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Current and Future Management of Malignant Mesothelioma: A Consensus Report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation

      Abstract

      On March 28– 29, 2017, the National Cancer Institute (NCI) Thoracic Malignacy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation convened the NCI–International Association for the Study of Lung Cancer– Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting in Bethesda, Maryland. The goal of the meeting was to bring together lead academicians, clinicians, scientists, and the U.S. Food and Drug Administration to focus on the development of clinical trials for patients in whom malignant pleural mesothelioma has been diagnosed. In light of the discovery of new cancer targets affecting the clinical development of novel agents and immunotherapies in malignant mesothelioma, the objective of this meeting was to assemble a consensus on at least two or three practice-changing multimodality clinical trials to be conducted through NCI’s National Clinical Trials Network.

      Keywords

      Introduction

      Malignant pleural mesothelioma (MPM) is a rare and highly lethal cancer associated with exposure to asbestos. In the Surveillance, Epidemiology, and End Results database, MPM peaked in the 1980s to 1990s and is now plateauing. In men, the incidence has been stable at 1.8 cases per 100,000 for the past 10 years, with peak values in the early 1990s (2.5 cases per 100,000), whereas in women, the rate has been 0.4 cases per 100,000 and has not changed substantially over time.
      • Liu B.
      • van Gerwen M.
      • Bonassi S.
      • Taioli E.
      International Association for the Study of Lung Cancer Mesothelioma Task Force
      Epidemiology of environmental exposure and malignant mesothelioma.
      • Carbone M.
      • Kanodia S.
      • Chao A.
      • et al.
      Consensus report of the 2015 Weinman International Conference on Mesothelioma.
      However between 1999 and 2015, the overall rates of death due to mesothelioma continued to increase.
      • Mazurek J.M.
      • Syamlal G.
      • Wood J.M.
      • Hendricks S.A.
      • Weston A.
      Malignant Mesothelioma Mortality–United States, 1999-2015.
      Women with MPM have a threefold better 5-year survival rate than men.
      • Taioli E.
      • Wolf A.S.
      • Camacho-Rivera M.
      • Flores R.M.
      Women with malignant pleural mesothelioma have a threefold better survival rate than men.
      There are more than 400 fibrous minerals present in nature, but regulatory organizations have identified only six asbestos mineral fibers that have widespread commercial use and are carcinogenic.
      • Baumann F.
      • Ambrosi J.P.
      • Carbone M.
      Asbestos is not just asbestos: an unrecognised health hazard.
      Although occupational exposure to asbestos has been greatly reduced in industrial nations, development of rural areas has led to an increase in environmental exposure to asbestos and other fibers such as erionite.
      • Carbone M.
      • Kanodia S.
      • Chao A.
      • et al.
      Consensus report of the 2015 Weinman International Conference on Mesothelioma.
      • Carbone M.
      • Baris Y.I.
      • Bertino P.
      • et al.
      Erionite exposure in North Dakota and Turkish villages with mesothelioma.
      • Baumann F.
      • Buck B.J.
      • Metcalf R.V.
      • McLaurin B.T.
      • Merkler D.J.
      • Carbone M.
      The presence of asbestos in the natural environment is likely related to mesothelioma in young individuals and women from Southern Nevada.
      In recent years, a considerable proportion of mesothelioma cases have had no identifiable source of asbestos exposure, suggesting that traditional questionnaires do not properly identify sources of environmental exposure and that improved biomarkers of exposure are needed. Additionally, an inherited predisposition to mesothelioma, as well as to several other cancers, has been associated with germline alterations in BRCA-associated protein-1 gene (BAP1).
      • Testa J.R.
      • Cheung M.
      • Pei J.
      • et al.
      Germline BAP1 mutations predispose to malignant mesothelioma.
      This supports a potential standard role for germline genetic profiling in patients with BAP1-mutated tumors.
      As MPM is an orphan disease, the National Cancer Institute (NCI) Thoracic Malignacy Steering Committee, International Association for the Study of Lung Cancer (IASLC), and Mesothelioma Applied Research Foundation (MARF) organized the NCI-IASLC-MARF Mesothelioma Clinical Trials Planning Meeting (CTPM) to focus on identifying knowledge gaps and designing at least two or three practice-changing multimodality clinical trials that would be perfomed through the NCI’s National Clinical Trials Network (NCTN). A group of basic scientists, clinicians (specializing in radiology, pulmonary medicine, thoracic medical oncology, thoracic surgery, thoracic radiation oncology, and pathology), epidemiologists, and patient advocates and representatives of the U.S. Food and Drug Administration (FDA) convened in Bethesda, Maryland, to participate in the panel discussions. This subsequent article details the discussion and recommendations from the NCI-IASLC-MARF Mesothelioma CTPM.

