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H.L. Kindler

Moderator of

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    ED13 - Treatment of Malignant Pleural Mesothelioma (ID 282)

    • Event: WCLC 2016
    • Type: Education Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 6
    • Now Available
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      ED13.01 - Biomarkers in Malignant Pleural Mesothelioma (Now Available) (ID 6495)

      H. Pass

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ED13.02 - Tissue-Based Biomarkers (Now Available) (ID 6496)

      G. Reid, S. Kao, N. Van Zandwijk

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Introduction: Malignant pleural mesothelioma (MPM) is difficult to diagnose and accurate prediction of patient outcomes still relies on a range of clinical scores. Despite extensive efforts in the last decade, there are few tumour-based molecular markers that can accurately contribute to diagnosis and prediction of disease course. Recent reports describing the mutational and transcriptional landscape of MPM tumours have revealed a number of changes that may yield clinically useful biomarkers following further development and validation studies. Diagnosis: The definitive MPM diagnosis relies on a tissue biopsy and demonstration of invasion. Diagnostic markers consist of a combination the expression of mesothelial-specific proteins and absence of markers of adenocarcinoma. Recent advances have shown that the mutation of the tumour suppressor BAP1 leads to loss of nuclear staining, and that this is highly specific for discriminating mesothelioma from benign conditions. As in some cases MPM has neither BAP1 mutation nor loss of nuclear staining, sensitivity is lacking, but this can be improved by incorporating detection of CDKN2A genomic loss using FISH. Assessment of additional mutations and fusion genes recently identified in MPM may represent useful markers for future development. Characteristic changes in microRNA expression are present in MPM, and these form the basis of a highly accurate molecular test for the differential diagnosis of MPM from other tumours affecting the pleura. Prognosis: Clinical and pathological parameters remain the best predictors of disease outcome, and although some molecular markers have demonstrated prognostic significance, these are yet to be validated. Histopathological subtype is an accurate prognostic indicator, with the epithelioid subtype associated with significantly better outcomes than the non-epithelioid biphasic and sarcomatoid types. The variation within epithelioid tumours is well recognised, and epithelioid tumours with a pleomorphic morphology have poor prognosis, similar to patients with non-epithelioid tumours. Recent results from transcriptomic analyses have revealed subsets within epithelioid and non-epithelioid tumours which more accurately describe prognosis. These include the two-cluster C1/C2 classification system based on a 3 gene predictor, and the 4 clusters (sarcomatoid, epithelioid, biphasic-epithelioid and biphasic-sarcomatoid) derived from RNA-seq analysis. MicroRNA expression has also been linked to outcome. Early studies revealed prognostic significance of miR-29c-3p, with higher levels corresponding to longer survival. More recently, microRNA expression profiles differing between long and short survivors yielded a 6-microRNA score that predicted outcome in two surgical series. Whether TCGA data confirm these observations remains to be determined. In addition to RNA and protein biomarkers, the cellular composition of tumours influences patient outcomes. It is likely that the mix of cell types within tumour samples also contributes to biomarker expression, especially for RNA extracted from whole tumours. For some proteins, differential expression in the stromal and tumour compartments is of prognostic value, for example in the case of SPARC expression. The importance of the immune cell infiltrate was recently investigated in a large number of epithelioid samples revealing that greater numbers of tumour-infiltrating CD4+ and CD8+ T lymphocytes (TILs), as well as fewer tumour-associated macrophages (TAMs) of the M2-type correlate with survival. In addition, the ratio of the TAMs/TILs was also shown to predict outcome in epithelioid MPM. Other cell populations associated with vascular and lymphatic invasion are also linked to survival. Prediction: Unlike lung cancer, few actionable mutations are present in MPM that predict sensitivity to targeted agents, and clinical trials with these drugs have yielded disappointing results. Markers for single agent chemotherapy and the standard cisplatin/pemetrexed doublet have also been investigated in retrospective studies attempting to link patient outcomes with gene (mRNA and protein) expression and polymorphisms. Multiple reports have linked levels of TS protein, but not mRNA, to outcomes with pemetrexed-based chemotherapy. As expected from a multi-targeted agent, other levels of other proteins such as folypoly-glutamate synthase (FGPS) and the reuced folate carrier (RFC) were also associated with tumour response and patient outcomes. However, a subsequent study with a similar number of patients suggested that both TS and FPGS lack predictive value. With respect to DNA repair genes involved in cisplatin activity, ERCC1 and others have been evaluated, but results are again inconclusive. The picture is complicated by assessment of target genes in patients treated with two interacting agents (with or without subsequent surgery), and the true value of these genes awaits carefully controlled prospective analyses. The recent breakthrough success of immune checkpoint inhibiting antibodies targeting CTLA4 and the PD-1/PD-L1 axis in melanoma and lung cancer has seen these agents applied to MPM patients. With response rates of around 25% for PD-1 targeting antibodies pembrolizumab and nivolumab in MPM, new predictive markers are needed to improve patient selection and for health economics reasons. Although the Keynote trial included patients based on positivity of PD-L1 staining, PD-L1 status appears to have little value in predicting response rate. Ongoing research into immune cell involvement may shed more light on this. Future directions: Continuing research in this area should learn from limitations of the biomarker studies of the last decades to improve the search for useful molecular markers. Large prospective trials are needed to carefully evaluate predictive markers. Alternative approaches such as the analysis of live cell populations taken from fine-needle aspirates and investigation of circulating tumour cells and tumour-derived markers in the circulation (DNA, exosomes) may yield novel markers. Conclusions: Extensive research into tumour-based markers for MPM is gradually making progress. New markers to assist in diagnosis and prognosis have been identified, but the selection of accurate predictive markers has so far remained elusive. Next-generation sequencing has identified multiple new candidate markers requiring further investigation, and may provide breakthroughs in the future.

