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Page 4 of 16 Offin et al. J Cancer Metastasis Treat 2023;9:21 https://dx.doi.org/10.20517/2394-4722.2022.140

VEGF TKIs. In contrast to VEGFi antibodies, VEGF TKIs have failed to demonstrate improved efficacy
compared to standard-of-care regimens [Table 1]. The 1L phase 2 SWOG S0905 trial of cediranib (TKI with
activity against VEGF and PDGFR) with cisplatin and pemetrexed did not show significant clinical efficacy
over chemotherapy alone [38,39] and the phase 2 trial of cediranib monotherapy in patients with ≤ 1 prior line
of treatment showed modest clinical benefit but at an intolerable dose level . The 1L phase 3 LUME-Meso
[40]
trial of cisplatin/pemetrexed with nintedanib (a multi-kinase TKI with activity against PDFG, FGF2, TGFβ,
and VEGF) failed to show significant clinical benefit compared to chemotherapy , and the phase 2 trial of
[41]
nintedanib in previously treated patients with DPM did not meet its prespecified progression-free survival
(PFS) endpoint . To date, there are no approved nor recommended VEGF TKIs for patients with DPM.
[42]

Mesothelin: Mesothelin (MSLN) is a membrane-anchored cell surface glycoprotein that is highly expressed
in several solid tumors including DPM [11,43] . In preclinical models, MSLN overexpression promotes
tumorigenesis and tumor invasion [12,44] . Over the last several decades, there have been several attempts to
therapeutically exploit the overexpression of MSLN in DPM using multiple novel constructs, including
antibody-drug conjugates (ADCs), immunotoxins, and adoptive cellular therapies .
[45]
Mesothelin Antibodies. Trials of MSLN targeting antibodies have produced mixed results. The chimeric,
humanized IgG1 monoclonal antibody amatuximab was evaluated in a phase 2, single-arm trial in DPM,
where it was combined with cisplatin and pemetrexed for six cycles, followed by maintenance amatuximab
until disease progression. While the combination was found to be tolerable, the primary endpoint of PFS
was not improved in the treatment arm compared to chemotherapy alone, and the construct has not
progressed to a phase 3 investigation .
[46]
SS1P is a mesothelin-targeting antibody attached to a truncated fragment of Pseudomonas exotoxin A. With
preclinical data suggesting pseudomonas exotoxin A induces immunogenic cell death in DPM , there was
[47]
a rationale to test whether SS1P could lead to a tolerable therapeutic index and efficacy signal in DPM. The
drug was evaluated in a phase 1 trial in combination with cisplatin and pemetrexed for 1L treatment of
DPM . In 20 evaluable patients, there was an initial efficacy signal with an overall response rate of 60%;
[48]
however, neutralizing antidrug antibody formation within the first cycle limited its initial clinical
development in DPM. Lymphodepleting regimens (pentostatin/cyclophosphamide) to delay antidrug
[49]
antibody formation showed some early promise but, at present, are not being actively investigated in
larger prospective trials for DPM.

A second-generation immunotoxin, LMB-100, was subsequently designed to be less immunogenic than
[50]
SS1P to avoid the development of neutralizing antibodies, which were thought to limit single-agent
activity. A phase I trial of LMB-100 in advanced MSLN-expressing cancers found that the drug was indeed
less immunogenic. However, most patients developed antidrug antibodies after two cycles of the drug,
prompting the researchers to conclude that this formulation would have similarly limited single-agent
[51]
activity as SS1P . While a planned phase II study examining LMB-100 in combination with
pembrolizumab (NCT03644550) in the later-line setting was withdrawn due to the evolving 1L landscape
after the integration of CheckMate743, a study evaluating the role of normothermic intrapleural LMB-100
after cytoreductive surgery (NCT0537825) is soon to open.

Under the current investigation is the novel MSLN-directed protein construct HPN536. HPN536 is a T-cell-
activating protein-based construct targeting MSLN-expressing tumor cells and engaging CD3ε on T cells via
an albumin linker. HPN536 tethers T cells and MSLN-expressing target cells together, enabling the
formation of a cytolytic synapse resulting in T cell-dependent cellular cytotoxicity (TDCC) with preclinical