      Background Genomics of Disease

      MPM is largely characterized by loss of tumor suppressor genes. Genomic studies have demonstrated that except for mutations in BAP1 and cyclin dependent kinase inhibitor 2A gene (CDKN2A), driver mutations are rare in mesothelioma.
      • 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.
      • Lo Iacono M.
      • Monica V.
      • Righi L.
      • et al.
      Targeted next-generation sequencing of cancer genes in advanced stage malignant pleural mesothelioma: a retrospective study.
      • Guo G.
      • Chmielecki J.
      • Goparaju C.
      • et al.
      Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural 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.
      However, recent studies
      • 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.
      have revealed that minute deletions (i.e., DNA deletions <3 kb) are frequent in mesothelioma and are often missed by comparative genomic hybridization arrays and next-generation sequencing. Therefore, it is likely that current genomic information underestimates the true incidence of genetic mutations and tumor suppressor gene inactivation in 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.
      The Cancer Genome Atlas mesothelioma program integrated exome sequencing, copy number, gene expression, noncoding RNA (microRNA and long noncoding RNA) expression, DNA methylation, and proteomic data from 74 chemonaive patients with MPM and identified histology-independent prognostic subtypes and reported that a high epithelial-mesenchymal transition score, mesothelin promoter methylation, deletion of CDKN2A, and upregulation of the Ras-mitogen-activated protein kinase and phosphoinositide 3-kinase/mechanistic target of rapamycin (mTOR) signaling pathways all adversely affect survival.
      • Hmeljak J.
      • Sanchez-Vega F.
      • et al.
      Integrative molecular characterization of malignant pleural mesothelioma.
      Although there are many MPM cell lines available for biological and preclinical studies, the efforts to establish patient-deriived xenograft (PDX) models from MPM have been limted.
      • Kalra N.
      • Zhang J.
      • Thomas A.
      • et al.
      Mesothelioma patient derived tumor xenografts with defined BAP1 mutations that mimic the molecular characteristics of human malignant mesothelioma.
      Wu et al.
      • Wu L.
      • Allo G.
      • John T.
      • et al.
      Patient-derived xenograft establishment from human malignant pleural mesothelioma.
      successfully established a PDX from 20 of 50 surgically obtained MPM tumors (40%) by implanting them subcutaneously into nonobese diabetic/severe combined immunodeficient (NOD-SCID) mice and serially passaged them for up to five generations. Histological and biomarker profiles (including BAP1 and CDKN2A status) of the PDX models closely resembled those of the parent tumors, and genomic aberrations found in these models recapitulated previously reported changes. Incorporating PDX development as a translational correlate in clinical trials would be beneficial in advancing the field.

      Background Therapies in Early-Stage MPM

      Although there is no level I evidence to support surgery for MPM, some patients benefit from a surgery-based approach, especially those with an epithelioid subtype, lower-volume disease, and/or minimal to no nodal involvement.
      • Sugarbaker D.J.
      • Richards W.G.
      • Bueno R.
      Extrapleural pneumonectomy in the treatment of epithelioid malignant pleural mesothelioma: novel prognostic implications of combined N1 and N2 nodal involvement based on experience in 529 patients.
      The optimal outcome of MPM surgery is a macroscopic complete resection, with either lung-sparing or lung-sacrificing surgery. Whereas lung-sacrificing surgery has been clearly defined and highly standardized as an extrapleural pneumonectomy (EPP), efforts to standardize the technique for lung-sparing have been limited by lack of randomized trials. In the absence of data, various combinations of extended surgery performed by pleurectomy/decortication (P/D) have recently emerged.
      Currently, there is no consensus regarding the optimal multimodality approach to patients with resectable MPM.
      • 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.
      As complete surgical resection (R0 resection) remains elusive in most patients with MPM, local recurrence represents the most common form of disease relapse. To address this, many places throughout the world use multimodality therapy with neoadjuvant or adjuvant chemotherapy and radiation despite the lack of evidence-based data from randomized trials. Some experts also believe that additional intraoperative cytoreductive treatment can decrease local recurrence rates. Various intraoperative treatments under investigation include hyperthermic chemotherapy lavage (typically cisplatin with or without other agents), hyperthermic povidone iodine lavage, fibrin-associated cisplatin (applied as a spray), and photodynamic therapy. Photodynamic therapy
      • 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.
      is currently the only modality being studied in a phase II randomized clinical trial (NCT02153229). Broad surface cautery using the argon beam coagulator and/or Aquamantys bipolar cautery (Medtronic, Minneapolis, MN) also continues to be studied, as does cryotherapy as intraoperative adjuvant therapy (NCT02464904). Given the accessibility of mesothelioma, local immunotherapy and intrapleural gene therapy (NCT01997190) are also being investigated in mesothelioma.
      • Davidson J.A.
      • Musk A.W.
      • Wood B.R.
      • et al.
      Intralesional cytokine therapy in cancer: a pilot study of GM-CSF infusion in mesothelioma.
      • Nelson D.
      • Fisher S.
      • Robinson B.
      The "Trojan horse" approach to tumor immunotherapy: targeting the tumor microenvironment.
      Radiotherapy (RT) is used in the management of MPM in the adjuvant, neoadjuvant, and palliative settings. It is standard practice to deliver adjuvant conventially fractionated RT (50–60 Gy) to the ipsilateral hemithorax in patients who receive an EPP.
      • Krug L.M.
      • Pass H.I.
      • Rusch V.W.
      • et al.
      Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma.
      • Rusch V.W.
      • Rosenzweig K.
      • Venkatraman E.
      • et al.
      A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma.
      Neoadjuvant accelerated hemithoracic intensity-modulated RT (IMRT) before EPP has recently emerged as a viable treatment approach and is associated with long-term disease control and survival in clinically node-negative patients.
      • Cho B.C.
      • Feld R.
      • Leighl N.
      • et al.
      A feasibility study evaluating surgery for mesothelioma after radiation therapy: the "SMART" approach for resectable malignant pleural mesothelioma.
      • de Perrot M.
      • Feld R.
      • Leighl N.B.
      • et al.
      Accelerated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma.
      This approach of five fractions of 5 to 6 Gy each relies on the complete resection of the lung shortly after the completion of RT to avoid the risk of life-threating radiation pneumonitis of the ipsilateral lung. This approach remains experimental at this time and is offered only at certain centers.
      In patients who receive lung-sparing operations, there is no standard recommendation for adjuvant RT because of the potential high risk of radiation pneumonitis. Recently, adjuvant hemithoracic pleural radiation therapy to 50 to 60 Gy in conventional fractionation was found to be safe, feasible, and efficacious at centers with experience in using this complex RT technique.
      • Minatel E.
      • Trovo M.
      • Bearz A.
      • et al.
      Radical radiation therapy after lung-sparing surgery for malignant pleural mesothelioma: survival, pattern of failure, and prognostic factors.
      • 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.
      • Rosenzweig K.E.
      • Zauderer M.G.
      • Laser B.
      • et al.
      Pleural intensity-modulated radiotherapy for malignant pleural mesothelioma.
      Arc therapy, which is an advanced form of IMRT that delivers precisely sculpted three-dimensional dose distribution with 360-degree rotation of the gantry in a single-arc or multiarc treatment, may further improve normal tissue dosimetry and target coverage.
      • Dumane V.A.
      • Rimner A.
      • Yorke E.D.
      • et al.
      Volumetric-modulated arc therapy for malignant pleural mesothelioma after pleurectomy/decortication.
      Additional randomized trials to study this technology are needed to demonstrate efficacy and clinical benefit before it can be adopted as standard practice.
      Advanced RT techniques may further facilitate novel roles for RT in the treatment of MPM, including whole pleural RT using proton therapy after P/D,
      • Pan H.Y.
      • Jiang S.
      • Sutton J.
      • et al.
      Early experience with intensity modulated proton therapy for lung-intact mesothelioma: a case series.
      stereotactic body radiation therapy for isolated recurrences alone or in combination with immunotherapy (NCT03399552, NCT02959463), and even the use IMRT or proton therapy to definitively target all gross disease.
      Advances in systemic therapy are clearly needed in this space. Neoadjuvant window-of-opportunity trials investigating novel therapies
      • Tsao A.S.
      • Lin H.
      • Carter B.W.
      • et al.
      Biomarker-integrated neoadjuvant dasatinib trial in resectable malignant pleural mesothelioma.
      have shown such approaches to trial design to be feasible, and several trials are currently investigating immunotherapies (NCT02592551, NCT02707666, and NCT02959463). The SWOG S1619 trial (NCT03228537) is evaluating neoadjuvant cisplatin-pemetrexed-atezolizumab. In the adjuvant space, interventions with vaccines may have promise. Galinpepimut-S Wilms tumor 1 vaccine was randomized against placebo in a double-blind trial
      • 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.
      ; when administered after macroscopic complete resection, the vaccine demonstrated superiority over control. The median progression-free survival (PFS) was 7.4 months versus 10.1 months, and the median overall survival (OS) was 18.3 months versus 22.8 months in the control and vaccine arms, respectively.
      • 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.

