Articles

Nivolumab, nivolumab–ipilimumab, and VEGFR-tyrosine

kinase inhibitors as first-line treatment for metastatic
clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven,
open-label, non-comparative, randomised, phase 2 trial
Yann-Alexandre Vano, Réza Elaidi, Mostefa Bennamoun, Christine Chevreau, Delphine Borchiellini, Diane Pannier, Denis Maillet,
Marine Gross-Goupil, Christophe Tournigand, Brigitte Laguerre, Philippe Barthélémy, Elodie Coquan, Gwenaëlle Gravis, Nadine Houede,
Mathilde Cancel, Olivier Huillard, Philippe Beuzeboc, Laure Fournier, Arnaud Méjean, Xavier Cathelineau, Nicolas Doumerc, Philippe Paparel,
Jean-Christophe Bernhard, Alexandre de la Taille, Karim Bensalah, Thibault Tricard, Thibaut Waeckel, Géraldine Pignot, Elena Braychenko,
Stefano Caruso, Cheng-Ming Sun, Virginie Verkarre, Guillaume Lacroix, Marco Moreira, Maxime Meylan, Antoine Bougouïn, Letuan Phan,
Christelle Thibault-Carpentier, Jessica Zucman-Rossi, Wolf Herman Fridman, Catherine Sautès-Fridman*, Stéphane Oudard*

Summary
Lancet Oncol 2022; 23: 612–24 Background We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma
Published Online groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-
April 4, 2022 cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab–ipilimumab. We therefore
https://doi.org/10.1016/
aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab–ipilimumab, and VEGFR-tyrosine
S1470-2045(22)00128-0
kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups.
See Comment page 555
*Contributed equally to the work
Methods This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from
Department of Medical
Oncology (Y-A Vano MD,
15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern
Prof J Zucman-Rossi MD, Cooperative Oncology Group performance status of 0–2, and had previously untreated metastatic clear-cell renal cell
Prof S Oudard MD), ARTIC— carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab
Association pour la Recherche or nivolumab–ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab–ipilimumab (ccrcc2 and
de Thérapeutiques Innovantes
en Cancérologie (R Elaidi PhD,
ccrcc3 groups). Patients assigned to nivolumab–ipilimumab received intravenous nivolumab 3 mg/kg plus
E Braychenko MD, L Phan MSc), ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients
Department of Radiology assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs
(Prof L Fournier MD), received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The
Department of Urology
(Prof A Méjean MD), and
primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in
Department of Pathology Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one
(V Verkarre MD), Hôpital dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials
Européen Georges Pompidou, Register, EudraCT 2016-003099-28, and is closed to enrolment.
Institut du Cancer Paris
CARPEM, AP-HP Centre,
Université de Paris Cité, Paris, Findings Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were
France; Centre de Recherche randomly assigned to treatment (61 to nivolumab, 101 to nivolumab–ipilimumab, 40 to a VEGFR-TKI). In the
des Cordeliers, INSERM, nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient
Université de Paris Cité,
Sorbonne Université, Paris,
was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6–18·4). In the
France (Y-A Vano, S Caruso PhD, ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16–45) of 42 patients with nivolumab and 16 (39%;
C-M Sun PhD, G Lacroix MSc, 24–55) of 41 patients with nivolumab–ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25–1·56]). In the ccrcc4 group,
M Moreira, M Meylan, PhD,
objective responses were seen in seven (44%; 95% CI 20–70) of 16 patients with nivolumab and nine (50% 26–74) of
A Bougouïn,
Prof J Zucman-Rossi, 18 patients with nivolumab–ipilimumab (OR 0·78 [95% CI 0·20–3·01]). In the ccrcc2 group, objective responses were
Prof W H Fridman MD, seen in 18 (50%; 95% CI 33–67) of 36 patients with a VEGFR-TKI and 19 (51%; 34–68) of 37 patients with nivolumab–
Prof C Sautés-Fridman PhD); ipilimumab (OR 0·95 [95% CI 0·38–2·37]). In the ccrcc3 group, no objective responses were seen in the four patients
Department of Medical
who received a VEGFR-TKI, and in one (20%; 95% CI 1–72) of five patients who received nivolumab–ipilimumab.
Oncology (M Bennamoun MD)
and Department of Urology The most common treatment-related grade 3–4 adverse events were hepatic failure and lipase increase (two [3%]
(Prof X Cathelineau MD), of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab–
Institut Mutualiste ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred
Montsouris, Paris, France;
in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab–ipilimumab group, and ten (25%) patients
Department of Medical
Oncology, Institut Universitaire in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab–
du Cancer Toulouse Oncopole, ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib.
Toulouse, France
(Prof C Chevreau MD);
Interpretation We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour
Department of Medical
Oncology, Hôpital Cochin, molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a
Institut du Cancer Paris VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma.

612 www.thelancet.com/oncology Vol 23 May 2022

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Funding Bristol Myers Squibb, ARTIC. CARPEM, AP-HP Centre,

Université de Paris Cité, Paris,
France (O Huillard MD);
Copyright © 2022 Elsevier Ltd. All rights reserved. Department of Medical
Oncology, Centre
Introduction Nearly half of the most responsive tumours to sunitinib Antoine Lacassagne, Université
During the past 5 years, immune-checkpoint inhibitors expressed an angiogenic-high and immune-high Côte d’Azur, Nice, France
(D Borchiellini MD); Department
have profoundly changed the frontline management of signature (ccrcc2).8 The smallest group with a good of Medical Oncology, Centre
patients with metastatic clear-cell renal cell carcinoma.1 response to sunitinib had molecular and pathological Oscar Lambret, Lille, France
After the approval of the nivolumab–ipilimumab features closest to normal kidney tissue (ccrcc3). A (D Pannier MD); Department of
(anti-PD-1–anti-CTLA-4) combination in patients with minimal classifier of 35 genes was developed to identify Medical Oncology, IMMUCARE
(D Maillet MD) and Department
International Metastatic Database Consortium (IMDC) these four groups.6 of Urology (Prof P Paparel MD),
intermediate-risk or poor-risk tumours,2 three other We hypothesised that the immune-high ccrcc4 Centre Hospitalier Lyon Sud,
combinations have enriched the landscape of meta­static tumours would be responsive to nivolumab-based Institut de Cancérologie des
clear-cell renal cell carcinoma first-line treatment: therapy, either with or without ipilimumab, because of Hospices de Lyon,
Pierre-Bénite, France;
pembrolizumab–axitinib,3 nivolumab–cabozantinib,4 and the immune-enriched tumour microenvironment, and Department of Medical
pembrolizumab–lenvatinib.5 Despite these achieve­ments, that the ccrcc1 tumours would respond better to Oncology, Centre Hospitalier
the majority of patients have tumour progression within nivolumab–ipilimumab than to nivolumab alone Universitaire de Bordeaux—
Hôpital Saint-André, Bordeaux,
the first 2 years of treatment in the absence of a predictive because of the need to recruit antitumour cytotoxic
France (M Gross-Goupil MD);
biomarker of efficacy available for their selection. T cells. Furthermore, we hypothesised that both VEGFR- INSERM, IMRB,
Our group has previously described four biologically tyrosine kinase inhibitors (VEGFR-TKIs; sunitinib or F-94010 Creteil, France
distinct clear-cell renal cell carcinoma tumour groups pazopanib) and nivolumab–ipilimumab would have a (Prof C Tournigand MD);
Department of Medical
(ccrcc1 to ccrcc4) based on transcriptomic data, associated high efficacy in patients with ccrcc2 tumours due to
Oncology (B Laguerre MD) and
with variable sensitivity to frontline sunitinib and related their pro-angiogenic profile and an immune-high Department of Urology
to distinct tumour microenvironment immune and angio­ infiltrate observed in nearly half of these tumours. (Prof K Bensalah MD), Centre
genic infiltration.6,7 Tumours that were less responsive to Regarding the low frequency ccrcc3 tumours, their non- Eugene—Marquis, Rennes,
France; Department of Medical
sunitinib had either a pro-inflammatory and immune- specific biological features did not allow us to formulate
Oncology, Institut de
high tumour micro­environment with a high expression of strong hypotheses on treatment efficacy. Thus, we Cancérologie Strasbourg
immunosup­pressive checkpoints (ccrcc4) or, by contrast, decided to evaluate VEGFR-TKIs versus nivolumab– Europe, Strasbourg, France
an immune-low tumour microenvironment (ccrcc1). ipilimumab in this group. (P Barthélémy MD); Department
of Medical Oncology, Centre de
Lutte Contre le Cancer François
Baclesse, Caen, France
Research in context (E Coquan MD); Department of
Medical Oncology
Evidence before this study we reported the ability of a 35-gene expression classifier to (Prof G Gravis MD) and
We searched PubMed on Nov 29, 2021, using the terms “renal identify four distinct profiles of clear-cell renal cell tumours Department of Surgical
cell carcinoma” AND “metastatic” AND “biomarker” for phase 2 (ccrcc1 to ccrcc4) and to predict sunitinib resistance in the Oncology(G Pignot MD),
or 3 clinical trials published with no restrictions on publication first-line treatment of metastatic renal cell carcinoma. Institut Paoli-Calmettes,
Aix-Marseille University, CRCM,
date or language. We mainly found post-hoc biomarker We further detailed the distinctive tumour microenvironment Marseille, France; Department
analyses from single-arm, phase 2 trials or from more recent of these four groups, allowing us to generate research of Medical Oncology, Institut
randomised, phase 3 trials. No biomarker-driven trials in hypotheses supporting the BIONIKK trial. de cancérologie du Gard,
Nimes, Montpellier University,
metastatic renal cell carcinoma have been published. Recent
Added value of this study France (Prof N Houede MD);
post-hoc analyses from randomised phase 2/3 trials Department of Medical
To our knowledge, this is the first study to show the feasibility of
strengthened the predictive role of treatment efficacy of Oncology, Centre Hospitalier
prospective patient and treatment selection based on tumour
tumour microenvironment-related gene expression signatures: Universitaire Bretonneau,
gene expression in metastatic renal cell carcinoma. By allocating Tours, France (M Cancel MD);
an angiogenesis signature above the median expression (high)
treatment according to tumour molecular group, we enriched the Department of Medical
was associated with improved progression-free survival with Oncology, Hôpital Foch,
population who achieved an objective response with nivolumab,
sunitinib, but not with atezolizumab or atezolizumab– Suresnes, France
nivolumab–ipilimumab, and VEGFR tyrosine kinase inhibitors
bevacizumab, whereas a T effector-high signature was (P Beuzeboc MD); Urology and
(VEGFR-TKIs). Transplantation Department,
associated with improved progression-free survival with
Centre Hospitalier Universitaire
atezolizumab–bevacizumab, but not with sunitinib. Similarly, Implications of all the available evidence de Toulouse, Hôpital Rangueil,
in the Javelin Renal 101 trial, an immune-high signature was Our results confirm that the response to nivolumab alone or Toulouse, France
associated with improved progression-free survival with with ipilimumab and to VEGFR-TKIs is different depending on (N Doumerc MD); Department
of Urology, Centre Hospitalier
avelumab–axitinib, but not with sunitinib. Nevertheless, these the characteristics of the tumour and its microenvironment.
Universitaire de Bordeaux -
gene-expression signatures have been established in whole The feasibility of prospectively selecting patients by their Hôpital Saint-André, Bordeaux,
cohorts in a post-hoc manner. Moreover, none of these molecular group for treatment choice opens the way to larger France (Prof J-C Bernhard MD);
signatures were able to predict better progression-free survival biomarker-based trial designs. Department of Urology
(Prof A de la Taille MD) and
or overall survival with nivolumab–ipilimumab. In 2015,
Department of Medical

