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Bongiovanni et al. J Cancer Metastasis Treat 2022;8:44 https://dx.doi.org/10.20517/2394-4722.2022.78 Page 3 of 12

Figure 1. Selected most relevant studies with ICIs in mesothelioma patients.

Targeting CTLA-4
The phase II MESOT-TREM 2008 trial was the first study that opened the path towards this novel
therapeutic approach. In this study, 29 pretreated MPM and peritoneal malignant mesothelioma patients
underwent anti-CTLA-4 mAb tremelimumab therapy at the dose of 15 mg/kg every 90 days until disease
progression or unacceptable toxicity. Although the primary endpoint was not reached due to the low ORR
(6.9%), preliminary signs of antitumor activity were noted, in particular in terms of mOS which was 10.7
[13]
months . Therefore, a second study, MESOT-TREM 2012, started. In this phase II trial, based on the
[14]
pharmacokinetic analysis generated in previous studies , tremelimumab was given at the intensified dose
of 10 mg/kg every four weeks for six cycles, followed by maintenance every 12 weeks. Opposite to MESOT-
TREM-2008, in this study, the primary endpoint was reached with an immune-related ORR of 13.8% .
[15]
Moreover, the study showed a good safety profile, with grade 3-4 toxicity observed in only 7% of treated
patients . In light of these promising results, the phase IIb, placebo-controlled, double-blind DETERMINE
[15]
study started. Overall, 568 patients affected by pretreated MPM or peritoneal malignant mesothelioma were
randomized to receive tremelimumab, given at the same intensified dose utilized in the MESOT-TREM-
2012 study, or placebo. Unfortunately, the primary endpoint was not reached: tremelimumab failed to
demonstrate an improvement in OS, compared to placebo (7.7 and 7.3 months, respectively; HR = 0.92;
P = 0.41) .
[16]
Targeting PD1/PDL1 axis
The development of a second generation of immunomodulating mAb directed against the PD-1/PD-L1 axis
aroused keen interest to explore in MPM patients because of their more promising profile in efficacy and
safety compared to that of anti-CTLA-4 mAb in different tumor types. Thus, various phase I/II trials were
conducted in MPM patients [11,12,17-21] . Among the most representative studies, the phase Ib Keynote 028 study
(NCT02054806) was conducted on 25 MPM patients treated with pembrolizumab. The results show a
response rate of 20% and a mOS of 18 months [20].