      Consensus Panel on Future Early-Stage MPM Clinical Trials

      The Consensus Early Stage Panel highlighted several limitations to future trial designs and recommended that firm standardization guidelines be published ahead of opening any NCTN studies. The following recommendations were offered to advance the field: (1) mesothelioma surgical trials should ideally be randomized, be conducted in limited institutions that have the ability to standardize surgical practice, collect data reliably, obtain patient-reported outcomes (PROs), perform the required translational correlates, and provide adequate safety for patients in a tertiary/quaternary care center; (2) a stable platform for surgical technique is needed, with standardization of required preoperative procedures (e.g., contrast computed tomography [CT], positron emission tomography [PET]-CT, and mediastinal sampling [endobronchial ultrasound, endoscopic ultrasound, mediastinoscopy, and peritoneal assessment with laparoscopy]), determination of which types of surgeries to perform, definition of what constitutes a “resectable” patient, identification of the standard follow-up period and interval, and specification of the necessary reporting components in all trial operative reports); (3) uniformity in pathologic reporting is also needed to denote the necessary reported components, define a core panel of biomarkers that should be conducted on the trial, and standardize specimen collection techniques for blood/pleural effusion/tumor tissue; (4) imaging techniques remain a major challenge because few radiologists are familiar with how to conduct assessment using the Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST in mesothelioma; as a result, an IASLC webinar is suggested to educate investigators on standard radiographic reporting, and discussion of the role of volumetric CT as a future potential improved measurement system is needed; (5) NCTN trials evaluating the sequence of trimodality and bimodality therapy are still needed, as are surgical comparator trials (EPP versus P/D) and RT trials (P/D with and without IMRT), although the feasibility of such trials is still debatable; and (6) window-of-opportunity trials are needed to collect data for translational studies, but the variability in surgical techniques and intraoperative adjunctive therapies need to be standardized first, in addition to which, any involved centers conducting these complicated studies would need to be accredited (as in American College of Surgeons Oncology Group trials).

      Background Therapies in Unresectable MPM

      To date, the only FDA- and European Medicines Agency–approved frontline regimen in unresectable MPM is cisplatin-pemetrexed.
      • 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.
      Platinum-pemetrexed for four to six cycles of therapy is commonly used throughout the world.

