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Progress in the Management of Malignant Pleural Mesothelioma in 2017

Open ArchivePublished:March 07, 2018DOI:https://doi.org/10.1016/j.jtho.2018.02.021

      Abstract

      Malignant pleural mesothelioma (MPM) is an uncommon, almost universally fatal, asbestos-induced malignancy. New and effective strategies for diagnosis, prognostication, and treatment are urgently needed. Herein we review the advances in MPM achieved in 2017. Whereas recent epidemiological data demonstrated that the incidence of MPM-related death continued to increase in United States between 2009 and 2015, new insight into the molecular pathogenesis and the immunological tumor microenvironment of MPM, for example, regarding the role of BRCA1 associated protein 1 and the expression programmed death receptor ligand 1, are highlighting new potential therapeutic strategies. Furthermore, there continues to be an ever-expanding number of clinical studies investigating systemic therapies for MPM. These trials are primarily focused on immunotherapy using immune checkpoint inhibitors alone or in combination with other immunotherapies and nonimmunotherapies. In addition, other promising targeted therapies, including pegylated adenosine deiminase (ADI-PEG20), which focuses on argininosuccinate synthase 1–deficient tumors, and tazemetostat, an enhancer of zeste 2 polycomb repressive complex 2 subunit inhibitor of BRCA1 associated protein 1 gene (BAP1)-deficient tumors, are currently being explored.

      Keywords

      Introduction and Background

      Malignant pleural mesothelioma (MPM) is a rare aggressive neoplasm that is closely linked to asbestos exposure. Median survival ranges between 6 and 8 months for patients treated with best supportive care and 12 and 16 months with pemetrexed-containing systemic cytotoxic therapy.
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      Malignant mesothelioma: facts, myths, and hypotheses.
      Therapy is generally palliative, improving symptoms and modestly increasing survival.
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      Mesothelioma from asbestos exposures: epidemiologic patterns and impact in the United States.
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      Occupational exposure to asbestos: population at risk and projected mortality–1980-2030.
      Although asbestos control regulations have significantly decreased occupational exposure, many individuals remain at risk.
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      Occupational exposure to asbestos: population at risk and projected mortality–1980-2030.
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      Malignant mesothelioma mortality—United States, 1999-2015.
      Asbestos is the commercial name used to identify six different commercially used fibers; however, there are more than 400 asbestiform fibers in nature, and many, including erionite and antigorite, have been proved to be carcinogenic.
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      Asbestos is not just asbestos: an unrecognised health hazard.
      The Centers for Disease Control identified 45,221 MPM-related deaths in the United States between 1999 and 2015, with a 4.8% increase in MPM deaths over that period that was seen across all ethnicities.
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      Malignant mesothelioma mortality—United States, 1999-2015.
      Furthermore, Eastern Europe and other rapidly industrializing regions, where asbestos production and commercial use continues unregulated, may experience an increased incidence of MPM in coming decades.
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      Improving the accuracy of mesothelioma diagnosis in China.
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      Consensus report of the 2015 Weinman International Conference on Mesothelioma.
      Fewer MPM cases have been reported from East and Southeast Asia. It is hypothesized that this is secondary to a more recent industrialization and that numbers in these regions will start to rise in years to come.
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      Malignant mesothelioma in Eastern Asia.
      The ongoing increase in mortality related to MPM underscores the urgent need for asbestos control, improved understanding of the disease pathogenesis, early detection, and better treatment options.
      Research output in this field has been increasing steadily. A comprehensive MEDLINE literature search identified relevant publications in 2017. On the basis of the expert opinion of the authors of this review, we elected and reviewed all publications relevant to the epidemiology, pathology, genomics, diagnosis, staging, and treatment of MPM that were published in 2017. In addition, we reviewed and included relevant abstracts of ongoing or recently completed MPM clinical trials presented at the 2017 Annual Meeting of the American Society of Clinical Oncology, 2017 European Society for Medical Oncology Congress, and the 2017 World Congress of Lung Cancer.

      Lessons in Epidemiology and Occupational Medicine

      Intraindividual biopersistence of asbestos fibers over time was analyzed in 12 longitudinally collected human lung tissue samples. The results suggested that the purportedly less carcinogenic chrysotile asbestos fibers also demonstrate a long biopersistence and therefore likely account for a proportion of MPM cases,
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      The asbestos fibre burden in human lungs: new insights into the chrysotile debate.
      confirming suggestions by preclinical studies.
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      • Jube S.
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      Continuous exposure to chrysotile asbestos can cause transformation of human mesothelial cells via HMGB1 and TNF-α signaling.
      A second large study provided insights into the dose-time-response relationship between occupational asbestos exposure and pleural mesothelioma, suggesting that initial high doses of asbestos followed by low doses thereafter are associated with the highest risk.
      • Lacourt A.
      • Leveque E.
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      • Gilg Soit Ilg A.
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      Dose-time-response association between occupational asbestos exposure and pleural mesothelioma.
      Moreover, nonoccupational asbestos exposure is an increasingly recognized risk factor for MPM. In this context, a recent review and meta-analysis supported the critical need to evaluate MPM risk in communities with ambient asbestos or other carcinogenic fiber exposure.
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      Non-occupational exposure to asbestos and risk of pleural mesothelioma: review and meta-analysis.
      Finally, in a large study across 230 countries over a 20-year period, the global burden of MPM deaths was extrapolated to about 38,400 per year, suggesting that the number might be even higher than the most recently reported values.
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      • Sorahan T.
      • et al.
      Estimation of the global burden of mesothelioma deaths from incomplete national mortality data.

      Developments in Diagnosis and Staging

      Blood-based biomarkers serve several potential roles in MPM: diagnostic, prognostic, or predictive of response to specific therapies. The most-studied blood-based biomarkers are mesothelin, osteopontin, fibulin-3,
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      • Yang S.
      Diagnostic and prognostic biomarkers for malignant mesothelioma: an update.
      and high mobility group box 1.
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      • Antoine D.J.
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      • et al.
      HMGB1 and its hyperacetylated isoform are sensitive and specific serum biomarkers to detect asbestos exposure and to identify mesothelioma patients.
      In 2017, three meta-analyses respectively confirmed that pretreatment thrombocytosis,
      • Zhuo Y.
      • Lin L.
      • Zhang M.
      Pretreatment thrombocytosis as a significant prognostic factor in malignant mesothelioma: a meta-analysis.
      increased neutrophil-to-lymphocyte ratio,
      • Chen N.
      • Liu S.
      • Huang L.
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      Prognostic significance of neutrophil-to-lymphocyte ratio in patients with malignant pleural mesothelioma: a meta-analysis.
      and high serum levels of soluble mesothelin
      • Tian L.
      • Zeng R.
      • Wang X.
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      Prognostic significance of soluble mesothelin in malignant pleural mesothelioma: a meta-analysis.
      are prognostic for poor survival. A recent study identified complement component 4d as a promising biomarker correlating with tumor volume, response to chemotherapy, and survival.
      • Klikovits T.
      • Stockhammer P.
      • Laszlo V.
      • et al.
      Circulating complement component 4d (C4d) correlates with tumor volume, chemotherapeutic response and survival in patients with malignant pleural mesothelioma.
      Other potentially useful blood-based diagnostic markers for mesothelioma include midkine, calretinin, and microRNA (miRNA).
      • Ak G.
      • Tada Y.
      • Shimada H.
      • et al.
      Midkine is a potential novel marker for malignant mesothelioma with different prognostic and diagnostic values from mesothelin.
      • Johnen G.
      • Gawrych K.
      • Raiko I.
      • et al.
      Calretinin as a blood-based biomarker for mesothelioma.
      • Cavalleri T.
      • Angelici L.
      • Favero C.
      • et al.
      Plasmatic extracellular vesicle microRNAs in malignant pleural mesothelioma and asbestos-exposed subjects suggest a 2-miRNA signature as potential biomarker of disease.
      • Weber D.G.
      • Gawrych K.
      • Casjens S.
      • et al.
      Circulating miR-132-3p as a candidate diagnostic biomarker for malignant mesothelioma.
      Deregulated miRNA levels of Let-7c-5p and miR-151a-5p in tissue may also be prognostic in MPM.
      • De Santi C.
      • Melaiu O.
      • Bonotti A.
      • et al.
      Deregulation of miRNAs in malignant pleural mesothelioma is associated with prognosis and suggests an alteration of cell metabolism.
      In addition, proteomic analysis of the secretome, including exosomes from MPM, cells identified proteins that potentially enhance the growth and stress response and inhibit adaptive immunity.
      • Greening D.W.
      • Ji H.
      • Chen M.
      • et al.
      Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo.
      • Creaney J.
      • Dick I.M.
      • Leon J.S.
      • Robinson B.W.
      A proteomic analysis of the malignant mesothelioma secretome using iTRAQ.
      Clinical and pathological staging is important to determine disease prognosis and facilitate patient selection for multimodality therapy. The International Association for the Study of Lung Cancer Mesothelioma Staging Project for the eighth edition of the American Joint Committee on Cancer/Union for International Cancer Control staging manual updated TNM staging in MPM.
      • Nowak A.K.
      • Chansky K.
      • Rice D.C.
      • et al.
      The IASLC Mesothelioma Staging Project: proposals for revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma.
      • Rusch V.W.
      • Chansky K.
      • Kindler H.L.
      • et al.
      The IASLC Mesothelioma Staging Project: proposals for the M descriptors and for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for mesothelioma.
      • Pass H.
      • Giroux D.
      • Kennedy C.
      • et al.
      The IASLC Mesothelioma Staging Project: improving staging of a rare disease through international participation.
      However, the project database still overrepresented surgically treated patients, and despite recent advances in cross-sectional anatomic and functional imaging and mediastinal lymph node sampling, clinical staging remains difficult. One challenge is the inability to distinguish tumor tissue from surrounding normal tissue for staging and follow-up by using standard anatomic cross-sectional imaging. Although the current version of the modified Response Evaluation Criteria in Solid Tumors guidelines for MPM is more applicable to mesothelioma than Response Evaluation Criteria in Solid Tumors 1.0 or 1.1, further research-based optimization of response criteria for MPM is still required. Tumor volume is increasingly recognized as an anatomic, imaging-based prognostic factor; however, valid and reliable measurement of this parameter across sites and software platforms is difficult.
      • Armato 3rd, S.G.
      • Li P.
      • Husain A.N.
      • et al.
      Radiologic-pathologic correlation of mesothelioma tumor volume.
      Attempts to create an automated volumetric assessment of tumor volume for treatment response and prognostication have been difficult on account of a lack of accuracy and reproducibility.
      • Ak G.
      • Metintas M.
      • Metintas S.
      • Yildirim H.
      • Ozkan R.
      • Ozden H.
      Three-dimensional evaluation of chemotherapy response in malignant pleural mesothelioma.
      • Armato 3rd, S.G.
      • Oxnard G.R.
      • Kocherginsky M.
      • Vogelzang N.J.
      • Kindler H.L.
      • MacMahon H.
      Evaluation of semiautomated measurements of mesothelioma tumor thickness on CT scans.
      • Frauenfelder T.
      • Tutic M.
      • Weder W.
      • et al.
      Volumetry: an alternative to assess therapy response for malignant pleural mesothelioma?.
      • Liu F.
      • Zhao B.
      • Krug L.M.
      • et al.
      Assessment of therapy responses and prediction of survival in malignant pleural mesothelioma through computer-aided volumetric measurement on computed tomography scans.
      • Plathow C.
      • Schoebinger M.
      • Fink C.
      • et al.
      Quantification of lung tumor volume and rotation at 3D dynamic parallel MR imaging with view sharing: preliminary results.
      • Labby Z.E.
      • Armato 3rd, S.G.
      • Dignam J.J.
      • Straus C.
      • Kindler H.L.
      • Nowak A.K.
      Lung volume measurements as a surrogate marker for patient response in malignant pleural mesothelioma.
      • Chaisaowong K.
      • Aach T.
      • Jager P.
      • Vogel S.
      • Knepper A.
      • Kraus T.
      Computer-assisted diagnosis for early stage pleural mesothelioma: towards automated detection and quantitative assessment of pleural thickening from thoracic CT images.
      • Sensakovic W.F.
      • Armato 3rd, S.G.
      • Straus C.
      • et al.
      Computerized segmentation and measurement of malignant pleural mesothelioma.
      • Labby Z.E.
      • Nowak A.K.
      • Dignam J.J.
      • Straus C.
      • Kindler H.L.
      • Armato 3rd, S.G.
      Disease volumes as a marker for patient response in malignant pleural mesothelioma.
      • Murphy D.J.
      • Gill R.R.
      Volumetric assessment in malignant pleural mesothelioma.
      The most promising results on the prognostic value of CT-based tumor volume were recently published from a multi-institutional group.
      • Noonan S.A.
      • Berry L.
      • Lu X.
      • et al.
      Identifying the appropriate FISH criteria for defining MET copy number-driven lung adenocarcinoma through oncogene overlap analysis.
      • Rusch V.W.
      • Gill R.
      • Mitchell A.
      • et al.
      A multicenter study of volumetric computed tomography for staging malignant pleural mesothelioma.
      de Perrot et al. published data suggesting that lower radiological tumor volume and smaller diaphragmatic tumor thickness predicted favorable outcomes in patients treated with neoadjuvant radiation followed by extrapleural pneumonectomy (EPP).
      • de Perrot M.
      • Dong Z.
      • Bradbury P.
      • et al.
      Impact of tumour thickness on survival after radical radiation and surgery in malignant pleural mesothelioma.
      • Perrot M.
      • Wu L.
      • Wu M.
      • Cho B.C.J.
      Radiotherapy for the treatment of malignant pleural mesothelioma.
      In addition, a group from the United Kingdom also reported a promising random walk–based computer-aided algorithm for image segmentation.
      • Chen M.
      • Helm E.
      • Joshi N.
      • Gleeson F.
      • Brady M.
      Computer-aided volumetric assessment of malignant pleural mesothelioma on CT using a random walk-based method.

