The n e w e ng l a n d j o u r na l of m e dic i n e

Review Article

Dan L. Longo, M.D., Editor

Perspectives on the Treatment of Malignant

Pleural Mesothelioma
Sam M. Janes, M.D., Ph.D., Doraid Alrifai, M.D., Ph.D.,
and Dean A. Fennell, M.D., Ph.D.​​

M
alignant mesothelioma is an aggressive tumor arising from From the Lungs for Living Research Cen-
the serosal outer linings of the lungs (pleurae), heart, abdomen, and tre, UCL Respiratory, University College
London (S.M.J., D.A.), the Department of
testes. Treatment trials have focused on malignant pleural mesothelio- Thoracic Medicine, University College
ma, which accounts for 90% of cases, is often diagnosed at an advanced stage, London Hospital (S.M.J.), London, and
and invariably leads to death. Malignant pleural mesothelioma has proved to be a the University of Leicester, Leicester
(D.A.F.) — all in the United Kingdom.
formidable challenge for clinicians and scientists, with the 5-year survival rate ­Address reprint requests to Dr. Janes at
continuing to languish at 5 to 10%.1 By far the most important risk factor for the Lungs for Living Research Centre, UCL
development of malignant mesothelioma is asbestos exposure, although other risk Respiratory, University College London,
5 University St., London, WC1E 6JF, United
factors, including related minerals, are beginning to emerge.2 The United States Kingdom, or at ­s​.­janes@​­ucl​.­ac​.­uk.
and other Western countries are seeing a gentle decline in cases of malignant
N Engl J Med 2021;385:1207-18.
mesothelioma as a result of transforming work practices. In the United States, DOI: 10.1056/NEJMra1912719
age-adjusted mortality has been reduced from almost 14 deaths per 1 million Copyright © 2021 Massachusetts Medical Society.

persons in 2000 to 11 deaths per 1 million in 2015.3 Britain (England, Scotland,

and Wales) has one of the highest death rates in the world at 77 deaths per 1 mil- CME
at NEJM.org
lion (from 2017 to 2019), although this rate is also in decline.4 However, regional
successes in prevention through eliminating clinically significant exposure to as-
bestos have not been matched by the development of new treatments.
In this review, we reflect on the limited effect of the few positive phase 3 ran-
domized, controlled studies, as well as recent trials examining the benefit of im-
munotherapy. We speculate about how rapid advances in our understanding of the
genetics and biology of malignant pleural mesothelioma could translate into more
effective therapies.

C ause s
Asbestos exposure is the most common cause of malignant mesothelioma. Argu-
ably the most notable case series that supports this relationship was reported in
the 1960s, in what was then the north west of Cape Province in South Africa,
where 33 cases were examined, all involving exposure to clinically significant
levels of asbestos.5 Asbestos is an excellent insulating material that is strong,
cheap, fire-resistant, and durable. Although its use has been banned in many
countries as a result of its link to malignant mesothelioma, mining continues,
with export for use in developing economies, which is expected to perpetuate the
global incidence of exposure (Fig. 1).6-8
Mesothelioma has a latency period of 20 to 50 years.9 Despite the identification
of asbestos as an indisputable precipitant of mesothelioma, the precise pathoge-
netic mechanisms behind the development of the disease remain unclear. Con-
tributing factors such as the persistence of mineral fibers (particularly asbestos)
and chronic inflammation, supported by mouse models, have been extensively

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A Countries with the Most Mined Asbestos in 2017 (estimated metric tons)
Russia
(710,200)

Kazakhstan China PACIFIC

ATLANTIC (192,700) (124,700) OCEAN
OCEAN

PACIFIC
OCEAN
INDIAN
Brazil OCEAN
(135,000)

Metric Tons
750,000

500,000

250,000

B Countries with the Greatest Use of Asbestos in 2017 (estimated metric tons)
Russia
(118,000)

China PACIFIC
Uzbekistan (235,000) OCEAN
ATLANTIC
OCEAN (97,000)
India
(318,000)

PACIFIC
OCEAN
INDIAN
OCEAN
Indonesia
(105,000)
Metric Tons
750,000

500,000

250,000

Figure 1. Global Asbestos Mining and Use of Asbestos.

