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Table 1. VEGF TKIs in mesothelioma
NCT ID Phase Product Target patient population Outcomes Reference
NCT01064648 2 Cisplatin/pemetrexed 92 patients with treatment naïve Combination vs. chemotherapy alone: [38,39]
+/- cediranib unresectable DPM PFS: 6.9 vs. 5.6 months (HR 0.77, 95%CI:
0.59-1.02); OS: 10.0 vs. 8.5 months (HR
0.88, 95%CI: 0.65-1.17)
NCT00309946 2 Cediranib 51 patients with DPM and ≤ 1 prior line PFS: 1.8 months, OS: 4.4 months. 45 mg [40]
of therapy dose level improved response rate but
intolerable toxicity
NCT01907100 3 Cisplatin/pemetrexed 458 treatment naïve patients with Combination vs. chemotherapy alone: [41]
+/- nintedanib DPM randomized 1:1 to chemotherapy PFS: 6.8 vs. 7.0 months (HR 1.01, 95%CI:
alone and combination 0.79-1.30)
NCT02568449 2 Nintedanib 20 patients with DPM who previously PFS: 1.8 months; OS: 4.2 months [42]
received chemotherapy

DPM: Diffuse pleural mesothelioma; PFS: progression-free survival; OS: overall survival; HR: hazards ratio; CI: confidence interval.

models demonstrating increased cell death and tumor growth inhibition . A phase I trial investigating the
[52]
safety and recommended phase 2 dose (RP2D) of this drug in MSLN-expressing advanced tumors,
including DPM, is open but closed to recruitment (NCT03872206).

Mesothelin Antibody-Drug Conjugate (ADC). Anetumab ravtansine is an ADC comprised of an IgG1 anti-
MSLN antibody conjugated to the maytansine derivative tubulin inhibitor DM4 via a reducible disulfide
linker. The payload induces cell cycle arrest and apoptosis and has significant antitumor activity in
[53]
preclinical xenograft mesothelioma models . The initial phase 1 trial noted a promising preliminary partial
response rate of 31% , prompting the randomized phase II ARCS-M trial examining anetumab ravtansine
[54]
for the treatment of mesothelin-positive DPM. The trial randomly assigned 248 patients whose disease had
progressed on prior platinum/pemetrexed with or without bevacizumab to receive anetumab ravtansine or
vinorelbine. Unfortunately, the primary endpoint of PFS was no better with anetumab ravtansine than
vinorelbine and there was no significant difference in OS between the groups [Table 2] . This large
[55]
negative prospective trial highlights the importance of further refining biomarker development and
[57]
mesothelin-ADCs in DPM to better characterize those most likely to benefit . Another phase I/2a
mesothelin-ADC clinical trial, BMS-986148, was recently published, showing an acceptable safety profile
and a modest signal of clinical benefit in patients with DPM, particularly when used in combination with
nivolumab (NCT02341625; Table 2) . Ongoing preclinical investigations seeking to refine mesothelin-
[56]
ADCs are underway [58,59] .

Mesothelin Chimeric Antigen Receptor (CAR) T Cells: CAR-T cells are engineered to identify cancer-specific
cell surface antigens and promote cell lysis via activation of an intracellular domain of the T cell receptor-
CD3 complex and, in some cases, additional intracellular co-stimulatory molecules . CAR-T cell products
[60]
are now available for patients with several different types of refractory hematologic malignancies [61-64] , and
[65]
there is keen interest in exploring their applicability in solid tumors . Given the overexpression of MSLN
in DPM, anti-MSLN CAR-T cell constructs are in active development [65-68] , with several approaches
examining these agents either as single agents or in combination under investigation.

While CAR-T therapy can lead to a durable response in hematologic malignancies, several qualities of solid
tumors have proven problematic, including heterogeneous antigen presentation, an inhospitable tumor
microenvironment, and T-cell infiltration into a solid tumor [65,66,69] . In DPM, there have been multiple
studies evaluating different MSLN-targeting CAR-T cell constructs and administration techniques (systemic
vs. intrapleural; Table 3). Evaluations to date have mostly been in phase I clinical trials focused on safety and