      Progresses in Pathology

      The histological diagnosis of MPM is relatively well established when performed by expert pathologists on the basis of positive markers of mesothelial lineage and negative markers of epithelial lineage. However, diagnostic uncertainty remains common, and continued efforts to improve the accuracy of diagnosis are needed.
      • Guo Z.
      • Carbone M.
      • Zhang X.
      • et al.
      Improving the accuracy of mesothelioma diagnosis in China.
      One of the most challenging differential diagnoses remains the distinction between sarcomatoid MPM and sarcomatoid carcinoma of the lung. In this respect, mucin 4, cell surface associated may be a novel sensitive and specific immunohistochemical biomarker for sarcomatoid carcinoma of the lung.
      • Amatya V.J.
      • Kushitani K.
      • Mawas A.S.
      • et al.
      MUC4, a novel immunohistochemical marker identified by gene expression profiling, differentiates pleural sarcomatoid mesothelioma from lung sarcomatoid carcinoma.
      Moreover, GATA binding protein 3 immunostaining may be useful to identify sarcomatoid and desmoplastic mesothelioma.
      • Carbone M.
      • Flores E.G.
      • Emi M.
      • et al.
      Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred tracing back nine generations to a common ancestor from the 1700s.
      • Berg K.B.
      • Churg A.
      GATA3 immunohistochemistry for distinguishing sarcomatoid and desmoplastic mesothelioma from sarcomatoid carcinoma of the lung.
      Disabled homolog 2 (DAB2) and intelectin-1 were reported as new positive immunohistochemical markers for epithelioid mesothelioma.
      • Kuraoka M.
      • Amatya V.J.
      • Kushitani K.
      • et al.
      Identification of DAB2 and intelectin-1 as novel positive immunohistochemical markers of epithelioid mesothelioma by transcriptome microarray analysis for its differentiation from pulmonary adenocarcinoma.
      Another challenging differentiation has been between MPM and reactive mesothelial hyperplasia. Although BRCA1 associated protein 1 (BAP1) immunohistochemistry and p16 fluorescence hybridization can effectively discriminate MPM from reactive mesothelial hyperplasia, methylthioadenosine phosphorylase loss may also be useful when identified in combination with BAP1 loss.
      • Hida T.
      • Hamasaki M.
      • Matsumoto S.
      • et al.
      Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: comparison with 9p21 FISH and BAP1 immunohistochemistry.
      In addition, several studies have focused on the evaluation of biomarkers of immunological activation and infiltrating immune cells, in particular, programmed death ligand 1 (PD-L1).
      • Valmary-Degano S.
      • Colpart P.
      • Villeneuve L.
      • et al.
      Immunohistochemical evaluation of two antibodies against PD-L1 and prognostic significance of PD-L1 expression in epithelioid peritoneal malignant mesothelioma: a RENAPE study.
      • Mansour M.S.I.
      • Seidal T.
      • Mager U.
      • Baigi A.
      • Dobra K.
      • Dejmek A.
      Determination of PD-L1 expression in effusions from mesothelioma by immuno-cytochemical staining.
      • Thapa B.
      • Salcedo A.
      • Lin X.
      • et al.
      The immune microenvironment, genome-wide copy number aberrations, and survival in mesothelioma.
      • Inaguma S.
      • Lasota J.
      • Wang Z.
      • et al.
      Expression of ALCAM (CD166) and PD-L1 (CD274) independently predicts shorter survival in malignant pleural mesothelioma.
      The “don’t eat me” signal CD47 was also shown to be overexpressed in diffuse malignant mesothelioma and was suggested as a potential diagnostic and therapeutic target of MPM.
      • Schurch C.M.
      • Forster S.
      • Bruhl F.
      • Yang S.H.
      • Felley-Bosco E.
      • Hewer E.
      The “don't eat me” signal CD47 is a novel diagnostic biomarker and potential therapeutic target for diffuse malignant mesothelioma.