The maps are based on data from the U.S. Geological Survey. In 2017, the countries with the most mined asbestos
(measured in metric tons) were Russia, Kazakhstan, Brazil, and China (Panel A), and the countries with the greatest
use of asbestos (measured in metric tons) were India, China, Russia, Indonesia, and Uzbekistan (Panel B).

reviewed elsewhere.10,11 Analysis of the mutational associated protein 1 (BAP1) have been shown
signature of malignant pleural mesothelioma, to accelerate asbestos-induced mesothelioma in
an emerging research tool for detecting genom- mice15 and are associated with a syndrome
ic footprints of damage, reveals mutational consisting of familial cancers in humans, in-
changes induced by reactive oxygen species. cluding malignant mesothelioma and uveal mel-
Asbestos-specific signatures have not yet been anoma.16 Other deleterious germline variants in
identified.12,13 DNA repair genes, such as PALB2 and BRCA1/2,
In more than 10% of patients with malignant also accelerate the development of asbestos-
mesothelioma, germline variants have been re- induced mesothelioma in preclinical models and
ported.14 Mutations in the gene encoding BRCA1- humans.17

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 Treatment of Malignant Pleur al Mesothelioma

His t opathol o gic a l a nd toms at diagnosis include breathlessness caused

Mol ecul a r He tero genei t y by a pleural effusion or tumor encasement of the
lung and the more sinister chest pain due to
Three distinct histologic subtypes of pleural direct invasion into the chest wall or mediasti-
mesothelioma phenotypes have traditionally been num. Fatigue, anorexia, weight loss, sweats, and
recognized: epithelioid mesothelioma (account- malaise may also be present and become more
ing for 50 to 60% of cases), which is associated frequent as the disease progresses.23
with the most favorable prognosis; sarcomatoid
mesothelioma (10% of cases), which is highly Di agnosis
invasive and drug-resistant; and biphasic meso-
thelioma (30 to 40% of cases), which is a mo- Contrast-enhanced computed tomography (CT)
saic of the other two subtypes. Recent insights of the chest and upper abdomen is recommend-
reveal an epithelioid–sarcomatoid continuum ed as the initial method of investigation.24 Other
rather than discrete subclasses, which correlates imaging techniques can be used to support the
strongly with molecular markers of epithelial CT findings. Positron-emission tomography
mesenchymal transition.18 The interpatient hetero- (PET) with CT has been shown to add diagnostic
geneity of the disease has almost certainly hin- value when the CT results are uncertain regard-
dered clinical trial design and results. The classic ing a malignant process, although PET-CT find-
histologic subgrouping has also been challenged ings should be interpreted with caution, since
by the use of deep learning. Examination of both areas of high metabolic activity may represent
tumor heterogeneity and surrounding tumor infection or inflammation.25 Magnetic resonance
stroma has revealed prognostic histopathologi- imaging can provide greater soft-tissue defini-
cal features such as inflammation, cellular diver- tion, offering more detailed information on iso-
sity, and vacuolization within the stroma.19 lated foci of disease, chest-wall invasion, or in-
Comprehensive genomic and transcriptomic filtration into surrounding structures.26 When
sequencing of mesothelioma has revealed exten- the diagnosis remains uncertain, the more inva-
sive genomic heterogeneity among patients, sive techniques of mediastinoscopy, laparoscopy,
which probably underpins the failure of one- endobronchial ultrasonography, and endoscopic
size-fits-all approaches to therapy. The muta- ultrasonography are occasionally used if a posi-
tional landscape of mesothelioma is dominated tive result would influence management.27 Several
by the inactivation of tumor suppressor genes, studies of serum-based and pleural fluid–based
which include BAP1, CDKN2A, NF2, and SETD2.20,21 biomarkers, such as soluble mesothelin-related
The protracted interval between initial expo- peptide and osteopontin, offer little evidence for
sure and diagnosis suggests that mesothelioma, their use in diagnosing malignant pleural meso-
like breast cancer and cervical cancer, has a thelioma or monitoring treatment effects.24
premalignant state. Indeed, loss of function of Diagnostic imaging guides histopathological
BAP1 has been shown to be associated with a confirmation of malignant pleural mesothelioma.
carcinoma in situ–like phenotype in the pleura Pleural biopsy is often the preferred diagnostic
and peritoneum, a potentially important finding method; however, examination of pleural fluid is
for our understanding of the pathogenesis of also an acceptable diagnostic method for epithe-
mesothelioma, which is likely to influence fu- lioid pleural mesothelioma. Diagnostic sensitiv-
ture work exploring preventive therapeutic inter- ity varies widely, and higher rates of successful
ventions.22 diagnoses are found in centers specializing in
cytologic assessment of pleural effusion.28,29
Ancillary studies are key in supporting a his-
Cl inic a l Pr e sen tat ion
topathological diagnosis of malignant pleural
Most patients with malignant pleural mesothe- mesothelioma. Immunohistochemical panels for
lioma present late in the course of the disease, biopsy specimens or cytologically derived cell
as a result of asymptomatic early development, a blocks usually include at least two mesothelial
sequela of the indolent biologic features of the markers (e.g., calretinin, cytokeratin 5/6, Wilms’
disorder. The most common presenting symp- tumor 1 antigen, or D2-40), which should be

