








































This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited.  
© 2022 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada.

Key Words Competing Interests Article Information

Refractory metastatic clear cell renal cell 
carcinoma, vascular endothelial growth 
factor receptor tyrosine kinase inhibitor, 
immunotherapy resistance

See "Acknowledgments" for details. Received on August 10, 2022 
Accepted on September 14, 2022 
This article has been peer reviewed.

Soc Int Urol J. 2022;3(6):478–484

DOI: 10.48083/KGTQ6832

2022 WUOF/SIU International Consultation on 
Urological Diseases: Therapies in Refractory 
Metastatic Renal Cell Carcinoma 

Stephanie Berg,1 Martin Angel,2 Kathryn E. Beckermann,3 Frede Donskov,4 Chung-Han Lee,5  
Pavlos Msaouel,6 Rana R. McKay,7 Tian Zhang8

1 Loyola University Chicago, Chicago, United States 2 Instituto Alexander Fleming, Buenos Aires, Argentina 3 Vanderbilt University Medical Center, Nashville,  
United States 4 University Hospital of Southern Denmark, Esbjerg, Denmark 5 Memorial Sloan Kettering Cancer Center, New York, United States 6 University of Texas 
MD Anderson Cancer Center, Houston, United States 7 University of California San Diego, Moores Cancer Center, San Diego, United States 8 UT Southwestern Medical 
Center, Harold C. Simmons Comprehensive Cancer Center, Dallas, United States

Abstract

As the therapeutic landscape for metastatic clear cell renal cell carcinoma (mccRCC) expands to include vascular 
endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) and immunotherapies, new challenges 
are in place for evaluating and treating refractory disease. Assessing and managing refractory disease has several 
elements: (1) the mechanism(s) of front-line treatment, (2) timing of progressive disease, (3) rapidity and sites of 
progressing disease, (4) use of adjuvant therapy, and (5) incorporation of surgical and radiation techniques. These 
variables all have distinct impact on the biology of refractory or resistant mccRCC. A better understanding of 
the essential mechanisms of both primary and secondary immunotherapy resistance will inform biomarker 
development and therapeutic strategies in the refractory setting. This paper addresses the current understanding 
of treatment sequencing in refractory mccRCC, focusing on treatment options with prospective clinical trial data, 
considers refractory mccRCC after adjuvant immunotherapy, and incorporates radiation or surgical resection for 
oligoprogressive disease. 

Introduction

Refractory metastatic clear cell renal cell carcinoma (mccRCC) poses unique challenges regarding treatment 
sequencing, selection, and integration of definitive surgery or stereotactic body radiation therapy (SBRT). Ultimately, 
one must consider choice of front-line treatment, resistance mechanisms, disease kinetics, and disease relapse after 
adjuvant immunotherapy to determine subsequent therapies at time of disease progression or relapse. Currently, no 
validated biomarkers are approved to help guide treatment selection; however, certain strategies exist to help one 
navigate this ever-changing landscape and will be reviewed in this article.

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https://orcid.org/0000-0001-6193-5350
https://orcid.org/0000-0002-1463-8887
https://orcid.org/0000-0002-4616-6140
https://orcid.org/0000-0002-8449-863X
https://orcid.org/0000-0001-5511-0635
https://orcid.org/0000-0001-6505-8308
https://orcid.org/0000-0002-0581-7963
https://orcid.org/0000-0001-8914-3531
mailto:Tian.Zhang%40UTSouthwestern.edu?subject=SIUJ
http://SIUJ.org


