EURURO Vol. 72 No. 6

963 1030

1. Introduction
As the treatment paradigm for advanced renal cell
carcinoma (aRCC) shifts in response to the development
and approval of new therapies, a deeper understanding of
patient baseline factors and/or disease characteristics
affecting clinical outcomes is necessary and may help in
guiding treatment decisions. Prognostic models for RCC
have been developed that incorporate factors such as
performance status, time from diagnosis to treatment,
hemoglobin, calcium and lactate dehydrogenase concen-
trations, and neutrophil and platelet counts . These
models are limited because they were developed before the
advent of modern immunotherapies and they do not
include other factors that have also been shown to be
associated with prognosis, such as the number and duration
of prior therapies, sites of metastases, and age . Further
investigation of prognostic factors is needed for the
development of risk models that more accurately reflect
the current treatment landscape.
The phase 3 CheckMate 025 study in previously treated
patients with aRCC demonstrated superior overall surviv-
al (OS) with nivolumab compared with everolimus
. Median OS was 25.0 mo (95% confidence interval
[CI] 21.8–not reached [NR]) for nivolumab versus 19.6 mo
(95% CI 17.6–23.1) for everolimus. The investigator-
assessed objective response rate (ORR) was 25% versus
5% (p < 0.001) , while the confirmed ORR was 22%
versus 4% . Treatment with nivolumab also provided an
OS benefit versus everolimus across prespecified sub-
groups of patients, including those with different Memo-
rial Sloan Kettering Cancer Center (MSKCC) risk, number
of prior antiangiogenic therapies, geographical region,
age, and sex. .
The objectives of this analysis were to investigate further
whether the OS and ORR benefits observed with nivolumab
versus everolimus in the overall population were also
observed in patients with poor prognostic baseline disease,
and if demographic and pretreatment characteristics,
including prior therapy, with an impact on outcomes with
nivolumab can be identified.
2. Patients and methods
2.1. Patients
Adults with histological confirmation of aRCC with a clear-cell
component were eligible. Additional eligibility criteria were reported
previously . Subgroups of patients were analyzed according to the
following characteristics at baseline: MSKCC risk score (favorable,
intermediate, poor) , International Metastatic Renal Cell Carcinoma
Database Consortium (IMDC) risk score (favorable, intermediate, poor),
age (<65 and 65 yr), number (1 and >1) and sites (bone, liver, lung) of
metastases, prior therapy (sunitinib, pazopanib, interleukin-2), duration
of first-line therapy (<6 and 6 mo), and number of prior therapies
(1 or 2). Analyses are based on data collected via a case report form
(data collected from an interactive voice response system was used in
the previous publication) .
2.2. Study design and treatments
This was a phase 3, randomized, open-label study of nivolumab versus
everolimus. The detailed study design was described previously
. Patients were randomized 1:1 to receive nivolumab 3 mg/kg
intravenously for 60 min every 2 wk or an everolimus 10-mg tablet
orally once daily.
2.3. Endpoints and assessments
The primary endpoint was OS, defined as time from randomization to
death; the key secondary endpoint was investigator-assessed ORR, defined
as the number of patients with complete response or partial response
divided by the number of randomized patients. Disease assessments
(per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1) were
performed using computed tomography ormagnetic resonance imaging at
baseline and every 8 wk following randomization for the first year, then
every 12 wk until progression or treatment discontinuation. Safety was
assessed at each clinic visit. Subgroups reported here were assessed for OS,
ORR, and safety.
2.4. Study oversight
This study was approved by the institutional reviewboard or independent
ethics committee at each center and conducted in accordance with Good
Clinical Practice guidelines defined by the International Conference on
prior therapy; and prior sunitinib, pazopanib, or interleukin-2 therapy. The benefit with
nivolumab versus everolimus was noteworthy for patients with poor MSKCC risk (hazard
ratio 0.48, 95% confidence interval 0.32–0.70). The mortality rate at 12 mo for all subgroups
was lower with nivolumab compared with everolimus. ORR also favored nivolumab. The
incidence of grade 3 or 4 treatment-related adverse events across subgroups was lower
with nivolumab. Limitations include the post hoc analysis and differing sample sizes
between groups.
Conclusion: The trend for OS and ORR benefit with nivolumab for multiple subgroups,
without notable safety concerns, may help to guide treatment decisions, and further
supports nivolumab as the standard of care in previously treated patients with aRCC.
Patient summary: We investigated the impact of demographic and pretreatment features
on survival benefit and tumor response with nivolumab versus everolimus in advanced
renal cell carcinoma (aRCC). Survival benefit and response were observed for multiple
subgroups, supporting the use of nivolumab as a new standard of care across a broad range
of patients with previously treated aRCC.
The trial is registered on ClinicalTrials.gov as NCT01668784.
# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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