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A D E
Brain
3%

Nodes
53% Thyroid
B 7%

F
Heart
58%

C
Spleen
Liver
11%
32%

Peritoneum
24%

Bone
14%

Figure 2. Histopathological Features, Anatomical Distribution, and Radiologic Detection of Malignant Mesothelioma.
Panel A shows sheets of epithelioid tumor cells with focal necrosis in lung tissue (hematoxylin and eosin). Panel B shows loss of BAP1
nuclear staining in tumor cells, with BAP1 staining retained in alveolar and inflammatory cells (pink). Panel C shows calretinin (tumor
cells with both cytoplasmic and nuclear staining [brown]). Panel D shows some sites of extrapleural dissemination of disease from ma-
lignant pleural mesothelioma on the basis of postmortem studies.33 Nodes represent those in hilar, mediastinal, and abdominal loca-
tions, and the heart represents pericardium and myocardium. Other sites of extrapleural disease, such as the kidney (9%) and adrenal
glands (10%), are not shown. Panel E shows pleural mesothelioma detected on a chest radiograph, and Panel F shows detection on
positron-emission tomography–CT.

positive, and two adenocarcinoma markers (e.g., mortem studies often show widespread, unsus-
thyroid transcription factor 1, carcinoembryonic pected dissemination. These findings suggest
antigen, or Ber-EP4), which should be negative. that metastases may be missed at the initial pre-
However, the sensitivity and specificity of thesesentation, potentially leading to understaging.33
markers for the sarcomatoid subtype are poor. Several iterations of staging systems for ma-
The absence of nuclear expression of BAP1 has lignant pleural mesothelioma have been pro-
emerged as an important diagnostic tool. Nuclear posed; the most recent is the eighth edition
expression has been shown to be lost in up to of the International Association for the Study of
60% of cases, most often in the epithelioid sub- Lung Cancer tumor–node–metastasis (TNM)
type.30 In addition to BAP1, p16INK4A and me- grading system.34 Its role in quantifying disease
thylthioadenosine phosphorylase, which are fre- by measuring pleural infiltration, lymph-node
quently deleted on chromosome 9p21.3, have involvement, and distant metastatic sites allows
been shown to be helpful as markers of a malig- for identification of patients who would be can-
nant process24,31,32 (Fig. 2). didates for participation in clinical trials of
surgery and radiotherapy. Patients known to
have advanced disease often proceed to conven-
S taging
tional systemic treatment or clinical trial enroll-
Patients usually present with localized pleural ment. The recognized discrepancy between ra-
disease on radiologic assessment. However, post- diologic and postmortem findings complicates