www.thelancet.com/oncology Vol 23 May 2022 613

 Articles
Oncology (Prof C Tournigand),
Hôpital Henri-Mondor,
AP-HP Université de Paris Est,
Créteil France; Department of
Surgical Oncology, Nouvel
Hôpital Civil, Hôpitaux
Universitaires de Strasbourg,
Strasbourg, France
(T Tricard MD); Urology and
Transplantation Department,
CHU de Caen, Avenue de
Côte de Nacre, Caen, France
(T Waeckel MD); IGBMC—CNRS
UMR 7104-Inserm U 1258,
Université de Strasbourg,
Illkirch, France
(C Thibault-Carpentier PhD);
INSERM U970, PARCC, Paris,
France (Prof S Oudard)
Corresponding author:
Dr Yann-Alexandre Vano,
Department of Medical
Oncology, Hôpital Européen
Georges Pompidou, Institut du
Cancer Paris CARPEM,
AP-HP Centre, Université de Paris
Cité, 75015 Paris, France
yann.vano@aphp.fr
See Online for appendix
614 www.thelancet.com/oncology Vol 23 May 2022
Based on these hypotheses, we designed the BIONIKK
study, aiming to evaluate the efficacy and tolerability of
nivolumab, nivolumab–ipilimumab, and VEGFR-TKIs
as a first-line treatment for patients with metastatic clear-
cell renal cell carcinoma.
Methods
Study design and participants
BIONIKK was a biomarker-driven, open-label, non-
comparative, randomised, phase 2 trial including patients
from 15 university hospitals or expert cancer centres in
France (appendix p 2). Eligible patients were aged 18 years
or older, had newly diagnosed or recurrent stage IV renal
cell carcinoma (according to the American Joint Com­
mission on Cancer classification, seventh edition), had an
Eastern Cooperative Oncology Group performance-status
of 0–2, had one or more measurable lesions per Response
Evaluation Criteria in Solid Tumors (RECIST) version 1.1,
and had not received previous systemic therapy for
metastatic disease. Other key inclusion criteria were
availability of tumour tissue specimens (both frozen
and formalin-fixed paraffin-embedded specimens) and
adequate organ function according to local laboratory tests
up to 14 days before random assignment (including white
blood cell count ≥2000 per µL, neutrophils ≥1500 per µL,
haemoglobin >9 g/dL, platelets ≥100 000 per µL, and
creatinine clearance ≥40 mL/min). A full list of inclusion
criteria is in the appendix (p 3).
Key exclusion criteria included any uncontrolled or
symptomatic brain metastases, any history of
autoimmune disease or any other condition requiring
systemic corticosteroids more than 10 mg/day, and any
previous active malignancy within the past 3 years. A full
list of exclusion criteria is in the appendix (pp 3–5). All
patients provided written, informed consent.
The trial protocol and subsequent amendments
(available in the appendix) were approved by the French
Health authorities and ethics committee. The trial was
conducted in accordance with Good Clinical Practice
guidelines. An independent data and safety monitoring
committee assessed safety data after random assignment
of 100 patients.
Randomisation and masking
Eligible patients were enrolled by investigators and
randomly assigned (1:1) to receive either nivolumab or
nivolumab–ipilimumab in the ccrcc1 and ccrcc4 groups,
and to receive nivolumab–ipilimumab or VEGFR-TKI
(sunitinib or pazopanib) in the ccrcc2 and ccrcc3 groups
(trial design in appendix p 14). Initially, adaptive
randomisation was planned, which consisted of adapting
the randomisation probabilities according to the outcome
(objective response rate at 22 weeks) in order to favour
what appeared to be the better treatment for each group.
However, on the basis of anticipated disadvantages (risk
of major disequilibrium between groups for a given
group) at a late stage and experts’ recent publications,9,10
we changed to a conventional randomisation approach.
In order not to affect the schedule of the study, no
protocol amendment had been submitted to the health
authorities. We considered that a conventional
randomisation method would not change the health
authorities’ evaluation of the study. Randomisation was
done using permuted blocks of different sizes to avoid
any possible disclosure of the next allocated therapy
(since this was an open-label trial). The allocation
sequence method was implemented by the methodologist
(RE), and treatment assignment was done automatically
through the electronic case report form on the basis of a
randomisation list. Due to the open-label trial design,
patients, investigators, and the study sponsor were not
masked to the study treatment. Further details of the
randomisation procedure are in the appendix (p 5).
Procedures
Molecular group determination was done before
randomisation as described in the appendix (p 6). Briefly,
molecular group was determined on frozen tumour
samples from the primary or a metastatic lesion, using a
35-gene expression classifier previously described. This
classifier is composed of two subsets of genes: the first
subset of 27 genes was used to discriminate ccrcc1 and
ccrcc4 from ccrcc2 and ccrcc3 tumours; the second subset
of eight genes, related to immune infiltrate, was used to
discriminate ccrcc1 from ccrcc4 tumours. Patients in the
nivolumab groups received intravenous nivolumab 240 mg
every 2 weeks. Patients in the nivolumab–ipilimumab
groups received intravenous nivolumab 3 mg/kg plus
ipilimumab 1 mg/kg every 3 weeks for four doses (three or
more doses were mandatory to continue study treatment)
followed by intravenous nivolumab 240 mg every 2 weeks.
Patients in the VEGFR-TKI groups received sunitinib
50 mg orally once daily for 4 weeks (6-week cycle) or oral
pazopanib 800 mg once daily continuously according to
the investigator’s choice. Treatments were administered
until the end of the study at 18 months, or until disease
progression or death, unacceptable toxicity, or physician or
patient decision. At the end of the study, patients without
criteria to discontinue treatment were able to continue
treatment outside the study protocol. Dose reductions or
dose escalations of nivolumab or ipilimumab were not
permitted. Dose reductions of VEGFR-TKIs were allowed
in accordance with their summary of product char­
acteristics. Nivolumab–ipilimumab administration was
delayed for any of the following drug-related adverse
events: grade 2 or worse non-skin adverse event or grade 3
or worse skin adverse event (any abnormal biological or
laboratory value of grade or worse according to National
Cancer Institute Common Terminology Criteria for
Adverse Events). Dose delays for sunitinib or pazopanib
were based on instructions in the approved product label
and were considered for any severe or intolerable drug-
related adverse events. Details of permitted dose reductions
or interruptions are in the protocol (appendix).