      Antiangiogenics

      Angiogenesis inhibitors are among the most widely studied agents for treating mesothelioma. Although minimal activity was observed in several single-arm phase II studies
      • Campbell N.P.
      • Kunnavakkam R.
      • Leighl N.
      • et al.
      Cediranib in patients with malignant mesothelioma: a phase II trial of the University of Chicago Phase II Consortium.
      • Garland L.L.
      • Chansky K.
      • Wozniak A.J.
      • et al.
      Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509.
      • Laurie S.A.
      • Hao D.
      • Leighl N.B.
      • et al.
      A phase II trial of dovitinib in previously-treated advanced pleural mesothelioma: the Ontario Clinical Oncology Group.
      • Dubey S.
      • Janne P.A.
      • Krug L.
      • et al.
      A phase II study of sorafenib in malignant mesothelioma: results of Cancer and Leukemia Group B 30307.
      • Papa S.
      • Popat S.
      • Shah R.
      • et al.
      Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-containing chemotherapy.
      • Laurie S.A.
      • Gupta A.
      • Chu Q.
      • et al.
      Brief report: a phase II study of sunitinib in malignant pleural mesothelioma. the NCIC Clinical Trials Group.
      • Nowak A.K.
      • Millward M.J.
      • Creaney J.
      • et al.
      A phase II study of intermittent sunitinib malate as second-line therapy in progressive malignant pleural mesothelioma.
      • Baas P.
      • Boogerd W.
      • Dalesio O.
      • Haringhuizen A.
      • Custers F.
      • van Zandwijk N.
      Thalidomide in patients with malignant pleural mesothelioma.
      • Jahan T.
      • Gu L.
      • Kratzke R.
      • et al.
      Vatalanib in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (CALGB 30107).
      of monotherapy vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors, the Mesothelioma Avastin Cisplatin Pemetrexed Study trial demonstrated a survival benefit with the addition of bevacizumab to cisplatin-pemetrexed.
      • 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.
      The addition of bevacizumab yielded a superior median PFS of 9.2 versus 7.3 months (hazard ratio [HR] = 0.61, p < 0.0001) and a median OS of 18.8 versus 16.1 months (HR = 0.77, p = 0.0167).
      • 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.
      This regimen was added to the National Comprehensive Cancer Network guidelines in 2015 as a category 2A recommendation
      • Ettinger D.S.
      • Wood D.E.
      • Akerley W.
      • et al.
      NCCN guidelines insights: malignant pleural mesothelioma, version 3.2016.
      ; however, it is currently not approved by either the FDA or the European Medicines Agency.
      Additional antiangiogenic tyrosine kinase inhibitor/chemotherapy combinations have demonstraterd preliminary promising results in early-phase studies. The phase IB/randomized phase II SWOG S0905 trial
      • Tsao A.S.
      • Moon J.
      • Wistuba II,
      • et al.
      Phase I trial of cediranib in combination with cisplatin and pemetrexed in chemonaive patients with unresectable malignant pleural mesothelioma (SWOG S0905).
      combined pemetrexed/cisplatin with cediranib (VEGF receptor and platelet derived growth factor receptor inhibitor) and initially reported a favorable median OS in phase IB at 16.2 months (95% confidence interval: 10.5–28.7 months). The randomized SWOG 0905 phase II presented at the 2018 American Society of Clinical Oncology annual meeting showed a significant benefit with the triplet combination for response rate by the modified RECIST (50% versus 20% [p = 0.01]) but did not reach statistical significance for survival, median PFS (7.2 versus 5.6 months [HR = 0.71, p = 0.12]), or median OS (10 versus 8.5 [HR = 0.88, p = 0.56]).
      • Tsao A.
      • Miao J.
      • Wistuba I.
      • et al.
      SWOG 0905: a randomized phase II study of cediranib versus placebo in combination with cisplatin-pemetrexed in chemonaive patients with unresectable malignant pleural mesothelioma (MPM) [abstract].
      The LUME-Meso trial,
      • 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.
      which was a randomized phase II trial investigating pemetrexed/cisplatin plus placebo or nintedanib (VEGF receptor, platelet derived growth factor receptor, and fibroblast growth factor receptor inhibitor), demonstrated that the triplet regimen improved response rates (57% versus 44%) and resulted in a higher median PFS (9.4 versus 5.7 months [HR = 0.54, p = 0.010]) and a trend for improved OS (median 18.3 versus 14.2 months [HR = 0.77, p = 0.319, study not powered for OS]).
      • 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.
      The ongoing phase III LUME-Meso trial recently completed accrual and is limited to patients with epithelioid mesothelioma, representing the subgroup of patients who benefited the most from the addition of nintedanib in the phase II study.
      • 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.

      Novel Targeted Agents

      Despite recent advances in personalized therapies for cancer, genetic and epigenetic predictive biomarkers are only beginning to emerge for mesothelioma. After identification of argininosuccinate synthetase 1 loss in mesothelioma, which leads to arginine auxotrophy, the ADAM trial demonstrated that the arginine depletor pegylated adenosine deiminase is active in argininosuccinate synthetase 1–deficient 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.
      This finding, as well as promising data from the TRAP trial (NCT02029690) combining pegylated adenosine deiminase with chemotherapy,
      • 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.
      led to a registration phase III trial, ATOMIC-Meso (NCT02709512), focusing on biphasic and sarcomatoid disease.
      BAP1 is a frequently inactivated tumor suppressor gene in mesothelioma that up-regulates the epigenetic silencing machinery regulated by enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2).
      • LaFave L.M.
      • Beguelin W.
      • Koche R.
      • et al.
      Loss of BAP1 function leads to EZH2-dependent transformation.
      Inhibition of EZH2 is synthetic lethal to BAP1-negative tumors, and a phase II multicenter trial using EZH2 inhibitor tazemetostat (NCT 02860286) recently completed accrual. BAP1 loss also leads to homologous repair deficiency, suggesting that poly(ADP-ribose) polymerase 1 inhibition may be more active in this genetic subgroup. Accordingly, a proof of concept study is currently being developed.
      CDKN2A is frequently deleted in mesothelioma, leading to loss of p14ARF and p16INK4A.
      • Lopez-Rios F.
      • Chuai S.
      • Flores R.
      • et al.
      Global gene expression profiling of pleural mesotheliomas: overexpression of aurora kinases and P16/CDKN2A deletion as prognostic factors and critical evaluation of microarray-based prognostic prediction.
      Large scale drug-gene interaction screens have identified cyclin-dependent kinase 4/6 inhibition as being active in CDKN2A-negative tumors,
      • Campbell J.
      • Ryan C.J.
      • Brough R.
      • et al.
      Large-scale profiling of kinase dependencies in cancer cell lines.
      warranting a phase II proof of concept study that is currently in development.
      The spindle poison vinorelbine exhibits some activity in relapsed mesothelioma
      • Zauderer M.G.
      • Kass S.L.
      • Woo K.
      • Sima C.S.
      • Ginsberg M.S.
      • Krug L.M.
      Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma.
      • Stebbing J.
      • Powles T.
      • McPherson K.
      • et al.
      The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma.
      • Zucali P.A.
      • Perrino M.
      • Lorenzi E.
      • et al.
      Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma.
      and the randomized Vinorelbine in Mesothelioma trial (NCT 02139904) aims to evaluate loss of the essential, spindle assembly checkpoint regulator use BRCA1 as a predictive biomarker of de novo resistance.
      Finally, inactivation of neurofibromin 2 (which encodes Merlin) has been proposed to be synthetic lethal with focal adhesion kinase inhibition
      • Shapiro I.M.
      • Kolev V.N.
      • Vidal C.M.
      • et al.
      Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship.
      ; however, this was not borne out in the COMMAND trial (NCT01870609). Similarly, phosphoinositide 3-kinase/mTOR inhibition has shown modest efficacy.
      • Dolly S.O.
      • Wagner A.J.
      • Bendell J.C.
      • et al.
      Phase I study of apitolisib (GDC-0980), dual phosphatidylinositol-3-kinase and mammalian target of rapamycin kinase inhibitor, in patients with advanced solid tumors.
      Other approaches to exploit neurofibromin 2 aberrations, such as neural precursor cell expressed, developmentally down-regulated 8 inhibition, especially in combination with mTOR blockade,
      • Cooper J.
      • Xu Q.
      • Zhou L.
      • et al.
      Combined inhibition of NEDD8-activating enzyme and mTOR suppresses NF2 loss-driven tumorigenesis.
      may be more promising and a proof of concept study (NCT03319537) is under way.