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 Treatment of Malignant Pleur al Mesothelioma

the development of predictive prognostic tools.33,35 oma and Radical Surgery (MARS) feasibility
Furthermore, other key prognostic variables, such study.40 Patients treated with standard-of-care,
as histologic subtype, are not considered in platinum-based chemotherapy were randomly
TNM staging, making prognosis difficult to es- assigned, if their cancer had not progressed, to
tablish with the use of this approach alone. either surgery and radiotherapy or observation
alone. Not only was the median overall survival
shorter in the surgical group (14.4 months vs.
Cur r en t T r e atmen t L a ndsc a pe
19.5 months), but morbidity was significantly
Treatment of malignant pleural mesothelioma is higher. Although the adjusted hazard ratio for
guided by staging, histologic subtype, and the extrapleural pneumonectomy as compared with
patient’s functional status. Patients with inoper- no extrapleural pneumonectomy was very high
able disease are assessed for the use of systemic (2.75, P = 0.02), it has been argued that this
treatment or active symptom control. The latter negative study was not sufficiently well powered.
approach, which focuses on symptom manage- The considerable dropout rate from the origi-
ment, is a fundamental aspect of patient care. nally screened 301 patients to 50 patients was
However, delivering it early rather than when problematic. Of the 24 patients randomly as-
required was not shown to improve quality-of- signed to surgery, only 16 (67%) proceeded with
life measures in the United Kingdom–based surgery and only half of those received post-
RESPECT-Meso randomized trial.36 operative radiotherapy. Furthermore, patients who
did not undergo surgery had more favorable bio-
Pleural Fluid Management logic disease than those who did undergo sur-
Patients frequently present with pleural effusions gery, which may have influenced the final out-
requiring drainage for both symptom relief and come.24,32 In response to these findings, MARS2,
diagnostics. Temporary catheterization of the a randomized phase 3 trial, is assessing whether
pleural space to draw off fluid is usually accom- extended pleurectomy–decortication (a less radi-
panied by talc administration. The success rate cal procedure than extrapleural pneumonectomy)
with this approach is similar to the rates with (Fig. 3) plus chemotherapy prolongs survival, as
indwelling catheterization and surgical proce- compared with chemotherapy alone.41 If the re-
dures such as partial pleurectomy and pleurec- sults of this trial are negative, the role of surgery
tomy–decortication, although the surgical pro- in such patients will be seriously undermined.
cedures have higher complication rates and
require a longer hospital stay.37,38 Radiotherapy
Randomized, controlled evaluation of radio-
Surgery therapy has, to date, not shown any improve-
Surgical resection for mesothelioma is always ment in associated survival. Although conducted
incomplete and should be considered palliative only as a phase 2 investigation, SAKK 17/04 is
(Fig. 3). Median survival after the most radical probably the most important study to highlight.
form of surgery, extrapleural pneumonectomy, is Patients treated with neoadjuvant chemotherapy
18 months, with a 5-year survival rate of 14%.39 and extrapleural pneumonectomy in whom mac-
It remains unclear whether cytoreductive surgery roscopic clearance of disease was achieved were
prolongs median survival for patients with ma- randomly assigned to either high-dose radio-
lignant pleural mesothelioma. Studies to date therapy or surveillance. The trial failed to meet
have not provided a clear measure of the magni- its primary end point of locoregional relapse-
tude of benefit (vs. risk). Geographic inconsis- free survival; however, this outcome was marred
tencies in the recommendation of treatment for by slow enrollment of patients undergoing extra-
patients with early-stage disease are well recog- pleural pneumonectomy and by poor macro-
nized. To measure the efficacy of surgery for scopic clearance, with only a third of the origi-
mesothelioma, appropriately controlled and well- nally recruited patients randomly assigned to
powered randomized trials are essential. either hemithoracic radiotherapy or observation.42
The only reported data from a randomized The individual benefit of radiotherapy is chal-
trial directly comparing surgery with no surgery lenging to ascertain in a trimodal approach in
are from the United Kingdom–based Mesotheli- which both neoadjuvant chemotherapy and radi-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Partial Pleurectomy Pleurectomy–Decortication

Parietal pleura

Visceral pleura Variable

removal or
peeling away
LU NG LU N G
Surgical
removal
HEAR T H E A RT

Pericardium
Surgical
Mesothelioma Mesothelioma removal

Diaphragm

Extended Pleurectomy–Decortication Extrapleural pneumonectomy

Variable
removal or Surgical
peeling away removal

LU NG LU N G

HEAR T Surgical H E A RT
removal

Mesothelioma Mesothelioma

Figure 3. Surgical Approaches to the Treatment of Malignant Pleural Mesothelioma.

