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This section considers the characteristic features and biology of malignant pleural mesothelioma and the challenges in its clinical management. It includes key ongoing clinical trials and emerging therapies as well as an expert perspective on how treatment of malignant pleural mesothelioma may change in the next 5 years.
Malignant pleural mesothelioma (MPM) is a rare but aggressive malignancy.1 The large majority of cases are caused by exposure to asbestos,2 and MPM has also been associated with exposure to other naturally occurring mineral particles.3 The disease is characterised by a long latency period (30–50 years) between exposure to asbestos and the development of symptoms.2 Once a country introduces asbestos control measures, the number of MPM cases is expected to peak and then fall,4,5 as observed in the United States.6 However, many regions continue to use asbestos, and in these regions a corresponding increase in the prevalence of MPM is expected. Consequently, the incidence of MPM is predicted to increase globally over the course of the next two decades.1,5,6
The pathologic profile of MPM is far from straightforward, making diagnosis and prognosis difficult. Inhalation of asbestos fibres is known to promote an inflammatory response. Over time, this can lead to malignant transformation via multiple mechanisms, including:1
Perhaps reflecting this multifaceted pathogenesis, MPM tumours often show a high degree of intratumoural heterogeneity. This feature may partly account for the observation that they quickly become resistant to systemic therapy.1
Are biomarkers used to inform treatment decisions in MPM?
Use of biomarkers in the clinic has so far been extremely limited. Although a serum mesothelin assay has been approved by the US Food and Drug Administration (FDA),7 serum levels of soluble mesothelin have variable utility in diagnosis and in ascertaining treatment response and prognosis.8–10 A recent meta-analysis did not identify a single serum or pleural fluid biomarker that could be recommended for routine clinical practice.9 Currently, there are no validated biomarkers for screening people who have been exposed to asbestos for MPM,3 although research is ongoing and earlier diagnosis may have considerable impact on the course of disease.1 There is also a pressing need to identify and validate biomarkers to guide the development of new therapies in MPM or to inform patient selection for specific treatments. With the possible exception of BAP1, no driver mutations have been identified.1 Even then, although BAP1 occurs in 47–67% of MPM tumours, the mechanism by which it is involved in malignant transformation has yet to be firmly established.11 Further research has shown that the genetic alterations in MPM tumours mostly occur in the p53/DNA repair pathway, the cell cycle, the mitogen-activated protein kinase pathway and the phosphoinositide 3-kinase (PI3K)/AKT pathway.12 These pathways may therefore warrant further research to investigate novel targeted treatments in MPM.
Patients with MPM are typically diagnosed with disease that has already spread to regional or distant sites.13 They have a poor prognosis, with only 5% of patients surviving to 5 years.13 In fact, mortality rates in MPM have fallen only 0.5% per year over the past 40 years; survival has barely improved in decades.13 This highlights the urgent need for improvement in both the early diagnosis of MPM and in treatment options for patients.
Diagnosis and staging of MPM are also challenging. Interpretation of radiological images can be difficult as MPM tumours may only show minimal pleural thickening and often have a heterogeneous growth pattern. Sampling of pleural fluid for cytological investigation is also part of the diagnostic process, but cytological yield is often low and a biopsy is usually required to obtain a definitive diagnosis.14
Prof Nowak describes the biggest challenges that she faces in treating patients with MPM
Patients with MPM have yet to benefit from the recent advances in targeted therapies and immunotherapy that have been made in non-small cell lung cancer (NSCLC); however, a number of therapies are currently in late-stage clinical trials. This is partly because MPM is less common and therefore has been studied less extensively. Treatment of MPM remains a challenge, in particular in patients who are diagnosed with later-stage disease who may not have the option of undergoing surgery and radiotherapy.1
Surgery and radiotherapy
Even if surgical resection is possible, residual microscopic disease persists, making adjuvant treatment a necessity. Radiation therapy has limited clinical use owing to the fact that MPM often covers a wide area, and high-dose radiation therapy can cause severe side effects including pneumonitis, myocarditis and myelopathy. For this reason, radiation therapy in MPM is largely used in combination with surgery or is restricted to palliative care.1 Use of hemithoracic intensity-modulated pleural radiotherapy in conjunction with surgery and chemotherapy – trimodality therapy – has been associated with increased overall survival and may reduce the risk of certain side effects.15 However, the majority of patients are diagnosed with late-stage, unresectable MPM; for these patients, chemotherapy is the only option.1
The current evidence base supports first-line systemic treatment with pemetrexed and cisplatin; results of a Phase III study reported an increase of 2.8 months in overall survival with the doublet regimen compared with cisplatin alone (12.1 vs 9.3 months).16 Combination treatment with cisplatin and pemetrexed is now the standard first-line therapy worldwide, although carboplatin is sometimes used in place of cisplatin as it is perceived to have a better side effect profile and is simpler to administer.14,17 No other first-line treatment options are supported by the high-level evidence.2
In the open-label, Phase III MAPS study, the addition of bevacizumab to pemetrexed/cisplatin followed by maintenance bevacizumab significantly increased median overall survival compared with chemotherapy alone (18.8 vs 16.1 months; hazard ratio [HR]=0.77, p=0.017).18 These data contribute to a growing body of evidence that supports inhibition of angiogenesis as a viable therapeutic strategy in MPM.
