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Enrico Ruffini

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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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    MS08 - Management of Thymic Carcinoma (ID 71)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 5
    • Now Available
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      MS08.01 - Adjuvant Radiotherapy for Resected Thymic Carcinoma (Now Available) (ID 3481)

      14:00 - 15:30  |  Presenting Author(s): Anthony Brade

      • Abstract
      • Presentation
      • Slides

      Abstract

      Thymic carcinoma is a rare malignancy with peak incidence in the 4th-6th decade. In contrast to thymoma, it is commonly associated with higher rates of both lymph node and distant metastatic spread and also with shorter disease free survival. For localized or locally advanced disease, surgical resection, with the intention of complete disease extirpation, remains the standard of care. Due to its rarity however, definitive clinical trial data regarding optimal and appropriate addition of adjuvant therapy is lacking. Thus decision making for post-operative patients is guided by data from large institutional, national or international retrospective series or databases (evidence level IV or V).

      Recommendations for adjuvant therapy for thymic carcinoma are influenced principally by stage and adequacy of resection (R0 vs R1 vs R2). Thymic carcinoma is classically staged us the Masaoka-Koga (MK) system but, based on recommendation to the AJCC by the IASLC Staging Prognostic Factors Committee and the International Thymic Malignancy Interest Group (ITMIG), using a database of more than 10 000 patients (Detterbeck et al 2014), a TNM-based system has now been incorporated into the 8th Edition of the AJCC/UICC TNM Classification of Malignant Tumours. However, since much of the published data regarding thymic malignancies is based on the Masaoka-Koga system, at present this remains commonly used for clinical decision-making but, as data continues to accumulate, will likely be superseded by the TNM system over time.

      Post-operative radiotherapy is routinely recommended for patients with MK stage III (TNM Stage I – T1bN0, Stage II, IIIA/B) thymic carcinoma following R0 resection. Similarly, adjuvant radiation is recommended following R1 resection, regardless of stage, with adjuvant chemoradiation recommended following R2 resection.

      Adjuvant radiotherapy is not recommended for MK I or IIA (TNM Stage 1 T1aN0 with no extension to mediastinal fat) disease.

      Controversy exists regarding the utility of adjuvant radiotherapy in the management of MK IIB (TNM Stage I – T1aN0 with extension to mediastinal fat) disease but can be considered for this group of patients.

      The optimal adjuvant radiotherapy dose remains undefined for thymic carcinoma patients but typical doses reported in the literature for patients in the above recommended groups range from 45-50 Gy in 1.8-2 Gy per fraction daily. Following R1 resection, 50-54 Gy in 1.8-2 Gy per fraction is typically recommended. Following R2 resection, 60-70 Gy (with or without concurrent chemotherapy) is considered standard.

      Nodal involvement is much more frequent in patients with thymic carcinoma compared with thymoma. Resected, unexpectedly N+ patients are typically recommended to receive adjuvant RT to 45-60 Gy if complete resection was obtained or 60-70 Gy (with or without concurrent chemotherapy) if residual nodal disease is suspected/documented. Under the TNM staging system, N1 nodes are defined as those in the anterior mediastinal compartment (IASLC levels 1, 3a, 6 and/or supradiaphragmatic/inferior phrenics/pericardial) and N2 nodes are defined as deep intrathoracic or cervical nodes (IASLC levels 2, 4, 5, 7, 10 and/or internal mammary nodes). Whether inclusion of N1 or N2 nodal compartments in adjuvant RT target volumes is of benefit for N0 or completely resected N1 or N2 patients remains unknown but may be prudent to consider during radiotherapy planning based on clinical factors.

      Radiotherapy should conform to modern standards with CT-based simulation with photon-based 3D conformal or beam-modulated treatment delivery, motion management and image guidance to reduce margins and dose to organs at risk. The utility of adjuvant proton-based RT for patients with resected thymic malignancy remains the focus of ongoing study but may offer some dosimetric advantages with respect to OAR dose (e.g. lung or heart).

      Selected References:

      N. Girard et al., Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 26 (Supplement 5): v40–v55, 2015

      Imbimbo et al., Treatment guidelines: Best practices for the management of thymic epithelial tumors: A position paper by the Italian collaborative group for ThYmic MalignanciEs (TYME)
      Cancer Treatment Reviews 71 (2018) 76–87

      Detterbeck et al. The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposal for an evidence-based stage classification system for the forthcoming (8th) edition of the TNM classification of malignant tumors. J Thorac Oncol 2014; 9(Suppl 2): S65–S72.