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      ED13.03 - Surgery with Adjuvant or Induction Radiotherapy (Now Available) (ID 6497)

      M. De Perrot

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ED13.04 - Systemic Induction Therapy of Malignant Pleural Mesothelioma (Now Available) (ID 6498)

      P. Baas

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Over the last 3 decades clinical researchers have focused on the optimal treatment of patients with mesothelioma (MPM). In the 80’s surgery had become a standard approach in some centers but it became clear that a complete resection (R0) was not achievable. The anatomical location of the mesothelioma simply does not allow a resection with save margins of normal tissue. Therefore additional therapies were looked for and a different number of approaches have been taken. To answer the question if any systemic induction therapy is considered the best, this can be answered with a clear No. reasons for this is the lack of randomized studies in this patient population and the fact that patients with MPM are grouped together despite differences in pathology, surgical approach (EPP vs Pleurectomy decortication) and biological behavior. There has been a number of preferential approaches with chemotherapy in this disease ranging from Induction chemotherapy; Intracavitary therapy and Adjuvant chemotherapy. (table) In the case of induction therapy it is clear that one aims at reducing the tumor bulk and to prevent metastases during surgery. The preferred treatment is cisplatin with pemetrexed since this is considered to be the standard of this disease.(1) Other regimens have been tested in small extend but usually involved. The use of intra-cavitary treatment has attracted attention since MPM cells show the tendency to stay localized in the thoracic cavity for a relative long period. The administration of a local cytotoxic drug would allow an improvement in local control and limited systemic effects. Cisplatin has been used frequently during surgery and were combined with heating of the lavage fluid to 40[0]Celsius. (2) Special precautions for this so-called Hyperthermic lavage approach have to be taken in the operating suite with protection of the staff to avoid exposure to the drugs. In general the lavage procedure adds another hour to the debulking surgery. Measurements of platin adducts in the blood during this procedure have shown that there is no important systemic levels measured. Unfortunately there has not been any comparison of these approaches. Most series only report the feasibility of the treatment with sometimes impressive survival figures. These are partly due to the strong selection of patients for the studies. A relative new approach is the use of a platin containing fibrin glue that can be applied to the thoracic wall after debulking using a spray system. The initial results indicate that the treatment is fast and serial biopsies show that the effect is sustained for many weeks.(3) Finally, adjuvant therapies can be applied. In this field, there are no data to support any specific treatment and the choices are generally defined based on the study protocol. No prospective trials have been reported Most of the studies are trimodality therapies where RT is an important part of the protocol. One typical example is the EORTC study where the feasibility of trimodality therapy in a phase II trial (EORTC 08031) with clearly defined timelines was tested(5). Patients with pathologically proven mesothelioma received induction chemotherapy (3 courses cisplatin and pemetrexed ) followed by EPP within 21–56 days after the last dose of chemotherapy in the absence of progressive disease and unacceptable toxicity. A ‘‘success of treatment’’ was defined as a patient who had received the full protocol and was alive after 90 days without progressive disease and without grade 3 or 4 toxicity. Of the 57 patients included, 42 had EPP (73.7%) after induction therapy. The 90-day mortality was 6.5% with an overall survival time of 18.4 months and progression-free median survival time of 13.9 months. Only 24 (42.1%) patients met the definition of success, thereby failing the primary endpoint. This study shown how difficult it is to complete a trimodality study in this patient group and only when a standard is defined, proper comparative studies can be performed. Other important studies addressing the neo-adjuvant approach are presented in the table. 1.Baas P, Fennel D, Kerr K, van Schil PE. Malignant Pleural Mesothelioma: Guidelines for Diagnosis, treatment and follow-up. Annals Oncology 2015 2.Sugarbaker DJ, Gill RR, Yeap BY, Wolf AS, DaSilva MC, Baldini EH, Bueno R, Richards WG. Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural Mesothelioma undergoing surgical macroscopic complete resection. J Thorac Cardiovasc Surg. 2013 Apr;145(4):955-63. 3.Opitz I. Use of fibrin glue in malignan pleural mesothelioma, presented at the xxth IMIG conference Birmingham UK 4.Van Schil P, Baas P, Gafaar R, Maat AP, van der Pol M, Hassan B et al. Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial. 5.Weder W, Stahel RA, Bernhard J, Bodis S, Vogt P, Ballabeni P, et al. Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. Ann Oncol 2007;18:1196-202 6.Cao C, Tian D, Manganas C, Matthews P, Yan TD. Systematic review of trimodality therapy for patients with malignant pleural mesothelioma. Ann Cardiothor Surg 2012;1:428-37 Table

      Study type # pts drugs Completed Chemotherapy Completed Surgery Completed Radiotherapy Outcome (mOS)
      SAKK 17/04 Lancet Onc 2015;16;1651 Neo-adj 151 Cis/pem 145 125 23/27 in 2nd stage 7.6-9.4
      Frederico BMC Cancer 2013;13;22 Neo-adj 54 Cis/pem 96% 83% 41% 15.5
      Krug JCO 2009;27;3007 Neo-adj 77 Cis/pem 83% 74% 52% 16.8
      Weder JCO 2004;22;3451 Neo-adj 20 Cis/gem 90% 80% n.a. 23
      Van Schil ERJ 2010;36;1362 Neo-adjuvant 59 Cis/pem 93% 79% 65% 18.4
      Richards JCO 2006;24;1561 intracavitary 61 Cispl 50-225 n.a. 72% n.a. 9.0
      Tilleman JTCS 2009;138;405 intracavitary 121 Cispl 225 n.a 79% n.a. 12.8


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      ED13.05 - Systemic Therapy of Inoperable Malignant Pleural Mesothelioma (Now Available) (ID 6499)