Tumour response was assessed according to RECIST 1.1
guidelines per investigator assessment, with CT scan or
MRI of the chest, abdomen, and pelvis, at baseline, at
week 10, and every 12 weeks thereafter. Progressive disease
was confirmed by a consecutive assessment 6 weeks later.
Patients without subsequent confirmation of disease
progression and with a clinically stable condition could
continue treatment until confirmed progression.
Local laboratory tests including blood counts,
ionogram, liver enzymes, and calculated creatinine
clearance (a full list of tests is in the appendix pp 5–6)
were done at baseline; on days 1, 14, and 28 in the first
two cycles (6-week cycle); on days 1, 14, and 28 in
subsequent cycles for nivolumab with or without
ipilimumab, and on day 1 of each subsequent cycle for
VEGFR-TKI; and at study treatment discontinuation.
Adverse events were evaluated continuously during
treatment until the end of study, according to the National
Cancer Institute Common Terminology Criteria for
Adverse Events (version 4.0). Treatment-related adverse
events were defined as any adverse event with a causal
relationship to any study drug (nivolumab, ipilimumab, or
VEGFR-TKI). Serious adverse events, defined by adverse
events that result in death, required either inpatient
hospitalisation or the prolongation of hospitalisation,
were life-threatening, or resulted in a persistent or clini­
cally significant disability or incapacity, were assessed
throughout the treatment period until the end of the study.
Outcomes
The primary endpoint was the investigator-assessed
objective response rate (defined as the proportion of
patients with a confirmed complete response or
confirmed partial response at the time of data cutoff), per
molecular group and treatment group. Secondary
endpoints were the objective response rate at 22 weeks
(defined as the proportion of patients with an objective
response per investigator assessment at the first post-
baseline imaging evaluation [scheduled at week 22]),
investigator-assessed progression-free survival (defined
as time from the first study dose to first documentation
of disease progression or death; or, if neither occurred,
the date of last available tumour assessment), overall
survival (defined as time from the first study dose to
death from any cause), investigator-assessed duration of
response (defined as the time from when the criteria for
a partial response or complete response were met to the
date of confirmed disease progression or death), duration
of treatment (defined as the time from the first to the last
study dose), and safety and tolerability. Exploratory
analyses, which will be reported separately, are detailed
in the protocol (appendix).
Statistical analysis
The BIONIKK trial was non-comparative, so a formal
sample size calculation was not mandatory. Moreover, at
the study design stage, the following uncertainties would
www.thelancet.com/oncology Vol 23 May 2022 615
Articles
have made a formal sample size calculation difficult: the
effect size in the different molecular groups were
unknown; the overall efficacy of immunotherapy in the
first-line setting was unavailable; and few data were
available to accurately estimate molecular group
prevalence. Therefore, the target sample size was set at
200 patients, based on the anticipated number of eligible
patients at the selected sites and accrual time.
Efficacy and safety were assessed in the analysis
popula­tion, comprising all randomly assigned patients
who received at least one dose of investigational drug.
Patients were assessable if they had a baseline and a post-
baseline (at week 10 ± 7 days) imaging assessment. The
response rate was calculated as the number of patients
with at least one response on RECIST 1.1 during
participation as a proportion of the total number of
patients. We calculated the 95% CIs of the binomial
success rate using a binomial exact method. The Kaplan–
Meier method was used to estimated progression-free
survival, duration of response, and overall survival.
We calculated the 95% CIs using a log transformation.
The log-rank test was used to assess between-group
differences for progression-free survival and overall
survival. A Cox proportional-hazards model was used to
assess the magnitude of the time-to-event endpoints.
While the main results were obtained using a
frequentist framework, a hierarchical Bayesian model
borrowing strength across molecular groups within each
treatment group was used as a sensitivity analysis.
Post-hoc analyses assessed the median time to
subsequent (second-line) therapy (defined as the time
between random assignment and the beginning of second-
line therapy or death), time to response (defined as the
time from the first study dose to the date when the criteria
for a partial response or complete response were met),
time to events (objective [complete or partial] response,
progression, grade 3 or worse toxicity, or death) in patients
with a response, as well as the percentage change in sums
of diameters of target lesions from baseline to nadir. We
also did post-hoc exploratory analyses to investigate the
ability of the eight immune-related genes of the classifier
known to discriminate ccrcc1 and ccrcc4 to also identify
responders in patients with ccrcc2 tumours.6 To further
explore molecular groups in light of clinical and biological
features, we did post-hoc descriptive exploratory analyses
of IMDC risk groups, sarcomatoid component, and PDL-1
tumour cell expression effects on objective response rate.
We also assessed disease control rate and progression-free
survival according to IMDC risk group. Among the
patients in the favourable IMDC risk group and treated
with a VEGFR-TKI, we did an exploratory post-hoc analysis
of the objective response rate of patients in the ccrcc2
group. We decided to do this exploratory analysis knowing
that patients in the favourable IMDC risk group are
enriched in patients of the ccrcc2 group and vice versa, and
that VEGFR-TKIs give particularly high objective response
rates in these patients.
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303 patients assessed for eligibility

67 ineligible
10 met clinical exclusion criteria
14 no frozen tissue
40 low frozen tissue quality or quantity
3 investigator decision

236 patients had molecular group determination

34 ineligible
30 met clinical exclusion criteria
3 consent withdrawal
1 investigator decision

202 randomly assigned

61 assigned to nivolumab 101 assigned to nivolumab–ipilimumab 40 assigned to VEGFR-TKI (sunitinib or pazopanib)

3 excluded*

42 discontinued treatment 71 discontinued treatment 27 discontinued treatment

36 disease progression 44 disease progression 14 disease progression
4 toxicity 26 toxicity 8 toxicity
1 consent withdrawal 1 consent withdrawal 1 consent withdrawal
1 investigator decision 3 investigator decision
1 other†

16 treatment ongoing at 18 months 30 treatment ongoing at 18 months 13 treatment ongoing at 18 months

58 included in analysis population‡ 101 included in analysis population‡ 40 included in analysis population‡

Figure 1: Trial profile

TKI=tyrosine kinase inhibitor. *Two patients had a serious adverse event before receiving the first administration of allocated treatment and were therefore
excluded from the trial; one patient had an urothelial carcinoma instead of a clear-cell renal cell carcinoma, which was confirmed after the second pathological
review (first pathological review done on a biopsy sample before inclusion, second pathological review done on a surgical specimen obtained at the end of the
study). †One patient developed a second locally advanced cancer requiring specific treatment. ‡Analysis population: all randomly assigned patients who received
at least one dose of investigational drug.

An interim analysis for toxicity was planned after Results

random assignment of 100 patients for review by the data
and safety monitoring board.
Statistical analyses were done using SAS (version 9.4)
and R (version 3.6.1). Posterior probabilities of a
hierarchical Bayesian model were obtained from
OpenBUGS. The full statistical analysis plan is available
in the protocol.
This study is registered with ClinicalTrials.gov,
NCT02960906, and with the EU Clinical Trials Register,
EudraCT 2016-003099-28.
Role of the funding source
The funders of the study had no role in study design,
data collection, data analysis, data interpretation, or
writing of the report.
Between June 28, 2017, and July 18, 2019, 303 patients
were screened, of whom 236 (78%) patients had molecular
group determination (figure 1), with a median turnaround
time from tumour sample reception to molecular result
of 9 days (IQR 7–12). 202 eligible patients were randomly
assigned (61 to nivolumab, 101 to nivolumab–ipilimumab,
40 to VEGFR-TKI), 200 (99%) of whom received allocated
treatment (two patients had a serious adverse event [one
had acute respiratory failure and one had pulmonary
embolism] before the first study dose, both allocated to
nivolumab; figure 1). The main reasons for exclusion
before molecular grouping and before randomisation are
described in figure 1. One patient treated with nivolumab
was later excluded from all analyses because the histo­
logical diagnosis was sub­sequently corrected to urothelial