Tyrosine Kinase Inhibitors in mccRCC
The mainstay for mccRCC treatments relies on targeting 
angiogenesis and the vascular endothelial growth factor 
receptor (VEGFR); these become upregulated following 
loss of the von Hippel-Lindau (VHL) protein and 
accumulation of hypoxia-inducible factor (HIF), leading 
to aberrant signaling in angiogenesis, proliferation, and 
metabolism[1,2]. Multiple therapies, predominantly 
antiangiogenic tyrosine kinase inhibitors (TKIs), were 
developed to target the vascular endothelial growth 
factor (VEGF) pathway, and seven of these therapies 
are currently by the United States Food and drug 
Administration (FDA) and listed on the National 
Comprehensive Cancer Network (NCCN) guidelines: 
axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, 
sunitinib, and tivozanib[3]. While these therapies have 
served as the backbone of treatment, responses are 
heterogeneous, with some patients exhibiting intrinsic 
resistance and many patients developing acquired 
resistance despite initial response or disease stability. 
Several mechanisms of resistance have been defined 
including upregulation of other angiogenic drivers and 
increased tumor invasiveness using alternative pathways 
(MET or AXL), which led to VEGF resistance and 
eventual disease progression[4,5]. Multiple trials in the 
second line after prior exposure to anti-VEGF therapies 
have been conducted and demonstrated improvements 
in progression-free and overall survival. Three TKI 
therapeutics (axitinib, cabozantinib, and tivozanib) 
received their FDA approval specifically for patients who 
have progressed on at least one or more prior systemic 
therapies[6–8]. The first phase 3 trial of axitinib versus 
sorafenib, entitled AXIS, and including patients who 
progressed after sunitinib or cytokines, demonstrated 
a progression-free survival (PFS) for axitinib over 
sorafenib (hazard ratio [HR], 0.66; 95% CI, 0.544–0.812; 
P  <  0.001)[6]. Tolerability of axitinib was similar to 
sorafenib and also led to higher objective response rates 

(ORRs), 19% for axitinib and 9% for sorafenib, and did 
not demonstrate a statistically significant difference 
in median overall survival between the two arms, but 
more than half the patients on each arm went on to 
subsequent therapy. Cabozantinib inhibits the activity 
of c-MET, VEGFR, AXL, and other tyrosine kinases, 
thereby leading to reduced tumor angiogenesis, motility, 
and invasiveness, which make it an ideal choice in the 
refractory mccRCC setting[7]. The phase 3 trial of 
cabozantinib versus everolimus, entitled METEOR, 
demonstrated both an improvement in PFS and overall 
survival (OS) for cabozantinib over everolimus (HR, 
0.66; 95% CI, 0.53–0.83; P = 0.00026)[7]. Tivozanib, 
which received FDA approval in 2021, functions by 
selectively inhibiting the phosphorylation of VEGFR-1, 
VEGFR-2, and VEGFR-3, and due to this potency and 
selectively it may confer less toxicity and improved 
tolerability for patients[8]. TIVO-3, a phase 3 clinical 
trial of tivozanib versus sorafenib, studied patients 
who had disease progression on at least two prior 
therapies including anti-VEGF and immune checkpoint 
inhibitors. The trial met its primary endpoint, and 
tivozanib as a third- or fourth-line agent improved PFS 
compared with sorafenib (HR, 0.73; 95% CI, 0.56–0.94; 
P = 0.016)[9]. Finally, combination therapy targeting the 
mammalian target of rapamycin (mTOR) pathway and 
VEGFR proved beneficial for patients in the refractory 
mccRCC setting. In a multicenter, open-label, phase 2 
trial of lenvatinib plus everolimus versus lenvatinib or 
everolimus monotherapy, lenvatinib plus everolimus 
yielded a strong signal toward improved PFS compared 
w it h everolimus (HR, 0.40; 95% CI, 0.24– 0.68; 
P = 0.0005) but only a weak signal toward improved PFS 
compared with lenvatinib monotherapy (HR, 0.66; 95% 
CI, 0.39–1.10; P = 0.12)[10]. Exploiting these pathways 
in refractory mccRCC is important and with more 
specific TKIs approved—for example tivozanib, which 
has demonstrated improved PFS in heavily pretreated 
patients with better tolerability and manageable 
toxicity—should be the cornerstone of future treatment 
combinations. Key phase 3 trials are listed in Table 1.