      Molecular Advances

      Previous genomic analysis identified the loss of various tumor suppressor genes as the most common molecular event in MPM. Commonly inactivated tumor suppressor genes include cyclin-dependent kinase inhibitor 2A gene (CDKN2A), BRCA1 associated protein 1 gene (BAP1), neurofibromin 2 gene (NF2), and occasionally tumor protein p53 gene (TP53). These findings have been confirmed in a recent comprehensive genomic analysis (Fig 1).
      • Bueno R.
      • Stawiski E.W.
      • Goldstein L.D.
      • et al.
      Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.
      Enhanced understanding of MPM molecular aberrations has already informed the use of targeted therapies such as the focal adhesion kinase (FAK) inhibitor defactinib for tumors lacking NF2 (COMMAND study). Unfortunately, maintenance defactinib did not improve patient outcomes and the study was terminated early. A recent publication provides a comprehensive review of molecular advances in MPM.
      • Yap T.A.
      • Aerts J.G.
      • Popat S.
      • Fennell D.A.
      Novel insights into mesothelioma biology and implications for therapy.
      Figure thumbnail gr1
      Figure 1Genetic alterations in the malignant transformation of malignant pleural mesothelioma (MPM) and potential therapeutic targets. Neurofibromin 2 gene (NF2) encodes the merlin protein, which regulates the Hippo pathway. Loss of NF2 function leads to inactivation of the Hippo pathway and activation of the YY1 associated protein (YAP) transcriptional coactivator, ultimately promoting cell proliferation and survival. Defactinib is a focal adhesion kinase (FAK) inhibitor that was created for potential action on the NF2 pathway but was unsuccessful in MPM treatment. Phosphatase and tensin homolog gene (PTEN) is a negative regulator of the phosphoinositide 3-kinase (PI3K)/AKT pathway, and loss of phosphatase and tensin homolog gene (PTEN) function results in overactivation of this pathway, leading to cell growth and proliferation. BRCA1 associated protein 1 gene (BAP1) is a tumor suppressor gene. Without it, the elevated enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) component of the polycomb repressive complex 2 is activated, leading to trimethylation of histone 3 lysine 27 (H3K27) and, ultimately, to malignant transformation. Tazemetostat is an EZH2 inhibitor. Cyclin-dependent kinase inhibitor 2A gene (CDK2NA) encodes p14ARF and p16INK4a. p14ARF interacts with MDM2 proto-oncogene (MDM2), resulting in MDM2 degradation and ultimate activation of p53. Loss of p14ARF expression increases MDM2 levels and decreases p53 function, resulting in increased cell survival. p16INK4a is essential in hyperphosphorylation and subsequent inhibition of the retinoblastoma pathway. Loss of this cyclin-dependent kinase inhibitor leads to unchecked activation of the retinoblastoma pathway and, ultimately, to cell cycle progression. Tumor protein p53 gene (TP53) encodes p53, and loss of this gene results in loss of p53 and subsequent cell proliferation and survival.
      The role of heredity in familial predisposition to MPM, even without occupational asbestos exposure, has finally been proved by the discovery of germline BAP1 mutations,
      • Testa J.R.
      • Cheung M.
      • Pei J.
      • et al.
      Germline BAP1 mutations predispose to malignant mesothelioma.
      and supported by murine modeling.
      • Xu J.
      • Kadariya Y.
      • Cheung M.
      • et al.
      Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma.
      • Napolitano A.
      • Pellegrini L.
      • Dey A.
      • et al.
      Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma.
      As a result, the tumor-predisposing BAP1 cancer syndrome
      • Carbone M.
      • Ferris L.K.
      • Baumann F.
      • et al.
      BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs.
      has been increasingly recognized and characterized.
      • Carbone M.
      • Flores E.G.
      • Emi M.
      • et al.
      Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred tracing back nine generations to a common ancestor from the 1700s.
      • Haugh A.M.
      • Njauw C.N.
      • Bubley J.A.
      • et al.
      Genotypic and phenotypic features of BAP1 cancer syndrome: a report of 8 new families and review of cases in the literature.
      BAP1 is a deubiquitinating enzyme with several roles in regulating DNA repair and gene expression.
      • Carbone M.
      • Yang H.
      • Pass H.I.
      • Krausz T.
      • Testa J.R.
      • Gaudino G.
      BAP1 and cancer.
      In addition to germline mutations predisposing to mesothelioma and other cancers, BAP1 is the most frequent acquired (somatic) mutation in sporadic mesothelioma.
      • Nasu M.
      • Emi M.
      • Pastorino S.
      • et al.
      High incidence of somatic BAP1 alterations in sporadic malignant mesothelioma.
      • Yoshikawa Y.
      • Emi M.
      • Hashimoto-Tamaoki T.
      • et al.
      High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma.
      In 2017, both pleural and peritoneal mesotheliomas were shown to have loss of BAP1 in more than 60% of cases,
      • Joseph N.M.
      • Chen Y.Y.
      • Nasr A.
      • et al.
      Genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X.
      • Leblay N.
      • Lepretre F.
      • Le Stang N.
      • et al.
      BAP1 is altered by copy number loss, mutation, and/or loss of protein expression in more than 70% of malignant peritoneal mesotheliomas.
      confirming previous findings.
      • Nasu M.
      • Emi M.
      • Pastorino S.
      • et al.
      High incidence of somatic BAP1 alterations in sporadic malignant mesothelioma.
      Novel functions of BAP1 that likely contribute to its role in cancer in general, and in MPM in particular, have been identified. Specifically, BAP1 is a master regulator of calcium-induced apoptosis through regulation of the inositol 1,4,5-triphosphate receptor type 3 receptor ubiquitination,
      • Bononi A.
      • Giorgi C.
      • Patergnani S.
      • et al.
      BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation.
      as well as a regulator of cellular glycolytic metabolism
      • Bononi A.
      • Yang H.
      • Giorgi C.
      • et al.
      Germline BAP1 mutations induce a Warburg effect.
      and a radical of oxygen homeostasis.
      • Hebert L.
      • Bellanger D.
      • Guillas C.
      • et al.
      Modulating BAP1 expression affects ROS homeostasis, cell motility and mitochondrial function.
      A novel alternative splice isoform of BAP1 that is missing part of the catalytic domain has also been described, and it appears to regulate DNA damage response and influence drug sensitivity.
      • Parrotta R.
      • Okonska A.
      • Ronner M.
      • et al.
      A novel BRCA1-associated protein-1 isoform affects response of mesothelioma cells to drugs impairing BRCA1-mediated DNA repair.
      Furthermore, frequent germline mutations in other genes associated with DNA repair have been identified in asbestos-exposed individuals with development of MPM, suggesting that these pathways are associated with MPM predisposition.
      • Betti M.
      • Casalone E.
      • Ferrante D.
      • et al.
      Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma.
      Interestingly, common germline BAP1 variants appear to mediate the risk of development of renal cell carcinoma and lung cancer,
      • Lin M.
      • Zhang L.
      • Hildebrandt M.A.T.
      • Huang M.
      • Wu X.
      • Ye Y.
      Common, germline genetic variations in the novel tumor suppressor BAP1 and risk of developing different types of cancer.
      and possibly also MPM.
      • Rizzardi C.
      • Athanasakis E.
      • Cammisuli F.
      • et al.
      Puzzling results from BAP1 germline mutations analysis in a group of asbestos-exposed patients in a high-risk area of northeast Italy.
      When mesothelioma develops in carriers of germline BAP1 mutations, these malignancies have a much better prognosis, and survival of 5 or more years is commonly seen.
      • Baumann F.
      • Flores E.
      • Napolitano A.
      • et al.
      Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival.
      In 2017, the role of BAP1 immunohistochemistry in MPM diagnosis and possibly prognosis was also the focus of several studies. Specifically, BAP1 loss was shown to reliably differentiate MPM from chronic pleuritis, benign mesothelial hyperplasia, and other benign mesothelial lesions, as well as from other malignancies such as NSCLC and ovarian serous tumors.
      • Hida T.
      • Hamasaki M.
      • Matsumoto S.
      • et al.
      Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: comparison with 9p21 FISH and BAP1 immunohistochemistry.
      • Wang L.M.
      • Shi Z.W.
      • Wang J.L.
      • et al.
      Diagnostic accuracy of BRCA1-associated protein 1 in malignant mesothelioma: a meta-analysis.
      • McCroskey Z.
      • Staerkel G.
      • Roy-Chowdhuri S.
      Utility of BRCA1-associated protein 1 immunoperoxidase stain to differentiate benign versus malignant mesothelial proliferations in cytologic specimens.
      • Shinozaki-Ushiku A.
      • Ushiku T.
      • Morita S.
      • Anraku M.
      • Nakajima J.
      • Fukayama M.
      Diagnostic utility of BAP1 and EZH2 expression in malignant mesothelioma.
      • McGregor S.M.
      • McElherne J.
      • Minor A.
      • et al.
      BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma.
      • Chapel D.B.
      • Husain A.N.
      • Krausz T.
      • McGregor S.M.
      PAX8 Expression in a subset of malignant peritoneal mesotheliomas and benign mesothelium has diagnostic implications in the differential diagnosis of ovarian serous carcinoma.
      The identification of hereditary factors in MPM pathogenesis has also led to increased interest in the characterization of young patients. In 2017 it was reported that these patients show distinctive clinical, pathological, and genetic features, such as higher likelihood of a history of mantle radiation, family history of breast cancer, and lower rates of CDKN2A deletion than in older patients.
      • Vivero M.
      • Bueno R.
      • Chirieac L.R.
      Clinicopathologic and genetic characteristics of young patients with pleural diffuse malignant mesothelioma.
      Moreover, a subset of mesotheliomas in young patients (15%) were associated with recurrent EWS RNA binding protein 1 gene (EWSR1)/FUS RNA binding protein gene (FUS)ADP ribosylation factor 1 gene (ATF1) fusions.
      • Desmeules P.
      • Joubert P.
      • Zhang L.
      • et al.
      A subset of malignant mesotheliomas in young adults are associated with recurrent EWSR1/FUS-ATF1 fusions.
      Most importantly, the presence of clinically actionable ALK receptor tyrosine kinase gene (ALK) rearrangements was described in about 10% of peritoneal mesothelioma, most commonly in younger women.
      • Hung Y.P.
      • Dong F.
      • Watkins J.C.
      • et al.
      Identification of ALK rearrangements in malignant peritoneal mesothelioma.

      Systemic Therapies

      Targeting Angiogenesis

      Systemic cytotoxic chemotherapy with pemetrexed plus cisplatin remains the only U.S Food and Drug Administration–approved therapy for MPM and represents the current standard of care. With treatment response rates of approximately 40%, it extends median overall survival (OS) to 12 to 16 months.
      • Vogelzang N.J.
      • Rusthoven J.J.
      • Symanowski J.
      • et al.
      Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.
      As vascular endothelial growth factor (VEGF) signaling is important in the pathophysiology of MPM, VEGF inhibition is being explored as a potential treatment option.
      • Strizzi L.
      • Catalano A.
      • Vianale G.
      • et al.
      Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma.
      • Robinson B.W.
      • Lake R.A.
      Advances in malignant mesothelioma.
      • Masood R.
      • Kundra A.
      • Zhu S.
      • et al.
      Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF-C autocrine loops.
      • Filho A.L.
      • Baltazar F.
      • Bedrossian C.
      • Michael C.
      • Schmitt F.C.
      Immunohistochemical expression and distribution of VEGFR-3 in malignant mesothelioma.
      The results of the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) demonstrated a statistically significant improvement in OS when bevacizumab was added to first-line cisplatin and pemetrexed chemotherapy.
      • Zalcman G.
      • Mazieres J.
      • Margery J.
      • et al.
      Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.
      However, because of the observed relatively small increase in OS, the addition of bevacizumab to chemotherapy has not become the standard of care in most parts of the world, and it is recommended as optional in the National Comprehensive Cancer Network guidelines.
      • Zalcman G.
      • Mazieres J.
      • Margery J.
      • et al.
      Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.
      A cost-effectiveness analysis published in 2017 did not support the addition of bevacizumab.
      • Zhan M.
      • Zheng H.
      • Xu T.
      • Yang Y.
      • Li Q.
      Cost-effectiveness analysis of additional bevacizumab to pemetrexed plus cisplatin for malignant pleural mesothelioma based on the MAPS trial.
      Another antiangiogenic, nintedanib, is a small molecule tyrosine kinase inhibitor targeting VEGF receptors, fibroblast growth factor receptors, and platelet-derived growth factor receptors. The LUME-MESO study is an ongoing randomized, double-blind, placebo-controlled phase II/III trial examining the efficacy and safety of adding nintedanib to standard chemotherapy in patients non–surgically treated MPM; phase II results were reported in 2017.
      • Grosso F.
      • Steele N.
      • Novello S.
      • et al.
      Nintedanib plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma: phase II results from the randomized, placebo-controlled LUME-Meso trial.
      In 87 evaluable patients (44 receiving nintedanib and 43 receiving placebo), nintedanib improved progression-free survival (PFS) by 3.7 months as compared with placebo (p = 0.01), most notably in those with epithelioid histological features (4 months PFS [p = 0.006]). There was a trend toward improved OS (median 18.3 months versus 14.2 months) in favor of the nintedanib group; however, this difference was not statistically significant and the study was not powered to examine OS. The addition of nintedanib to standard chemotherapy was safe, and these results support the rationale for the ongoing phase III study (Table 1).
      • Grosso F.
      • Steele N.
      • Novello S.
      • et al.
      Nintedanib plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma: phase II results from the randomized, placebo-controlled LUME-Meso trial.
      • Scagliotti G.V.
      • Gaafar R.
      • Nowak A.K.
      • et al.
      LUME-Meso: Design and rationale of the phase III part of a placebo-controlled study of nintedanib and pemetrexed/cisplatin followed by maintenance nintedanib in patients with unresectable malignant pleural mesothelioma.
      • Kindler H.L.
      • Novello S.
      • Fennell D.
      • et al.
      OA 02.01. Randomized phase II study of anetumab ravtansine or vinorelbine in patients with metastatic pleural mesothelioma.
      • Szlosarek P.W.
      • Steele J.P.
      • Nolan L.
      • et al.
      Arginine deprivation with pegylated arginine deiminase in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma: a randomized clinical trial.
      • Beddowes E.
      • Spicer J.
      • Chan P.Y.
      • et al.
      Phase 1 dose-escalation study of pegylated arginine deiminase, cisplatin, and pemetrexed in patients with argininosuccinate synthetase 1-deficient thoracic cancers.
      Table 1Clinical Studies on MPM That Were Published in 2017, Non–Immunotherapy-Related
      StudyPatientsInterventionRR, %Stable disease, %PFS (OS), moPhaseStatusClinical Trial Identifier
      Antiangiogenesis therapy
       LUME-Meso
      • Grosso F.
      • Steele N.
      • Novello S.
      • et al.
      Nintedanib plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma: phase II results from the randomized, placebo-controlled LUME-Meso trial.
      87Nintedanib