      Shepherd et al. Thymic Carcinoma Management Patterns among International Thymic Malignancy Interest Group (ITMIG) Physicians with Consensus from the Thymic Carcinoma Working Group. J Thorac Oncol 2017;12:745-51

      Weksler et al., Impact of Positive Nodal Metastases in Patients with Thymic Carcinoma and Thymic Neuroendocrine Tumors. J Thorac Oncol. 2015;10: 1642–1647

      Willmann and Rimner. The expanding role of radiation therapy for thymic malignancies. J Thorac Dis 2018;10(Suppl 21):S2555-S2564.

      Vogel J, Lin L, Litzky LA, et al. Predicted rate of secondary malignancies following adjuvant proton versus photon radiation therapy for thymoma. Int J Radiat Oncol Biol Phys. 2017;99:427–433

      Vogel J, Lin L, Simone CB, et al. Risk of major cardiac events following adjuvant proton versus photon radiation therapy for patients with thymic malignancies. Acta Oncol. 2017;56: 1060–1064.

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      MS08.02 - Induction Therapy for Locally Advanced Thymic Carcinoma (Now Available) (ID 3482)

      14:00 - 15:30  |  Presenting Author(s): Robert Korst

      • Abstract
      • Presentation
      • Slides

      Abstract

      Thymic carcinoma (TC) is a rare mediastinal malignancy that occurs in approximately 10% of all patients with thymic epithelial tumors. There are several different histologic subtypes of TC with squamous cell carcinoma predominating. TC is an aggressive lesion, and frequently presents in more advanced stages and metastasizes to other organs compared to thymoma. This biologic behavior is reflected in the survival rates associated with TC, which are significantly shorter than that of thymoma. Clinical trials conducted exclusively in TC patients have been scarce with only a handful of studies reported in the literature, all focused on advanced, nonsurgical patients.

      Locally advanced, nonmetastatic disease is a common presentation of TC. In the largest retrospective series reported to date, locally advanced disease was the most common stage at presentation, accounting for 45% of patients in whom pathologic stage was recorded1. The importance of complete resection for patients with locally advanced TC cannot be overemphasized. Virtually all reported series of exclusively TC patients that undergo surgical resection have determined that the ability to perform a complete resection is an independent favorable prognostic factor. Despite this, the rate of complete resection in the large, aforementioned series for locally advanced TC was only 64%.

      Given that thymic epithelial tumors (thymoma and TC) are sensitive to both chemotherapy and radiotherapy, an approach that has been favored for patients with locally advanced disease is to administer one or both of these agents preoperatively (neoadjuvant therapy). This strategy is thought to increase the chances of performing a complete resection for marginally resectable or unresectable tumors. Although no clinical trials have been reported exclusively for TC patients using the neoadjuvant strategy, two retrospective reports in TC patients utilizing neoadjuvant chemotherapy or chemoradiation demonstrated complete resection rates of 86% and 69% in marginally resectable or unresectable locally advanced disease2,3. In a phase II clinical trial of neoadjuvant chemoradiotherapy for locally advanced thymic tumors, the complete resection rate for the seven patients that had thymic carcinoma was 71%4. Despite these data, the ability of neoadjuvant therapy to definitively enhance the resectability of locally advanced TC has not been demonstrated due to the absence of randomization and a control group in these studies.

      Some published data have also suggested that TC may respond better to neoadjuvant therapies when compared to the thymoma histotypes. In the previously described phase II trial of neoadjuvant chemoradiotherapy, the patients with TC not only had a better radiographic response to treatment, they were more likely to have a near complete pathologic response (<10% viable tumor) than the patients with thymoma (57% versus 8%)4. Similarly, in a retrospective pathologic analysis of 49 patients with unresectable thymic tumors that underwent neoadjuvant therapy followed by surgical resection at a single institution, the median percent viable tumor in the surgical specimen was significantly less in the TC specimens compared to thymoma (20% versus 91%)5. These two studies also suggest that TC may respond better to chemoradiotherapy than chemotherapy alone.

