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Table 2. Mesothelin-ADCs in mesothelioma
NCT ID Phase Product Target patient population Outcomes Reference
NCT02610140 2 Anetumab 248 patients with DPM randomized 2:1 to Anetumab ravtansine vs. vinorelbine: [55]
ravtansine anetumab ravtansine versus vinorelbine PFS: 4.3 vs. 4.5 months (HR 1.22, 95%CI:
0.85-1.74); OS: 11.6 vs. 9.5 months (HR
1.07, 95%CI 0.76-1.51)
NCT02341625 1/2a BMS-986148 96 patients received BMS-986148 Monotherapy: DCR: 56% (n = 14) and [56]
+/- nivolumab monotherapy (n = 44 with DPM) and 30 ORR: 4% (n = 1) in DPM patients
received combination (n = 16 with DPM) Combination: DCR: 85% (n = 11) and
ORR: 23% (n = 3) in DPM patients

DPM: Diffuse pleural mesothelioma; PFS: progression-free survival; OS: overall survival; HR: hazards ratio; CI: confidence interval; DCR: disease
control rate (stable disease + partial response).

tolerability, limiting our ability to speak to definitive efficacy. Furthermore, exploration of the combination
of a CD28-costimulated mesothelin CAR-T with the iCaspase-9 safety gene and pembrolizumab has shown
preliminary promise with a median OS of 23.9 months, 8 patients achieving stability for 6 months or more,
and 2 patients with a complete response . Larger prospective studies of novel CAR-T constructs and
[75]
combinations are needed to better determine the safety, efficacy, and proper patient population to deploy
this exciting treatment strategy.

BRCA1-associated protein 1 (BAP 1): BAP1 is a ubiquitin c-terminus hydrolase which functions as a key
[14]
tumor suppressor based on its role in both epigenetic modulation and DNA damage response . Somatic
[77]
and germline mutations in BAP1 are associated with multiple solid malignancies, including a significant
proportion of mesotheliomas [16,78-80] , melanomas (uveal and cutaneous), clear cell renal cell carcinomas, and
lung adenocarcinomas [14,81] . BAP1 inactivation increases the expression of enhancer of zeste homolog 2
(EZH2; also known as histone-lysine N-methyltransferase), which has itself been implicated as an oncogenic
[82]
driver in DPMs . Thus, BAP1 loss may sensitize such tumors to EZH2 inhibition. With nearly two-thirds
of DPM tumors having inactivation of BAP1, [16,82] it is a key biomarker under clinical development [Table 4].

The EZH2 inhibitor tazemetostat is approved for later-line treatment of constitutively EZH2-activated
tumors including epithelioid sarcomas with INI1/SMARCB1 loss and follicular lymphomas harboring
[89]
[90]
EZH2 mutations . Given the enrichment of BAP1 inactivation in DPM, tazemetostat was explored in
BAP1-inactivated DPM in a single-arm open-label phase 2 trial in 74 patients who were previously treated
with platinum-based chemotherapy . While the response rate was low (ORR 3% [n = 2]), the disease
[83]
control rate (DCR) was 54% at 12 weeks. This trial highlights a rationally designed targeted therapeutic
approach for patients with DPM. Studies are ongoing to refine the population most likely to benefit from
tazemetostat, as well as investigations into novel combinations.

Other efforts have focused on leveraging the role BAP1 plays in DNA repair and attempted to create
conditions of synthetic lethality by employing poly ADP-ribose polymerase (PARP) inhibitors. PARP
inhibitors have known efficacy across several solid tumors including approval in patients with ovarian [91,92]
or breast cancers harboring a germline BRCA mutation. The non-comparative multi-arm phase 2
[93]
Mesothelioma-Stratified Therapy 1 (MiST 1) trial was a novel clinical research platform study designed to
stratify patients with DPM to targeted therapies after progression on first-line chemotherapy. Arm 1 of this
trial enrolled 26 patients with cytoplasmic-BAP1-deficient or BRCA1-deficient mesotheliomas after
platinum-based chemotherapy . Patients received oral rucaparib twice daily for 24 weeks. DCR was 58% at
[85]
12 weeks and 23% at 24 weeks; partial responses were observed in three patients (12%). Furthermore, a
similar single-arm phase II trial enrolled 23 patients with refractory mesothelioma to receive the PARP
[86]
inhibitor olaparib . Patients in this trial were not selected by BAP1 alterations/loss (although 14 [61%]