      A. Scherpereel

      • Abstract
      • Presentation
      • Slides

      Abstract:
      To date, the treatment of malignant pleural mesothelioma (MPM), a rare and aggressive tumor usually induced by previous asbestos exposure, relies mostly on chemotherapy and best supportive care (BSC). But medical treatment has been so far quite deceptive with median overall survival (mOS) about one year at its best for the last 13 years with recommended first line chemotherapy by cisplatin (or carboplatin) and pemetrexed in patients fitted for it. The optimal duration of first line chemotherapy is unknown but a maximum of 6 cycles is recommended. There was no evidence supporting maintenance treatment by pemetrexed or other drug. Pathogenesis of MPM includes overexpression of growth factors, many genetic and epigenetic alterations and/or mutations of malignant cells responsible for cell proliferation and resistance to apoptosis, pleural inflammation and local immunosuppression induced by the tumor and favoring its growth. These elements provide the rationale for many targeted therapies and immunotherapy. But so far, very few drugs exhibited sufficient value to deserve further trials. Thus, first trials assessing anti-angiogenic drugs in MPM did not support their use in this cancer despite the key role of VEGF. A phase III testing thalidomide as maintenance treatment after cisplatin/pemetrexed (Cis/Pem) was negative, as well as phase II trial of bevacizumab (anti-VEGF antibodies) combined with first line cisplatin/gemcitabine. But other phase II trials evaluating bevacizumab with Cis or Carbo/Pem were promising with progression-free survival (PFS) of 6.9 months. Therefore, a phase III randomized (1:1) « MAPS » trial recruited 448 unresectable MPM patients to test Cis/Pem with (arm B) or without (arm A) bevacizumab. Arm B non-progressive patients received bevacizumab maintenance until progression or toxicity. Median overall survival (mOS) was significantly longer in the B arm: 18.8 [95%CI: 15.9-22.6] vs. 16.1 months [14.0-17.9] in the A arm, (adj.HR= 0.76, p=0.012). Thus, bevacizumab addition to Cis/Pem provided a significantly longer survival in MPM patients with acceptable toxicity, making this triplet a new treatment paradigm for this cancer. Moreover, there was no detrimental effect of bevacizumab on quality of life (QoL) despite its higher specific but manageable toxicity. There was no significant difference between arms for the percentages of drug delivery or of second line treatment to explain why adding bevacizumab to Cis/Pem significantly increased mOS, even if MAPS standard arm patients had a longer OS than patients from historical series or previous trials. Based on the same rationale than the MAPS trial, nintedanib, a drug targeting VEGF, FGF and PDGF receptors, is currently tested versus placebo in MPM patients treated by first line Cis/Pem chemotherapy in a large phase II/III randomized trial. Early I or II trials assessing drugs targeting mesothelin, a mesothelial cell surface molecule overexpressed in (mostly epithelioïd) MPM, showed promising results in combination with