      Whether targeted or immune therapies can be used successfully in the neoadjuvant setting for TC remains to be determined. Active targeted agents against this disease have remained elusive and immunotherapy may be associated with autoimmune toxicities that may preclude their use in this approach6.

      In summary, the use of induction therapy for locally advanced TC is based on the premise that this approach may enhance resectability of these aggressive tumors, which is an overwhelmingly positive prognostic indicator. However, no published data has conclusively determined that this strategy is effective in enhancing resectability due to a lack of controlled studies. TC may respond better to induction therapy when compared to thymoma, and chemoradiotherapy may induce more radiographic and pathologic responses than chemotherapy alone, but these data are preliminary.

      References.

      Ahmad U, Yao X, Detterbeck F, et al. Thymic carcinoma outcomes and prognosis: Results of an international analysis. J Thorac Cardiovasc Surg 2015;149:95-101.

      Kawasaki H, Taira N, Ichi T, et al. Weekly chemotherapy with cisplatin, vincristine, doxorubicin and etoposide followed by surgery for thymic carcinoma. Eur J Surg Oncol 2014;40:1151-1155.

      Shintani Y, Masayoshi I, Tomohiro K, et al. Multimodality treatment for advanced thymic carcinoma: outcomes of induction therapy followed by surgical resection in 16 cases at a single institution. Gen Thorac Cardiovasc Surg 2015;63:159-63.

      Korst RJ, Bezjak A, Blackmon S, et al. Neoadjuvant chemoradiotherapy for locally advanced thymic tumors: A phase II, multi-institutional clinical trial. J Thorac Cardiovasc Surg 2014;147:36-46.

      Johnson GB, Aubry MC, Yi ES, et al. Radiologic response to neoadjuvant treatment predicts histologic response in thymic epithelial tumors. J Thorac Oncol 2016;12:354-67.

      Giaccone G, Kim C, Thompson J, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol 2018;19:347-355.

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      MS08.03 - Optimal Management of Metastatic Thymic Carcinoma (Now Available) (ID 3483)

      14:00 - 15:30  |  Presenting Author(s): Guiseppe Giaccone

      • Abstract
      • Presentation
      • Slides

      Abstract

      Thymic carcinoma represents approximately 10-15% of all thymic epithelial tumors, it is more aggressive than thymomas and also somewhat less sensitive to chemotherapy. More often than thymomas, thymic carcinomas are not resectable and therefore the use of systemic therapies and radiation are more often required than in thymomas. In general the sensitivity of thymic carcinomas to chemotherapy is lower than with thymomas, with response rates usually less than 50% in metastatic disease, and somewhat higher in locally advanced disease.

      In presence of borderline operable cases, neoadjuvant chemotherapy is indicated, in order to make the tumor more easily operable. Because thymic carcinomas often infiltrate surrounding tissues, radical resection are sometimes not achievable. The use of postoperative radiation is indicated even if margins are clear. Several chemotherapy regimens have been used, and the more commonly employed remain platinum combinations, with or without an anthracycline (mainly doxorubicin). More recently data the combination carboplatin-paclitaxel has been added to the potential chemotherapy regimens and it is often preferred becasue of its milder toxicity profile. When radiation is planned, the use of doxorubicin is contraindicated, becasue of the enhanced toxicity. The role of debulking surgery, reoperation and metastasectomy is much more controversial in thymic carcinomas than in thymomas, given the more aggressive behaviour. However, the histological diagnosis sometimes is not paralleled by an aggressive phenotype and individual treatment decisions should always be considered.

      Unfortunately thymic carcinoma have the tendency to metastatize wildly to virtually all organs, and brain metastases are all but rare. Complete staging procedures, including brain MRI are therefore indicated in patients with thymic carcinoma. In patients with metastatic disease, chemotherapy is indicated as first line therapy, and the CAP regimen (cisplatin, doxorubicin, cyclophosphamide) or carboplatin-paclitaxel, are the preferred regimens, with response rates in the range of 30-50%. Unfortunately, chemotherapy at this stage is not curative and most patients will require further systemic therapies after failure of chemotherapy. There have been a number of studies in recent years, which have established activity of a few agents, such as sunitinib and pembrolizumab in thymic carcinomas. Both of them are now listed in the NCCN guidelines and have a response rate of about 25%. Pembrolizumab however has a much longer duration of response, albeit the frequency of severe autoimmune disorders is higher than in other diseases in which immune checkpoint inhibitors are used. Further chemotherapy also has some activity, such and the combination gemcitabine-capecitabine and other single agents, with responses in the 20-30% range.