      C/P
      56.8NR3.7II/IIIANCT01907100
      Mesothelin-targeted therapy
       Mesothelin
      • Kindler H.L.
      • Novello S.
      • Fennell D.
      • et al.
      OA 02.01. Randomized phase II study of anetumab ravtansine or vinorelbine in patients with metastatic pleural mesothelioma.
      248Anetumab ravtansine8.4NR4.3 (10.1)IIANCT02610140
      Arginine deprivation therapy
       ADAM
      • Szlosarek P.W.
      • Steele J.P.
      • Nolan L.
      • et al.
      Arginine deprivation with pegylated arginine deiminase in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma: a randomized clinical trial.
      68ADI-PEG20NR523.2IIANCT01279967
       TRAP
      • Beddowes E.
      • Spicer J.
      • Chan P.Y.
      • et al.
      Phase 1 dose-escalation study of pegylated arginine deiminase, cisplatin, and pemetrexed in patients with argininosuccinate synthetase 1-deficient thoracic cancers.
      9ADI-PEG20781007.7IRNCT02029690
      Note: These studies were included in this table because they are non–immunotherapy-related clinical trials on human patients with some published results in 2017. This is a complete list as of November 2017.
      MPM, malignant pleural mesothelioma; RR, response rate; PFS, progression-free survival; OS, overall survival; NR, not reported; A, active, not recruiting; R, recruiting; ADI-PEG20, pegylated adenosine deaminase.

      Blocking Immune Checkpoints

      In 2017 immunotherapy was clearly the focus of the largest number of clinical trials investigating new therapies for MPM. Cytotoxic T-lymphocyte–associated antigen 4 (CTLA4) is expressed on T cells, reducing the amplitude of CD28-mediated T-cell activation.
      • Pardoll D.M.
      The blockade of immune checkpoints in cancer immunotherapy.
      CTLA4 inhibition enhances T-cell activation and increases antitumor efficacy in other cancers.
      • Wolchok J.D.
      • Weber J.S.
      • Maio M.
      • et al.
      Four-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials.
      Phase II studies investigating tremelimumab, a selective human monoclonal antibody against CTLA4, showed favorable PFS responses and toxicity profiles.
      • Calabro L.
      • Morra A.
      • Fonsatti E.
      • et al.
      Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial.
      • Calabro L.
      • Morra A.
      • Fonsatti E.
      • et al.
      Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study.
      In 2017, the double-blind study comparing tremelimumab to placebo in subjects with previously treated unresectable malignant mesothelioma (DETERMINE) disappointingly failed to demonstrate differences in OS or PFS between the treatment and control groups (Table 2).
      • Maio M.
      • Scherpereel A.
      • Calabro L.
      • et al.
      Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.
      • Hassan R.
      • Thomas A.
      • Patel M.R.
      • et al.
      Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: safety, clinical activity, and PD-L1 expression.
      • Quispel-Janssen J.
      • Zago G.
      • Schouten R.
      • et al.
      OA13.01 A phase II study of nivolumab in malignant pleural mesothelioma (NivoMes): with translational research (TR) biopies.
      • Goto Y.
      • Okada M.
      • Kijima T.
      • et al.
      MA 19.01 A phase II study of nivolumab: a multicenter, open-label, single arm study in malignant pleural mesothelioma (MERIT).
      • Alley E.W.
      • Lopez J.
      • Santoro A.
      • et al.
      Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial.
      • Kindler H.
      • Karrison T.
      • Carol Tan Y.-H.
      • et al.
      OA13.02. Phase II trial of pembrolizumab in patients with malignant mesothelioma (MM): interim analysis.
      • Scherpereel A.
      • Mazieres J.
      • Greillier L.
      • et al.
      Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: results of the IFCT-1501 MAPS2 randomized phase II trial.
      • Calabro L.
      • Morra A.
      • Giannarelli D.
      • et al.
      Tremelimumab in combination with durvalumab in first or second-line mesothelioma patients: safety analysis from the phase II NIBIT-MESO-1 study.
      • Disselhorst M.
      • Harms E.
      • Van Tinteren H.
      • et al.
      OA 02.02 Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma: a phase II study.
      Table 2Clinical Studies on MPM Immunotherapy Published in 2017
      StudyPatientsDrugRR, %Stable disease, %DCR, %PFS, moTargetPhaseStatusClinical Trial Identifier
      Single-agent immunotherapy
       Anti-CTLA4
      DETERMINE
      • Maio M.
      • Scherpereel A.
      • Calabro L.
      • et al.
      Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.
      571Tremelimumab4.527.716.82.8CTLA4IIANCT01843374
       Anti–PD-1/PD-L1
      JAVELIN
      • Hassan R.
      • Thomas A.
      • Patel M.R.
      • et al.
      Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: safety, clinical activity, and PD-L1 expression.
      53Avelumab927564.3PD-L1IANCT01772004
      NivoMes
      • Quispel-Janssen J.
      • Zago G.
      • Schouten R.
      • et al.
      OA13.01 A phase II study of nivolumab in malignant pleural mesothelioma (NivoMes): with translational research (TR) biopies.
      34Nivolumab1535503.6PD-1IICNCT02497508
      MERIT
      • Goto Y.
      • Okada M.
      • Kijima T.
      • et al.
      MA 19.01 A phase II study of nivolumab: a multicenter, open-label, single arm study in malignant pleural mesothelioma (MERIT).
      34Nivolumab2939686.1PD-1II
      Information not available.
      International study not listed at ClinicalTrials.gov.
      KEYNOTE-028
      • Alley E.W.
      • Lopez J.
      • Santoro A.
      • et al.
      Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial.
      25Pembrolizumab2052725.4PD-1IANCT02054806
      Chicago Phase II
      • Kindler H.
      • Karrison T.
      • Carol Tan Y.-H.
      • et al.
      OA13.02. Phase II trial of pembrolizumab in patients with malignant mesothelioma (MM): interim analysis.
      35Pembrolizumab2159806.2PD-1IIRNCT02399371
      MAPS-2
      • Scherpereel A.
      • Mazieres J.
      • Greillier L.
      • et al.
      Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: results of the IFCT-1501 MAPS2 randomized phase II trial.
      54Nivolumab1726434.0PD-1IIANCT02716272
      Combination immunotherapy
       NIBIT-Meso-1
      • Calabro L.
      • Morra A.
      • Giannarelli D.
      • et al.
      Tremelimumab in combination with durvalumab in first or second-line mesothelioma patients: safety analysis from the phase II NIBIT-MESO-1 study.
      40Durvalumab

      Tremelimumab
      2037.562.5NRPD-L1

      CTLA4
      IIRNCT02588131
       INITIATE
      • Disselhorst M.
      • Harms E.
      • Van Tinteren H.
      • et al.
      OA 02.02 Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma: a phase II study.
      25Nivolumab

      Ipilimumab
      20472NRPD-1

      CTLA4
      IIRNCT03048474
       MAPS-2
      • Scherpereel A.
      • Mazieres J.
      • Greillier L.
      • et al.
      Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: results of the IFCT-1501 MAPS2 randomized phase II trial.
      54Nivolumab

      Ipilimumab
      2726525.6PD-1

      CTLA4
      IIANCT02716272
      Note: These studies were included in this table because they are immunotherapy clinical trials on human patients with some published results in 2017. This is a complete list as of November 2017.
      MPM, malignant pleural mesothelioma; RR, response rate; DCR, durable controlled response; PFS, progression-free survival; CTLA4, cytotoxic T-lymphocyte–associated antigen 4; PD-L1, programmed death ligand 1; PD-1, programmed cell death protein 1; NR, not reported; A, active, not recruiting; C, completed; R, recruiting.
      a Information not available.
      b International study not listed at ClinicalTrials.gov.
      Characterization of the immunological tumor microenvironment has been the subject of considerable research, and the immune status of MPM has been distinctly correlated to prognosis.
      • Chee S.J.
      • Lopez M.
      • Mellows T.
      • et al.
      Evaluating the effect of immune cells on the outcome of patients with mesothelioma.
      • Nguyen B.H.
      • Montgomery R.
      • Fadia M.
      • Wang J.
      • Ali S.
      PD-L1 expression associated with worse survival outcome in malignant pleural mesothelioma.
      Approximately 60% of MPM either expressed PD-L1 or displayed an “inflamed status” designated by a specific mRNA signature, indicating potential susceptibility to immune-directed therapy.
      • Mansfield A.S.
      • Roden A.C.
      • Peikert T.
      • et al.
      B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis.
      • Patil N.S.
      • Righi L.
      • Koeppen H.
      • et al.
      Molecular and histopathological characterization of the tumor immune microenvironment in advanced stage of malignant pleural mesothelioma.
      Human monoclonal antibodies against programmed cell death protein 1 (PD-1) and PD-L1 are approved for multiple malignancies, including first-line therapy for NSCLC alone for tumors with 50% or more PD-L1 staining
      • Reck M.
      • Rodriguez-Abreu D.
      • Robinson A.G.
      • et al.
      Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.
      • Reck M.
      Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer.
      or in combination with chemotherapy regardless of PD-L1 staining for adenocarcinoma.
      • Langer C.J.
      • Gadgeel S.M.
      • Borghaei H.
      • et al.
      Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study.
      There are many ongoing clinical trials investigating PD-1/PD-L1 checkpoint inhibitors alone and in combination.