As things stand, response rates to standard first-line chemotherapy in MPM remain low, with 41% of patients responding in one Phase III study,16 yet there is no reliable biomarker to identify who these patients are likely to be.14 There is no clearly established second-line treatment.1,2
Prof Nowak, Prof Fennell and Prof Novello consider limitations in the first-line standard-of-care treatment and the absence of standard-of-care second-line and maintenance therapies.
Ongoing clinical studies
A number of therapies are currently in late-stage clinical trials in MPM. These include agents that target the immune system, e.g. nivolumab,19 pembrolizumab,20 tremelimumab21 and durvalumab.22 Although there are early indications that immunotherapy shows promise in MPM,23 the majority of ongoing clinical studies are taking place in later-line treatment rather than first-line treatment, and no Phase III results have been reported to date. Agents that target mesothelin, e.g. the mesothelin-directed antibody drug conjugate anetumab ravtansine24,25 and the chimeric antimesothelin antibody amatuximab,24,26 are also being investigated in clinical trials. Again, these agents have yet to progress beyond Phase II.
Some key ongoing Phase III studies are:
CTLA-4, cytotoxic T-lymphocyte-associated protein 4; MPM, malignant pleural mesothelioma; OS, overall survival; PD-1, programmed death receptor-1; PFS, progression-free survival.
Several clinical trials have evaluated novel compounds in combination with the cisplatin/pemetrexed doublet. So far, there have been few advances, but targeting angiogenesis in MPM has seen clinical benefit.18,30 Vascular endothelial growth factor (VEGF) signalling plays an important role in mesothelioma pathophysiology, and high levels of VEGF in patients with MPM have been associated with more advanced disease and a worse prognosis.31–35 Targeting more than one contributing signalling pathway may have the potential to increase the clinical benefit in patients with MPM. Other pathways, such as signalling via Src/Abl and fibroblast growth factor (FGF), are also thought to be involved in the pathogenesis of MPM.36–39 This is the rationale for investigating nintedanib* – an angiokinase inhibitor that targets VEGF receptors 1–3, platelet-derived growth factor (PDGF) receptors α/β, FGF receptors 1–3 and Src and Abl kinase signalling40,41 – in MPM. Preclinical data support this, showing that nintedanib has direct antitumour activity in MPM cell lines, reducing their colony-forming capacity and migratory activity; it also inhibits tumour growth in MPM xenograft models.42,43
In a Phase II, randomised, double-blind study, the addition of nintedanib to cisplatin/pemetrexed resulted in improved progression-free survival compared with placebo plus cisplatin/pemetrexed.30 A Phase III study is currently underway.27
Prof Fennell and Prof Nowak outline potential improvements in the treatment of MPM in the next 5 years.
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*Nintedanib is approved in the EU under the brand name VARGATEF® for use in combination with docetaxel in adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy. For the full list of country-specific information please click here. Nintedanib is not approved in other oncology indications. Nintedanib is being investigated in malignant pleural mesothelioma (MPM) and is not approved for this use. The efficacy and safety of nintedanib in MPM have not been established.
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