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Medical School, University of Western Australia, Perth, AustraliaNational Center for Asbestos Related Diseases, University of Western Australia, Perth, Australia
Department of Thoracic Surgery, Zhejiang Cancer Hospital, Hangzhou, People's Republic of ChinaKey Laboratory Diagnosis and Treatment Technology on Thoracic Oncology of Zhejiang Province, Hangzhou, People's Republic of China
Corresponding author. Address for correspondence: Tobias Peikert, MD, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Gonda 18 South, Mayo Clinic, Rochester, MN.
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.
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.
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.
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.
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.
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.
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,
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.
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.
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.
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,
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.
Circulating complement component 4d (C4d) correlates with tumor volume, chemotherapeutic response and survival in patients with malignant pleural mesothelioma.
Plasmatic extracellular vesicle microRNAs in malignant pleural mesothelioma and asbestos-exposed subjects suggest a 2-miRNA signature as potential biomarker of disease.
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.
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.
The IASLC Mesothelioma Staging Project: proposals for revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma.
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.
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.
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.
Assessment of therapy responses and prediction of survival in malignant pleural mesothelioma through computer-aided volumetric measurement on computed tomography scans.
Computer-assisted diagnosis for early stage pleural mesothelioma: towards automated detection and quantitative assessment of pleural thickening from thoracic CT images.
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).
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.
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.
Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred tracing back nine generations to a common ancestor from the 1700s.
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.
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).
Immunohistochemical evaluation of two antibodies against PD-L1 and prognostic significance of PD-L1 expression in epithelioid peritoneal malignant mesothelioma: a RENAPE study.
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.
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).
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.
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,
Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred tracing back nine generations to a common ancestor from the 1700s.
In addition to germline mutations predisposing to mesothelioma and other cancers, BAP1 is the most frequent acquired (somatic) mutation in sporadic 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,
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.
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.
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.
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.
Utility of BRCA1-associated protein 1 immunoperoxidase stain to differentiate benign versus malignant mesothelial proliferations in cytologic specimens.
BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma.
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.
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.
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.
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.
As vascular endothelial growth factor (VEGF) signaling is important in the pathophysiology of MPM, VEGF inhibition is being explored as a potential treatment option.
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.
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.
Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 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.
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).
Nintedanib plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma: phase II results from the randomized, placebo-controlled LUME-Meso trial.
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.
Arginine deprivation with pegylated arginine deiminase in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma: a randomized clinical trial.
Phase 1 dose-escalation study of pegylated arginine deiminase, cisplatin, and pemetrexed in patients with argininosuccinate synthetase 1-deficient thoracic cancers.
Nintedanib plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma: phase II results from the randomized, placebo-controlled LUME-Meso trial.
Arginine deprivation with pegylated arginine deiminase in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma: a randomized clinical trial.
Phase 1 dose-escalation study of pegylated arginine deiminase, cisplatin, and pemetrexed in patients with argininosuccinate synthetase 1-deficient thoracic cancers.
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.
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.
Phase II studies investigating tremelimumab, a selective human monoclonal antibody against CTLA4, showed favorable PFS responses and toxicity profiles.
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).
Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.
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.
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.
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.
Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.
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.
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.
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.
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.
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.
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.
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.
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
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.
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).
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.
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.
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.
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.
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),
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.
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.
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.
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.
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.
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.
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)
International study not listed at ClinicalTrials.gov.
PrECOG
Durvalumab C/P
PD-L1
II
R
NCT02899195
SWOG
Atezolizumab C/P Surgery w/wo radiation
PD-L1
I
R
NCT03228537
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 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
(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.
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.
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.
Cancer antigen profiling for malignant pleural mesothelioma immunotherapy: expression and coexpression of mesothelin, cancer antigen 125, and Wilms tumor 1.
(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
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.
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.
Efficacy of anti-mesothelin immunotoxin RG7787 plus Nab-paclitaxel against mesothelioma patient-derived xenografts and mesothelin as a biomarker of tumor response.
Argininosuccinate synthetase 1 (ASS1) is the rate-limiting enzyme in arginine production, and cell lines deficient in ASS1 usually require exogenous arginine supplementation
(Fig. 3). Intratumoral ASS1 deficiency has been identified in 63% of archived mesothelioma lines and is associated with increased tumorigenesis and more aggressive disease.
ASS1 as a novel tumor suppressor gene in myxofibrosarcomas: aberrant loss via epigenetic DNA methylation confers aggressive phenotypes, negative prognostic impact, and therapeutic relevance.
Incidence and distribution of argininosuccinate synthetase deficiency in human cancers: a method for identifying cancers sensitive to arginine deprivation.
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)
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.
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.
Phase 1 dose-escalation study of pegylated arginine deiminase, cisplatin, and pemetrexed in patients with argininosuccinate synthetase 1-deficient thoracic cancers.
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 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 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.
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.
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.
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.
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.
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
[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].
Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer.
Eradication of intraperitoneal and distant tumor by adenovirus-mediated interferon-beta gene therapy is attributable to induction of systemic immunity.
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.
Other promising therapeutic candidates include the monopolar spindle 1 kinase, a kinase of the spindle assembly checkpoint that controls cell division and cell fate
; 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
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.
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.
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.
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.
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.
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.
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.
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.
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.
The ostensible goal of surgery in MPM has been macroscopic complete resection. Surgical resection alone is associated with frequent locoregional recurrences,
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.
Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial.
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.
Phase II study of hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) as part of lung-sparing multimodality 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.
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.
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.
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).
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.
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).
Effect of an indwelling pleural catheter vs talc pleurodesis on hospitalization days in patients with malignant pleural effusion: the AMPLE randomized clinical trial.
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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