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ccrcc1 ccrcc4 ccrcc2 ccrcc3

Nivolumab Nivolumab– Nivolumab Nivolumab– VEGFR-TKI* Nivolumab– VEGFR-TKI* Nivolumab–
(n=42) ipilimumab (n=16) ipilimumab (n=36) ipilimumab (n=4) ipilimumab
(n=41) (n=18) (n=37) (n=5)
Age, years 61 (52–68) 65 (54–73) 64 (56–66) 65 (56–72) 66 (56–71) 65 (57–69) 64 (55–68) 59 (49–63)
Sex
Female 16 (38%) 7 (17%) 3 (19%) 4 (22%) 11 (31%) 4 (11%) 3 (75%) 3 (60%)
Male 26 (62%) 34 (83%) 13 (81%) 14 (78%) 25 (69%) 33 (89%) 1 (25%) 2 (40%)
ECOG performance status
0 26 (62%) 28 (68%) 13 (81%) 15 (83%) 25 (69%) 32 (86%) 3 (75%) 3 (60%)
1 12 (29%) 11 (27%) 1 (6%) 3 (17%) 11 (31%) 5 (14%) 1 (25%) 2 (40%)
2 4 (10%) 2 (5%) 2 (13%) 0 0 0 0 0
Previous nephrectomy 28 (67%) 30 (73%) 11 (69%) 14 (78%) 27 (75%) 29 (78%) 3 (75%) 2 (40%)
IMDC risk group
Favourable 10 (24%) 9 (22%) 3 (19%) 4 (22%) 14 (39%) 16 (43%) 2 (50%) 1 (20%)
Intermediate 17 (40%) 25 (61%) 8 (50%) 11 (61%) 18 (50%) 15 (41%) 2 (50%) 2 (40%)
Poor 15 (36%) 7 (17%) 5 (31%) 3 (17%) 4 (11%) 6 (16%) 0 2 (40%)
Number of metastatic sites
1 10 (24%) 9 (22%) 5 (31%) 5 (28%) 11 (31%) 11 (30%) 0 0
≥2 32 (76%) 32 (78%) 11 (69%) 13 (72%) 25 (69%) 26 (70%) 4 (100%) 5 (100%)
Metastasis sites
Lung 32 (76%) 28 (68%) 9 (56%) 16 (89%) 26 (72%) 30 (81%) 2 (50%) 5 (100%)
Lymph nodes 16 (38%) 24 (59%) 8 (50%) 9 (50%) 13 (36%) 15 (41%) 2 (50%) 2 (40%)
Liver 13 (31%) 12 (29%) 2 (12%) 4 (22%) 8 (22%) 2 (5%) 3 (75%) 2 (40%)
Bone 11 (26%) 9 (22%) 5 (31%) 4 (22%) 6 (17%) 3 (8%) 1 (25%) 2 (40%)
Sarcomatoid 12 (29%) 12 (29%) 5 (31%) 13 (72%) 7 (19%) 2 (5%) 2 (50%) 0
carcinoma
Evaluable PD-L1 26 (62%) 34 (83%) 10 (63%) 17 (94%) 31 (86%) 27 (73%) 3 (75%) 3 (60%)
Tumour cells ≥1%† 6 (23%) 4 (12%) 2 (20%) 3 (18%) 0 4 (15%) 2 (67%) 0
Data are median (IQR) or n (%). ccrcc=clear-cell renal cell carcinoma. ECOG=Eastern Cooperative Oncology Group. IMDC=International Metastatic Database Consortium.
TKI=tyrosine kinase inhibitor. *Of the 40 patients who received VEGFR-TKI, 33 received sunitinib and seven received pazopanib. †Percentages are calculated in evaluable patients.

Table 1: Demographic and clinical characteristics at baseline

carcinoma. Conse­ quently, 199 (99%) of 202 enrolled
patients were eligible for the efficacy and safety endpoints
(analysis population), 58 treated with nivolumab,
101 treated with nivolumab–ipilimumab, and 40 treated
with a VEGFR-TKI (including 33 with sunitinib, and
seven with pazopanib). Molecular group, obtained from
kidney primary lesions in 144 (72%) of 199 patients and
from metastases in 55 (28%) patients, were distributed as
follows: 83 (42%) ccrcc1, 73 (37%) ccrcc2, 34 (17%) ccrcc4,
and nine (5%) ccrcc3. Patient demographic and baseline
characteristics are sum­marised in table 1. Despite the
observed differences in the frequency of some patient
characteristics, random­ isation to each ccrcc subgroup
ensured comparability. Owing to the small number of
patients in the ccrcc3 group (n=9), some efficacy results
related to secondary endpoints are not reported.
After a median follow-up in the analysis population of
18·0 months (IQR 17·6–18·4), 59 (30%) of 199 patients
continued receiving treatment; 40 (20%) patients had
died, four (2%) were withdrawn from the study by
investigator’s decision, and three (2%) had withdrawn
consent (figure 1).
The primary endpoint (objective response rate by
investigator assessment per RECIST 1.1) was met in
19 (33%; 95% CI 21–46) of 58 patients treated with
nivolumab alone, 45 (45%; 35–55) of 101 patients treated
with nivolumab–ipilimumab, and 18 (45%; 29–62) of
40 patients treated with a VEGFR-TKI, including
complete responses in three (5%), ten (10%), and one
(3%) patient, respectively. In the ccrcc1 cohort, 12 (29%;
95% CI 16–45) of 42 patients in the nivolumab group
and 16 (39%; 24–55) of 41 patients in the nivolumab–
ipilimumab group had an objective response (odds ratio
[OR] 0·63 [95% CI 0·25–1·56]), whereas in the ccrcc4
cohort, seven (44%; 95% CI 20–70) of 16 patients in the
nivolumab group and nine (50%; 26–74) of 18 patients
in the nivolumab–ipilimumab group had an objective
response (OR 0·78 [95% CI 0·20–3·01]; table 2). In the
ccrcc2 cohort, 18 (50%; 95% CI 33–67) of 36 patients in
the VEGFR-TKI group and 19 (51%; 34–68) of 37 patients
in the nivolumab–ipilimumab group had an objective
response (OR 0·95 [95% CI 0·38–2·37]). Median
duration of response was not reached in any group
except with VEGFR-TKIs in the ccrcc2 group (table 2).

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ccrcc1 ccrcc4 ccrcc2 ccrcc3

Nivolumab (n=42) Nivolumab– Nivolumab (n=16) Nivolumab– VEGFR-TKI* (n=36) Nivolumab– VEGFR-TKI* (n=4) Nivolumab–
ipilimumab (n=41) ipilimumab (n=18) ipilimumab (n=37) ipilimumab (n=5)
Objective response 12 (29%; 16–45) 16 (39%; 24–55) 7 (44%; 20–70) 9 (50%; 26–74) 18 (50%; 33–67) 19 (51%; 34–68) 0 1 (20%; 1–72)
rate
Odds ratio 0·63 (0·25–1·56) 1 (ref) 0·78 (0·20–3·01) 1 (ref) 0·95 (0·38–2·37) 1 (ref) NE 1 (ref)
(95% CI)
Best overall response†
Complete 2 (5%) 2 (5%) 1 (6%) 2 (11%) 1 (3%) 6 (16%) 0 0
response
Partial response 10 (24%) 14 (34%) 6 (38%) 7 (39%) 17 (47%) 13 (35%) 0 1 (20%)
Stable disease 12 (29%) 14 (34%) 2 (13%) 3 (17%) 8 (22%) 12 (32%) 2 (50%) 2 (40%)
Progressive 17 (40%) 11 (27%) 6 (38%) 6 (33%) 6 (17%) 5 (14%) 2 (50%) 1 (20%)
disease
Not evaluable 1 (2%) 0 1 (6%) 0 4 (11%) 1 (3%) 0 1 (20%)
Duration of NR (6·0–NR) NR (8·3–NR) NR (NR–NR) NR (11·6–NR) 14·7 (10·7–NR) NR (11·8–NR) NE NR (NR–NR)
response, months
Time to response, 2·4 (2·3–NR) 2·5 (2·2–5·3) 2·2 (2·2–NR) 4·5 (2·3–NR) 4·9 (2·8–16·5) 2·4 (2·3–5·0) NE NR (2·2–NR)
months
Data are n (%; 95% CI), n (%), or median (95% CI), except where otherwise stated. ccrcc=clear-cell renal cell carcinoma. NE=not evaluable. NR=not reached. TKI=tyrosine kinase inhibitor. *Of the 40 patients who
received VEGFR-TKI, 33 received sunitinib and seven received pazopanib. †Percentages might not total 100 due to rounding.