first-line Cis/Pem, justifying further, randomised and larger studies. Thus, very interesting trials are ongoing with anti-mesothelin monoclonal antibodies (mAbs) alone (amatuximab, a chimeric IgG1 antibody), or planned with immunotoxins (mAbs combined with anti-tubulin (anetumab ravsantine) or Listeria toxins (CRS-207) versus placebo combined with Cis/Pem too. For non-epithelioïd MPM patients, another hope might come from the dependence to arginin exhibited by argininosuccinate synthetase -1 (ASS-1) tumors such as mesothelioma, and the good results of Pegylated Arginine Deiminase (ADI-PEG 20) alone or in combination with Cis/Pem, assessed in the phase I « TRAP » trial recently presented by Szlosarek and al. A phase II/III trial (Polaris), comparing first line Cis/Pem with ADI-PEG 20 or placebo, will start in 2017 for biphasic (mixed) or sarcomatoïd MPM only because they exhibit ASS-1 defect twice more frequently than epithelioïd subtype. Finally, other innovative drugs also candidates for first line treatment in combination with Cis/Pem, after preliminary positive clinical trials, include gene therapy, cell therapy using chimeric antigen receptors (CARs) or dendritic cells (DC), or oncovirotherapy, and will be assessed as first line treatment in MPM very soon or later. For example, the European “DENIM” phase III trial will test DC based immunotherapy with allogenic tumor cell lysate as maintenance treatment after Cis/Pem chemotherapy in MPM patients. But, as in lung cancers, immune checkpoint inhibitors (ICI) seem to represent presently the most exciting tool for MPM patients. In fact, even if a recent, large phase II trial (n=564; “Determine”) with anti-CTLA-4 mAb (tremelimumab) versus placebo in 2[nd]/3[rd] line treatment did not meet its first endpoint (mOS) (21), early data of a phase Ib basket trial with anti-PD-1 mAb (pembrolizumab) showed promising response rate (RR) of 28% and DCR of 76% in PD-L1 positive MPM (22). Other trials with checkpoint inhibitors are ongoing with anti-PD-1 alone (nivolumab, pembrolizumab), or a combination of anti-PD-1 (nivolumab) or anti-PD-L1 (durvalumab) and anti-CTLA-4 (tremelimumab or ipilimumab) as first or 2[nd]/3[rd] lines treatment. Interestingly, new clinical trials are already underway to assess value of ICI, such as nivolumab + ipilimumab combo, versus Cis/Pem as first line treatment. In conclusion, the triplet cisplatin/pemetrexed/bevacizumab may be a new first line standard of care for patients eligible for bevacizumab, and not candidate to multimodal treatment trials. Second line and further lines treatments are very limited with no validated options except pemetrexed in case of late relapse after platinum/pemetrexed. But exciting drugs and strategies were tested in this testing, in particular ICI. But remaining key questions include which predictive biomarkers for these innovative, thrilling but expensive treatments to target the best patients for each drug? And how to potentially combine these drugs versus, or in combination with, standard chemotherapy? Thus real hopes seem closer for our MPM patients with new systemic treatments.