      Single-Agent Immunotherapy Trials

      Between 20% and 40% of patients with MPM express PD-L1 at various levels, and PD-L1 expression correlates with a poorer prognosis.
      • Mansfield A.S.
      • Roden A.C.
      • Peikert T.
      • et al.
      B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis.
      • Cedrés S.
      • Ponce-Aix S.
      • Zugazagoitia J.
      • et al.
      Analysis of expression of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM).
      In the KEYNOTE-028 trial, the efficacy and safety of pembrolizumab as subsequent-line therapy was evaluated in 25 patients with PD-L1–positive MPM (≥1% PD-L1 positivity).
      • Alley E.W.
      • Lopez J.
      • Santoro A.
      • et al.
      Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial.
      Twenty percent of patients achieved a partial response and 52% demonstrated stable disease, with a 12-month median duration of response. Furthermore, the median PFS (5.4 months) and the median OS (18 months) were notably longer than in patients not receiving second-line therapy. PD-L1 positivity and level of expression were not clearly linked to likelihood of clinical response.
      • Alley E.W.
      • Lopez J.
      • Santoro A.
      • et al.
      Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial.
      The Netherlands Cancer Institute is currently conducting a similar phase II trial of a PD-1 inhibitor, nivolumab, in patients with relapsed MPM. Preliminary results reported a disease control rate of 50% at 12 weeks and 33% at 24 weeks, with a median PFS of 3.6 months.
      • Quispel-Janssen J.
      • Zago G.
      • Schouten R.
      • et al.
      OA13.01 A phase II study of nivolumab in malignant pleural mesothelioma (NivoMes): with translational research (TR) biopies.
      Avelumab, an anti–PD-L1 antibody, also demonstrated clinical activity against MPM in the JAVELIN study, with a response rate of 9.4%, stability in 47% of patients, and median PFS of 4.3 months.
      • Hassan R.
      • Thomas A.
      • Patel M.R.
      • et al.
      Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: safety, clinical activity, and PD-L1 expression.
      Similar results have been reported from a phase II trial of pembrolizumab
      • Kindler H.
      • Karrison T.
      • Carol Tan Y.-H.
      • et al.
      OA13.02. Phase II trial of pembrolizumab in patients with malignant mesothelioma (MM): interim analysis.
      and the nivolumab MERIT study.
      • Goto Y.
      • Okada M.
      • Kijima T.
      • et al.
      MA 19.01 A phase II study of nivolumab: a multicenter, open-label, single arm study in malignant pleural mesothelioma (MERIT).
      The ongoing phase III CONFIRM study randomizes patients requiring second-line therapy to nivolumab or placebo (NCT03063450). The PROMISE-Meso study, which is comparing pembrolizumab to gemcitabine or vinorelbine in patients with pretreated, non–surgically treated MPM, is also currently recruiting (NCT02991482).

      Immunotherapy Combination Trials

      In 2017, preliminary findings of several ongoing studies investigating combination immune checkpoint inhibition pairing anti–PD-1/PD-L1 therapy with anti-CTLA4 therapy were also reported. Preliminary results of the NIBIT-MESO (tremelimumab and durvalumab),
      • Calabro L.
      • Morra A.
      • Giannarelli D.
      • et al.
      Tremelimumab in combination with durvalumab in first or second-line mesothelioma patients: safety analysis from the phase II NIBIT-MESO-1 study.
      MAPS-2,
      • Scherpereel A.
      • Mazieres J.
      • Greillier L.
      • et al.
      Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: results of the IFCT-1501 MAPS2 randomized phase II trial.
      and INITIATE (both ipilimumab and nivolumab)
      • Disselhorst M.
      • Harms E.
      • Van Tinteren H.
      • et al.
      OA 02.02 Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma: a phase II study.
      trials demonstrated potential efficacy for second-line therapy for mesothelioma. MAPS-2 is a phase II study including 108 evaluable patients treated with nivolumab versus nivolumab plus ipilimumab. Although the results in the nivolumab arm were promising, the 54 patients in the combination arm had a higher durable controlled response rate (51.6%), although three treatment-related deaths were also reported.
      • Scherpereel A.
      • Mazieres J.
      • Greillier L.
      • et al.
      Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: results of the IFCT-1501 MAPS2 randomized phase II trial.
      Sixty percent of patients in the NIBIT-MESO trial experienced adverse events, with three patients requiring study discontinuation on account of treatment-related toxicity.
      • Calabro L.
      • Morra A.
      • Giannarelli D.
      • et al.
      Tremelimumab in combination with durvalumab in first or second-line mesothelioma patients: safety analysis from the phase II NIBIT-MESO-1 study.
      INITIATE appears to be the most favorable thus far on the basis of preliminary data from a 12-week analysis, with a durable controlled response rate of 72% and only 29% of patients experiencing grade 3 or 4 toxicity.
      • Disselhorst M.
      • Harms E.
      • Van Tinteren H.
      • et al.
      OA 02.02 Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma: a phase II study.
      Checkmate 743 is an ongoing randomized controlled phase III study comparing the combination of ipilimumab and nivolumab with pemetrexed/cisplatin as first-line therapy in 600 patients; it is approaching completion of enrolment.
      • Zalcman G.
      • Peters S.
      • Mansfield A.S.
      • et al.
      Checkmate 743: a phase 3, randomized, open-label trial of nivolumab (nivo) plus ipilimumab (ipi) vs pemetrexed plus cisplatin or carboplatin as first-line therapy in unresectable pleural mesothelioma.
      Further studies are addressing combinations of anti–PD-1/PD-L1 therapy with chemotherapy. The DREAM study is evaluating the effect of durvalumab (anti–PD-L1) plus standard chemotherapy followed by durvalumab alone; it has completed recruitment.
      • Nowak A.
      • Kok P.-S.
      • Livingstone A.
      • et al.
      P2.06–025. DREAM—a phase 2 trial of durvalumab with first line chemotherapy in mesothelioma with a safety run in.
      Other similar studies, such as CCTG (cisplatin/pemetrexed versus cisplatin/pemetrexed plus pembrolizumab [NCT02784171]), PrECOG (durvalumab plus cisplatin/pemetrexed [NCT02899195]), and SWOG (cisplatin/pemetrexed plus atezolizumab and surgery [NCT03228537]) are recruiting (Table 3).
      Table 3Clinical Studies on MPM (Yet to Be Published)
      StudyDrugTargetPhaseStatusClinical Trial Identifier
      Single-agent immunotherapy
       CONFIRMNivolumabPD-1IIIRNCT03063450
       PROMISE-MesoPembrolizumabPD-1IIIRNCT02991482
      Combination immunotherapy
       Checkmate 743Nivolumab

      Ipilimumab
      PD-1

      CTLA4
      IIIRNCT02899299
      Immunotherapy plus chemotherapy
       CCTGPembrolizumab

      C/P
      PD-1IIRNCT02784171
       DREAMDurvalumab

      C/P
      PD-L1II
      Information not available.
      International study not listed at ClinicalTrials.gov.
       PrECOGDurvalumab

      C/P
      PD-L1IIRNCT02899195
       SWOGAtezolizumab

      C/P

      Surgery w/wo radiation
      PD-L1IRNCT03228537
      Note: These studies were included in the table because they are ongoing clinical trials on human patients but have yet to publish results. This is a complete list as of November 2017.
      MPM, malignant pleural mesothelioma; PD-1, programmed cell death protein 1; R, recruiting; CTLA4, cytotoxic T-lymphocyte–associated antigen 4; C/P, cisplatin/pemetrexed; PD-L1, programmed death ligand 1; w/wo, with or without.
      a Information not available.
      b International study not listed at ClinicalTrials.gov.
      On the basis of recent evidence suggesting a role for focal adhesion kinase in regulation of the immunosuppressive microenvironment
      • Serrels A.
      • Lund T.
      • Serrels B.
      • et al.
      Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity.
      and synergy between FAK and PD-1 inhibition,
      • Jiang H.
      • Hegde S.
      • Knolhoff B.L.
      • et al.
      Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy.
      a proof of concept phase 1b/2A clinical trial of pembrolizumab and FAK is ongoing and includes a mesothelioma cohort (NCT02758587).
      Although PD-1/PD-L1–targeted checkpoint inhibition has demonstrated promising clinical responses in early-phase studies, the results of the ongoing phase III studies described are needed to better define the role of this approach. It is unclear whether the potentially small additional benefit of combination immune checkpoint inhibition will justify the increased toxicity.

      Promising Targeted Therapies

      BAP1 Loss in MPM

      BAP1 plays an independent role in epigenetic regulation and malignant transformation. BAP1 loss results increased trimethylated histone H3 lysine 27 (H3K27me3), increased enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) expression, and enhanced repression of polycomb repressive complex 2 (PRC2) targets. In preclinical models EZH2 inhibition has been shown to be beneficial in MPM with BAP1 loss
      • LaFave L.M.
      • Beguelin W.
      • Koche R.
      • et al.
      Loss of BAP1 function leads to EZH2-dependent transformation.
      (see Fig. 1). A phase II clinical trial investigating the EZH2 inhibitor tazemetostat in MPM completed enrollment, and results should be available soon (NCT02860286). BAP1 inactivation alters double-strand DNA repair through homologous recombination.
      • Bononi A.
      • Yang H.
      • Giorgi C.
      • et al.
      Germline BAP1 mutations induce a Warburg effect.
      • Yu H.
      • Pak H.
      • Hammond-Martel I.
      • et al.
      Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair.
      However, the potential implications for poly(ADP ribose) polymerase (PARP) inhibitor sensitivity in mesothelioma have not yet been evaluated, although the MiST 1 study is currently in development in the United Kingdom.

