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Page 4 of 12 Bongiovanni et al. J Cancer Metastasis Treat 2022;8:44 https://dx.doi.org/10.20517/2394-4722.2022.78

In the MERIT II study, a flat dose of nivolumab administration (240 mg every two weeks) was evaluated in
34 Japanese pretreated MPM patients. The mOS was 17.3 months, three-year survival was 23.5%, mPFS was
[21]
6.1 months, and ORR was 29%, regardless of the histotype . Because of these results, nivolumab received
[21]
approval as second-line therapy for MPM patients in Japan .

Following these positive results, two phase III studies, PROMISE-Meso and CONFIRM, started [22,23] . In the
first one, 144 unresectable, pretreated MPM patients were randomized to receive chemotherapy
(gemcitabine or vinorelbine) or pembrolizumab. Crossover to pembrolizumab was allowed. After a median
follow-up of 11.8 months, no differences were seen in mOS and mPFS between pembrolizumab and
chemotherapy (mOS, 10.7 vs. 12.4 months; HR = 1.12; 95%CI: 0.74-1.69; P = 0.59; mPFS, 2.5 vs. 3.4 months;
[21]
HR = 1.06; 95%CI: 0.73-1.53; P = 0.76) . However, in the group treated with pembrolizumab, an increase in
response rate was recorded (22% vs. 6% treated with chemotherapy, P = 0.004). The PD-L1 expression was
not predictive of better survival with pembrolizumab .
[22]

In the CONFIRM trial, 332 second- or third-line MPM patients were randomized to receive nivolumab or
placebo. In this trial, cross-over was not permitted. Median OS was slightly higher with nivolumab than in
[23]
the placebo group (9.2 vs. 6.6 months; HR = 0.72; 95%CI: 0.55-0.94; P = 0.018) . Opposite to CheckMate
743, an improvement in OS was seen in patients with epithelioid histology (9.4 vs. 6.6; HR = 0.71; 95%CI:
0.53-0.95; P = 0.021) but not in those with non-epithelioid histology (5.9 vs. 6.7 months; HR = 0.79; 95%CI:
0.35-1.79; P = 0.572) [8,22] . The grade 3 and 4 adverse event rates were 13.1% in the nivolumab arm and 2.7%
in the placebo arm .
[23]

Although the results generated from these studies demonstrate an overall antitumor efficacy of CTLA-4 or
PD-1/PD-L1 inhibition, the latter seems to be limited to a subgroup of subjects, probably because the
immune-modulating effect of these agents may not be enough to overcome the strong immunosuppressive
microenvironment of MPM if used as monotherapy.

Co-targeting of CTLA-4 and PD1/PDL1 axis
In the last few years, great efforts have been made on combination regimens targeting ICIs to enhance the
efficacy of immunotherapeutic agents and overcome primary resistance to treatment observed in a large
proportion of cancer patients. Several mechanisms of resistance have been thus far identified , and
[24]
strategies to overcome them represent an area of strong investigation.

Along this line, co-targeting CTLA-4 and PD-1/PD-L1 axis represents an optimal combination regimen in
view of a complementary mechanism of action of these molecules. Indeed, CTLA-4 and PD-1/PD-L1
molecules act in two different phases of T-cell activation; therefore, they are non-redundant and cooperative
pathways. The antitumor efficacy of CTLA-4 and PD-1/PD-L1 blockade has been largely investigated and,
recently, obtained approval for several cancer types, including microsatellite instability (MSI)-positive
colorectal cancer (CRC), renal cell carcinoma, non-small cell lung cancer (NSCLC) (in combination with
chemotherapy), and gastrointestinal cancer [25,26] .

NIBIT-MESO-1 was the first study that investigated the potential efficacy of ICI combination regimens in
mesothelioma patients. In this phase II study, 40 MPM or peritoneal mesothelioma patients received, in first
or second line, tremelimumab at 1 mg/kg in combination with durvalumab at 20 mg/kg every four weeks
for four cycles (induction phase), for non- progressor patients, followed by maintenance with only
durvalumab, at the same dose, every 4 weeks for a maximum of nine cycles. Noteworthy, patients who
experienced disease progression during the maintenance or follow-up phase were allowed to restart the