Table 2: Tumour responses

Objective response rate at 22 weeks is shown in the
appendix (p 7).
After a median follow-up for progression-free survival
of 16·2 months (IQR 15·9–17·3), 128 patients had an
event (seven died and 121 progressed): 40 (69%) of
58 with nivolumab, 67 (66%) of 101 with nivolumab–
ipilimumab, and 21 (53%) of 40 with a VEGFR-TKI.
Median progression-free survival was 5·3 months
(95% CI 2·4–9·1) with nivolumab, 10·4 months (7·7–13·8)
with nivolumab–ipilimumab, and 13·5 months (7·8–not
reached) with VEGFR-TKIs. In the ccrcc1 cohort, median
progression-free survival was 5·2 months (95% CI
2·4–9·1) with nivolumab and 7·7 months (5·0–12·9) with
nivolumab–ipilimumab (hazard ratio [HR] for nivolumab
vs nivolumab–ipilimumab 1·27 [95% CI 0·77–2·11];
figure 2A). In the ccrcc4 cohort, median progression-free
survival was 7·8 months (95% CI 2·3–not evaluable) with
nivolumab and 13·0 months (2·5–not evaluable) with
nivolumab–ipilimumab (HR for nivolumab vs nivolumab–
ipilimumab 1·37 [95% CI 0·57–3·29]; figure 2B). In the
ccrcc2 cohort, median progression-free survival was
14·4 months (95% CI 10·6–not evaluable) with a VEGFR-
TKI and 11·1 months (7·7–23·2) with nivolumab–
ipilimumab (HR for VEGFR-TKI vs nivolumab–ipilimumab
0·75 [95% CI 0·40–1·39]; figure 2C). In the ccrcc3 cohort,
median progression-free survival was 3·2 months (95% CI
1·8–4·9) with a VEGFR-TKI and 16·1 months (2·0–not
evaluable) with nivolumab–ipilimumab.
After a median follow-up of 18·0 months
(IQR 17·6–18·4) for overall survival, 40 (20%) of
199 patients had died: 17 (29%) of 58 patients treated with
nivolumab, 15 (15%) of 101 treated with nivolumab–
ipilimumab, and eight (20%) of 40 treated with a
VEGFR-TKI. Median overall survival was not reached in
any treatment group.
Median duration of treatment was 7·4 months
(IQR 3·0–17·3) in the nivolumab group, 8·4 months
(4·0–17·2) in the nivolumab–ipilimumab group, and
8·1 months (2·8–17·5) in the VEGFR-TKI group.
Post-hoc analysis of the best percentage changes in
sums of diameters of target lesions from baseline to nadir
according to investigator assessment is shown in the
appendix (p 14). 33 (57%) of 58 patients in the nivolumab
group, 65 (64%) of 101 patients in the nivolumab–
ipilimumab group, and 29 (72%) of 40 patients in the
VEGFR-TKI group had a decrease in the sum of the target
lesions. Post-hoc analysis of time to events in patients
with a response is shown in the appendix (p 15). The
majority of objective responses were obtained at the first
imaging assessment (week 10), particularly in the
nivolumab group (16 [84%] of 19 patients). Post-hoc
analysis of the median time to response in each group is
shown in table 2.
Of the 140 patients who discontinued treatment,
114 (81%) received subsequent therapy: 36 (86%) of
42 patients after nivolumab, 58 (82%) of 71 after
nivolumab–ipilimumab, and 20 (74%) of 27 after
VEGFR-TKI. Corresponding median time to sub­
sequent treatment (post-hoc analysis) was 11·0 months
(95% CI 6·4–not reached) after nivolumab, 14·4 months
(13·1–23·2) after nivolumab–ipilimumab, and
15·0 months (9·6–not reached) after VEGFR-TKI.
Median time to subsequent treatment by ccrcc group is
shown in the appendix (p 7). Of the patients in the
ccrcc1, ccrcc4, ccrcc2, and ccrcc3 groups who progressed
on nivolumab–ipilimumab, three (10%) of 29, three

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(30%) of ten, three (12%) of 25, and zero did not receive A
a subsequent line of treatment. Among patients who 100 Drug Events/ Median HR (95% CI)
progressed on nivolumab, four (13%) of 31 patients in 90
patients (95% CI)
the ccrcc1 group and one (10%) of ten patients in the 80 Nivolumab–ipilimumab 29/41 7·7 (5·0–12·9) 1 (ref)

Progression-free survival (%)

ccrcc4 group did not receive a subsequent line of Nivolumab 31/42 5·2 (2·4–9·1) 1·27 (0·77–2·11)
70
treatment. Of the patients who progressed on a VEGFR-
60
TKI, one (6%) of 17 patients in the ccrcc2 group and
50
none in the ccrcc3 group did not receive a subsequent
line of treatment. 40

Estimated ORs and HRs from hierarchical Bayesian 30

models were similar to their frequentist counterparts 20
Nivolumab–ipilimumab
(appendix p 7). This sensitivity analysis only applied to 10 Nivolumab
patients in the ccrcc1 and ccrcc4 groups who shared the 0
0 6 12 18
same treatments, with the ccrcc3 sample size being too
Number at risk
small to share information with the ccrcc2 population. (number censored)
Post-hoc descriptive exploratory analyses of objective Nivolumab–ipilimumab 41 (0) 25 (0) 14 (0) 2 (10)
response rate, disease control rate, and median Nivolumab 42 (1) 19 (1) 11 (1) 0 (11)

progression-free survival according to IMDC risk groups B

are shown in the appendix (p 8). Of the patients in the 100 Drug Events/ Median HR (95% CI)
IMDC favourable risk group and treated with a VEGFR- 90 patients (95% CI)
TKI, 14 (88%) of 16 belonged to the ccrcc2 group. Nine
80 Nivolumab–ipilimumab 10/18 13·0 (2·5–NE) 1 (ref)
(64%) of these 14 patients had an objective response.
Progression-free survival (%)

70 Nivolumab 10/16 7·8 (2·3–NE) 1·37 (0·57–3·29)

Exploratory post-hoc analyses of objective response rates
60
by tumour sarcomatoid component and tumour cell
PD-L1 expression of 1% or more are reported in the 50

appendix (p 8). Patients whose tumours had a sarcomatoid 40

component had higher objective response rates with 30
nivolumab–ipilimumab than those without, but not with a 20
VEGFR-TKI or with nivolumab. Patients with tumour cell 10
PD-L1 expression of 1% or more had higher objective 0
response rates with nivolumab and nivolumab– 0 6 12 18

ipilimumab than those without, but not with a VEGFR- Number at risk
(number censored)
TKI (appendix p 8). Nivolumab–ipilimumab 18 (0) 12 (0) 10 (0) 1 (7)
In view of the high response rates with both Nivolumab 16 (0) 9 (0) 6 (1) 0 (6)
nivolumab–ipilimumab and VEGFR-TKI in the ccrcc2
C
group, we wondered whether it could be divided into
Drug Events/ Median HR (95% CI)
two subgroups with different sensitivity to treatments. patients (95% CI)
Thus, we did a post-hoc analysis to explore the response 100
Nivolumab–ipilimumab 25/37 11·1 (7·7–23·2) 1 (ref)
rate according to an immune signature, measured by 90 VEGFR-TKI 17/36 14·4 (10·6–NE) 0·75 (0·40–1·39)
the expression of eight immune-related genes from our 80
Progression-free survival (%)

classifier (used to separate groups 1 and 4; appendix p 6). 70

When applying these eight genes to ccrcc1 and ccrcc4 60
tumours, we discriminated these two groups as expected 50
(upregulated in ccrc4 and downregulated in ccrcc1;
40
appendix p 15). When applied to the 67 patients in the
30
ccrcc2 group, we identified two groups (appendix p 16):
20
immune-low to intermediate (n=45), and immune-
Nivolumab–ipilimumab
high (n=22) with distinct response rates, favouring 10
VEGFR-TKI
VEGFR-TKI or nivolumab–ipilimumab (appendix p 8). 0
0 6 12 18
54 (93%) of 58 patients in the nivolumab group,
Time from randomisation (months)
100 (99%) of 101 in the nivolumab–ipilimumab group, and Number at risk
(number censored)
38 (95%) of 40 in the VEGFR-TKI group had a treatment- Nivolumab–ipilimumab 37 (0) 28 (0) 16 (1) 2 (11)
related adverse event (table 3). The most common VEGFR-TKI 36 (4) 24 (4) 19 (4) 1 (18)
treatment-related grade 3–4 adverse events were hepatic
Figure 2: Progression-free survival
failure and lipase increase (two [3%] of 58 patients for (A) Progression-free survival in the ccrcc1 group. (B) Progression-free survival in the ccrcc4 group. (C) Progression-
each) in the nivolumab group, lipase increase and free survival in the ccrcc2 group. Tick marks represent censored patients. ccrcc=clear-cell renal cell carcinoma.
hepatobiliary disorders (six [6%] of 101 patients for each) NE=not evaluable. TKI=tyrosine kinase inhibitor.