      Targeting Mesothelin

      Mesothelin is a cell surface glycoprotein expressed on cells lining the pleura, peritoneum, and pericardium, as well as on MPM cancer cells.
      • Morello A.
      • Sadelain M.
      • Adusumilli P.S.
      Mesothelin-targeted CARs: driving T Cells to solid tumors.
      • Pastan I.
      • Hassan R.
      Discovery of mesothelin and exploiting it as a target for immunotherapy.
      It is an attractive potential target in MPM owing to its high surface expression
      • Inaguma S.
      • Wang Z.
      • Lasota J.
      • et al.
      Comprehensive immunohistochemical study of mesothelin (MSLN) using different monoclonal antibodies 5B2 and MN-1 in 1562 tumors with evaluation of its prognostic value in malignant pleural mesothelioma.
      • Eguchi T.
      • Kadota K.
      • Mayor M.
      • et al.
      Cancer antigen profiling for malignant pleural mesothelioma immunotherapy: expression and coexpression of mesothelin, cancer antigen 125, and Wilms tumor 1.
      and its suspected involvement in tumorigenesis.
      • Li M.
      • Bharadwaj U.
      • Zhang R.
      • et al.
      Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer.
      Mesothelin-targeted therapies involving antimesothelin immunotoxins (SSP1), chimeric antimesothelin antibodies (amatuximab), mesothelin-directed antibody-drug conjugates (anetumab ravtansine), Listeria-based vaccines (CRS-207), and chimeric antigen receptor expressing T-cells (CAR-T-cells) have shown some promise in early-phase studies
      • Hassan R.
      • Thomas A.
      • Alewine C.
      • Le D.T.
      • Jaffee E.M.
      • Pastan I.
      Mesothelin immunotherapy for cancer: ready for prime time?.
      (Fig. 2), and further studies are ongoing. The recently reported randomized, open-label, active-controlled, multicenter superiority phase II study investigating anetumab ravtansine versus vinorelbine as second-line treatment in patients with mesothelin-positive MPM (248 patients) did not show a difference between the treatment groups
      • Kindler H.L.
      • Novello S.
      • Fennell D.
      • et al.
      OA 02.01. Randomized phase II study of anetumab ravtansine or vinorelbine in patients with metastatic pleural mesothelioma.
      (see Table 1).
      Figure thumbnail gr2
      Figure 2Potential therapeutic targets of mesothelin surface proteins. This figure demonstrates the proposed mechanisms of mesothelioma treatment specifically targeting mesothelin, including through monoclonal antibodies, immunotoxins, antibody-drug conjugates, virus-packed vaccine therapy, and chimeric antigen receptor (CAR) T-cell therapy. APC, antigen presenting cell; CRS207, attenuated strain of Listeria engineered to express mesothelin; DM4, tubulin inhibitor; PE38, pseudomonas exotoxin A-38; SS1P, mesothelin-binding antibody; TCR, T-cell receptor; MHC, major histocompatibility complex.
      However, there are additional promising preclinical models. Recently, a preclinical study combining direct tumor injection of mesothelin immunotoxin with intraperitoneal injection of anti-CTLA4 therapy demonstrated an 86% complete response (CR) rate in directly treated tumors and a 56% CR of a second untreated tumor, whereas no CR occurred when both drugs were given separately.
      • Leshem Y.
      • O'Brien J.
      • Liu X.
      • et al.
      Combining local immunotoxins targeting mesothelin with CTLA-4 blockade synergistically eradicates murine cancer by promoting anticancer immunity.
      A similar combination approach using an antimesothelin immunotoxin (RG7787) plus nab-paclitaxel (albumin-bound paclitaxel) in mesothelioma cell lines was also published. Three of four lines revealed durable CR, and studies in human patients began in 2017.
      • Zhang J.
      • Khanna S.
      • Jiang Q.
      • et al.
      Efficacy of anti-mesothelin immunotoxin RG7787 plus Nab-paclitaxel against mesothelioma patient-derived xenografts and mesothelin as a biomarker of tumor response.

      Arginine Deprivation Therapy

      Argininosuccinate synthetase 1 (ASS1) is the rate-limiting enzyme in arginine production, and cell lines deficient in ASS1 usually require exogenous arginine supplementation
      • Szlosarek P.W.
      • Klabatsa A.
      • Pallaska A.
      • et al.
      In vivo loss of expression of argininosuccinate synthetase in malignant pleural mesothelioma is a biomarker for susceptibility to arginine depletion.
      (Fig. 3). Intratumoral ASS1 deficiency has been identified in 63% of archived mesothelioma lines and is associated with increased tumorigenesis and more aggressive disease.
      • Szlosarek P.W.
      • Klabatsa A.
      • Pallaska A.
      • et al.
      In vivo loss of expression of argininosuccinate synthetase in malignant pleural mesothelioma is a biomarker for susceptibility to arginine depletion.
      • Huang H.Y.
      • Wu W.R.
      • Wang Y.H.
      • et al.
      ASS1 as a novel tumor suppressor gene in myxofibrosarcomas: aberrant loss via epigenetic DNA methylation confers aggressive phenotypes, negative prognostic impact, and therapeutic relevance.
      • Rabinovich S.
      • Adler L.
      • Yizhak K.
      • et al.
      Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis.
      In vitro studies of arginine deprivation with adenosine deaminase (ADI-PEG20) show improved PFS with low toxicity.
      • Izzo F.
      • Marra P.
      • Beneduce G.
      • et al.
      Pegylated arginine deiminase treatment of patients with unresectable hepatocellular carcinoma: results from phase I/II studies.
      • Ascierto P.A.
      • Scala S.
      • Castello G.
      • et al.
      Pegylated arginine deiminase treatment of patients with metastatic melanoma: results from phase I and II studies.
      • Glazer E.S.
      • Piccirillo M.
      • Albino V.
      • et al.
      Phase II study of pegylated arginine deiminase for nonresectable and metastatic hepatocellular carcinoma.
      • Yang T.S.
      • Lu S.N.
      • Chao Y.
      • et al.
      A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients.
      • Dillon B.J.
      • Prieto V.G.
      • Curley S.A.
      • et al.
      Incidence and distribution of argininosuccinate synthetase deficiency in human cancers: a method for identifying cancers sensitive to arginine deprivation.
      Szlosarek et al. applied this concept to mesothelioma, conducting the first prospective biomarker-driven randomized controlled trial in this disease.
      • Szlosarek P.W.
      • Steele J.P.
      • Nolan L.
      • et al.
      Arginine deprivation with pegylated arginine deiminase in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma: a randomized clinical trial.
      A total of 41 patients received ADI-PEG20 plus best supportive care and 24 patients received best supportive care only, with predetermined interval imaging to assess for progression of disease. They observed a median PFS of 3.2 months in the treatment group as compared with 2.0 months in the control group (p = 0.03)
      • Szlosarek P.W.
      • Steele J.P.
      • Nolan L.
      • et al.
      Arginine deprivation with pegylated arginine deiminase in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma: a randomized clinical trial.
      (see Table 2). These findings led to a phase I study of ADI-PEG20 combined with standard-of-care chemotherapy in patients with ASS1-deficient mesothelioma and NSCLC.
      • Beddowes E.
      • Spicer J.
      • Chan P.Y.
      • et al.
      Phase 1 dose-escalation study of pegylated arginine deiminase, cisplatin, and pemetrexed in patients with argininosuccinate synthetase 1-deficient thoracic cancers.
      Nine patients (five with MPM) received escalating weekly doses of ADI-PEG20 with standard chemotherapy. No dose-limiting toxicities were encountered, and only nine reported adverse events (most commonly rash) were related to ADI-PEG20. All patients experienced stable disease, and seven (78%) achieved a partial response, including one with sarcomatoid MPM. These results suggested that coadministration of standard chemotherapy and arginine deprivation therapy in ASS1-negative patients was well tolerated and could improve tumor response over chemotherapy alone.
      • Beddowes E.
      • Spicer J.
      • Chan P.Y.
      • et al.
      Phase 1 dose-escalation study of pegylated arginine deiminase, cisplatin, and pemetrexed in patients with argininosuccinate synthetase 1-deficient thoracic cancers.
      A phase II/III trial is currently recruiting patients with MPM with 75% loss of ASS1.
      • Szlosarek P.W.
      • Baas P.
      • Ceresoli G.L.
      • et al.
      ATOMIC-Meso: a randomized phase 2/3 trial of ADI-PEG20 or placebo with pemetrexed and cisplatin in patients with argininosuccinate synthetase 1-deficient non-epithelioid mesothelioma.
      Figure thumbnail gr3
      Figure 3Effect of arginine deprivation on tumor cells. (A) In cells with fully functional argininosuccinate synthetase 1 (ASS1), arginine required for the urea cycle can be created from citrulline through the ASS1 enzyme or through direct uptake from the plasma. (B) In cells deficient in ASS1, its ability to convert citrulline to arginine is decreased at baseline. Pegylated adenosine deaminase (ADI-PEG20) is an enzyme that breaks down arginine in the plasma into citrulline and ammonia (NH3). Giving ADI-PEG20 to cells already deficient in arginine further depletes a cell of arginine, inhibiting urea cycle function and eventually leading to cell death.

      NF2-Targeted Therapies

      NF2 is a gene that is commonly inactivated in MPM. This gene encodes Merlin, which regulates the Hippo tumor suppressive signaling pathway. Hippo pathway dysregulation leads to constitutive activation of YY1 associated protein 1/tafazzin transcriptional coactivators and enhances malignant phenotypes of malignant mesothelioma cells.
      • Kakiuchi T.
      • Takahara T.
      • Kasugai Y.
      • et al.
      Modeling mesothelioma utilizing human mesothelial cells reveals involvement of phospholipase-C beta 4 in YAP-active mesothelioma cell proliferation.
      Although the progress of MPM research based on NF2 alteration was limited in 2017, novel therapeutic strategies against YY1 associated protein 1/tafazzin have been developed for a variety of human malignancies, including MPM.
      • Woodard G.A.
      • Yang Y.L.
      • You L.
      • Jablons D.M.
      Drug development against the hippo pathway in mesothelioma.
      Merlin can also accumulate in the nucleus and suppresses tumorigenesis by inhibiting the cullin E3 ubiquitin ligase CRL4DCAF1. Combining an NEDD8-activating enzyme inhibitor, which suppresses CRL4DCAF1, and mammalian target of rapamycin/phosphoinositide 3-kinase inhibitor suppresses the growth of in NF2-mutant mesothelioma and schwannoma cells.
      • Cooper J.
      • Xu Q.
      • Zhou L.
      • et al.
      Combined inhibition of NEDD8-activating enzyme and mTOR suppresses NF2 loss-driven tumorigenesis.

