent surgery was planned in patients who showed no apparent tumor progression. In our hospital, P/D was introduced in September 2012, and since then P/D was main operative method for MPM. After P/D, If the patients keep good general condition, the patients underwent adjuvant chemotherapy consisted of pemetreced follow by cisplatin. The subjects were 90 patients who underwent NAC followed by P/D from September 2012 to December 2017. Survival and recurrence were calculated by the Kaplan-Meier method using the log rank test. Clinical factors related to survival after recurrence was assed by a multivariable analysis using Cox proportional hazards model.

      Result

      Between September 2012 and December 2017, 140 consecutive patients were eligible for multimodality treatment. All patients completed neoadjuvant chemotherapy. Of these, 112 patients proceeded to surgery, and the remaining 28 patients didn’t because of progressive disease (N= 20) or because they refused to provide consent (N= 8). Of 112 patients who proceeded to surgery, 12 patients underwent Extrapleural pneumonectomy, 10 patients underwent exploratory thoracotomy. Finally, 90 patients underwent P/D.

      Of 90 patients, 65 patients (72.2%) completed multimodality treatment. The 1-year and 3-year overall survival rates after diagnosis were 93.3% and 65.3%, respectively. A recurrence developed in 57 (63.3%). The median time to recurrence was 19.0 months. 1-year and 3-year recurrence free survival were 69.7% and 34.0%, respectively.

      In the initial recurrence, local recurrence only was developed in 39 patients (68.4%), distant recurrence only in 6 patients (10.5%), and both local and distant recurrence in 12 patients (21.1%). 1-year survival rates after recurrence was 59.5%. 43 patients (75.4%) received a treatment for recurrence. On multivariable analysis, treatment for recurrence (hazard ratio, 0.16; 95% confidence interval, 0.06–0.41: P < 0.0001) and disease-free interval greater than 12 months (hazard ratio, 0.34; 95% confidence interval, 0.14 –0.79; P = 0.01) were identified as independently significant prognostic factors of survival after recurrence.

      Conclusion

      The local recurrence remain the most frequent pattern of recurrence after P/D. Most of patients who had recurrence after P/D enabled treatment for recurrence. Treatment for recurrence and disease-free interval greater than 12 months are important prognostic factors of survival after recurrence.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-62 - TCR Repertoire Analysis of Peripheral CD8+PD-1+ T Cells Is Effective as a Predictive Biomarker for Response to the Immune Checkpoint Inhibitor (ID 1668)

      10:15 - 18:15  |  Author(s): Seiki Hasegawa

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors are effective in NSCLC patients. As patient selection is important, many biomarkers have been studied. We developed a method to predict the effect of immune checkpoint inhibitors using peripheral blood. Tumor infiltrating lymphocyte (TIL) sensitizes to neoantigens, some of them migrate to peripheral blood. We measured tumor mutation burden (TMB) of resected specimen and T-cell receptors (TCRs) diversity of peripheral CD8+PD-1+ T cells, examined response rate and prognosis.

      Method

      The study included NSCLC patients who relapsed after surgery and chemotherapy failed. Peripheral blood mononuclear cells (PBMC) was collected from patients before 1st administration of nivolumab. CD8+PD-1+ T cells were subjected to FACS sorting, NGS-based TCR repertoire analysis was performed by Repertoire Genesis Inc., and TCR diversity was evaluated statistically.

      Result

      There were no differences in the proportion of PD-1+ in CD8+ T cells between responders and non-responders. TCR α diversity based on DE50 was significantly higher among responders than non-responders (P < 0.01). TCR β diversity was also significantly higher among responders than non-responders (P < 0.01). Progression-free survival (PFS) and Overall survival (OS) were better in TCR diversity high group than that TCR diversity low group (P=0.01). TMB was not significantly different between responder and non-responder. PFS and OS were not significantly different between TMB high (10) group and TMB low (<10) group.

      Conclusion

      Significant therapeutic effect of nivolumab was observed in NSCLC patients whose peripheral CD8+ PD-1+ T cells had highly diverse TCR. This study suggests the TCR diversity of peripheral CD8+PD-1+ T cells is effective as a predictive biomarker for response to the immune checkpoint inhibitor.

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