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      ED13.06 - Mesothelioma in a Setting of Germline BAP1 Mutations (Now Available) (ID 6500)

      M. Carbone, H. Pass, H. Yang

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Individuals that are born with germline BAP1 mutations are affected by the BAP1 cancer syndrome. All individuals affected by this cancer syndrome have developed one or more malignancies in the course of their life. Mesothelioma, uveal and cutaneous melanomas –tumors often associated with exposure to environmental carcinogens-, are the most common malignancies, although almost any tumor type has been detected in carriers of this cancer syndrome. In addition, BAP1 mutant carriers develop multiple benign melanocytic tumors –histologically different from other SPITZ-like tumors- that we have called melanocytic BAP1 associated intradermal tumors (MBAITs) that can alert the physician that the patients is a carrier of the BAP1 cancer syndrome. Most malignancies develop after the 4[th] decade of life, although cancers in individuals as young as 19 years old have been detected. Because many of these malignancies, for example melanomas, can be cured by early detection, it is important to identify BAP1 mutant carriers that can be screened for early detection and curative resection. Moreover, carriers of germline BAP1 mutation may be at increased risk of developing mesothelioma and melanoma following exposure to low doses of asbestos, sunlight and X-Rays, thus cancer preventive measures can be implemented. When cancer develops in a setting of BAP1 germline mutations, these patients have a much better prognosis compared to patients with the same malignancies when they occur sporadically (i.e., not in carriers of BAP1 mutations). Familial mesotheliomas in these individuals occur in either the pleura or peritoneum (frequency ratio 1:1) at a median age of 56.3 years, have a male-to-female ratio of 0.73:1, and are associated with prolonged survival of 5 to 10 or more years, compared with a median age at diagnosis of 72, a pleural-to-peritoneal ratio of 86:14, a male-to-female ratio of 4:1, and a median survival of less than 1 year in sporadic mesothelioma. About 100 families with this mutated BAP1 cancer syndrome have been described in the United States, Europe, and New Zealand. Genetic studies demonstrated that these mutations are transmitted across multiple generations over the course of several centuries, and some US families carrying BAP1 mutations descend from a Swiss family that immigrated in the US in the early 1700s. An International Consensus Meeting sponsored by the IASLC supported medical screening for at-risk people who are carriers of BAP1 germline mutations as follows: (1) annual dermatological screening for early detection of melanoma at age 18 or younger; (2) annual eye examination/ophthalmoscopy for uveal melanoma at age 18 or younger; and (3) skin and eye examinations every 6 months after age of 30, when the frequency of cancer among carriers of germline BAP1 mutations starts to increase. It was also recommended that genetic counseling should be offered to all individuals tested for BAP1. Moreover, those with BAP1 germline mutations should be ncouraged to participate in studies to improve early detection of mesothelioma (Carbone M. et al., Journal of Thoracic Oncology 11, 1246-1262, 2016).