      Other Potential Systemic Therapies

      Promising results in the adjuvant setting using the WT-1 peptide vaccine galinpepimut-S after multimodality therapy were shown in a randomized phase II trial, but the trial lacked statistical power to draw stronger conclusions.
      • Zauderer M.G.
      • Tsao A.S.
      • Dao T.
      • et al.
      A randomized phase II trial of adjuvant galinpepimut-S, WT-1 analogue peptide vaccine, after multimodality therapy for patients with malignant pleural mesothelioma.
      Autologous monocyte-derived dendritic cell immunotherapy pulsed with allogenic tumor cell line lysate was effective in mice and safe in nine patients with MPM in a phase I trial.
      • Aerts J.G.
      • de Goeje P.L.
      • Cornelissen R.
      • et al.
      Autologous dendritic cells pulsed with allogeneic tumor cell lysate in mesothelioma: from mouse to human.
      A novel therapeutic strategy currently at a preclinical stage for MPM is the inhibition of the protumor alarmin high mobility group box 1 by a number of compounds such as ethyl pyruvate
      • Pellegrini L.
      • Xue J.
      • Larson D.
      • et al.
      HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma.
      and aspirin.
      • Yang H.
      • Pellegrini L.
      • Napolitano A.
      • et al.
      Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression.
      The antitumoral properties of various viruses have been demonstrated in a number of malignancies.
      • Kaufmann J.K.
      • Chiocca E.A.
      Glioma virus therapies between bench and bedside.
      • Hartkopf A.D.
      • Fehm T.
      • Wallwiener D.
      • Lauer U.M.
      Oncolytic virotherapy of breast cancer.
      • Xia Z.J.
      • Chang J.H.
      • Zhang L.
      • et al.
      [Phase III randomized clinical trial of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with cisplatin-based chemotherapy in treating squamous cell cancer of head and neck or esophagus].
      • Patel M.R.
      • Jacobson B.A.
      • Belgum H.
      • et al.
      Measles vaccine strains for virotherapy of non-small-cell lung carcinoma.
      • Andtbacka R.H.
      • Kaufman H.L.
      • Collichio F.
      • et al.
      Talimogene laherparepvec improves durable response rate in patients with advanced melanoma.
      MPM has been the target of many such investigations,
      • Pease D.F.
      • Kratzke R.A.
      Oncolytic viral therapy for mesothelioma.
      and promising preclinical data regarding adenovirus oncotherapy
      • Smythe W.R.
      • Hwang H.C.
      • Elshami A.A.
      • et al.
      Treatment of experimental human mesothelioma using adenovirus transfer of the herpes simplex thymidine kinase gene.
      • Hwang H.C.
      • Smythe W.R.
      • Elshami A.A.
      • et al.
      Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer.
      • Cordier Kellerman L.
      • Valeyrie L.
      • Fernandez N.
      • et al.
      Regression of AK7 malignant mesothelioma established in immunocompetent mice following intratumoral gene transfer of interferon gamma.
      • Odaka M.
      • Sterman D.H.
      • Wiewrodt R.
      • et al.
      Eradication of intraperitoneal and distant tumor by adenovirus-mediated interferon-beta gene therapy is attributable to induction of systemic immunity.
      prompted human studies. Herpes simplex virus-1 oncotherapy has shown dramatic responses in vitro,
      • Adusumilli P.S.
      • Stiles B.M.
      • Chan M.K.
      • et al.
      Imaging and therapy of malignant pleural mesothelioma using replication-competent herpes simplex viruses.
      • Adusumilli P.S.
      • Chan M.K.
      • Chun Y.S.
      • et al.
      Cisplatin-induced GADD34 upregulation potentiates oncolytic viral therapy in the treatment of malignant pleural mesothelioma.
      • Adusumilli P.S.
      • Chan M.K.
      • Hezel M.
      • et al.
      Radiation-induced cellular DNA damage repair response enhances viral gene therapy efficacy in the treatment of malignant pleural mesothelioma.
      and preliminary results in human patients revealed a 50% disease stability rate.
      • Danson S.
      • Woll P.
      • Edwards J.
      • et al.
      366PD. Oncolytic herpesvirus therapy for mesothelioma: a phase I/IIa trial of intrapleural administration of HSV1716 (NCT01721018).
      In murine xenografted models of mesothelioma, intrapleural oncolytic vaccinia virus administration resulted in improved 30-day survival.
      • Belin L.J.
      • Ady J.W.
      • Lewis C.
      • et al.
      An oncolytic vaccinia virus expressing the human sodium iodine symporter prolongs survival and facilitates SPECT/CT imaging in an orthotopic model of malignant pleural mesothelioma.
      There have also been several promising studies of MPM and intrapleural administration of oncolytic measles viruses,
      • Li H.
      • Peng K.W.
      • Dingli D.
      • Kratzke R.A.
      • Russell S.J.
      Oncolytic measles viruses encoding interferon beta and the thyroidal sodium iodide symporter gene for mesothelioma virotherapy.
      • Achard C.
      • Boisgerault N.
      • Delaunay T.
      • et al.
      Sensitivity of human pleural mesothelioma to oncolytic measles virus depends on defects of the type I interferon response.
      and a phase I study to evaluate efficacy in humans is ongoing.
      • Peikert T.
      • Mandrekar S.
      • Mansfield A.
      • et al.
      OA13.07. Intrapleural modified vaccine strain measles virus therapy for patients with malignant pleural mesothelioma.
      Other promising therapeutic candidates include the monopolar spindle 1 kinase, a kinase of the spindle assembly checkpoint that controls cell division and cell fate
      • Szymiczek A.
      • Carbone M.
      • Pastorino S.
      • et al.
      Inhibition of the spindle assembly checkpoint kinase Mps-1 as a novel therapeutic strategy in malignant mesothelioma.
      ; the mammalian target of rapamycin/phosphoinositide 3-kinase/AKT axis for the aggressive subset of MPM harboring simultaneous inactivating mutations of the genes LATS2 and NF2
      • Tranchant R.
      • Quetel L.
      • Tallet A.
      • et al.
      Co-occurring mutations of tumor suppressor genes, LATS2 and NF2, in malignant pleural mesothelioma.
      ; the sialylated protein heart development protein with EGF like domains 1, which can be targeted by a specific monoclonal antibody
      • Tsuji S.
      • Washimi K.
      • Kageyama T.
      • et al.
      HEG1 is a novel mucin-like membrane protein that serves as a diagnostic and therapeutic target for malignant mesothelioma.
      ; and targeting of v-myc avian myelocytomatosis viral oncogene homolog MYC, which is up-regulated in MPM cells.
      • Tan Y.
      • Sementino E.
      • Chernoff J.
      • Testa J.R.
      Targeting MYC sensitizes malignant mesothelioma cells to PAK blockage-induced cytotoxicity.
      The first-in-human phase I trial of anti-CD26 antibody, YS110, was also conducted with 33 patients, including 22 with MPM.
      • Angevin E.
      • Isambert N.
      • Trillet-Lenoir V.
      • et al.
      First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers.
      Several mRNAs have been reported as potential therapeutic targets with proof of concept in clinical trials (e.g., the miRNA-15/16 family,
      • Schelch K.
      • Kirschner M.B.
      • Williams M.
      • et al.
      A link between the fibroblast growth factor axis and the miR-16 family reveals potential new treatment combinations in mesothelioma.
      • van Zandwijk N.
      • Pavlakis N.
      • Kao S.C.
      • et al.
      Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study.
      or miRNA-137, through its control of YB-1).
      • Johnson T.G.
      • Schelch K.
      • Cheng Y.Y.
      • et al.
      Dysregulated expression of the microRNA miR-137 and its target YB-1 contribute to the invasive characteristics of malignant pleural mesothelioma.
      Interestingly, miRNAs have been shown to contribute to the regulation of PD-L1 expression,
      • Kao S.C.
      • Cheng Y.Y.
      • Williams M.
      • et al.
      Tumor suppressor microRNAs contribute to the regulation of PD-L1 expression in malignant pleural mesothelioma.
      opening to novel potential combinations between miRNA-targeting drugs and immune checkpoint inhibitors.
      To further bridge preclinical and clinical results, the availability of relevant in vitro and in vivo models is crucial. In this respect, the establishment of primary MPM culture systems to test novel drugs

      Schunselaar L, Quispel-Janssen JM, Kim Y, et al. Chemical profiling of primary mesothelioma cultures defines subtypes with different expression profiles and clinical responses [e-pub ahead of print]. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-17-1345, accessed November 30, 2017.

      • Quispel-Janssen J.M.
      • Badhai J.
      • Schunselaar L.
      • et al.
      Comprehensive pharmacogenomic profiling of malignant pleural mesothelioma identifies a subgroup sensitive to FGFR inhibition.
      and patient-derived xenografts from pleural mesothelioma
      • Wu L.
      • Allo G.
      • John T.
      • et al.
      Patient-derived xenograft establishment from human malignant pleural mesothelioma.
      represented a significant scientific advance in 2017.