      The biology of thymic carcinoma does not appear to provide clues to specific treatments, although mutations in epigenetic genes have been found in a significant number of patients. No easily targetable mutations or genetic abnormalities have so far been found. The most common mutation is in the p53 gene, in about 30% of cases, which is not targetable and is associated with a poorer survival.

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      MS08.04 - Novel Biomarkers for Thymic Carcinoma (Now Available) (ID 3484)

      14:00 - 15:30  |  Presenting Author(s): Mirella Marino  |  Author(s): Beatrice Casini, Enzo Gallo, Enrico Melis, Fabiana Letizia Cecere, Valentina Laquintana, Virna Cerasoli, Francesco Facciolo, Edoardo Pescarmona, Francesco Fazi

      • Abstract
      • Presentation
      • Slides

      Abstract

      Thymic carcinoma (TC), the rarer among Thymic Epithelial Tumors (TET), occur with an incidence rate of 0.2-0.5/million/yr. Difficulties in the evaluation of molecular aspects derive from the extreme rarity of these tumors. The Squamous cell carcinoma (SQCC) is the most frequently analyzed, however the other rarer histotypes could differ both in molecular pathogenesis and in clinical behaviour. The Cancer Genome Atlas Thymoma study (TCGA-THYM) in a series of ten TC cases including four SQCC, four undifferentiated carcinoma and both one large cell neuroendocrine carcinoma as well as one TC, NOS, identified a few genes rarely mutated, including KIT, HRAS, NRAS and TP53, reflecting the low mutational burden of these tumors (1). In the last years, only a limited number of TC has been investigated by other groups and only a limited number of relevant alterations has been identified. In addition to genomic events, however, epigenetic factors could contribute to TET carcinogenesis. Wang et al. in 2014 performed targeted sequencing of 197 cancer-associated genes in 78 advanced-stage TET patients, including 47 TC and 31 thymoma (THYM) cases. They reported that TC showed a higher incidence of somatic non-synonymous mutations than THYM. Moreover, they found that mutations of epigenetic regulatory genes involved in chromatin modification pathways are common in TC in comparison to THYM (2).

      In the last years we have been interested in the characterization of genomic and epigenetic findings related to TET development. In our earlier microRNA (miR) study, we reported, among other findings, preliminary data on mature microRNAs differentially expressed in TC vs THYM, as revealed by microarray-based unsupervised clustering analysis. Among the differentially expressed miRs, 3 were validated by RT-qPCR (miR128, miR142-5p and miR-181c-5p) (3). By a different approach, we analyzed by Next Generation Sequencing (NGS) thirteen TC cases and one Atypical Type A thymoma case. The tissues derived from Formalin-fixed, paraffin embedded (FFPE) material including biopsies/surgical specimens of tumors and a single case of matched peritumoral thymus. The percentage of neoplastic cells was not < 70-80% of total cells. The DNA was extracted using the QIAcube and QIAamp DNA FFPE Tissue Kit (Qiagen, Valencia, CA) from microdissected 5 μm FFPE tissue sections. The NGS platform Ion S5 (Thermofisher) and the Ion AmpliSeq™Cancer Hotspot Panel v2 were used. This panel is designed to amplify 207 amplicons covering over 2,800 COSMIC mutations from 50 oncogenes and tumor suppressor genes. Libraries from Ion AmpliSeq Cancer Hotspot Panel v2 were prepared and sequenced by Ion Chef and S5 system. Data analysis was conducted by using the dedicated Ion Reporter Software. Among other genomic variants (polymorphysms and mutations were found in four cases), in one out of these four TC cases a KIT mutation (c.1900C>T; p.R634W, exon 13), already reported in TC, was identified. Moreover, a further KIT mutation ( c.1718C>T p.P573L, exon11) was found in a second case. In addition, a missense TP53 mutation ( c.824G>T; p.C275F), occurring in exon 8, was observed in a single case of TC, NOS. The patient harbouring a TC with this TP53 mutation had a R0 robotic-assisted thymectomy of a pT2 Thymic carcinoma (according to the 8th TNM edition), and after adjuvant chemotherapy and radiotherapy is alive and in complete remission with a follow-up of 22 months . The recent case of Atypical Type A thymoma showed a NOTCH1 c.4732_4734delGTG p.V1578del in exon 26 of uncertain significance.