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Nivolumab (n=58) Ipilimumab–nivolumab (n=101) VEGFR-TKI* (n=40)

Grade 1–2 Grade 3 Grade 4 Grade 5 Grade 1–2 Grade 3 Grade 4 Grade 5 Grade 1–2 Grade 3 Grade 4 Grade 5
All events 45 (76%) 8 (14%) 1 (2%) 0 55 (54%) 33 (33%) 11 (11%) 1 (1%) 12 (30%) 23 (58%) 1 (3%) 2 (5%)
Serious events 1 (2%) 0 1 (2%) 0 8 (8%) 25 (25%) 4 (4%) 1 (1%) 2 (5%) 6 (15%) 0 2 (5%)
Events leading to treatment 1 (2%) 1 (2%) 1 (2%) 0 6 (6%) 15 (15%) 2 (2%) 1 (1%) 1 (3%) 3 (8%) 0 2 (5%)
discontinuation
Events leading to dose reduction NA† NA† NA† NA† NA† NA† NA† NA† 4 (10%) 8 (20%) 0 0
Treatment-related adverse events‡
Fatigue 29 (50%) 1 (2%) 0 0 53 (52%) 2 (2%) 1 (1%) 0 26 (65%) 0 1 (3%) 0
Diarrhoea 8 (14%) 1 (2%) 0 0 32 (32%) 2 (2%) 0 0 21 (53%) 4 (10%) 0 0
Nausea 6 (10%) 0 0 0 17 (17%) 0 0 0 14 (35%) 0 0 0
Oral mucositis 3 (5%) 0 0 0 12 (12%) 0 0 0 17 (43%) 0 0 0
Hypothyroidism 4 (7%) 0 0 0 19 (19%) 1 (1%) 0 0 13 (33%) 1 (3%) 0 0
Pruritus 14 (24%) 0 0 0 31 (31%) 0 0 0 1 (3%) 0 0 0
Anorexia 4 (7%) 0 0 0 18 (18%) 1 (1%) 0 0 9 (23%) 0 0 0
Dysgeusia 1 (2%) 0 0 0 3 (3%) 0 0 0 17 (43%) 0 0 0
Skin and subcutaneous tissue 9 (16%) 0 0 0 11 (11%) 0 0 0 7 (18%) 1 (3%) 0 0
disorders
Hyperthyroidism 8 (14%) 0 0 0 14 (14%) 2 (2%) 0 0 3 (8%) 0 0 0
Palmar–plantar 0 0 0 0 2 (2%) 0 0 0 13 (33%) 3 (8%) 0 0
erythrodysesthesia syndrome
Maculopopular rash 10 (17%) 1 (2%) 0 0 14 (14%) 1 (1%) 1 (1%) 0 1 (3%) 1 (3%) 0 0
Thrombotic thrombocytopenic 0 0 0 0 0 0 0 0 0 1 (3%) 0 0
purpura
Gastroesophageal reflux disease 0 0 0 0 0 0 0 0 0 1 (3%) 0 0
Renal and urinary disorders 0 0 0 0 0 1 (1%) 0 0 0 0 0 0
Proteinuria 0 0 0 0 0 0 0 0 0 1 (3%) 0 0
Blood and lymphatic system 0 0 0 0 0 1 (1%) 0 0 0 1 (3%) 0 1 (3%)
disorders
Papulopustular rash 0 0 0 0 0 1 (1%) 0 0 0 0 0 0
Pancreatitis 0 0 0 0 0 0 0 0 0 1 (3%) 0 0
Anaemia 0 0 0 0 0 1 (1%) 0 0 0 1 (3%) 0 0
Platelet count decreased 0 0 0 0 0 0 0 0 0 1 (3%) 0 0
Fever 0 0 0 0 0 1 (1%) 0 0 0 0 0 0
Acneiform rash 0 0 0 0 0 0 1 (1%) 0 0 1 (3%) 0 0
Bone marrow hypocellular 0 0 0 0 0 0 0 0 0 1 (3%) 0 0
Skin infection 0 0 0 0 0 1 (1%) 0 0 0 0 0 0
Hepatic failure 0 2 (3%) 0 0 0 1 (1%) 0 1 (1%) 0 1 (3%) 0 0
Hepatobiliary disorders 0 0 0 0 0 5 (5%) 1 (1%) 0 0 0 0 0
Neutrophil count decreased 0 0 0 0 0 0 0 0 0 4 (10%) 0 0
Endocrine disorders 0 0 1 (2%) 0 0 2 (2%) 0 0 0 0 0 0
Myocarditis 0 0 0 0 0 1 (1%) 0 0 0 0 0 0
Other musculoskeletal and 0 0 0 0 0 1 (1%) 0 0 0 0 0 0
connective tissue disorder
Aspartate aminotransferase 0 0 0 0 0 1 (1%) 1 (1%) 0 0 1 (3%) 0 0
increased
Lipase increase 0 2 (3%) 0 0 0 2 (2%) 4 (4%) 0 0 1 (3%) 0 0
Investigations 0 1 (2%) 0 0 0 0 0 0 0 0 0 0
Allergic reaction 0 0 0 0 0 0 0 0 0 1 (3%) 0 0
Infections and infestations 0 0 0 0 0 1 (1%) 1 (1%) 0 0 0 0 0
Immune system disorders 0 0 0 0 0 0 1 (1%) 0 0 0 0 0
Dyspnoea 0 0 0 0 0 2 (2%) 0 0 0 1 (3%) 0 0
Back pain 0 0 0 0 0 1 (1%) 0 0 0 0 0 0
Epistaxis 0 0 0 0 0 0 0 0 0 1 (3%) 0 0
(Table 3 continues on next page)

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Nivolumab (n=58) Ipilimumab–nivolumab (n=101) VEGFR-TKI* (n=40)

Grade 1–2 Grade 3 Grade 4 Grade 5 Grade 1–2 Grade 3 Grade 4 Grade 5 Grade 1–2 Grade 3 Grade 4 Grade 5
(Continued from previous page)
Arthritis 0 0 0 0 0 3 (3%) 0 0 0 0 0 0
Colitis 0 0 0 0 0 2 (2%) 0 0 0 0 0 0
Hypoglycaemia 0 0 0 0 0 2 (2%) 0 0 0 0 0 0
Adrenal insufficiency 0 0 0 0 0 3 (3%) 0 0 0 0 0 0
Febrile neutropenia 0 0 0 0 0 1 (1%) 0 0 0 2 (5%) 0 0
Pneumonitis 0 0 0 0 0 3 (3%) 0 0 0 0 0 0
Blood bilirubin increased 0 0 0 0 0 0 0 0 0 1 (3%) 0 0
γ glutamyltransferase increased 0 0 0 0 0 1 (1%) 0 0 0 0 0 0
Cardiac troponin I increased 0 0 0 0 0 1 (1%) 0 0 0 0 0 0
Hypertension 0 0 0 0 0 0 0 0 0 6 (15%) 0 0
Serum amylase increased 0 1 (2%) 0 0 0 2 (2%) 0 0 0 0 0 0
Hyperglycaemia 0 1 (2%) 0 0 0 2 (2%) 0 0 0 0 0 0
Heart failure 0 0 0 0 0 0 0 0 0 0 0 1 (3%)
Bronchial infection 0 0 0 0 0 1 (1%) 0 0 0 1 (3%) 0 0
Urticaria 0 1 (2%) 0 0 0 0 0 0 0 0 0 0
Abdominal pain 0 0 0 0 0 0 0 0 0 1 (3%) 0 0
Acute kidney injury 0 0 0 0 0 1 (1%) 0 0 0 1 (3%) 0 0
Alanine aminotransferase 0 0 0 0 0 3 (3%) 0 0 0 1 (3%) 0 0
increased
Arthralgia 0 0 0 0 0 1 (1%) 0 0 0 0 0 0
Creatine phosphokinase 0 0 0 0 0 0 1 (1%) 0 0 0 0 0
increased
Hypercalcaemia 0 0 0 0 0 1 (1%) 0 0 0 0 0 0
Data are n (%). NA=not applicable. TKI=tyrosine kinase inhibitor. *Sunitinib: n=33; pazopanib: n=7. †Dose reduction was not allowed for nivolumab or ipilimumab. ‡Grade 1–2 events occurring in ≥10% of
patients or grade 3–5 events occurring in ≥1% of patients are shown.