Partial pleurectomy entails partial removal of malignant pleural mesothelioma and effusion management. With pleurectomy–decortica-
tion, the affected pleura is removed, as is any visible tumor. Extended pleurectomy–decortication consists of pleurectomy–decortication
plus removal of the pericardium and hemidiaphragm. Extrapleural pneumonectomy entails removal of the lung, pleura, pericardium,
and hemidiaphragm, with the goal of macroscopic clearance of disease.

cal surgery remain under scrutiny. Other approach- ies, Prophylactic Irradiation of Tracts (PIT)45 and
es, such as intensity-modulated radiotherapy and Surgical and Large-Bore Procedures in Malig-
proton therapy, may reduce off-target damage. nant Pleural Mesothelioma and Radiotherapy
Intensity-modulated radiotherapy is being explored trial (SMART).46 Efforts to ascertain the role of
in a phase 3 clinical trial.43,44 radiotherapy in pain control are under way in the
Radiotherapy used as a prophylactic interven- randomized SYSTEMS-2 study.47
tion to prevent chest-wall invasion after the use
of diagnostic or therapeutic procedures has been Tumor-Treating Fields
widely abandoned because of negative results The noninvasive delivery of alternating electric
from two randomized, open-label phase 3 stud- fields to mesothelioma tumors in combination

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 Treatment of Malignant Pleur al Mesothelioma

with platinum-based chemotherapy has shown tients with relapsed disease,54 combination im-
activity in a single-group, phase 2 study of epi- munotherapy with nivolumab and ipilimumab,
thelioid disease. As a result, this combination targeting the immune checkpoints programmed
has been approved by the Food and Drug Ad- cell death 1 (PD-1) and cytotoxic T-lymphocyte
ministration (FDA) as part of its Humanitarian antigen 4, respectively, has shown superiority as
Device Exemption program. The approval sur- a front-line treatment as compared with stan-
prised many researchers, given the lack of ran- dard-of-care chemotherapy (survival, 18.1 months
domization. Randomized data would provide valu- vs. 14.1 months), particularly in patients with
able insight into the relative magnitude of the nonepithelioid mesothelioma. This prespecified
clinical benefit, toxicity, and cost-effectiveness.48 interim analysis led to FDA approval of the com-
bination immunotherapy in 2020, the only sys-
Systemic Therapy temic treatment for malignant pleural mesothe-
Until very recently, clinically meaningful ad- lioma to be approved by the FDA since 2004.55
vances in systemic treatment for advanced ma- The adverse-event profile of this regimen in
lignant pleural mesothelioma have been lacking. older, more frail patients, as compared with the
In the United States, over half of the patients trial participants, will be observed with interest.
never receive chemotherapy, largely because of Nivolumab alone is also the first drug to be as-
older age, poor performance status, associated sociated with a significant improvement in over-
coexisting conditions, and ultimately, personal all survival among patients with relapsed meso-
preference.49 The EMPHACIS study defined the thelioma. The recently reported Checkpoint
first standard-of-care front-line treatment, which Blockade for Inhibition of Relapsed Mesothelio-
received FDA approval in 2004. The study showed ma (CONFIRM) study showed a 3-month im-
a significant increase in median overall survival provement in overall survival with nivolumab as
from 9.3 months with cisplatin alone to 12.1 compared with placebo.56 The benefit was inde-
months with cisplatin combined with peme- pendent of programmed death ligand 1 (PD-L1)
trexed.50 Raltitrexed combined with cisplatin expression, a predictive marker of the response
was also shown to be superior to cisplatin alone, to anti–PD-1 therapy in patients with other tu-
supporting the use of antifolate treatment for mors.57 Survival updates are eagerly awaited, with
malignant pleural mesothelioma.51 the hope that a subgroup of patients will have
The Mesothelioma Avastin plus Pemetrexed- durable responses, as observed in patients with
Cisplatin Study (MAPS) showed that standard- other immunotherapy-sensitive tumors (Table 1).
of-care chemotherapy combined with bevacizu­ No phase 3 trial of maintenance therapy (long-
mab, a monoclonal antibody targeting vascular term treatment to delay a relapse after induction
endothelial growth factor, improved survival chemotherapy) has shown an improvement in
(18.8 months, vs. 16.1 months with chemother- overall survival.58-60 Treatment with gemcitabine
apy alone). Despite the small survival advantage, chemotherapy immediately after front-line chemo-
this treatment regimen was never filed for a license. therapy (called switch maintenance) offers prom-
Doubt remains regarding the value of adding ise and warrants exploration in a phase 3 study.61
bevacizumab to chemotherapy for patients with When durable responses have been observed
malignant pleural mesothelioma, especially in with front-line chemotherapy, a rechallenge of
view of the increased adverse-event profile as- platinum–pemetrexed can be useful in some
sociated with combination therapy despite im- patients.62 Vinorelbine, another cytotoxic chemo-
provements in certain quality-of-life measures therapeutic agent, has shown some activity,63
such as pain.52 A subsequent study of the multi- and the results of a randomized trial should be
targeted antiangiogenic kinase inhibitor ninte- available in 2021 (ClinicalTrials.gov number,
danib had negative results.53 NCT02139904).64
Immune checkpoint inhibition leading to
tumor-suppressive T-cell activation has trans- The F u t ur e L a ndsc a pe
formed systemic therapy for multiple solid tu-
mors. Two important studies will imminently Chemoimmunotherapy
alter the way mesothelioma is treated in the fu- Combining an immune checkpoint inhibitor with
ture. On the basis of promising activity in pa- chemotherapy has proved to be synergistic and