      Basing on the relatively few cases reported in the literature, analyzed by different techniques for their genomic alterations, it appears that the mutation status of TC is highly heterogeneous. In the cases examined so far by NGS we didn’t find recurrent genetic aberrations, but a variety of alterations. Each case, with the panel available, revealed either polymorphisms or, in few cases, mutations in cancer-associated genes, both oncogenic and oncosuppressor. Among the genes involved, both the KIT reported variants could be considered relevant for targeted therapy. Moreover, the tumor suppressor gene TP53 is already known for its importance and frequency of mutations particularly in TC. Moreira et al reported recurrent TP53 mutations with unfavorable prognostic value (4). The TP53 mutation found in one of our cases (previously reported in cases of SQCC of upper respiratory tract, in lung, head & neck and esophageal carcinoma) affects, among others, the DNA damage repair, the cell cycle and the apoptosis pathways. In human thymus, the Notch pathway, activated in thymic EC, is crucial to T cell differentiation; moreover the Notch signaling is also involved in hematological and in solid tumors. The NOTCH1 c.4732_4734delGTG p.V1578del in exon 26 we reported in a Atypical case A thymoma was already described in lymphoid tissues. The clinical and prognostic value of the genomic alterations we observed needs to be definied.

      1) Radovich M, et al., The integrated genomic landscape of thymic epithelial tumors - Cancer Cell, 2018 Feb 12;33(2):244-258

      2) Wang Y, et al., Mutations of epigenetic regulatory genes are common in thymic carcinomas - Sci Rep. 2014 Dec 8;4:7336

      3) Ganci F, et al., MicroRNAs Expression Profiling of Thymic Epithelial Tumors - Lung Cancer 2014, 85 (2) 197–204

      4) Moreira AL, et al, Massively parallel sequencing identifies recurrent mutations in TP53 in thymic carcinoma associated with poor prognosis - J Thorac Oncol. 2015 Feb;10(2):373-80

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      MS08.05 - Basic Pathological Features (Now Available) (ID 3485)

      14:00 - 15:30  |  Presenting Author(s): Cesar Moran

      • Abstract
      • Presentation
      • Slides

      Abstract

      IASLC WCLC 2019

      MS08 – Management of Thymic Carcinoma

      Cesar A. Moran, MD

      Professor of Pathology

      M D Anderson Cancer Center

      Houston, TC

      USA

      Pathologic Features

      The basic pathological features of thymic carcinomas are essentially those seeing in other tumors elsewhere and require the presence of conventional features such mitotic activity, cellular and nuclear atypia, and necrosis among others. However, the diagnosis of thymic carcinoma contrary to the diagnosis of carcinomas in other anatomical areas requires a more strict radiological correlation, as thymic carcinoma can show similar histological features as other tumors such lung or head and neck area. Therefore, the clinical information of an anterior mediastinal mass in the absence of tumor elsewhere becomes an important diagnostic tool in the assessment of thymic carcinoma.

      The histopathological features of thymic carcinomas are vast and highly heterogeneous. It is possible that such heterogeneity may be due the different cell types that may be encountered in the normal thymus. However, in general terms, thymic carcinomas can be separated into neuroendocrine and non-neuroendocrine carcinomas, and further sub-divided into: 1) low grade and 2) high grade carcinomas (see table 1). Among the neuroendocrine carcinomas, similar spectrum as in other organ systems has been recognized, including: low grade, intermediate grade, and high grade neuroendocrine carcinoma. Some of these tumors may have special association with particular syndromes. Aside from the neuroendocrine carcinomas, the vast majority of thymic carcinomas are of the squamous type, which can show diversity in their growth pattern from well-differentiated keratinizing to the high-grade lymphoepithelioma-like carcinoma and anaplastic/pleomorphic carcinoma. In addition, the tumors may show different cell types and growth patterns that may include: papillary, micropapillary, clear cell, sarcomatoid carcinomas, and micronodular among others. In addition, it is important to highlight the occurrence of salivary gland type carcinomas in the thymus, examples of that include: mucoepidermoid carcinoma, adenoid cystic carcinoma and epithelial-myoepithelial carcinoma. More interesting is the fact that a small subset of thymic carcinomas will belong to the adenocarcinoma type, with similar features as those adenocarcinomas in other organ systems – mainly a malignant glandular proliferation. These tumors may also show variability in their growth pattern and may show a solid glandular proliferation or a predominantly mucinous component. Needless to say, these thymic adenocarcinomas can mimic metastatic disease from other organ systems such as lung or colon. Therefore, a close clinical correlation is also highly suggested before determining site of origin. It is due to this heterogeneity that the diagnosis of primary thymic carcinoma requires more strict clinical-radiological-pathological criteria, as there are no pathognomonic features that can define a thymic carcinoma, mainly in cases in which there is only a small mediastinoscopic biopsy for evaluation.