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Author of

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    OA13 - Immunotherapy in Malignant Pleural Mesothelioma: Current Status of Trials and New Approaches (ID 392)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
    • Now Available
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      OA13.02 - Phase II Trial of Pembrolizumab in Patients with Malignant Mesothelioma (MM): Interim Analysis (Now Available) (ID 6232)

      H.L. Kindler

      • Abstract
      • Presentation
      • Slides

      Background:
      Pembrolizumab showed significant activity in PD-L1+ MM in a phase IB study (Alley, 2015). We are conducting a phase II trial (NCT02399371) of pembrolizumab in previously-treated MM patients to further characterize its activity in a larger, non-selected population, determine a PD-L1 expression threshold, and interrogate the microenvironment.

      Methods:
      Eligible patients have histologically-confirmed pleural or peritoneal MM, measurable disease, PS 0-1, disease progression on/after pemetrexed/platinum, 1-2 prior regimens, normal organ function, and available tissue. Patients receive 200 mg pembrolizumab IV Q21 days and CT scans Q9 weeks. Primary objectives: 1) determine the objective response rate in: A] an unselected population and, B] a PD-L1 positive population; 2) determine the optimal threshold for PD-L1 expression using the 22C3 antibody-based IHC assay (Qualtek). Exploratory correlatives profile the inflammatory microenvironment via: a) multi-color immunofluorescence of tumor infiltrating lymphocytes (TILs) and macrophages, b) RNA-based inflammation signatures/pathway activation, c) characterizing underlying mutations/copy number changes. Proceeding to a 2[nd] stage requires ≥3 responses in 35 patients. If an optimal threshold for PD-L1 expression is determined, the 2[nd] stage only enrolls above that threshold.

      Results:
      35 patients enrolled 5/15-2/16. 1 withdrew. Male 82%; median age 63 (range 26-85); PS 0/1 63%/37%; epithelial/sarcomatoid/biphasic/NOS: 69%/26%/3%/3%; pleural/peritoneal 86%/14%; 1 prior regimen: 60%. Mean cycles: 8.5 (range 1-18). Median progression-free survival: 6.2 months (95% CI: 3.2, 8.2). Median overall survival has not been reached. Partial response: 7 (21%), stable disease (SD): 19 (56%); progression: 6 (18%); early death: 2 (6%). Ten patients received treatment beyond progression; 20% subsequently achieved SD. Grade 3/4 toxicity: pneumonitis 6%, fatigue 6%, adrenal insufficiency 6%, colitis 3%, confusion 3%, hyponatremia 3%, neutropenia 3%. Grade 1/2 immune-related toxicities: hypothyroidism 17%, rash 14%, pruritus 11%, diarrhea 9%, uveitis 6%, arthralgia 6%, hepatitis 3%, infusion reaction 3%, mucositis 3%. Grade 5 toxicities: autoimmune hepatitis 3%, unknown 3%. PD-L1 expression by tumor proportion score (N=31): none (< 1%): 55%; low (1%-49%): 19%; high (≥ 50%): 26%. PD-L1 expression did not correlate with response (ROC area 0.62; 95% CI: 0.32, 0.94).

      Conclusion:
      Pembrolizumab has robust activity in PD-L1 unselected, previously-treated MM patients, with a response rate of 21% and a disease control rate of 76%. An optimal PD-L1 threshold could not be established in this small sample. The 2nd stage is enrolling an additional 30 patients without PD-L1 pre-selection. Correlative studies including CD8 TILs, macrophage characterization, and presence of T-regulatory cells will be presented. Funded by a grant from the Mesothelioma Applied Research Foundation.

