EURURO Vol. 72 No. 3

369 476

1. Introduction
Some patients with a wide range of cancers, including renal
cell carcinoma (RCC)[7_TD$DIFF], benefit from treatment with targeted
therapy after initial Response Evaluation Criteria in Solid
Tumors (RECIST) progression . The immune check-
point inhibitor nivolumab was approved for previously
treated patients with advanced RCC (aRCC) based on
the superior overall survival (OS) of nivolumab versus
everolimus in an international, randomized, phase 3 study
. Because of the novel mechanism of action of
immunotherapies like nivolumab, response patterns may
differ from other targeted therapies and may provide a
rationale for considering treatment beyond RECIST progres-
sion . Tumor flare in patients treated with immu-
notherapies may be due to transient immune cell
infiltration into the tumor or to tumor growth that can
occur while the immune system is priming for an antitumor
response . Tumor flare may result in patients
discontinuing therapy before demonstration of a true
clinical benefit . Interpatient differences with immune
checkpoint inhibitors have also been noted in a series of
case reports that highlight the heterogeneity of radiograph-
ic responses with these treatments .
In a subgroup analysis of previously treated patients
with aRCC from a phase 2 study, 69% (25/36) of patients
treated beyond RECIST progression (TBP) with nivolumab
experienced tumor reduction or stabilization in target
lesion after first progression .
Here, we investigated the potential benefit of treatment
with nivolumab beyond RECIST-defined progression in the
context of the large, randomized, open-label, phase
3 CheckMate 025 study (NCT01668784) of previously
treated patients with aRCC. Additionally, we identified
characteristics of patients who are most likely to be TBP.
2. Patients and methods
2.1. Design and participants
The detailed design of CheckMate 025 was previously published
. This was a protocol preplanned subgroup analysis of patients
TBP and not treated beyond progression (NTBP) with nivolumab 3 mg/kg
intravenously every 2 wk or an everolimus 10-mg tablet orally once
daily. Results from the everolimus arm are beyond the scope of this
article and are described in the Supplementary data (Supplementary
Table [8_TD$DIFF]1, Supplementary Figs. 1–3). Treatment beyond investigator-
assessed RECIST v1.1-defined first progression was allowed if
patients tolerated therapy and exhibited investigator-assessed clinical
benefit. Patients who discontinued nivolumab were not eligible for
nivolumab treatment beyond progression, but a temporary hold to
manage a toxicity before first progression was allowed. First progression
(RECIST) was defined as 20% increase in the sum of target lesions or
appearance of 1 new lesion , occurring with or without an initial
response.
Patients signed a new consent form before being TBP and were not
permitted to receive other anticancer agents while being TBP. Patients
TBP discontinued study therapy upon evidence of further progression,
defined as an additional 10% increase in tumor burden from time of
first progression (target lesions, new lesions of [2_TD$DIFF]10 mm diameter
[ 15 mm for pathological lymph nodes]).
Patients TBP received study therapy for 4 wk after first progression;
patients NTBP received 0 wk to <4 wk of therapy after first progression
(investigator assessment). Patients with <4 wk of study therapy were
included among patients NTBP because brief treatment beyond
progression may have been due to a lack of availability of scan results
at next dosing, rather than true intention to treat beyond progression.
2.2. Outcomes
Efficacy assessments occurred from: (1) baseline to first RECIST-defined
progression, (2) at first progression, and (3) from first progression to
death or discontinuation. Disease assessments were performed by
computed tomography or magnetic resonance imaging at baseline and
every 8 wk for the 1st yr, then every 12 wk until progression.
Quality of life (QoL) was assessed using the kidney disease-specific
Functional Assessment of Cancer Therapy-Kidney Symptom Index-
Disease Related Symptoms questionnaire; a meaningful difference was a
2-point change from baseline . Safety assessments were from
baseline to first progression and after progression.
2.3. Statistical analyses
This analysis was not designed for formal statistical testing or
comparison. Descriptive statistics for continuous variables are presented
as medians and ranges; categorical variables as frequencies and
percentages. Data are presented at baseline, at first progression, and
in patients TBP and NTBP, respectively. Differences in clinical characteristics assessed at
first progression between patients TBP versus NTBP included better Karnofsky performance
status, less deterioration in Karnofsky performance status, shorter time to response, lower
incidence of new bone lesions, and improved quality of life. Postprogression, 13% of all
patients TBP (20/153) had 30% tumor burden reduction including patients with prepro-
gression and postprogression tumor measurements (n = 142) and complete/partial re-
sponse (28%, 8/29), stable disease (6%, 3/47), and progressive disease (14%, 9/66) as
their best response before being TBP. Incidence of treatment-related adverse events in
patients TBP was lower after (59%) versus before (71%) progression. Limitations included
potential bias from the nonrandomized nature of the analysis.
Conclusions: A subset of patients with advanced renal cell carcinoma and RECIST progres-
sion experienced tumor reduction postprogression with nivolumab, and had an acceptable
safety profile. Clinical judgment remains essential when switching therapy. ClinicalTrials.-
gov Identifier: NCT01668784.
Patient summary: A subset of patients with advanced renal cell carcinoma and disease
progression may continue to benefit from nivolumab treatment beyond progression as
evidenced by tumor reduction postprogression and an acceptable safety profile.
# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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