      Surgical Resection

      Optimal treatment of MPM remains controversial, particularly the role of localized therapies such as surgery and radiation. Historically, operable patients underwent EPP, which has significant complications and substantial mortality with no appreciable benefit to the patient demonstrated by the small randomized MARS pilot study.
      • Treasure T.
      • Lang-Lazdunski L.
      • Waller D.
      • et al.
      Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study.
      Pleurectomy/decortication (P/D) was then introduced in an attempt to offer a lung-sparing macroscopic resection of the tumor. Previous uncontrolled studies have suggested that this procedure is associated with fewer adverse events, with equivalent to improved survival benefits.
      • Burt B.M.
      • Cameron R.B.
      • Mollberg N.M.
      • et al.
      Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality.
      • Taioli E.
      • Wolf A.S.
      • Flores R.M.
      Meta-analysis of survival after pleurectomy decortication versus extrapleural pneumonectomy in mesothelioma.
      • Bovolato P.
      • Casadio C.
      • Bille A.
      • et al.
      Does surgery improve survival of patients with malignant pleural mesothelioma? a multicenter retrospective analysis of 1365 consecutive patients.
      • Friedberg J.S.
      • Simone 2nd, C.B.
      • Culligan M.J.
      • et al.
      Extended pleurectomy-decortication-based treatment for advanced stage epithelial mesothelioma yielding a median survival of nearly three years.
      • Batirel H.F.
      • Metintas M.
      • Caglar H.B.
      • et al.
      Adoption of pleurectomy and decortication for malignant mesothelioma leads to similar survival as extrapleural pneumonectomy.
      • Flores R.M.
      • Pass H.I.
      • Seshan V.E.
      • et al.
      Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients.
      • Cao C.
      • Tian D.
      • Park J.
      • Allan J.
      • Pataky K.A.
      • Yan T.D.
      A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma.
      Despite these findings, clinical equipoise regarding the true benefit of either operation remains. In 2017, two large observational studies using the National Cancer Database were conducted. In the first, propensity score matching analysis showed that surgery-based multimodality therapy was associated with improved survival and may offer therapeutic benefit among carefully selected patients.
      • Nelson D.B.
      • Rice D.C.
      • Niu J.
      • et al.
      Long-term survival outcomes of cancer-directed surgery for malignant pleural mesothelioma: propensity score matching analysis.
      A second study evaluated 271 patients who underwent EPP and 1036 patients who received P/D. They found no statistically significant differences in OS (19 months in the EPP group and 16 months in the P/D group [p = 0.120]), 30-day mortality (5% [p = 0.999]), or 30-day readmission rates (7% versus 5% [p = 0.292]), implying that either technique is a realistic option for surgical candidates.
      • Verma V.
      • Ahern C.A.
      • Berlind C.G.
      • et al.
      National Cancer Database report on pneumonectomy versus lung-sparing surgery for malignant pleural mesothelioma.
      To further complicate the debate, a relatively large retrospective multicenter study suggested that extended P/D or nonextended P/D (i.e., P/D without resection of the diaphragm and/or pericardium) had similar outcomes in terms of early results and survival rate.
      • Marulli G.
      • Breda C.
      • Fontana P.
      • et al.
      Pleurectomy-decortication in malignant pleural mesothelioma: are different surgical techniques associated with different outcomes? Results from a multicentre study.
      A recently published comprehensive review on quality of life in MPM showed that quality of life was generally better for patients undergoing P/D than for those undergoing EPP.
      • Schwartz R.M.
      • Watson A.
      • Wolf A.
      • Flores R.
      • Taioli E.
      The impact of surgical approach on quality of life for pleural malignant mesothelioma.
      Presently, the ongoing MARS2 trial is comparing P/D versus no surgery; in 2017 the study surpassed its futility end point and patient enrollment will continue.
      • Trialists M.
      • Lim E.
      OA 02.07. Surgical selection in pleurectomy decortication for mesothelioma—an overview from screening and selection from MARS 2 Pilot.

      Advances in RT

      The ostensible goal of surgery in MPM has been macroscopic complete resection. Surgical resection alone is associated with frequent locoregional recurrences,
      • Flores R.M.
      • Pass H.I.
      • Seshan V.E.
      • et al.
      Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients.
      • Kostron A.
      • Friess M.
      • Crameri O.
      • et al.
      Relapse pattern and second-line treatment following multimodality treatment for malignant pleural mesothelioma.
      suggesting that adjuvant or neoadjuvant radiotherapy (RT) in a multimodality approach may have a role in improving recurrence control. However, the role of RT after EPP has been questioned on the basis of a recently published randomized controlled study.
      • Stahel R.A.
      • Riesterer O.
      • Xyrafas A.
      • et al.
      Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial.
      A systematic review assessing the role of RT after lung-sparing surgery (P/D) in MPM
      • Ashton M.
      • O'Rourke N.
      • Currie S.
      • Rimner A.
      • Chalmers A.
      The role of radical radiotherapy in the management of malignant pleural mesothelioma: a systematic review.
      concluded that RT can be delivered safely, with encouraging survival data and acceptable levels of toxicity after a lung-sparing procedure in MPM. Memorial Sloan-Kettering Cancer Center has been at the forefront of research regarding intensity-modulated radiation therapy (IMRT) after P/D, with studies demonstrating encouraging OS without a significant increase in radiation pneumonitis.
      • Rosenzweig K.E.
      • Zauderer M.G.
      • Laser B.
      • et al.
      Pleural intensity-modulated radiotherapy for malignant pleural mesothelioma.
      • Rimner A.
      • Spratt D.E.
      • Zauderer M.G.
      • et al.
      Failure patterns after hemithoracic pleural intensity modulated radiation therapy for malignant pleural mesothelioma.
      • Rimner A.
      • Zauderer M.G.
      • Gomez D.R.
      • et al.
      Phase II study of hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) as part of lung-sparing multimodality therapy in patients with malignant pleural mesothelioma.
      Shaikh et al. evaluated the effect of hemithoracic IMRT compared with conventional RT in patients treated with P/D.
      • Shaikh F.
      • Zauderer M.G.
      • von Reibnitz D.
      • et al.
      Improved outcomes with modern lung-sparing trimodality therapy in patients with malignant pleural mesothelioma.
      The study analyzed 209 patients (131 undergoing conventional RT and 78 undergoing IMRT) and demonstrated a statistically improved OS in the IMRT arm (median 20.2 versus 12.3 months [p = 0.001]). Notably, patients in this arm were also more likely to have achieved a macroscopically complete resection (p = 0.01), epithelioid histological features (p = 0.003), and higher Karnofsky performance scores upon initial receipt of RT (p = 0.01), and they were less likely to experience esophagitis (p = 0.0007) according to multivariable analysis. There were no significant differences in rates of local recurrence.
      • Shaikh F.
      • Zauderer M.G.
      • von Reibnitz D.
      • et al.
      Improved outcomes with modern lung-sparing trimodality therapy in patients with malignant pleural mesothelioma.
      Another promising approach has been neoadjuvant high-dose RT to the ipsilateral lung followed by EPP. Pioneered by the Toronto group led by Drs. de Perrot and Cho, this approach has been shown to be safe and has demonstrated a very favorable OS.
      • de Perrot M.
      • Feld R.
      • Leighl N.B.
      • et al.
      Accelerated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma.
      • Mordant P.
      • McRae K.
      • Cho J.
      • et al.
      Impact of induction therapy on postoperative outcome after extrapleural pneumonectomy for malignant pleural mesothelioma: does induction-accelerated hemithoracic radiation increase the surgical risk?.
      This group treated 90 patients between November 2008 and February 2017, with a median survival of 28.3 months for the intention-to-treat population. This approach may be most beneficial in patients with epithelial tumors, low tumor volume, and no lymph node metastasis.
      • de Perrot M.
      • Dong Z.
      • Bradbury P.
      • et al.
      Impact of tumour thickness on survival after radical radiation and surgery in malignant pleural mesothelioma.
      • Stahel R.A.
      • Riesterer O.
      • Xyrafas A.
      • et al.
      Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial.
      Of note, carriers of germline BAP1 mutations may have a high risk for development of a second malignancy when treated with RT. Therefore, RT should be used with caution, which is similar to the treatment guidelines for patients with Li-Fraumeni syndrome.

      Advances in Palliative Care

      In contrast to lung cancer, a recently reported randomized study did not demonstrate any benefit of early implementation of palliative care for MPM (RESPECT-Meso Study).
      • Brims F.
      • Gunatilake S.
      • Lawrie I.
      • et al.
      OA 02.05. RESPECT-MESO: an international randomized controlled trial to assess early specialist palliative care in malignant pleural mesothelioma.
      It is worth noting that the RESPECT study was conducted in the United Kingdom and Australia by centers with significant nursing support for patients and its conclusions do not necessarily negate the potential benefit of palliative care in other health care settings. In addition, the recently presented PIT Study demonstrated that prophylactic intervention track site radiation did not prevent the occurrence and symptoms of tract site metastasis. The frequency of tract site metastasis was not significantly different: 3.2% in the RT group and 5.3% in the control group.
      • Bayman N.
      • Appel W.
      • Ashcroft L.
      • et al.
      OA 02.03. Prophylactic irradiation of tracts (PIT) in patients with pleural mesothelioma: results of a multicenter phase III trial.
      Furthermore, recent data demonstrated that the use of an indwelling pleural catheter resulted in fewer hospital days and fewer subsequent interventions than talc slurry pleurodesis in a randomized study of 144 patients (approximately 25% of patients in each group had MPM).
      • Thomas R.
      • Fysh E.T.H.
      • Smith N.A.
      • et al.
      Effect of an indwelling pleural catheter vs talc pleurodesis on hospitalization days in patients with malignant pleural effusion: the AMPLE randomized clinical trial.
      It is important to note, however, that clinical concern remains for seeding along a chest tube tract in patients with MPM.
      • van Ooijen B.
      • Eggermont A.M.
      • Wiggers T.
      Subcutaneous tumor growth complicating the positioning of Denver shunt and intrapleural port-a-cath in mesothelioma patients.

      Conclusion

      The year 2017 was characterized by several important advances in this field, although only a minority would be considered practice changing. As of today, pemetrexed-based cytotoxic chemotherapy with or without bevacizumab remains the standard of care for most patients. Immunotherapy trials remain an exciting area of investigation, though whether the benefits of combination anti-CTLA4 and anti–PD-1/PD-L1 immunotherapy will outweigh the increased risk of toxicity remains unclear. Many single-agent and combination immunotherapy trials are ongoing, and additional results are expected for 2018–2019. Although physician-directed immune checkpoint inhibitor therapy has now been included in the current National Comprehensive Cancer Network guidelines as an option for second-line therapy for MPM, the efficiency of this approach remains unproved, and as such these patients should primarily be encouraged to enroll in ongoing clinical trials.
      Improved understanding of MPM molecular biology and the immunological tumor microenvironment provide future therapeutic applications, most notably through the BAP1 pathway.
      Although the role of multimodality therapy including surgery remains controversial, it is encouraging that there are several new approaches and ongoing multicenter studies. The MARS-2 study surpassed its futility end point and preliminary findings are expected in the upcoming years. The 2017 advances will, it is hoped, be followed by significant clinical translation and result in the urgently needed improved therapeutic strategies for this devastating disease.

      Acknowledgments

      The authors thank Kevin Youel from Creative Media for his assistance in creating the images.

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