EURURO Vol. 72 No. 3

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percentage of PD-L1 expressing tumor and tumor-infiltrat-
ing immune cells relative to the total number of tumor cells.
Patients in all subgroups experienced benefit from pem-
brolizumab treatment irrespective of PD-L1 expression. In
both pembrolizumab- and chemotherapy-treated patients,
shorter OS was observed in those with high PD-L1
expression, defined as a combined positive score of 10%.
3.2.2. Renal cell cancer
For advanced RCC and mRCC, three RCTs evaluating the
efficacy of nivolumab were identified, including two
dose-controlled trials (phases 1b and 2) and one active
comparator-controlled phase 3 trial with everolimus. In these
three trials, only clear cell histology was allowed and patients
were mainly pretreated with antiangiogenic therapy.
In the two dose-controlled trials, patients were random-
ized to nivolumab at a dose of 0.3, 2, or 10 mg/kg every 3 wk.
These phase 1b and 2 trials were different in patient
population, design, and objectives. The phase 1b study
demonstrated immune pharmacodynamic effects (eg,
changes in circulating chemokines and tumor-associated
lymphocytes) irrespective of dose whereas the phase
2 study did not show a significant dose–response effect .
In the phase 3 trial, 821 patients with previously treated
advanced RCC or mRCC were randomized to everolimus or
nivolumab at a dosage of 3 mg/kg every 2 wk . Nivo-
lumab treatment was associated with significantly
improved median OS (25.0 vs 19.6 mo, HR 0.73 [98.5% CI,
0.57–0.93], p = 0.002). Although the ORR was significantly
higher in the nivolumab group than in the everolimus group
(25% vs 5%, odds ratio 5.98 [95% CI, 3.68–9.72], p < 0.001),
there was no difference in PFS (4.6 vs 4.4 mo, HR 0.88 [95%
CI, 0.75–1.03], p = 0.11). Overall, eight out of 1080 (<1%)
nivolumab-treated patients in the three RCTs (phases 1b, 2,
and 3) had a complete response.
In the phase 2 and 3 trials with nivolumab, pretreatment
tumor PD-L1 expression was determined as the percentage
of PD-L1–positive tumor cells relative to the total number or
tumor cells . In the phase 2 dosing study, a beneficial
effect of higher PD-L1 expression ( 5%) was observed, with
a higher ORR and longer OS whereas the phase 3 study
showed shorter OS in nivolumab-treated patients with high
PD-L1 expression ( 1%; 27.4 vs 21.8 mo) .
3.2.3. Prostate cancer
For mCRPC, two RCTs were selected in which chemotherapy-
naive (n = 602) and docetaxel-pretreated patients (n = 799)
were randomized to ipilimumab or placebo In one
study, single-dose bone-directed radiotherapy (8 Gy) was
givenprior to administration of ipilimumabor placebo . In
both studies, ipilimumab failed to show survival benefit over
placebo. However, there was a trend toward improved PFS
and a prostate-specific antigen response in ipilimumab-
treated patients , suggesting some efficacy.
3.3. Safety of ICIs in urological cancer
AEs reported in the selected randomized studies are
presented in .
3.3.1. Urothelial cell cancer
Compared with chemotherapy-treated UCC patients,
patients treated with pembrolizumab experienced fewer
AEs (90.2% vs 60.9% AEs of any grade) . In addition,
the incidence of grade 3–4 AEs was more than three
times higher in chemotherapy-treated patients. In
pembrolizumab-treated patients, grade 3–4 immune-
related AEs were observed in 4.5% of the patients, including
pneumonitis, colitis, and nephritis. In both treatment
groups, four treatment-related AEs resulted in patient
death. Treatment-related deaths in the pembrolizumab
group resulted from pneumonitis (n = 1), urinary tract
obstruction (n = 1), malignant neoplasm progression (n = 1),
and unspecified cause (n = 1).
3.3.2. Renal cell cancer
In mRCC patients treated with nivolumab, fewer treatment-
related AEs were reported compared with those in patients
in the everolimus group (79% vs 88%) In nivolumab-
treated patients, the most common grade 3–4 AEs were
fatigue, nausea, and diarrhea. Overall, the incidence of
immune-related AEs was limited. In the phase 2 study, there
was no association between nivolumab dosage and the
number of AEs .
3.3.3. Prostate cancer
In the RCT without radiotherapy, the incidence of grade 3–4
AEs in mCRPC patients treated with ipilimumab was
approximately 40%, including 31% grade 3–4 immune-
related AEs and nine (2%) treatment-related deaths
. The most frequently reported AEs included diarrhea
(15%), rash (3%), and fatigue (3%). In the RCT with single-
dose radiotherapy, grade 3–4 immune-related AEs were
reported both in the ipilimumab and in the placebo group
(26% vs 11%) .
3.4. Discussion
3.4.1. Principal findings
Although UCC and RCC have totally different tumor
characteristics, varying from a high mutational load in
UCC to high vascularization and chemotherapy
resistance in RCC , immune modulating therapies have
a great potential in at least a subgroup of both populations.
In patients with advanced UCC and RCC, the ICIs pem-
brolizumab and nivolumab, respectively, have shown
proven efficacy as evidenced by survival improvement, as
well as a favorable AE profile in randomized comparator
controlled trials, thereby changing treatment paradigms in
second-line treatment. Immune checkpoint blockade with
the anti-CTLA-4 antibody ipilimumab, though, did not show
survival benefit combined with a relatively high risk of
toxicity in mCRPC patients.
3.4.2. Efficacy and future perspectives
3.4.2.1. Urothelial cell cancer. The success of ICIs in UCC is likely
associated with its high mutational load , thereby
potentially sensitizing UCC to immune checkpoint blockade
Based on an almost 3 mo OS benefit , the U.S. Food
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