      Immunotherapies

      The immune system may be an important therapeutic target in MPM, as evidenced by the positive prognostic impact of tumor-infiltrating lymphocytes,
      • Anraku M.
      • Cunningham K.S.
      • Yun Z.
      • et al.
      Impact of tumor-infiltrating T cells on survival in patients with malignant pleural mesothelioma.
      • Yamada N.
      • Oizumi S.
      • Kikuchi E.
      • et al.
      CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection.
      the reports of spontaneous regression of mesothelioma,
      • Moser J.C.
      • Peikert T.
      • Roden A.C.
      • Midthun D.E.
      • Mansfield A.S.
      Spontaneous regression of malignant pleural mesothelioma in a patient with new-onset inflammatory arthropathy.
      • Robinson B.W.
      • Robinson C.
      • Lake R.A.
      Localised spontaneous regression in mesothelioma–possible immunological mechanism.
      and responses to immunotherapy in patients.
      • 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.
      • Alley E.W.
      • Katz S.I.
      • Cengel K.A.
      • Simone 2nd, C.B.
      Immunotherapy and radiation therapy for malignant pleural mesothelioma.
      High programmed death ligand-1 (PD-L1) immunohistochemical expression has been associated with a negative prognosis
      • Cedres 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).
      • 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.
      and may have predictive capability with regard to checkpoint inhibitors in MPM.
      • 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.
      • Alley E.W.
      • Katz S.I.
      • Cengel K.A.
      • Simone 2nd, C.B.
      Immunotherapy and radiation therapy for malignant pleural mesothelioma.
      However, this biomarker has several limitations; there are emerging data indicating that PD-L1 expression is heterogeneous and dynamic in many tumor types, including mesothelioma.
      • Mansfield A.S.
      • Murphy S.J.
      • Peikert T.
      • et al.
      Heterogeneity of programmed cell death ligand 1 expression in multifocal lung cancer.
      • Terra S.B.S.P.
      • Mansfield A.S.
      • Dong H.
      • Peikert T.
      • Roden A.C.
      Temporal and spatial heterogeneity of programmed cell death 1-ligand 1 expression in malignant mesothelioma.
      This supports continued translational efforts to comprehensively profile the local immunologic environment and to incorporate these data with genomic, transcriptomic, proteomic, demographic, and outcome data, as has been done in other malignancies such as lung cancer.
      • Sepesi B.
      • IconTeam
      • Heymach J.
      • et al.
      Prospective immunogenomic profiling of non-small cell lung cancer - the ICON Project.
      • Sepesi B.
      • Lacerda L.
      • Zhang J.
      • et al.
      Immunogenomic profiling of non-small cell lung cancer: the ICON project.
      Immunotherapies are under active investigation in the salvage and frontline space. In the salvage space, the DETERMINE study utilizing the cytotoxic T-lymphocyte associated protein 4 inhibitor tremelimumab demonstrated no benefit over placebo.
      • 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.
      In contrast, single-arm clinical trials targeting programmed death (PD-1) or PD-L1 have shown response rates ranging from 10% to 20% and a small proportion of long-term responders.
      • 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.
      • Alley E.W.
      • Katz S.I.
      • Cengel K.A.
      • Simone 2nd, C.B.
      Immunotherapy and radiation therapy for malignant pleural mesothelioma.
      Confirmation of these results is under way in randomized phase III trials of single-agent immunotherapy against placebo (CONFIRM, NCT03063450) or chemotherapy (PROMISE, NCT 02991482). Ongoing combination strategies include combining PD-1/PD-L1 inhibitors with anti–cytotoxic T-lymphocyte associated protein 4 (tremelimumab-durvalumab, nivolumab-ipilimumab) in the first or second line, or anti-VEGF or focal adhesion kinase or AXL receptor tyrosine kinase inhibition in the relapsed setting. The Mesothelioma Avastin Cisplatin Pemetrexed Study II trial (NCT02716272), which evaluated two parallel arms of nivolumab and nivolumab with ipilimumab, reported a 27.8% objective response rate (ORR), 50% disease control rate, and median PFS of 5.6 months with the ipilimumab-nivolumab arm.
      • 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.
      These data led to the addition of pembrolizumab (with PD-L1 expression ≥1%) and nivolumab with and without ipilimumab to the National Comprehensive Cancer Network guidelines.
      • Ettinger D.S.
      • Wood D.E.
      • Akerley W.
      • et al.
      NCCN guidelines insights: malignant pleural mesothelioma, version 3.2016.
      In the frontline space, checkpoint inhibitors are being studied in combination with chemotherapy or compared against chemotherapy (NCT02899299).
      With increasing evidence that higher effector T-cell responses can improve survival in mesothelioma,
      • Zeltsman M.
      • Dozier J.
      • McGee E.
      • Ngai D.
      • Adusumilli P.S.
      CAR T-cell therapy for lung cancer and malignant pleural mesothelioma.
      adoptive cell therapy using mesothelin (a cancer cell surface antigen) targeted chimeric antigen receptor–transduced T cells has been translated to phase I clinical trials with administration both intrapleurally (NCT02414269) and systemically (NCT03054298). PD-1/PD-L1 checkpoint blockade agents have augmented functional persistence of chimeric antigen receptor T cells in preclinical models.
      • Chen N.
      • Morello A.
      • Tano Z.
      • Adusumilli P.S.
      CAR T-cell intrinsic PD-1 checkpoint blockade: a two-in-one approach for solid tumor immunotherapy.
      Several other mesothelin-targeted therapies, including antimesothelin immunotoxin (LMB-100) and antibody-drug conjugates targeting mesothelin (anetumab ravtansine), are currently in clinical trials either as a single agent or in combination with chemotherapy or immunotherapy.
      • Hassan R.
      • Thomas A.
      • Alewine C.
      • Le D.T.
      • Jaffee E.M.
      • Pastan I.
      Mesothelin immunotherapy for cancer: ready for prime time?.
      The reduced immunogenicity antimesothelin immunotoxin LMB-100 is currently being evaluated in phase I/II studies for treatment of patients with treatment-refractory pleural and peritoneal mesothelioma.
      • 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.
      In a phase I clinical trial, anetumab ravtansine showed promising efficacy for advanced disease.
      • Hassan R.
      • Bendell J.C.
      • Blumenschein G.
      • et al.
      Phase I study of anti-mesothelin antibody drug conjugate anetumab ravtansine.
      However, in a randomized phase II trial of second-line therapy, there was no difference in PFS between anetumab ravtansine and vinorelbine.
      • Kindler H.L.
      • Novello S.
      • Fennell D.
      • et al.
      Randomized phase II study of anetumab ravtansine or vinorelbine in patients with metastatic pleural mesothelioma.
      Ongoing studies are evaluating anetumab ravtansine plus pemetrexed and cisplatin in mesothelioma (NCT02639091).