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Notable Phase 3 Clinical Trials of Immunotherapeutic Approaches to Malignant Pleural Mesothelioma (MPM).

ClinicalTrials.gov
Study Name Description Number Study Treatments Status
Dendritic Cell Immunotherapy for Randomized, open-label phase 2–3 NCT03610360 MesoPher plus best sup- Active but not
Mesothelioma (DENIM) study of dendritic cells loaded portive care vs. best recruiting
with allogeneic tumor-cell ly- supportive care
sate as maintenance treatment
(MesoPher [Amphera]) after
chemotherapy
Pembrolizumab Immunotherapy Multicenter, randomized phase 3 NCT02991482 Pembrolizumab vs. stan- Negative
versus Standard trial comparing pembrolizumab dard chemotherapy
Chemotherapy for Advanced with standard chemotherapy for
Pre-treated Malignant Pleural advanced, pretreated MPM
Mesothelioma (PROMISE-
meso)
Checkpoint Blockade for Inhibition Phase 3, double-blind, placebo- NCT03063450 Nivolumab vs. placebo Positive
of Relapsed Mesothelioma controlled trial to evaluate
(CONFIRM) the efficacy of nivolumab in
relapsed MPM
Pembrolizumab in Patients with Phase 2–3 randomized study of NCT02784171 Pemetrexed–cisplatin vs. Active but not
Advanced Malignant Pleural pembrolizumab in patients with pemetrexed–cisplatin recruiting
Mesothelioma advanced MPM plus pembrolizumab
vs. pembrolizumab
(phase 2 only)
CheckMate 743* Phase 3, randomized, open label NCT02899299 Nivolumab plus ipilim- Positive at pre-
trial of nivolumab plus ipi- umab vs. pemetrexed specified interim
limumab vs. pemetrexed and and platinum analysis
platinum as first-line therapy in
unresectable MPM
INFINITE* Phase 3, open-label, randomized, NCT03710876 rAd-IFN plus oral celecox- Active but not
parallel group study to evalu- ib and gemcitabine, recruiting
ate the efficacy and safety of then maintenance
intrapleural administration of gemcitabine vs. oral
adenovirus-delivered interferon celecoxib and gem-
alfa-2b (rAd-IFN) in combina- citabine, then mainte-
tion with celecoxib and gem- nance gemcitabine
citabine in patients with MPM
Bevacizumab and Atezolizumab Multicenter, randomized phase 3 NCT03762018 Bevacizumab plus Recruiting
in Malignant Pleural trial comparing atezolizumab chemotherapy vs.
Mesothelioma (BEAT-meso) plus bevacizumab and standard atezolizumab plus
chemotherapy with bevacizumab bevacizumab plus che-
and standard chemotherapy motherapy
as first-line treatment for ad-
vanced MPM
Durvalumab with Chemotherapy Phase 3 randomized trial of dur- NCT04334759 Durvalumab plus chemo- Recruiting
as First Line Treatment valumab with chemotherapy as therapy, then mainte-
in Advanced Pleural first-line treatment in advanced nance durvalumab vs.
Mesothelioma (DREAM3R) pleural mesothelioma chemotherapy, then
observation