      From the immunohistochemical point of view, thymic carcinomas commonly express keratin, keratin 5/6, p63, p40, CD5. In addition, it is also well known that some neuroendocrine markers such as synaptophysin may be seen positive in otherwise conventional thymic carcinomas. On the other hand, thymic adenocarcinomas may express different immunohistochemical phenotype that may include: keratin 7, keratin 20, CDX-2, and CEA. In cases of neuroendocrine carcinomas the use of neuroendocrine markers including chromogranin, synaptophysin, and CD56 may prove useful. However, the grade of differentiation still can be done on morphological grounds. More recently, it has been identified a poorly differentiated carcinoma the so-called NUT carcinoma that by histology most likely represents a poorly differentiated squamous carcinoma but that shows positive staining using the immunohistochemical stain for NUT and also may show more specific cytogenetic and chromosomal abnormalities. Such diagnosis should be suspected in poorly differentiated carcinomas.

      Regarding the prognosis of thymic carcinoma, it has been identified that the presence of lymph node metastasis, regardless of the location of the lymph node, plays an important role in the clinical outcome of these patients. Therefore, thymic carcinomas are best suited for a TNM staging, contrary to the use of the TNM for thymomas.

      TABLE 1

      Histological Variants of Thymic Carcinoma

      Low grade High grade Neuroendocrine

      Mucoepidermoid carcinoma lymphoepithelioma-like Low grade (carcinoid)

      Basaloid carcinoma P.D. squamous cell Ca Intermediate (atypical carcinoid)

      Epithelial-myoepithelial Ca Anaplastic Ca High-grade (Small cell Ca)

      Well-diff. Squamous cell Ca Sarcomatoid Ca

      Rhabdoid Ca

      Hepatoid Ca

      Micronodular Ca

      Papillary/micropapillary Ca

      Clear Cell Ca

      NUT carcinoma

      Adenocarcinoma

      REFERENCES

      1.Shimosato Y, Kameya T, Nagai K, Suemasu K. Squamous cell carcinoma of the thymus. Analysis of 8 cases. Am J Surg Pathol 1977; 1:109-121.

      2.Snover DC, Levine GD, Rosai J. Thymic carcinoma. Five distinctive histological variants. Am J Surg Pathol 1982; 6:451-470.

      3.Suster S, Moran CA. Thymic carcinoma. Spectrum of differentiation and histologic types. Pathology 1998; 30:111-112.

      4.Moran CA, Suster S. Thymic carcinoma. Current concepts and histological features. Hematol Oncol Clin N Am 2008; 22:393-407.

      5. Suster S, Rosai J. Thymic carcinoma. A clinicopathologic study of 60 cases. Cancer 1991; 67:1025-1032.

      6.Weissferdt A, Moran CA. Thymic carcinoma, part I. A clinicopathologic and immunohistochemical study of 65 cases. Am J Clin Pathol 2012; 138: 103-114.

      7.Weissferdt A, Moran CA. Thymic carcinoma, part 2. A clinicopathologic correlation of 33 cases with a proposed staging system. Am J Clin Pathol 2012; 138:115-121.

      8.Kalhor N, Moran CA. Primary thymic adenocarcinomas: a clinicopathological and immunohistochemical study of 16 cases with emphasis on the morphological spectrum of differentiation. Hum Pathol 2018; 74:73-82.

      9.Moran CA, Suster S. Neuroendocrine carcinomas (Carcinoid Tumor) of the thymus. A clinicopathologic analysis of 80 cases. Am J Clin Pathol 2000; 114:100-110.