Immune Checkpoint Inhibition in mccRCC
mRCC is an immunogenic tumor, and therapies 
utilizing humanized monoclonal antibodies to block the 
negative regulatory signal between programmed death 
1 (PD-1) on the T-cell and its ligand programmed death 
1 ligand 1 (PD-L1) on the tumor cell, termed immune 
checkpoint inhibitors (ICIs), have shown remarkable and 
durable responses. ICI monotherapy has been studied in 
refractory mccRCC with the PD-1 inhibitor nivolumab. 
CheckMate-025 was a phase 3 clinical trial comparing 
nivolumab versus everolimus, where all patients 
had progressed on at least one prior antiangiogenic 
t herapy. Nivolumab monot herapy improved t he 

Abbreviations 
CTLA-4 cytotoxic T-lymphocyte-associated protein 4
ICI immune checkpoint inhibitor
mccRCC metastatic clear cell renal cell carcinoma 
ORR objective response rate 
OS overall survival 
PD-1 programmed death 1 
PFS progression-free survival 
SBRT stereotactic body radiation therapy
TKI tyrosine kinase inhibitor
VEGF vascular endothelial growth factor 
VEGFR vascular endothelial growth factor receptor
FDA United States Food and drug Administration

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ORR over everolimus (25% vs. 5%; odds ratio, 5.98; 
95% CI, 3.68–9.72; P < 0.001) and demonstrated a 
median OS benefit of 25 months compared with 19.6 
months (HR, 0.73; 98.5% CI, 0.57–0.93; P = 0.002)
[11]. Another immunogenic pathway in T-cell surface 
receptor signaling involves the cytotoxic T-lymphocyte 
associated protein 4 (CTLA-4), which is a coreceptor 
that controls peripheral tolerance and development of 
autoimmunity. Ipilimumab is a humanized monoclonal 
antibody against CTLA-4 and was combined with 
nivolumab in the first-line setting for mRCC in the 
pivotal first-line mccRCC trial CheckMate-214. This 
phase 3 clinical trial compared the combination of 
nivolumab plus ipilimumab versus sunitinib[12]. The 
OS and ORR were higher with the combination of 
nivolumab plus ipilimumab compared with sunitinib 
amid patients with International Metastatic RCC 
Database Consortium (IMDC) intermediate- and poor-
risk disease and remains superior at 4-year follow-up 
(HR, 0.65; 95% CI, 0.54–0.78)[13]. For the refractory 
mRCC setting, several trials have tested the dual ICI 
combination ipilimumab plus nivolumab (ipi-nivo). 
FRACTION-RCC was a phase 2 clinical trial that 
tested the combination ipi-nivo in heavily pretreated 
patients with mccRCC who had previously received 
and progressed on ICIs. The study demonstrated a 
meager ORR of 15.2% as well as a median PFS of only 

16.1 weeks[14]. Furthermore, risk-adaptive trials have 
been conducted with varying responses. Three phase 
2 clinical trials (TITAN-RCC, OMNIVORE, HCRN 
GU16–620) investigated treatment intensification with 
the addition of ipilimumab after progression or lack of 
response on PD-1 monotherapy[15–17]. All three studies 
showed modest activity of ipilimumab in the salvage 
setting after nivolumab with limited responses, and the 
use of CTLA-4 after PD-1 refractory disease remains 
uncertain. 

