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Page 6 of 11 Fitzgerald et al. J Cancer Metastasis Treat 2021;7:54 https://dx.doi.org/10.20517/2394-4722.2021.97

expression in at least 1% of cells was associated with significantly higher rates of objective response to
immunotherapy when assessed with both the DAKO 28-8 and SP-263 assays, and high PD-L1 expression
(defined as PD-L1 > 25%, measured by 28-8 assay) was associated with an 86% disease control rate and a
71% objective response rate. Although non-comparative, this trial suggested strong rationale for
immunotherapy combination over monotherapy when designing subsequent first line immunotherapy
trials for MPM, based on the signal of increased efficacy in this group, and suggested that benefit was likely
to be highest with PD-L1 expressing disease.

Randomized trials of PD1 inhibitors in the second-line setting have shown variable results. The phase III
immunotherapy trial (PROMISE-MESO), randomized patients with relapsed or progressive unresectable
[19]
MPM to receive pembrolizumab or single-agent chemotherapy (gemcitabine or vinorelbine) . The study
failed to demonstrate PFS or OS benefit regardless of PDL-1 status, though it did demonstrate improved
response rates in the immunotherapy arm, and toxicity profile was similar. The results of the phase II
[20]
KEYNOTE-158, which was reported more recently, were in line with these findings . In the 118 patients
with previously treated MPM who received pembrolizumab monotherapy in this trial, the authors reported
a 10% ORR with mPFS of only 2.1 months, without distinction by PD-L1 expression.

On the other hand, the phase III CONFIRM trial, presented at the 2021 virtual IASLC World Conference on
Lung Cancer, compared single-agent nivolumab with placebo for patients with relapsed or refractory MPM
after progression with 2 or more lines of standard therapy [21-23] . The study was powered for primary
endpoints of PFS and OS; although the data are still immature, the authors report that the trial has met its
primary endpoints, with mOS 9.2 months with nivolumab vs. 6.6 months with placebo, (commensurate
with historical survival data in untreated patients). These results appear to have been primarily driven by
patients with epithelioid histology, where a hazard ratio of 0.71 favoring immunotherapy was observed.
Only 13 patients enrolled on the CONFIM trial had non-epithelioid histology limiting data interpretation;
however, in this cohort mOS was 5.9 months with nivolumab and 6.7 months with placebo, a difference that
was not statistically significant. Notably, 96% of patients randomized received nivolumab as ≥ 3rd line
therapy. While encouraging, the results in all second- or third-line immunotherapies may quickly become
difficult to interpret, as patients receiving prior immunotherapy for MPM were excluded.

First-line immunotherapy
As alluded to above, combination nivolumab plus ipilimumab is rapidly becoming the international
standard of care for eligible patients based on the results of the Checkpoint 743 phase III trial, incorporated
[6]
in the NCCN guidelines with a category 1 recommendation and securing FDA approval late in 2020 . The
trial randomized patients with relapsed or unresectable MPM without prior systemic treatment to undergo
treatment with either dual checkpoint blockade (nivolumab 3 mg/kg IV every 2 weeks plus ipilimumab
1 mg/kg every 6 weeks) vs. Cisplatin or Carboplatin plus Pemetrexed at standard dosing. Bevacizumab was
not included in the chemotherapy arm. The strength of the study design included its large size (> 700
patients) and the decision to power for a primary endpoint of overall survival ; randomization stratified
[24]
for both histology (epithelioid vs. non-epithelioid) and gender. PDL-1 was positive (TPS ≥ 1%) in a large
proportion of patients in both arms, at > 70% of the cohort. At a prespecified interim analysis after a median
follow up of 29.7 months, mOS for the immunotherapy arm was 18.1 months vs. 14.1 months in the
chemotherapy arm, with a HR 0.74 favoring immunotherapy [Figure 1] .
[10]
Unlike results in the second line CONFIRM trial , substantial benefit was noted for patients with non-
[22]
epithelioid tumors. Although dual checkpoint blockade outperformed chemotherapy in all randomized
patients, this effect was amplified in patients with non-epithelioid tumor histology, where mOS was 18.1