      Consensus Panel on Future Unresectable MPM Clinical Trials

      The metastatic panel discussion focused on trial designs for NCI sponsorship. Several proposed trials were offered, and recommendations and conclusions from the panel included the following: (1) all future NCTN mesothelioma trials should collect translational correlates before and during (ideally) study treatment as well as after disease progression; (2) translational correlates should include specimens from blood, pleural effusion, and tumor (primary and metastatic); (3) standard operating procedures for collection techniques for all biospecimens are needed and should be applied to all future NCTN mesothelioma trials; (4) metastatic clinical trials require careful consideration of the end points given the current limitations in radiographic reporting (although OS is the criterion standard, the required large sample size remains challenging for mesothelioma studies); (5) additional obstacles to successful mesothelioma NCTN studies include limited accrual of patient numbers, thus emphasizing the need for more reasonable and lenient inclusion/exclusion criteria; (6) critical components for future NCTN trial design include avoiding replication with pharmaceutical studies and focusing on scientific questions instead of on regulatory drug development; (7) reproducing a single center’s trial experience (i.e., neoadjuvant chemoradiation or IMRT after lung-sparing surgery) in a multicenter environment to standardize or validate a therapy is a reasonable strategy; (8) PROs are critical components to all studies (mesothelioma-specific PROs are under development and will require validation, potentially in NCTN trials); and (9) the IASLC could potentially be the primary site for a large international clinical database for mesothelioma.