Table 3: Summary of treatment-related adverse events

in the nivolumab–ipilimumab group, and hypertension
(six [15%] of 40 patients) in the VEGFR-TKI group (table 3).
Treatment-related adverse events in each ccrcc group are
shown in the appendix (pp 9–12). Treatment-related
serious adverse events of any grade occurred in two (3%)
of 58 patients with nivolumab, 38 (38%) of 101 patients
with nivolumab–ipilimumab, and ten (25%) of 40 patients
with VEGFR-TKIs (table 3), of which the most common
events were hypophysitis and Meniere’s disease
(n=1 [2%] each) with nivolumab, adrenal insufficiency
(n=6 [6%]) with nivolumab–ipilimumab, and throm­
botic micro­ angio­
pathy and hepatic cytolysis (n=2 [5%]
each) with VEGFR-TKIs (appendix pp 12–13). Treatment-
related adverse events of any grade that led to treat­
ment discontinuation were observed in three (5%) of
58 patients with nivolumab, 24 (24%) of 101 patients with
nivolumab–ipilimumab, and five (13%) of 40 patients
with a VEGFR-TKI, of which the most common events
were hyphophysitis, diarrhoea, and rash (n=1 [2%]
each) with nivolumab, hepatic failure (n=6 [6%]) with
nivolumab–ipilimumab, and thrombotic microangio­
pathy (n=2 [5%]) with VEGFR-TKIs. In the nivolumab–
ipilimumab group, 78 (77%) of 101 patients received
four first co-admin­istrations of nivolumab and ipilimumab
and 11 (6%) received three first co-admin­ istrations of
nivolumab and ipilimumab. Treatment-related adverse
events of any grade that led to dose reduction were
observed in 12 (30%) of 40 patients with a VEGFR-TKI
(ten [30%] of 33 with sunitinib, two [29%] of seven with
pazopanib); dose reduction was not allowed with
nivolumab or nivolumab–ipilimumab.
Of the 40 patients who died during the study, 29 deaths
were related to disease progression (14 [24%] with
nivolumab, 12 [12%] with nivolumab–ipilimumab, and
three [8%] with a VEGFR-TKI) and three were related to
study treatment (one fulminant hepatitis related to both
nivolumab and ipilimumab, and one heart failure and
one thrombotic microangiopathy related to sunitinib;
table 3).
Discussion
To our knowledge, BIONIKK is the first reported ran­
domised trial in the first-line treatment of patients with
metastatic clear-cell renal cell carcinoma with treatment
allocation based on prospective molecular classification.
We demonstrate the feasibility of such a strategy by
providing the molecular group of the tumours within
15 days. Our results suggest potential improved efficacy of
nivolumab, nivolumab–ipilimumab, and VEGFR-TKI in
some molecular groups compared with published

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prospective cohorts,2,11 validating our initial assumptions.
Indeed, in the immune-desert ccrcc1 group,6,7 objective
response rate was increased and median progression-free
survival was longer with nivolumab–ipilimumab than with
nivolumab alone. By contrast, in the immune-infiltrated
and inflammatory ccrcc4 group, the objective response
rates were high and similar in both the nivolumab and
nivolumab–ipilimumab treatment groups. In addition, in
the ccrcc4 group, both nivolumab-based treatment groups
showed an increased objective response rate and prolonged
median progression-free survival compared with the ccrcc1
group or other prospective cohorts with unselected
patients.2,11 The lower efficacy of nivolumab-based
treatments in the ccrcc1 group, together with the previously
reported low efficacy of sunitinib,6 prompt us to explore
new treatment options. In the pro-angiogenic ccrcc2
group, both VEGFR-TKI and nivolumab–ipilimumab led
to high objective response rates, but median progression-
free survival was longer with a VEGFR-TKI than with
nivolumab–ipilimumab. The frequency of the reputed
normal-like ccrcc3 tumours was lower in our study than
previously reported6 and did not allow any conclusions to
be drawn for this subgroup.
Overall, our results suggest that patients with ccrcc4
tumours might be the best candidates to receive
nivolumab–ipilimumab. The efficacy results of the
combination are of particular interest in this group
because ccrcc4 tumours are associated with poor
prognostic factors (sarcomatoid component, IMDC poor
risk, and high PD-L1 expression) and low efficacy of
sunitinib and pazopanib.8,6,12 Irrespective of ccrcc group,
patients treated with nivolumab–ipilimumab and
belonging to the intermediate-to-poor IMDC risk group
had similar efficacy results to those of the pivotal
CheckMate 214 trial of this treatment combination
(objective response rate 42%, median progression-free
survival 11·6 months [95% CI 8·7–15·5]).2 Thus, the
increased objective response rate and prolonged
progression-free survival in ccrcc4 seem to be related to
molecular selection. Furthermore, the higher objective
response rate of the nivolumab–ipilimumab group in the
presence of a sarcomatoid component (in contrast to the
VEGFR-TKI group), present in three-quarters of patients
in the ccrcc4 group, reinforces the relevance of this
molecular group in predicting response to this
immunotherapy combination. In a post-hoc analysis of
the CheckMate 214 trial, Tannir and colleagues13 similarly
found an enhanced objective response rate (60·8%) with
nivolumab–ipilimumab in the presence of sarcomatoid
features. We found, as in previous studies,2 that a
substantial fraction of patients receiving nivolumab–
ipilimumab had progressive disease as a best response,
including patients in the ccrcc4 group. However, the large
difference in duration between median time to
subsequent therapy and median progression-free survival
suggests that there is a definite clinical benefit for some
patients to continue treatment beyond progression.
622 www.thelancet.com/oncology Vol 23 May 2022
Escudier and colleagues14 reported that 20 (13%) of
153 patients treated with nivolumab beyond progression
had a subsequent tumour burden reduction of 30% or
more, including nine (14%) of 66 patients with
progression at the first assessment. We observed that a
third of patients in the ccrcc4 group who progressed at
first assessment on nivolumab–ipilimumab did not need
to start second-line therapy during the entire follow-up
period of the study. These findings highlight the fact that
the high rate of early progression with nivolumab–
ipilimumab does not systematically reflect primary
resistance. Alternative endpoints such as time to
subsequent therapy might provide additional information
related to a true clinical benefit for these patients.
The results for nivolumab in the ccrcc4 group show, to
our knowledge, the highest objective response rate ever
reported in a prospective trial evaluating an anti-PD-1
agent alone.11,15–17 In the four trials that reported the
efficacy of nivolumab alone as first-line therapy, objective
response rates ranged from 13% to 32%.11,15–17 The
objective response rate was similar in our overall cohort
of patients treated with nivolumab (33%) but higher in
patients in the ccrcc4 group (44%). As reported
previously,18 median progression-free survival was short.
However, it was longer in patients in the ccrcc4 group
than in the ccrcc1 group and the median time to
subsequent therapy was substantially higher than
median progression-free survival (exceeding 12 months
in ccrcc4), again suggesting a potential prolonged clinical
benefit beyond progression. In an ancillary analysis of
the CheckMate 009 trial evaluating nivolumab alone, the
authors attempted to classify tumours into ccrcc groups
and observed a similar objective response rate (47%) in
their ccrcc4 group19 The TITAN-RCC trial, which
evaluated an ipilimumab boost in non-responding
patients to nivolumab alone in metastatic renal cell
carcinoma, showed a small increase in objective response
rate, from 28% with nivolumab alone to 36% with
ipilimumab boost in first-line.11 This selection strategy
based on early radiological response could be effectively
combined with our selection of ccrcc4 tumours to offer
nivolumab monotherapy as a treatment option in frail
patients who would not be suitable for upfront
combination with ipilimumab.
By contrast, VEGFR-TKI alone or in combination would
be the best option in patients with ccrcc2 tumours,
particularly in the IMDC favourable-risk group or with an
immune-low gene expression signature in accordance
with previous data.6,8 These results might be partly due to
a high proportion of patients in the IMDC favourable risk
group and a pro-angiogenic tumour micro­environment.8,20
Indeed, we found that the ccrcc2 cohort was enriched in
patients in the IMDC favourable risk group relative to the
other groups. Additionally, independently of the ccrcc
classification, objective response rate with a VEGFR-TKI
was higher in the IMDC favourable risk group (56%) than
in intermediate risk (40%) or poor risk groups (25%).