Combination ICI Plus VEGFR TKI in 
Refractory mccRCC
Additionally, front-line combinations of ICIs with 
or without VEGFR TKI are now standard of care for 
all IMDC-risk mccRCC patients, but single-center 
retrospective studies have shown that patients who 
progress on ICI plus VEGFR TKI or ICI plus ICI have 
an ORR of 25% and a median PFS of 12 months (95% 
CI, 8.2–24.5) when initiated on further treatments[18]. 
The CANTATA study was a phase 3 trial of cabozantinib 
plus telaglenastat, an oral glutaminase (GLS) inhibitor 
t hat block s g luta m i ne ut i l i z at ion a nd cr it ica l 
downstream pathways, versus cabozantinib plus placebo 
in previously treated mccRCC patients who received 
≥ 1 antiangiogenic therapy or ipi-nivo. In this study, 

TABLE 1. 

Key phase 3 clinical trials in refractory metastatic kidney cancer 

 AXIS METEOR TIVO-3 CheckMate-025 CANTATA

Treatment
Axitinib vs. 
sorafenib

Cabozantinib vs. 
everolimus

Tivozanib vs.  
sorafenib

Nivolumab vs. 
everolimus

Cabozantinib + 
telaglenstat vs. 

cabozantinib

mPFS  
(months)

6.7 7.4 5.6 4.6 9.2

HR 
(95% CI)

0.66
(0.544–0.812)

0.51
(0.42–0.62)

0.73
(0.56–0.94)

0.88
(0.75–1.03)

0.94
(0.74–1.21)

ORR (%) 19% 17% 12.3% 25% 31%

mOS
(months)

20.1 21.4 16.4 25 Not reported

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62% of the enrolled patients had progression on prior 
ICI. Cabozantinib plus telaglenastat demonstrated 
a median PFS of 9.2 months and cabozantinib plus 
placebo demonstrated a median PFS of 9.3 months (HR, 
0.94; 95% CI, 0.74–1.21; stratified log-rank P = 0.65), 
which was not statistically significant. However, in a 
prespecified subgroup analysis for patients who received 
prior ICI, cabozantinib plus telaglenastat yielded a 
numerically longer median PFS than cabozantinib plus 
placebo (11.1 vs. 9.2 months, respectively; unstratified 
HR, 0.77; 95% CI, 0.56–1.06)[19]. KEYNOTE-146 was a 
single-arm, phase 1b/2 clinical trial of the combination 
of lenvatinib plus pembrolizumab in treatment-naïve, 
previously treated ICI-naïve and ICI-pretreated mccRCC 
patients[20]. The objective response at week 24 in the 
ICI-pretreated cohort was 55.8% (95% CI, 45.7–65.5), 
and the median PFS was 12.2 months (95% CI, 9.5–17.7), 
but due to the single-cohort nature of the trial, it is 
difficult to ascertain the effectiveness of these individual 
study drugs in this setting. Current trials are ongoing to 
address the issue of ICI continuation after progression 
on ICI combination or monotherapy. CONTACT-03 
(NCT04338269) is a randomized phase 3 study of 
cabozantinib plus atezolizumab versus cabozantinib 
monotherapy in patients with mRCC (clear cell and 
non-clear cell, papillary or unclassified) who had 
radiographic disease progression during or following 
first- or second-line ICI treatment[21]. This trial has 
dual primary endpoints of PFS and OS that will further 
elucidate the role of cabozantinib plus atezolizumab in 
the ICI-refractory setting. CONTACT-03 enrollment 
was completed in 2022. Another ongoing trial, TiNivo-2 
(NCT04987203), is a randomized phase 3 trial of 
tivozanib plus nivolumab versus tivozanib monotherapy 
in patients who have previously progressed on 1 or 2 lines 
of therapy, including an ICI (during or within 6 weeks 
of treatment discontinuation)[22]. Both trials will likely 
be completed by 2025, and yield insight as to whether 
combination therapy with VEGF TKI and either PD-1 
or PD-L1 inhibition is superior to TKI monotherapy in 
ICI-refractory mccRCC. Other select ongoing studies in 
the refractory setting are listed in Table 2. 