      Consensus Panel on Translational Correlates in MPM Trials

      The investigation of noninvasive, possibly blood- and pleural fluid–based biomarkers for the early detection, diagnosis, prognostication, and monitoring of disease response should be incorporated into any and all prospective screening or therapeutic protocols. The lack of large prospective well-defined cohorts of patients with MPM with annotated samples collected in a uniform manner has contributed to an inability to validate several potential screening markers such as serum/plasma microRNAs,
      • Bononi I.
      • Comar M.
      • Puozzo A.
      • et al.
      Circulating microRNAs found dysregulated in ex-exposed asbestos workers and pleural mesothelioma patients as potential new biomarkers.
      • Kirschner M.B.
      • Cheng Y.Y.
      • Badrian B.
      • et al.
      Increased circulating miR-625-3p: a potential biomarker for patients with malignant pleural mesothelioma.
      • Lamberti M.
      • Capasso R.
      • Lombardi A.
      • et al.
      Two different serum MiRNA signatures correlate with the clinical outcome and histological subtype in pleural malignant mesothelioma patients.
      • Santarelli L.
      • Strafella E.
      • Staffolani S.
      • et al.
      Association of MiR-126 with soluble mesothelin-related peptides, a marker for malignant mesothelioma.
      fibulin-3,
      • Creaney J.
      • Dick I.M.
      • Meniawy T.M.
      • et al.
      Comparison of fibulin-3 and mesothelin as markers in malignant mesothelioma.
      • Kaya H.
      • Demir M.
      • Taylan M.
      • et al.
      Fibulin-3 as a diagnostic biomarker in patients with malignant mesothelioma.
      • Kirschner M.B.
      • Pulford E.
      • Hoda M.A.
      • et al.
      Fibulin-3 levels in malignant pleural mesothelioma are associated with prognosis but not diagnosis.
      • Pass H.I.
      • Levin S.M.
      • Harbut M.R.
      • et al.
      Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma.
      and high mobility group box 1,
      • Tabata C.
      • Kanemura S.
      • Tabata R.
      • et al.
      Serum HMGB1 as a diagnostic marker for malignant peritoneal mesothelioma.
      • Tabata C.
      • Shibata E.
      • Tabata R.
      • et al.
      Serum HMGB1 as a prognostic marker for malignant pleural mesothelioma.
      • Jube S.
      • Rivera Z.S.
      • Bianchi M.E.
      • et al.
      Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma.
      • Napolitano A.
      • Antoine D.J.
      • Pellegrini L.
      • et al.
      HMGB1 and its hyperacetylated isoform are sensitive and specific serum biomarkers to detect asbestos exposure and to identify mesothelioma patients.
      among others.
      • Carbone M.
      • Kanodia S.
      • Chao A.
      • et al.
      Consensus report of the 2015 Weinman International Conference on Mesothelioma.
      • Chen Z.
      • Gaudino G.
      • Pass H.I.
      • Cabone M.
      • Yang H.
      Diagnostic and prognostic biomarkers for malignant mesothelioma: an update.
      Presently, mesothelin is the only serum biomarker that has received FDA approval (humanitarian device exemption) for monitoring patients with epithelioid and biphasic mesothelioma. However, clinical trials sponsored by the NCI Early Detection Research Network and Department of Defense are being conducted to validate high mobility group box 1 as a biomarker of asbestos exposure and mesothelioma and fibulin as a biomarker for mesothelioma.
      The CTPM group recommended that sample collections be standardized and include both cellular and noncellular components of the blood and pleural fluid, including serum, plasma, buffy coat, and peripheral blood mononuclear cells, as well as pleural cells and pleural fluid. Moreover, the sample collections must follow standardized operating procedures to ensure ideal conditions for exosome and microvesicle harvest and fluids that can be used for cell-free DNA and next-generation sequencing. Decisions regarding the use of citrate, ethylenediaminetetraacetic acid, or heparin tubes and/or the use of PAXgene RNA/DNA tubes should be part of the discussion, and if needed, samples should be collected using various anticoagulants and specialized collection tubes.
      In surgical patients, collection should include blood and pleural fluid, fresh tumor samples for flow analysis after digestion, snap-frozen tumor with control tissue, and fixed samples for future studies. Given the heterogeneity of mesothelioma, samples from several areas of the tumor should be considered. When the microenvironment of either the tumor or the pleural fluid is being investigated, appropriate control “uninvolved” mesothelium should be made available from surgical cases. It is very important to recognize that pleural fluid from these patients remains a rich source for cell line development, microenvironment studies, and standardized proteomic or genomic platform investigations.
      The application of next-generation sequencing technologies has the potential to identify gene expression patterns that predict responses to immunotherapy or select novel synergistic drug combinations.
      • Lesterhuis W.J.
      • Rinaldi C.
      • Jones A.
      • et al.
      Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations.
      Furthermore, specific mutations within mesothelioma tumors detected by similar techniques may also lead to the development of mutation-directed immunotherapies such as personalized vaccine strategies.
      • Chee J.
      • Robinson B.W.
      • Holt R.A.
      • Creaney J.
      Immunotherapy for lung malignancies: from gene sequencing to novel therapies.
      • Creaney J.
      • Ma S.
      • Sneddon S.A.
      • et al.
      Strong spontaneous tumor neoantigen responses induced by a natural human carcinogen.
      For the translational correlates of any prospective trials to yield meaningful information, the approach must standardize collections, processing, and storage of specimens and also incorporate compulsive documentation of patient demographics, all in a way that will facilitate seamless adoption by the international community.

      Consensus Panel on Radiographic Assessments in MPM Clinical Trials

      Radiographic assessment of mesothelioma, even in large academic centers, is inadequate and possibly inconsistent for clinical trials.
      • van Klaveren R.J.
      • Aerts J.G.
      • de Bruin H.
      • Giaccone G.
      • Manegold C.
      • van Meerbeeck J.P.
      Inadequacy of the RECIST criteria for response evaluation in patients with malignant pleural mesothelioma.
      Magnetic resonance imaging and fludeoxyglucose PET-CT demonstrate incremental advantages over CT scans, which are clinically relevant in some settings. Magnetic resonance imaging is more useful in determining resectability by providing better anatomical detail and potential to provide information on angiogenesis, whereas CT scans have stronger value in assessing treatment response in patients undergoing systemic therapy and potentially providing prognostic information.
      • Gill R.R.
      • Umeoka S.
      • Mamata H.
      • et al.
      Diffusion-weighted MRI of malignant pleural mesothelioma: preliminary assessment of apparent diffusion coefficient in histologic subtypes.
      • Coolen J.
      • De Keyzer F.
      • Nafteux P.
      • et al.
      Malignant pleural disease: diagnosis by using diffusion-weighted and dynamic contrast-enhanced MR imaging—initial experience.
      • Nowak A.K.
      • Francis R.J.
      • Phillips M.J.
      • et al.
      A novel prognostic model for malignant mesothelioma incorporating quantitative FDG-PET imaging with clinical parameters.
      • Francis R.J.
      • Byrne M.J.
      • van der Schaaf A.A.
      • et al.
      Early prediction of response to chemotherapy and survival in malignant pleural mesothelioma using a novel semiautomated 3-dimensional volume-based analysis of serial 18F-FDG PET scans.
      Clinical staging in MPM is of limited value for clinical trials on account of high interobserver variability from its dependence on qualitative assessment of several of the T-stage descriptors, such as involvement of the visceral pleura, lung parenchyma, and diaphragm muscle, which cannot be reliably predicted by any imaging modality.
      • Gill R.R.
      • Gerbaudo V.H.
      • Sugarbaker D.J.
      • Hatabu H.
      Current trends in radiologic management of malignant pleural mesothelioma.
      Measurement of tumor volume on cross-sectional imaging has emerged as a potential quantitative tool with prognostic significance and is being evaluated as a surrogate of T category in clinical staging.
      • Pass H.I.
      • Temeck B.K.
      • Kranda K.
      • Steinberg S.M.
      • Feuerstein I.R.
      Preoperative tumor volume is associated with outcome in malignant pleural mesothelioma.
      • Gill R.R.
      • Richards W.G.
      • Yeap B.Y.
      • et al.
      Epithelial malignant pleural mesothelioma after extrapleural pneumonectomy: stratification of survival with CT-derived tumor volume.
      • Gill R.R.
      • Naidich D.P.
      • Mitchell A.
      • et al.
      North American Multicenter Volumetric CT Study for clinical staging of malignant pleural mesothelioma: feasibility and logistics of setting up a quantitative imaging study.
      Response assessment is prone to a high degree of intraobserver variability because of the complex rind-like morphology of this tumor. This challenge prompted the development of mesothelioma-specific modified RECIST criteria.
      • Byrne M.J.
      • Nowak A.K.
      Modified RECIST criteria for assessment of response in malignant pleural mesothelioma.
      Although widely used, these criteria remain limited in their ability to uniformly assess disease. Measurement of tumor volume has shown prognostic significance at a volume cutoff at of 500 cm2 and can therefore serve a dual purpose: staging patients and more accurately quantifying therapeutic response in prospective clinical trials.
      • Pass H.I.
      • Temeck B.K.
      • Kranda K.
      • Steinberg S.M.
      • Feuerstein I.R.
      Preoperative tumor volume is associated with outcome in malignant pleural mesothelioma.
      • Gill R.R.
      • Naidich D.P.
      • Mitchell A.
      • et al.
      North American Multicenter Volumetric CT Study for clinical staging of malignant pleural mesothelioma: feasibility and logistics of setting up a quantitative imaging study.
      • Perrot D.
      • Fernandez H.
      • Levaillant J.M.
      • Capmas P.
      Quality assessment of pelvic ultrasound for uterine myoma according to the CNGOF guidelines.
      Additional studies are needed to compare measurements of tumor volume with the established response criteria to refine the cutoffs for categorization of response. Undoubtedly, it is imperative that imaging and reporting protocols be homogenized across centers to allow pooling of data in this rare disease and also facilitate development of standardization metrics that will transition tumor volume into clinical practice.

