Page 104 - Read Online

Page 2 of 16 Offin et al. J Cancer Metastasis Treat 2023;9:21 https://dx.doi.org/10.20517/2394-4722.2022.140

INTRODUCTION
Diffuse pleural mesothelioma (DPM) is an aggressive malignancy of the mesothelial lining of the pleural
cavity with unacceptably poor outcomes, with less than 10% of patients surviving past 5 years .
[1]
Approximately 3,300 patients are diagnosed annually with DPM in the United States, and globally, the
[2-5]
incidence continues to rise in association with asbestos exposure . Despite recent advances, DPM remains
a recalcitrant disease, with even patients with early-stage disease having a high rate of recurrence despite
[6,7]
aggressive multimodality therapy .
DPM has been the subject of extensive genomic analyses making it a rich field for the pursuit of targeted
therapy. Whole exome sequencing of malignant mesotheliomas identifies significant mutational burdens in
BAP1, NF2, TP53, and SETD2, amongst many others . In addition to this extensive genomic profiling,
[8]
immunohistochemistry (IHC) has confirmed protein targets for investigation, such as WT1 [9,10] ,
mesothelin [11,12] , BAP1 [13-15] , and VISTA [16,17] and histologic subtype has shown both prognostic and possibly
predictive implications . As we gain further insights into the molecular landscape of mesothelioma, there
[18]
is hope that targeted therapeutic strategies akin to those seen in non-small cell lung cancers over the past
two decades will soon follow .
[19]
However, despite the myriad of efforts to drug these promising targets, in 2022, there exists not a single
FDA-approved targeted therapy for patients with DPM. Unresectable/metastatic DPM is traditionally
treated with systemic therapies. There are currently only two approved options for patients with DPM, both
[20]
of which are in the first-line (1L) setting: platinum doublet chemotherapy and combination immune
checkpoint inhibitor (ICI) therapy with ipilimumab and nivolumab . Both regimens are biomarker
[18]
agnostic, with the latter showing preferential benefit in non-epithelioid histology (biphasic and
sarcomatoid) but remaining an option for all histologic subtypes. There are currently no approved
treatment options for patients after progression on 1L therapy.

With our growing understanding of the genomic landscape of mesotheliomas [8,16,21,22] , the field is focused on
integrating these findings into the care of our patients. Efforts to comprehensively integrate next-generation
sequencing (NGS) findings as a prognosticator for patients with mesothelioma are ongoing, typified by the
recently published Oncocast-MPM, an open-source, web-accessible, machine-learning risk-prediction
model incorporating genomic profiling from patients with DPM which was validated to provide more
comprehensive prognostication . At present, there are no approved nor recommended, genomically
[22]
defined targeted therapies for patients with DPM. Targeted strategies are, at times, used off-label in the
proper clinical settings, including in those rare mesotheliomas harboring ALK rearrangements [23-25] , NTRK
fusions , and BRAF V600E mutations. These approaches have not been systematically evaluated as
[26]
[27]
therapeutic drug targets in mesothelioma, and the use of targeted medications for these indications is
extrapolated from data in other malignancies . Further exploration of predictive markers and their
[28]
actionability is needed.

In this review, we will focus on oncogenic targets under active clinical investigation for patients with DPM
[Figure 1].

THERAPEUTIC TARGETS OF INTEREST
Vascular endothelial growth factor (VEGF): activation of VEGF and its signaling cascade is critical for
tumorigenesis and cell survival across solid tumor types. Inhibition of VEGF signaling has been
[29]
extensively studied in DPM and is accomplished using targeted antibodies or VEGF tyrosine kinase
inhibitors (TKIs). Evidence supporting the use of VEGF inhibitors in DPM has led to their incorporation
into National Comprehensive Cancer Network (NCCN) guideline recommendations .
[30]