Treatment Selection After Adjuvant 
Treatment
Recently published data from the large, randomized, 
phase 3 clinical trial KEYNOTE-564 of pembrolizumab 
versus placebo in high-risk ccRCC post-nephrectomy 
established the role of ICI in the adjuvant setting. 
Pembrolizumab monotherapy significantly prolonged 
disease-free survival (DFS) compared with placebo  
(DFS at 24 months, 77.3% vs. 68.1%; HR for recurrence 
or death, 0.68; 95% CI, 0.53–0.87; P = 0.002 [two- 
sided])[23]. Thus, high-risk ccRCC patients who 
progress af ter adjuvant ICI pose a cha l lenging 

situation. One must factor in timing of relapse as 
well as incorporation of surgery or SBRT to sites of 
progression if amenable. When systemic therapy is 
required to treat relapsed disease, rechallenge with ICI 
is possible, but no current data exists to provide efficacy 
of these treatments post-adjuvant ICI therapy. Other 
tumor types may provide some clues: for example, 
in malignant melanoma, retrospective studies have 
shown that patients who progressed during anti–PD-1 
monotherapy had no response to subsequent anti–PD-1 
systemic therapy to treat metastatic disease. However, 
they were able to retain sensitivity to future anti–PD-1 
after completion of adjuvant therapy[24]. Consequently, 
since adjuvant ICI therapy was only approved in high-
risk ccRCC in 2021, no data is available to infer that any 
rechallenge after completion of adjuvant treatment with 
ICI would be beneficial. Randomized clinical trials have 
proven that VEGFR TKI monotherapy or VEGFR plus 
mTOR inhibitors in mccRCC post-ICI prolongs PFS and 
OS, and these regimens may be the preferred treatment 
approach prior to an ICI rechallenge. Rechallenge ICI in 
ccRCC patients after completion of adjuvant ICI should 
only be conducted in randomized clinical trials. Lastly, 
targeting other mechanisms will also depend on timing 
of disease relapse after completing adjuvant therapy.

Alternative Modalities in Refractory 
mccRCC
Incor poration of radiot herapy (RT) or surger y 
should be considered at time of first relapse or during 
oligometastatic progression. First, SBRT for extracranial 
sites and stereotactic radiosurgery (SRS) for intracranial 
sites can provide both local control for patients with 
oligometastatic progression and palliative relief[25,26]. 
Clinical studies have also examined the efficacy of SBRT 
with systemic VEGFR TKI or ICI. RAPPORT was a 
phase 1/2 trial that explored the safety and efficacy  
of total metastatic stereotactic ablative body radiotherapy 
(SABR) to oligometastatic mccRCC followed by anti–
PD-1 treatment. ORR was 63% in 30 evaluable patients 
and estimated 1- and 2-year OS rates were 90% and  
74% , respec t ively[27]. Ongoi ng cl i n ic a l t r ia ls 
(CYTOSHR INK [NCT04090710] and SAMUR AI 
[NCT05327686]) are now accruing to study how to 
effectively combine SBRT or SRS to the primary tumor, 
with systemic treatments to improve survival outcomes 
in f irst-line mccRCC[28]. Second, consolidative 
surgery remains an option in the refractory mccRCC 
setting. Either at the time of oligoprogression or for 
palliative purposes, surgical approaches can also be 
considered after the start of highly effective systemic 
therapy with ICI combinations. Two completed phase 
3 clinical trials, SURTIME and CARMENA, both 
demonstrated that cytoreductive nephrectomy (CN) 
may be delayed until a stable or partial response is 

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achieved on VEGFR TKI[29,30]. However, both trials 
completed enrollment prior to approval of current 
combination therapies (ICI plus ICI or ICI plus VEGFR 
TKI). There are three ongoing studies (NORDIC-SUN 
[NCT03977571], PROBE [NCT04510597], and CYTO-
KIK [NCT04322955]) which will provide prospective 
evidence regarding optimal timing of CN in the 
setting of ICI-based combinations in mccRCC. Lastly, 
surgical resection of metastases at time of progression 
is undefined. One must consider size and location of 
the metastatic site as well as tumor biology, along with 
patient performance status, before taking a surgical 

approach. Optimal management decisions require a 
multidisciplinary team approach.