* CheckMate 743 is the Study of Nivolumab Combined with Ipilimumab versus Pemetrexed and Cisplatin or Carboplatin as First Line Therapy in
Unresectable Pleural Mesothelioma Patients, and INFINITE is Efficacy and Safety of rAd-IFN Administered with Celecoxib and Gemcitabine
in Patients with Malignant Pleural Mesothelioma.

is now a standard of care for patients with non– of the results from MAPS67 and the premise that
small-cell lung cancer.65 Accordingly, for patients antiangiogenic agents encourage the differentia-
with mesothelioma, randomized trials targeting tion and activity of immune cells, the addition of
either PD-1 or its natural ligand, PD-L1, in com- the PD-L1 inhibitor atezolizumab to pemetrexed–
bination with chemotherapy have shown poten- carboplatin and bevacizumab is being evaluated
tial or are ongoing (NCT02784171).66 On the basis in a randomized phase 3 trial, Bevacizumab and

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 Treatment of Malignant Pleur al Mesothelioma

Atezolizumab in Malignant Pleural Mesothelioma peutically exploitable vulnerability with the use
(BEAT-meso; NCT03762018). of arginine deprivation. Treatment with pegylated
Delivery of adenovirus-mediated interferon arginine deiminase (ADI-PEG 20), which leads to
alfa-2b is currently being evaluated in the phase a decrease in arginine, has shown efficacy in a
3 INFINITE study, on the basis of encouraging randomized phase 2 trial71 and can be safely
phase 2 data showing a disease control rate of combined with chemotherapy.72 Since ASS1 loss
88%.68 Previously treated patients are randomly is most common in patients with nonepithelioid
assigned to receive either intrapleural adenovirus mesothelioma, a placebo-controlled phase 3 trial
treatment followed by treatment with celecoxib evaluating standard chemotherapy with or with-
and then gemcitabine or celecoxib and gemcita­ out ADI-PEG 20 in this subgroup of patients is
bine alone, until disease progression or termi- ongoing (NCT02709512).
nation of treatment because of toxic effects Tumor-suppressor gene losses, which pre-
(NCT03710876). Studies such as these rely on the dominate in mesothelioma, may confer sensitiv-
presence of accumulated pleural fluid to allow ity to new small molecules, providing an oppor-
for placement of an indwelling pleural catheter, tunity for drug development. BAP1 inactivation
meaning that if the treatment is successful, not leads to up-regulation of the oncogenic poly-
all patients are likely to benefit. Local treatment comb repressive complex 2. One of its subunits,
to the pleura has long been a goal for clinicians enhancer of zeste homolog 2 (EZH2), has been
because of concerns regarding tumor penetra- shown to lead to cancer progression.73 A phase 2
tion with the use of intravenous treatment. multicenter clinical trial of the EZH2 inhibitor
tazemetostat in BAP1-inactivated malignant
Cellular Therapy mesothelioma met its primary end point of dis-
Manipulating the immune system not only offers ease control at 12 weeks (51% of patients).74
the opportunity for longer-term disease control Master protocols (trials designed to assess
than with chemotherapy but also is associated multiple hypotheses) provide a platform that di-
with fewer toxic effects. Innovative ways of rectly addresses interpatient heterogeneity through
modifying the behavior of the immune system individualized therapy. Molecular stratification
have been explored. Genetically engineered T cells of mesothelioma as a basis for individualizing
called chimeric antigen receptor T (CAR-T) cells therapy is now possible. The Mesothelioma
have been designed to target mesothelin, an Stratified Therapy (MiST) trial is the first roll-
