EURURO Vol. 72 No. 6

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possibly because of the higher levels of lymphocytes
expressing immune inhibitory signals in the tumor
microenvironment that can be targeted by PD-1 inhibitors
. The improved OS with nivolumab versus ever-
olimus in patients with liver or bone metastases, which are
associated with high incidence and poor prognosis
further demonstrates that patients with poor
prognostic features benefit from treatment with nivolumab.
There are some suggestions that response to nivolumab
may be influenced by prior effect of tyrosine kinase
inhibitors on the tumor microenvironment or their potential
immune effect . Although this study did not
directly address the tumor microenvironment or the
sequence of therapy, we did observe that OS was improved
with nivolumab for all three prior therapies evaluated
(sunitinib, pazopanib, and interleukin-2). Interleukin-2 is
currently indicated in first-line treatment for a select group
of patients with excellent performance status and normal
organ function . The small number of patients with prior
interleukin-2 treatment enrolled and clinical selection
criteria that impact decisions to treat with interleukin-2
preclude substantial clinical inferences. However, the
favorable hazard ratio for nivolumab versus everolimus
may imply a special impact of immune systemmanipulation
by immunotherapies such as interleukin-2 that may result in
benefit from subsequent treatment with an immune
checkpoint inhibitor.
the superior OS for nivolumab was maintained regard-
less of the duration of first-line therapy, suggesting that a
switch from a tyrosine kinase inhibitor to nivolumab, either
for a lack of response or toxicity (subgroup with <6 mo of
first-line therapy) or following potentially successful first-
line therapy (subgroup with 6 mo of first-line therapy)
provides a survival benefit.
The incidence of all-grade and grade 3 or 4 TRAEs in each
subgroup was lower with nivolumab than with[5_TD$DIFF] everolimus
and was similar to TRAEs noted in the overall population
Notably, both younger and older patients had a similar
incidence of grade 3 or 4 TRAEs. This observation, coupled
with the improved OS with nivolumab versus everolimus in
younger and older patients, suggests that older age did not
preclude clinical benefit.
Some limitations should be noted, including the post hoc
nature of the analyses and the differing sample sizes within
subgroups. The small sample size in some subgroups limits
the interpretation of those results and may have contributed
to the large range for some 95% CIs associated with hazard
ratios for death and difference in ORR. Analyses with more
patients are needed to validate those results. Furthermore, in
the subgroup analyses of individual sites of metastases,
some patients with multiple sites of metastases were
represented in more than one subgroup, which complicates
interpretation of OS by number of sites of metastases.
The broad benefit of nivolumab versus everolimus in
terms of OS and ORR with respect to patient demographics,
clinical characteristics, and prior therapies may provide
additional insight that will allow clinicians to make
informed decisions. With the increasing number of thera-
pies available to treat aRCC, predicting outcomes, possibly
through the development of nomograms based on baseline
disease characteristics and prior therapies, will help to
increase the individualized approach to treatment in an
effort to improve survival Further research should
focus on the development of predictive models of outcomes
more aligned with immunotherapy in accordance with
findings from this study.
In conclusion, consistent with the benefit demonstrated
in the overall population from CheckMate 025 , a trend
for OS and ORR benefit with nivolumab versus everolimus
was observed for multiple subgroups, including prognostic
risk categories, age, number and sites of metastases, and
prior therapies, without specific safety concerns. Efficacy
with nivolumab is notable in patients with poor risk
features, including those in the poor MSKCC risk group,
those with bone metastases, and those with more than one
site of metastasis. These results further support the use of
nivolumab as a new standard of care for a broad
range of patients with previously treated aRCC.
Presented, in part, at the Annual Society of Clinical
Oncology–Genitourinary Cancers Symposium, San Fran-
cisco, California, USA, January 7–9, 2016.
Author contributions: Bernard Escudier 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: Motzer, Waxman.
Acquisition of data: Waxman, Zhao.
Analysis and interpretation of data: All authors.
Drafting of the manuscript: Escudier, Motzer.
Critical revision of the manuscript for important intellectual content: All
authors.
Statistical analysis: Zhao.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: None.
Other: None.
Financial disclosures: Bernard Escudier 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, consultan-
cies, honoraria, stock ownership or options, expert testimony, royalties,
or patents filed, received, or pending), are the following: Frede Donskov
has received institutional research funding from Novartis, GlaxoSmithK-
line[6_TD$DIFF], and Pfizer. Bernard Escudier has received honoraria from Bayer,
Novartis, Pfizer, Bristol-Myers Squibb, and Exelixis. Thomas Gauler owns
stock in Bayer AG; has received consulting or advisory fees from MSD,
Merck Serono, Novartis, and Bristol-Myers Squibb; and has received
travel and accommodation expenses from Boehringer Ingelheim, Merck
Serono, Novartis, MSD, Bayer Healthcare, Hoffmann[7_TD$DIFF]-La Roche, and
Bristol-Myers Squibb. Saby George has an immediate family member
employed by Amgen, and has received research funding from Bristol-
Myers Squibb, Novartis, Pfizer, Bayer, Acceleron, and Agensys. Howard
Gurney has received consulting or advisory fees from Astellas, Bristol-
Myers Squibb, Novartis, and Pfizer. Hans Hammers has received
consulting or advisory fees from Bristol-Myers Squibb, Exelixis, Pfizer,
and Cerulean, and research funding from SFJ, Bristol-Myers Squibb,
Exelixis, Newlink, Pfizer, GlaxoSmithKline, and Tracon. David McDer-
mott has received consulting or advisory fees from Bristol-Myers Squibb,
Merck, Genentech, Novartis, Pfizer, Eisai, and Exelixis, and institutional
research [8_TD$DIFF]funding from Promethius Labs. Robert Motzer has received
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