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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 5 of 12

combination treatment. The study reached its primary endpoint with an immune-related objective response
[27]
of 28%; the median duration of response was 16.1 months, DCR was 65%, and mOS was 16.5 months . The
[28]
three- and four-year OS rates were 20% and 15%, respectively . Among the 40 patients enrolled in the
NIBIT-MESO-1 study, 17 met the criteria for retreatment. Interestingly, 41% of retreated patients achieved a
DCR; moreover, no grade 3-4 immune-related adverse events were observed . Seeking to identify
[28]
predictive biomarkers for patient selection to retreatment, an assessment of tumor mutational burden
(TMB) was performed, and the results show a significantly (P = 0.02) higher mOS for retreated patients with
a TMB over the median (41.3 months) compared with those who had a TMB level under the median one
(17.4 months) .
[28]

Following the NIBIT-MESO-1 study, two additional combination trials have been conducted in MPM
patients. In the IFCT-1501 MAPS-2 study, 54 patients received nivolumab plus ipilimumab. Overall,
12-week disease control was achieved by 32/62 patients (52%), the mOS was 15.9 months and 26% had grade
3-4 toxicities . In the INITIATE study, 10/34 patients treated with ipilimumab plus nivolumab achieved a
[29]
partial response (PR) and 13 (38%) had stable disease (SD); mOS was not reached at the time the analysis
[30]
was performed. Grade 3-4 treatment-related adverse events were reported in 12 (34%) of 35 patients .
Table 1 summarizes the main clinical trials and results of ICI therapies.

The results generated from the NIBIT-MESO-1, MAPS-2, and INITIATE studies strongly contributed to
the activation of the randomized, phase III CheckMate 743 trial . In this study, 605 not pretreated MPM
[10]
patients were randomized (1:1) to receive nivolumab, at the dosage of 3 mg/kg every two weeks, in
combination with ipilimumab, at the dosage of 1 mg/kg every six weeks, for up to two years or the standard
first-line treatment with platinum compound and pemetrexed combination for a maximum of six cycles. In
the primary analysis, a statistically significant improvement in OS (the primary aim of the trial) was seen in
the immunotherapy arm compared with the chemotherapy one, with a mOS of 18.1 vs. 14.1 months
(HR = 0.74; P = 0.002). The benefit in OS was strongly relevant in patients with non-epithelioid histology
treated with ICI, but this seems to be caused by the well-known less responsiveness of sarcomatoid subtype
to chemotherapy. Additionally, in the experimental arm, there was no difference in median OS between
patients with PD-L1 expression of < 1% and ≥ 1% (17.3 vs. 18 months), while, in the chemotherapy arm,
median OS was statistically significantly longer in the first group than in the second one (16.5 vs. 13.3
months) . A possible explanation could be a worse outcome of MPM expressing PD-L1 > 1% compared
[10]
with those without PD-L1 expression. However, this exploratory analysis should be interpreted with caution
because the study was not designed to demonstrate this suggestive hypothesis. Further studies are needed.

Although no significant differences were seen in median progression-free survival (PFS) and objective
response rates (ORR) between the two arms, the median duration of response was significantly longer with
combination immunotherapy (11.0 vs. 6.7 months). Grade 3 and 4 treatment-related adverse events were
similar in the ICI (30%) and chemotherapy groups (32%). However, the incidence and severity of the
adverse events led to a greater rate of discontinuation in the ICI group (15%) than in the chemotherapy
group (7%), and three treatment-related deaths were reported in the ICI group compared with only one in
[10]
the chemotherapy arm . Concerning these latter aspects, the lesser experience of many oncologists in
immune-related toxicity management might have contributed to this difference. In the ICI arm, the most
frequent toxicities observed were dermatological, gastrointestinal, endocrine, hepatic, and pulmonary.
Noteworthy, approximately 35% of patients who discontinued treatment with nivolumab and ipilimumab
due to the onset of side effects had a persistent objective response and an improvement in mOS (25.4
[10]
months) compared to those observed in all patients treated with ICIs (18.1 months) . Furthermore,
nivolumab and ipilimumab combination improved disease-related symptoms and maintained QoL in