antigen predominantly but not exclusively seen ing, multigroup, phase 2 umbrella study that has
on mesothelioma cells. A phase 1 clinical trial been designed to rapidly evaluate new treat-
exploring intrapleural delivery of these CAR-T ments coupled to “multi-omic” interrogation and
cells, combined with an immune checkpoint in- to identify predictive biomarkers of an excep-
hibitor, in 19 patients with pleural mesothelioma tional response.75 In one MiST group (patients
showed a disease control rate of almost 60%, an with BAP1/BRCA1-deficient mesothelioma who
exciting finding in such an early-phase study.69 received rucaparib), the disease control rate was
58% at 12 weeks and 23% at 24 weeks.76 The
Molecularly Stratified Therapy MiST protocol is hypothesis-generating, with the
Currently, no predictive biomarkers are in rou- aim of accelerating and guiding future strati-
tine use for identifying patients who are likely to fied, randomized trials.
benefit from treatment for mesothelioma. How-
ever, a greater understanding of the biology of C onclusions
malignant mesothelioma has revealed molecular
targets, opening up the possibility of an indi- Progress in improving survival for patients with
vidualized approach (Fig. 4). mesothelioma has been slow. This can be partly
Epigenetic silencing of the enzyme arginino- explained by a lack of randomized trials, par-
succinate synthetase 1 (ASS1) represents the ticularly for surgical treatment. Extensive inter-
first target to undergo molecularly stratified patient heterogeneity represents another major
phase 3 evaluation in patients with mesothelio- barrier, warranting stratified therapy. To accel-
ma. Loss of ASS1 leads to a reliance on exoge- erate advances in the field, we must embrace
nous arginine for viability70 and exposes a thera- rational, well-controlled investigations, as well

n engl j med 385;13 nejm.org September 23, 2021 1215

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Inhaled
Asbestos Fibers

LU NG

HE AR T
20-to-50-year latency period
Mesothelioma
tumor

Considerations and Targets for Future Therapy

Phenotypic Histologic Subtypes Current and Future Systemic Approaches Genomic or Epigenomic Landscape
Chemotherapy Mutation Therapeutic Targets
Epithelioid
(50–60% of cases) Antibody-drug conjugates BAP1 EZH2; PARP
Immune checkpoint inhibition CDKN2A p16
(PD-1 or PD-L1 inhibition) NF2
Biphasic FAK; YAP-TEAD; mTOR and PI3K
(30–40% of cases) Ferroptosis inducers
ASS1 Arginine
Cellular therapy
(CAR-T cells targeting mesothelin)
Sarcomatoid
(10% of cases) Angiogenesis inhibition

Figure 4. Future Therapeutic Approaches to Malignant Pleural Mesothelioma.

Future treatment decisions may be based on morphologic differences, the immune microenvironment of the tumor, and the genomic or
epigenomic landscape that promotes a biomarker-based strategy.

as individualized approaches. Master protocols Disclosure forms provided by the authors are available with
could accelerate the discovery of new, effective the full text of this article at NEJM.org.
We thank Drs. Daisuke Nonaka and James Spicer, at Guy’s
treatments. Continued increases in the incidence Hospital, London, for providing the histopathological and ra-
of malignant pleural mesothelioma in develop- diologic images, respectively; Dr. Julia Ruston, at Lungs for
ing countries warrant ongoing scientific and Living Research Centre, for help with an earlier version of the
artwork; and Dr. Kate Gowers, at Lungs for Living Research
clinical pursuit of new, effective, and affordable Centre, for assistance with the preparation of an earlier version
treatments. of the manuscript.

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