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    P2.06 - Poster Session with Presenters Present (ID 467)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
    • Presentations: 2
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      P2.06-027 - Randomized Phase II Study of Anetumab Ravtansine or Vinorelbine in Patients with Metastatic Pleural Mesothelioma (ID 5671)

      H.L. Kindler

      • Abstract

      Background:
      Mesothelioma is a rare but aggressive cancer with a poor prognosis. Mesothelin is a cell surface protein that is highly expressed in mesothelioma and other epithelial cancers. Anetumab ravtansine (BAY 94-9343), a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DM4, has shown encouraging efficacy in mesothelioma patients in a phase I study. To further explore the possible benefit of antibody-drug conjugate therapy for mesothelioma, we initiated a randomized, open-label, active-controlled, phase II trial to evaluate the efficacy and safety of anetumab ravtansine in patients with metastatic pleural mesothelioma (MPM) overexpressing mesothelin and who have previously progressed on platinum/pemetrexed-based first-line chemotherapy (NCT02610140).

      Methods:
      Patients (≥18 years) with unresectable locally advanced or metastatic MPM are eligible. Patients should have recurrent or relapsing disease after having previously receiving first-line treatment with pemetrexed-based chemotherapy, with or without bevacizumab. Obligatory biomarker sampling will be performed on all patients at pre-screening and mesothelin-positivity as determined by Ventana MSLN (SP74) companion diagnostic assay as a requirement for entry. The primary objective is to test the superiority of anetumab ravtansine monotherapy over vinorelbine in progression-free survival (PFS) per modified RECIST criteria for MPM per central review. The secondary objectives of this study include overall survival, patient-reported outcomes (PRO), tumor response, and safety. Exploratory objectives include immunogenicity of anetumab ravtansine, pharmacokinetics, and biomarkers of response. Approximately 210 patients will be randomized in a 2:1 ratio to receive anetumab ravtansine 6.5 mg/kg Q3W or vinorelbine 30 mg/m[2] QW. Novel study methods include a grading system for AEs of special interest and the PRO instruments.

      Results:
      This trial is open and currently accruing patients globally.

      Conclusion:
      Section not applicable.

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      P2.06-029 - Pilot Window-Of-Opportunity Study of Pembrolizumab in Patients with Resectable Malignant Pleural Mesothelioma (MPM) (ID 6268)

      H.L. Kindler

      • Abstract

      Background:
      Although PD-1 inhibitors have demonstrated significant activity in MPM (Alley, WCLC 2015; Kindler, WCLC 2016), not all patients benefit. About 1/3 of MPM have high PD-L1 expression and a CD8+ infiltrative pattern with a gamma-interferon gene expression profile; this phenotype has been employed in tumors such as melanoma to predict for benefit from immune checkpoint blockade (Ribas, ASCO 2015; Seiwert, ASCO 2015). The mechanisms of anti-tumor response in a disease with a low mutational burden and a distinct macrophage-dominant immune microenvironment remain poorly understood. Due to the anatomy of MPM, access to tumor tissue for correlative studies can be problematic without surgery. We therefore initiated a window-of-opportunity study of pembrolizumab in patients with resectable MPM (NCT02707666) to better understand the dynamic changes occurring with PD-1 checkpoint blockade.