Updated results of CheckMate 214 and KEYNOTE 426
reported similar objective response rates (around 50%)
with sunitinib in patients in the IMDC favourable risk
group.21,22 However, combining the ccrcc2 group and
IMDC favourable risk group, the response rate (64%) was
higher than in either group, suggesting an additional
influence of molecular group on response to VEGFR-
TKIs. Our results support the positioning of a VEGFR-
TKI alone as a valid option for patients in the ccrcc2
group with a favourable IMDC risk. Indeed, the new
standard of care in patients with favourable IMDC
risk, pembrolizumab–axitinib,23,24 did not show any
progression-free survival or overall survival benefit in that
group. Interestingly, the exploratory analysis of the
subgroup of patients with an immune low-to-intermediate
signature within ccrcc2 tumours should be further
explored since it predicted different responses between
VEGFR-TKIs and nivolumab–ipilimumab.
Due to the expected small number of patients to be
accrued, the BIONIKK study was mainly designed to
generate hypotheses, and not to change practices. Thus,
our results have some limitations. First, BIONIKK was
designed as a non-comparative trial, impeding any
statistical comparison. Anticipating a possible low
accrual rate in a rapidly evolving landscape of frontline
treatment, we selected only highly experienced centres
that routinely freeze freshly acquired tumour samples.
Nevertheless, a randomised design was chosen to ensure
that per-group molecular group HRs would be unbiased
and to be able to generate new hypotheses. Second, the
combination of VEGFR-TKI plus anti-PD-1, which is now
a standard of care in first-line metastatic clear cell renal
cell carcinoma,23 had not yet been evaluated at the time of
the trial design. Nevertheless, our results suggest that a
VEGFR-TKI plus anti-PD-1 combination might provide
its best efficacy in the ccrcc2 cohort because both
immunotherapy and VEGFR-TKI led to good efficacy.
Despite the aforementioned limitations, we believe that
our results are reliable because our ccrcc groups show
biologically distinct entities linked to the main tumour
microenvironment features: angiogenesis (ccrcc2) and
T effector or immune infiltration (ccrcc4 or ccrcc1,
immune-infiltrated or immune-desert). Based on
multiomic analyses of the IMmotion 151 randomised,
phase 3 trial, Motzer and colleagues25 similarly described
seven distinct renal cell carcinoma tumour subtypes with
various responses to bevacizumab plus atezolizumab.25
To our knowledge, the BIONIKK study is the first step in
tailoring treatment on the basis of tumour molecular
phenotype in metastatic clear-cell renal cell carcinoma and
provides several elements that form a useful foundation
for larger prospective, biomarker-based, randomised trials.
Contributors
Y-AV, RE, WHF, CS-F, and SO conceived and designed the study.
Y-AV, RE, SO, and CS-F supervised the study. Y-AV, MB, CC, DB, DP,
DM, MG-G, CT, BL, PBa, EC, GG, NH, MC, OH, PBe, AM, XC, ND, PP,
J-CB, AdlT, KB, TT, TW, and GP acquired the data. RE and LP did the
statistical analysis. RE, LP, Y-AV, WHF, CS-F, and SO analysed and
www.thelancet.com/oncology Vol 23 May 2022 623
Articles
interpreted the data. Y-AV and RE drafted the manuscript. All authors
critically revised the manuscript. LF, SC, C-MS, VV, GL, MMo, MMe,
AB, CT-C, and JZ-R provided technical or material support. EB, RE,
and LP provided administrative management. Y-AV, RE, SO, WHF,
and CS-F obtained funding. Y-AV, LP, RE, and SO have accessed and
verified the data. All authors had full access to the data and control of the
final approval and decision to submit the manuscript for publication.
The authors had full access to all the raw data reported in the study.
The corresponding author had full access to all of the data and had final
responsibility to submit for publication.
Declaration of interests
Y-AV has received research funding from Bristol Myers Squibb (BMS)
and Ipsen (all fees for institution); has been on an advisory board or data
safety monitoring board for BMS and Roche; has received honoraria for
lectures and presentations from BMS, MSD, Ipsen, Merck, Pfizer,
Roche, Novartis, Janssen, Astellas, and Viatris; and has received support
for travel or meetings from BMS, MSD, Pfizer, Ipsen, and Roche.
MB has received honoraria for lectures or presentations from Janssen,
AstraZeneca, Ipsen, and Astellas. CC has been on an advisory board or
data safety monitoring committee for Ipsen, Pfizer, Esaï, and GSK;
and has received support for travel or meetings from Pfizer. DB has
received research funding from BMS, Roche, MSD, Astellas,
AstraZeneca, Janssen, Exelixis, and Infinity; has received consultancy
fees from MSD, Astellas, AstraZeneca, Pfizer, Ipsen, BMS, Janssen,
and Sanofi; and has received support for travel or meetings from BMS,
Pfizer, Roche, and Ipsen. MG-G has been on an advisory board or data
safety monitoring committee for BMS, MSD, Ipsen, and Pfizer; has
received honoraria for lectures or presentations from BMS, MSD, Ipsen,
and Pfizer; and has received support for travel or meetings from Ipsen
and Janssen. CT has received honoraria for lectures or presentations
from MSD and BMS; and support for travel or meetings from MSD.
BL has received honoraria for lectures or presentations from Pfizer,
BMS, and Ipsen; and support for travel or meetings from Pfizer. PBa has
received consultancy fees from BMS, Ipsen, MSD, Merck, Pfizer,
Janssen-Cilag, Astellas, and Amgen; honoraria for lectures or
presentations from BMS, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag,
Astellas, Bayer, Sanofi, Seagen, and Novartis; and support for travel or
meetings from BMS, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas,
Sanofi, Seagen, and Novartis. EC has received honoraria for lectures or
presentations from AstraZeneca, MSD, BMS, and Ipsen. GG has been
on an advisory board or data safety monitoring committee for BMS,
Janssen, Ipsen Sanofi/Aventis, MSD Oncology, Pfizer, Bayer, and
AstraZeneca; has received honoraria for lectures or presentations from
Janssen Oncology, Ipsen, BMS, Amgen, Sanofi/Aventis, MSD Oncology,
and Astellas Pharma (all fees for institution); and has received support
for travel or meetings from Janssen Oncology, BMS, Astellas Pharma,
Pfizer, Ipsen, Sanofi, and AstraZeneca. OH has received honoraria for
lectures or presentations from BMS, AstraZeneca, Sanofi, Pfizer, Merck,
Ipsen, Novartis, and MSD. LF has been on an advisory board or data
safety monitoring committee for Pandas Prodige, Joint French Clinical
Practice Guidelines issued by FRANCOGYN, CNGOF, SFOG,
and GINECO-ARCAGY, and endorsed by INCa French Guidelines on
management of ovarian cancer, European Organisation for Research and
Treatment in Cancer, European Society of Oncological Imaging, and
European Society of Urogenital Radiology; has received honoraria for
lectures or presentations from General Electric, Median Technologies,
and Sanofi; and received support for travel or meetings from Guerbet.
AdlT has received honoraria for lectures or presentations from Janssen,
AstraZeneca, Ipsen, and Astellas. KB has received honoraria for lectures
or presentations from Ipsen, BMS, MSD, and Intuitive Surgical. TW has
received support for travel or meetings from Astellas. GP has received
consultancy fees from Roche, Astellas, Bayer, Janssen, and Bouchara-
Recordati; and support for travel or meetings from Janssen and Ipsen.
SO has received consultancy fees from BMS and Pfizer; and honoraria
for lectures or presentations from BMS and Pfizer. All other authors
declare no competing interests.
Data sharing
Individual participant data that underlie the results reported in this
article, after deidentification (text, tables, figures, and appendices) will be
available, as well as the study protocol, statistical analysis plan, and
 Articles
informed consent form. Data will be available beginning 18 months and
ending 36 months following article publication upon proposal from
investigators whose proposed use of the data has been approved by an
independent review committee (“learned intermediary”) identified for
this purpose. Proposals should be directed to yann.vano@aphp.fr.
To gain access, data requestors will need to sign a data access agreement.
Acknowledgments
This study was funded by Bristol Myers Squibb (New York, NY, USA) and
ARTIC (Paris, France; BIONIKK contract (R17169DD). CS-F and WHF’s
team was supported by INSERM, Sorbonne Université, Université de
Paris, Ligue Nationale Contre le Cancer (Equipe labélisée), CARPEM
(Cancer Research for Personalized Medecine, programme of the Sites
Integrés de Recherche sur le Cancer; SIRIC), LabeX Immunooncology.
JZ-R and SC’s team was supported by INSERM and Plan cancer, HTE
program, SIRIC CARPEM and Labex ImmunoOncology (SC fundings).
JZ-R and SC’s team was also supported by Ligue Nationale contre le
cancer (Equipe labélisée). Y-AV received financial support from the SIRIC
CARPEM (Cancer Research for Personalized Medecine, programme of
the Sites Integrés de Recherche sur le Cancer) for a PhD position.
We thank the patients and families who made this study possible; all
investigators and clinical research assistants who participated in the study;
members of ARTIC (Association pour la recherche en thérapeutiques
innovantes en cancérologie) who participated in the study; Fouzia Azzouz
(study co-manager); the Cordelier’s lab team (Inflammation, Complement
and Cancer); members of the independent data monitoring committee of
the study (Marc Buyse, Antoine Thiery-Vuillemin, and Gabriel Malouf);
Aurélien de Reynies and Sylvie Job from the group Carte d’Identité des
Tumeurs (Ligue contre le Cancer) and Benoit Beuselinck for their input
on ccrcc molecular grouping; and Doulaye Dembele from the IGBMC
platform (IGBMC - CNRS UMR 7104-Inserm U 1258, Université de
Strasbourg, Illkirch, France). Medical writing assistance for the
preparation of this manuscript (ie, native English editing and formatting)
was provided by Andrea Bothwell with funding provided by ARTIC.
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