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that may change during several disease stages and
sequential therapies. To better understand PD-L1 dynamics,
future studies will focus on fresh biopsies from metastatic
lesions sequentially obtained during treatment with
ICIs.
In clinical practice, tools are needed to select patients for
immune checkpoint blockade. In particular, stratification
for combination strategies is required, as a number of
patients have already benefited frommonotherapy andmay
not benefit from an additional therapy with regard to
antitumor effect and higher risk of toxicity. Alternative tools
to stratify patients may include genomic subtype, interfer-
on-g gene expression signature, chemokine expression
signature, and mutational load. In addition, positron
emission tomography (PET) using 89Zr-labeled ICIs may
be valuable, as this noninvasive technique enables drug
uptake measurements in tumors, thereby revealing inter-
tumor heterogeneity . Future studies will showwhether
PET using 89Zr-labeled ICIs may be useful to select patients
for treatment with ICIs.
3.4.4. Safety
In UCC and RCC, anti-PD-1 therapy with pembrolizumab
and nivolumab, respectively, was associated not only with
fewer AEs , but also with better quality of life than
the comparator treatment, that is, chemotherapy and
everolimus, respectively . However, ipilimumab
was associated with a high risk of grade 3–4 toxicity in
approximately 40% of mCRPC patients which is
specifically associated with inhibition of CTLA-4 signaling.
Although blockade of PD-1 and PD-L1 signaling is associat-
ed with less toxicity, awareness and expertise for immune-
related toxicity such as colitis, endocrinopathies (eg,
hypothyroidism, type 1 diabetes), nephritis, and pneumo-
nitis are required as immune-related toxicities can develop
rapidly and severely, and, although rare, can even be fatal. In
addition, immune-related toxicities can even develop after
discontinuation of treatment. Early recognition and treat-
ment are necessary, as these toxicities can be treated
adequately with immune-suppressive agents, including
high-dose steroids, tumor necrosis factor-alpha blockers
(eg, infliximab), and, in case of endocrinopathies, hormone
replacement therapy Although combination strategies
with ICIs may enhance efficacy, they are also associated
with a higher risk of toxicity.
In rare cases, rapid disease progression is observed after
the initiation of ICIs, indicating that ICIs may be harmful for
some patients. Hyperprogressive disease during ICIs devel-
ops independently of tumor histology and is associated with
a poorer OS. So far, no predictive markers for hyperpro-
gressive disease have been identified .
For optimal patient selection and counseling, there is a
need for tools to identify patients with a high risk of severe
toxicity. Since antitumor activity of ICIs has also been
observed at low dosages and may even last after early
discontinuation of treatment, further optimization of dosage
and administration schedules is required, potentially
reducing toxicity and costs. To reduce the economic burden
of ICIs, future studies should focus on the optimal treatment
duration, value of treatment beyond disease progression
, and development of predictive tools for both tumor
response and toxicity.
3.4.5. Strengths and limitations of review
The strengths of this review are the prespecified and
systematic literature search, selecting only published RCTs.
As a result, only high-quality studies were selected.
However, an important limitation is the lack of unpublished
results from other phase 3 studies. To overcome this
limitation, potential landmark studies, which are not
published yet, are mentioned in the Discussion section. In
addition, early phase 1 and 2 studies, including those
potentially leading to FDA approval, and phase 3 studies are
mentioned in the Discussion section and presented in
Supplementary Tables 1 and 2.
4. Conclusions
In conclusion, ICIs show superior efficacy and safety
outcomes compared with conventional second-line treat-
ment in patients with advanced UCC and RCC. To date,
treatment paradigms with ICIs have not shown clinical
benefit in mCRPC patients. Ongoing studies, also assessing
novel combination strategies with ICIs, may further
enhance efficacy in earlier treatment lines and disease
stages of urological cancers. Since PD-L1 expression thus far
seems to be inconclusive as a predictive marker, future
research needs to focus on alternative markers.
Author contributions : Ronald de Wit had full access to all the data in the
study and takes responsibility for the integrity of the data and the accuracy
of the data analysis.
Study concept and design: Rijnders, van der Veldt.
Acquisition of data: Rijnders, van der Veldt.
Analysis and interpretation of data: Boormans, Lolkema, Rijnders, van der
Veldt, de Wit.
Drafting of the manuscript: Lolkema, Rijnders, van der Veldt, de Wit.
Critical revision of the manuscript for important intellectual content:
Boormans, Lolkema, van der Veldt, de Wit.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: van der Veldt, de Wit.
Other: None.
Financial disclosures: Ronald de Wit certifies that all conflicts of interest,
including specific financial interests and relationships and affiliations
relevant to the subject matter or materials discussed in the manuscript
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
stock ownership or options, expert testimony, royalties, or patents filed,
received, or pending), are the following: R. de Wit: advisory board fees
Merck and Roche. J.L. Boormans: advisory board fees MSD, Janssen
Nederland, and Roche. M.P.J. Lolkema: research funding Astellas, Johnson &
Johnson, and Sanofi. A.A.M. van der Veldt: advisory board fees BMS, Ipsen,
and Pfizer.
Funding/Support and role of the sponsor: None.
Acknowledgments: The authors would like to thank Gerdien B. de Jonge,
biomedical information specialist, Medical Library, Erasmus MC, for
support in the literature searching process.
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