      Methods:
      Eligible patients have previously untreated, histologically confirmed, epithelial or biphasic MPM amenable to maximal surgical debulking via extended pleurectomy/decortication. Measurable or evaluable disease, PS 0-1, no extra-thoracic disease, adequate pulmonary and cardiac function, and a free pleural space for video-thoracoscopy (VATS) are required. PET/CT and VATS to obtain tissue for correlative studies are performed at baseline. Patients receive 3 cycles of pembrolizumab, 200 mg IV Q21 days followed by repeat PET/CT. Extended pleurectomy/decortication is performed at least 4 weeks later. Adjuvant cisplatin/pemetrexed x 4 cycles is administered 6-8 weeks after surgery, followed by optional adjuvant pembrolizumab x 1 year. The primary objective is to assess an increase in gamma-interferon, measured via a gene expression profile (GEP), comparing matched pre- and post-treatment samples (IFN-G GEP response), and to identify additional candidate biomarkers that may predict benefit or constitutive resistance to pembrolizumab. Correlative studies include: a) multi-color immunofluorescence (CD8, CD4, PD-L1, FOXP3), b) evaluation of immune-related gene expression signatures (using Nanostring/RNAseq), c) evaluation of alternative immune checkpoints, d) determination of mutations in antigen presenting machinery, and e) assessment of activation of immunosuppressive signaling pathways. Radiologic correlatives use image-based texture analysis on PET/CT scans to evaluate therapy-induced changes in tumor composition. This is an exploratory trial. Fifteen patients will be enrolled, which provides a standard error for the estimated IFN-G GEP response rate of approximately 10% (assuming the true response rate is close to 20%). This will also provide 80% power to detect a 0.8 standard deviation change in pre-post treatment biomarker levels, using a paired t-test at the 0.05 alpha level.

      Results:
      Section not applicable.

      Conclusion:
      Section not applicable.

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

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      P3.03-036 - Prognostic Model for Mesothelioma Based on Cancer and Leukemia Group B (CALGB) Trials (Alliance) (ID 3976)

      H.L. Kindler

      • Abstract

      Background:
      Prognostic models play an important role in the design and analysis of mesothelioma treatment trials. The European Organisation for Research and Treatment of Cancer (EORTC) developed a well-known tool in 1998 to predict overall survival (OS) in patients with malignant mesothelioma. In this study, we built and assessed the performance of a new mesothelioma prognostic model OS using data from multiple CALGB clinical trials data.

      Methods:
      This study included 595 mesothelioma patients from fifteen completed CALGB treatment trials accrued between June 1984 and August 2009. We split the cohort of patients into two parts - 67% of patients as training and 33% as testing. We developed a Cox model using the training set with PS, age, WBC count, and platelet count as prognostic variables. To compare the EORTC and our new models, the concordance of predicted survival times and risk scores were estimated by concordance C (c-index) (Harrell et al. 1996) and AUC score at 6-months (Patrick et al. 2000). 95% confidence intervals were calculated for the c-index. Based on the prediction model fit from training set, we partitioned testing set patients into high-risk and low-risk groups using the median for their risk score values for the new model. For the EORTC model, the cut off of 1.27 from the original paper was used to assign the high-risk and low-risk groups. A Log-rank test was used to compare the survival curves of these two groups. We also compared our results with a model using PS alone.

      Results:
      For OS, the EORTC model c-index was 0.55 (0.52, 0.58) and P = 0.0007 comparing high- and low- risk patients for testing set. The new model c-index was 0.60 (0.56, 0.64), with P < 0.000001 for testing set. Using the new model, the median OS in the high-risk and low-risk groups in the testing set were 5.16 (4.70, 6.37) and 10.41 (7.95, 14.32) months, respectively. PS alone produced c-index of 0.55 (0.53, 0.57) and P = 0.0002 for testing set. The AUC scores at 6-months for testing set generated by EORTC and PS alone models are 0.62 and 0.66. The new model generated AUC scores at 6-months of 0.70.

      Conclusion:
      Our new model performs better than the EORTC model or PS alone for survival prognostication in patients with mesothelioma.

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    WS04 - Mesothelioma Workshop (Ticketed Session) (ID 416)

    • Event: WCLC 2016
    • Type: Workshop
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 12/04/2016, 08:00 AM - 11:00 AM, Stolz 2
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      WS04.02 - Debate – Immunotherapy Does Work in Mesothelioma (Now Available) (ID 6983)

      H.L. Kindler

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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