      10. Kalhor N, Moran CA. Mediastinal Pathology, Springer 2019, Chapter 8, pp 237-286.

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    MA20 - Thymic Tumors: From Molecular to Clinical Results and New Challenges in Other Rare Thoracic Tumors (ID 149)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 1
    • Now Available
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      MA20.07 - Thymomectomy and Total Thymectomy or Simple Thymomectomy for Early Stage Thymoma Without Myasthenia Gravis: An ESTS Thymic Working Group Study (Now Available) (ID 1683)

      11:30 - 13:00  |  Author(s): Enrico Ruffini

      • Abstract
      • Presentation
      • Slides

      Background

      Resection of thymic tumors has traditionally included removal of the tumor and the thymus gland (thymothymomectomy). Nevertheless, in recent years, some authors questioned the need to remove the thymus gland in non-MG thymomas, suggesting that resection of the tumor (simple-thymomectomy) is enough from an oncological point of view in Stage I (TNM stage classification) thymoma patients. The aim of our study was to compare short- and long-term outcome of thymothymomectomy vs. simple-thymomectomy using European Society of Thoracic Surgeons (ESTS) Thymic Database.

      Method

      We investigated 1131 patients with thymic epithelial tumors included in the ESTS-Thymic Database. Three-hundred twenty-four clinical stage I (cT1N0M0, according to the 8th edition of the UICC/AJCC TNM stage classification) without Myasthenia Gravis (non-MG) thymoma cases were evaluated from 23 contributing centers (2000-2017), of which 300 (93%) thymothymomectomy and 24 (7%) simple-thymomectomy. Surgical upstaging was evaluated. In pathological stage I, we compared the completeness of resection, the rate of complications, the 30-day mortality, the overall survival and the disease-free survival (DFS).

      Result

      Overall, we observed an upstaging to stage III in 10 (3%) patients. We did not observe any significant difference between the two techniques in terms of the completeness of resection, the rate of complications and the 30-day mortality. The 5-year overall survival rate was 94% in the thymothymomectomy group and 56% in the simple-thymomectomy group (Figure 1 - P= 0.0004). The 5-year DFS was 95% in the thymothymomectomy group and 82% in the simple-thymomectomy group (Figure 1 -P= 0.013).

      figure 1.png

      Conclusion

      Patients affected by stage I TNM non-MG thymoma submitted to thymothymomectomy presented a significantly better DFS and overall survival than those submitted to simple-thymomectomy. Thymothymomectomy should be considered the procedure of choice in Stage I TNM non-MG thymomas, also considering the not negligible rate of pathological upstaging.

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    P2.06 - Mesothelioma (ID 170)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.06-23 - The Accuracy of Video-Assisted Thoracic Surgery Pleural Biopsy in Patients with Suspected Malignant Pleural Mesothelioma: A Real-Life Study (Now Available) (ID 1690)

      10:15 - 18:15  |  Author(s): Enrico Ruffini

      • Abstract
      • Slides

      Background

      The heritage of occupational and environmental asbestos exposure in Piedmont, Italy, is an enduring epidemic of malignant pleural mesothelioma (MPM). Pleural biopsy (PB) performed via thoracoscopy (or video-assisted thoracic surgery (VATS)) remains the diagnostic gold standard for patients with suspected mesothelioma. The aim of our study was to investigate the accuracy of PB via VATS and to analyze the diagnostic path of the patients who experienced an initial MPM misdiagnosis.

      Method

      Patients who underwent PB by VATS for suspected MPM from 2004 to 2013 were analyzed . The Registry of Malignant Mesothelioma (RMM) records were examined to crosscheck incident cases and to recognize misdiagnosed MPM. Sensitivity and specificity of the initial PB assessment versus the final classification of cases by RMM were evaluated. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using log-rank test.