      Consensus Panel on End Points for MPM Clinical Trials

      The criterion standard end point for definitive trials in advanced mesothelioma is a demonstration of improvement in OS.
      • Blumenthal G.M.
      • Kluetz P.G.
      • Schneider J.
      • Goldberg K.B.
      • McKee A.E.
      • Pazdur R.
      Oncology drug approvals: evaluating endpoints and evidence in an era of breakthrough therapies.
      Pemetrexed, which is the only systemic treatment approved in mesothelioma, was approved in 2004 on the basis of an improvement in OS when combined with cisplatin compared with cisplatin alone.
      • 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.
      Other end points that are typically used in oncology drug development trials for advanced disease are tumor-based end points assessed radiographically, such as ORR, duration of response, and PFS. In this uniquely pleural-based disease, these end points are challenging. The modified RECIST criteria for mesothelioma may be acceptable to assess ORR and PFS for use in trials testing new agents, but given their limitations and challenges, central radiographic review is crucial. Additionally, PFS would be interpretable only in randomized clinical trials with a large magnitude of treatment effect to overcome the uncertainties surrounding assessment of this radiographic end point. Development of innovative alternative end points is needed.

      Consensus Panel on PROs in MPM Clinical Trials

      Malignant mesothelioma requires the administration of aggressive forms of therapy, which can result in a decrease in health-related quality of life (QOL). In some rare instances, these negative by-products may provoke noncompliance or refusal by the patient to receive subsequent chemotherapy treatments. To date, QOL studies have been limited to report only symptoms that occur during treatment. The Lung Cancer Symptom Scale adapted to mesothelioma (Meso-LCSS questionnaire), which has been used in several large studies
      • 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.
      • 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.
      • Krug L.M.
      • Kindler H.L.
      • Calvert H.
      • et al.
      Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial.
      is criticized for its lack of a comprehensive approach to the disease. In terms of the data collected, it does not reach the scope that mesothelioma experts and patients would like to obtain. The Patient Quality of Life Questionnaire Physical and Emotional, which is under development at Columbia University Medical Center, offers a comprehensive evaluation of QOL by using six different aspects of an individual’s life. As treatments become more advanced and research reveals the substantial connections between physical activity, emotional well-being, and physical well-being, investigators will need innovative comprehensive tools to evaluate the QOL of study participants.

      Consensus Panel Conclusion and Future Trial Recommendations

      In conclusion, the NCI-IASLC-MARF Mesothelioma CTPM established several recommendations for future strategies in NCTN mesothelioma clinical trials (Fig. 1). The main themes emphasized the need for generating science; avoiding duplicative trials that are already on industry drug development pathways; including multidisciplinary studies; standardizing surgical, radiation, and radiographic techniques; and always including translational and quality of life components. It was advised that the next national mesothelioma trials should avoid complexity and focus on the feasibility of standardizing surgical/radiation techniques and biospecimen sample collection, as well as on demonstrating reproducibility in multiple centers. The participants agreed on supporting two potential NCTN trials, one using IMRT after lung-sparing surgery and a second metastatic study (Meso-MATCH) harnessing known targets and pairing treatments along with immunotherapies. In addition, several future efforts focused on publishing standardized guidelines for surgical, radiographic, translational research, QOL/PROs, and radiation oncology techniques will be undertaken.
      Figure thumbnail gr1
      Figure 1The National Cancer Institute (NCI)–International Association for the Study of Lung Cancer (IASLC)–Mesothelioma Applied Research Foundation (MARF) Clinical Trials Planning Meeting (CTPM) selected six topics to develop consensus guidelines for all future National Clinical Trials Network clinical trials. These six articles will identify the knowledge gaps in the respective fields and propose the elements needed to advance clinical trial design and data collection. These guidelines are intended to have multicenter, NCI, and U.S. Food and Drug Administraiton input. In addition, two initial Clinical Trials Network clinical trials to utilize these new guidelines were proposed. IMRT, intensity-modulated radiotherapy; mRECIST, modified Response Criteria in Solid Tumors; iRECIST, immune Response Criteria in Solid Tumors; QOL, quality of life; PRO, patient-reported outcome; NRG, NRG Oncology.

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