      Result

      km_mpm.png

      Data of 552 patients were analyzed. Of those, MPM was diagnosed in 178 cases (32%) and no false-positive PBs were observed. Sensitivity and specificity were 93% and 100%, respectively. The number of false-negative PBs was 14 (2%). Of those, 10 (71%) had an initial diagnosis of chronic pleuritis, 3 (28.5%) of atypical mesothelial proliferation and 1 had reactive mesothelial proliferation. All of them reported a history of asbestos exposure and the correct diagnosis was reached after a median of 160 days (interquartile range 86-243) as follow: 9 (64%) after a further PB by VATS, 3 (22%) by cytology examination of a pleural effusion, 1 (7%) by fine-needle biopsy and 1 (7%) by open surgery . The median survival time of the patients with eventual MPM diagnosis was 13.8 months (CI 95%: 10.3-16.6). ). One- and 4-year survival were 52% and 10% in MPM PB positive cases and 50% and 19% in false-negative cases (P=0.66) (Figure 1).

      Conclusion

      When a history of asbestos exposure is reported and a strong clinical suspicion persists after a negative PB, iterative biopsy attempts should be considered. In high-volume centers, MPM misdiagnosis rate remains small and future advancement in diagnostic technologies could further increase the accuracy of diagnosis.

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    P2.17 - Treatment of Early Stage/Localized Disease (ID 189)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.17-29 - Impact of Second Predominant Pattern on Recurrence in Early Stage Resected Lung Adenocarcinoma: A Multicentric Study (Now Available) (ID 2515)

      10:15 - 18:15  |  Author(s): Enrico Ruffini

      • Abstract
      • Slides

      Background

      The ATS/ERS/IASLC adenocarcinoma classification allowed not only a better anatomical-pathological definition, but it showed a significant influence on long-term outcomes. It has been proposed that adenocarcinoma patterns could be divided in three groups according to their clinical and pathological behaviors: low (lepidic), moderate (papillary or acinar) and high grade (micropapillary and solid). Moreover, different patterns might mingle influencing biological features and prognosis. We focused on resected adenocarcinomas analyzing the impact of second predominant pattern on recurrence rate and Disease-Free Survival (DFS).

      Method

      We retrospectively collected all stage I and II lung adenocarcinoma operated on between January 2014 and December 2017 in seven European thoracic surgery departments. We selected all patients who underwent an anatomical resection with lymphadenectomy; patients with incomplete follow up, pure adenocarcinoma or those composed by more than two subtypes (if third pattern accounted for more than 10%) were excluded. Mucinous adenocarcinoma were considered separately from other patterns. DFS, incidence and localization of recurrence were calculated according to the second predominant pattern.

      Result

      Among 500 patients, 331 were selected. There were 186 male, mean age was 68.1 years (±SD 8.2) and 105 (31.7%) patients were active smokers at the moment of diagnosis. The majority of patients (271, 81.9%) underwent a lobectomy. Low, medium and high-grade first predominant pattern were 45 (13.6%), 208 (62.9%), 57 (17,2%) respectively and 21 cases were mucinous.

      Second predominant pattern was present as follow: acinar 96 (29%), lepidic 86 (26%), papillary 74 (22.4%), solid 29 (8.8%), micropapillary 26 (7.9%), 20 mucinous (6%). DFS analysis showed a significant impact of grade of the second predominant pattern (p=0.046), while first predominant pattern’s grade did not significantly impact on DFS (p=0.322). According to the subtypes of second predominant pattern, lepidic pattern showed a better mean DFS (56.1 versus 49.6 months, p=0.014) and a lower recurrence rate (p=0.018, and, in particular, a lower distant recurrence rate, p=0.016), while micropapillary had a worse DFS (42.3 versus 52.1 months, p=0014), higher recurrence rate (p=0.017, and in particular, a higher regional recurrence, p=0.038); moreover, also pleural invasion influenced DFS significantly (p=0.001). At multivariate analysis, lepidic second pattern and pleural invasion confirmed their influence on DFS (p=0.044, IC 0.28-0.98 and p=0.001, IC 1.36-3.4).

      When we analyzed the subgroup with only moderate grade (acinar and papillary) first predominant pattern (208 patients), lepidic and micropapillary second predominant patterns and pleural invasion confirmed their significant impact on DFS (p=0.015; p=0.021; 0.015 respectively).

      Conclusion

      Our multicentric study confirms the impact of adenocarcinoma patterns on recurrence rate and DFS. The second predominant pattern in early stage resected adenocarcinoma seems to play an important role in influencing the outcomes. Micropapillary and lepidic second pattern demonstrated to be significantly related to recurrence development and their presence should require different and dedicated postoperative management.

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