In conclusion, the treatment landscape is continually 
evolving in first-line mccRCC, and changes with 
preferred front-line options will dictate second-line 
therapy and beyond to limit cross-tolerance and 
overcome resistance mechanisms. Combining other 
modalities (SBRT and surgery) may have roles in 
specific refractory settings, and we must also consider 
patient preferences and tolerability factors in refractory 
mccRCC. 

TABLE 2.

Selected ongoing clinical trials in refractory mccRCC 

Treatment regimen NCT Phase Est. enrollment Est. completion date

Olaparib (post ICI/ VEGFR)  
w/DNA repair mutationsa

NCT03786796 2 20 March 2024

Lenvatinib + everolimus vs.  
cabozantinibb 

NCT05012371 2 90 April 2023

Atezolizumab + cabozantinib vs.  
cabozantinibb (CONTACT-03c)

NCT04338269 3 523 Dec 2024

Pazopanib ± abexinostat (RENAVIV)b
NCT03592472

3 413 June 2022

Belzutifan + lenvatinib vs.  
cabozantiniba

NCT04586231 3 708 Dec 2024

Tivozanib + nivolumab vs.  
tivozanibb,d (Ti-NIVO2) 

NCT04987203 3 326 Aug 2025

Nivolumab + rHuPH20 vs.  
Nivo (CM-67T)d,e

NCT04810078 3 454 Jan 2026

a Post ICI/VEGFR; b post ICI; cenrollment completed; d > 1 or 2 treatments; e post VEGFR TKI. 
mccRCC: metastatic clear cell renal cell carcinoma

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Acknowledgments
Stephanie Berg: Advising/Consulting: Exelixis, BMS, 
Eisai, Pfizer, SeaGen, Sanofi

Martin Angel: No relevant disclosures.

Kathryn E. Beckermann: Research funding: Bristol-
Myers Squibb-IASLC-LCFA. Advising/consulting: 
Aravive, Aveo, BMS, Exelexis, Sanofi, Seagen, Astellas.

Frede Donskov: No relevant disclosures.

Chung-Han Lee: Research funding: BMS, Calithera, 
Eisai, Eli Lilly, Exelixis, Merck, Pfizer; Advising/
Consulting: Amgen, Aveo, BMS, Exelixis, Eisai, Merck, 
Pfizer, EMD Serono, Cardinal Health; Honoraria: 
AiCME, IDEOlogy Health, Intellisphere, Research to 
Practice.

Pavlos Msaouel: Research funding: Takeda, BMS, 
Mirati Therapeutics, Gateway for Cancer Re-search, and 

UT MD Anderson Cancer Center; Advising/consulting: 
Mirati Therapeutics, BMS, Exelixis, Axiom Healthcare, 
Exelixis, Pfizer Takeda, Bristol Myers Squibb, Mirati 
Therapeutics, Gateway for Cancer Re-search, and UT 
MD Anderson Cancer Center.

Rana R. McKay: Research funding: Bayer, Tempus; 
Consulting: Aveo, Astra Zeneca, Bayer, BMS, Calithera, 
Caris, Dendreon, Exelixis, JNJ, Myovant, Merck, 
Novartis, Pfizer, Sanofi, Sorrento Therapeutics, Tempus.

Tian Zhang: PI/Research funding: Acerta, Novartis, 
Merrimack, Abbvie/StemCentrx, Merck, Regeneron, 
Mirati Therapeutics, Janssen, Astra Zeneca, Pfizer, 
OmniSeq, Personal Genome Diagnostics, Astellas, 
Eli Lilly, CPRIT; Advisory Board/Consultant: Merck, 
Exelixis, Sanofi-Aventis, Janssen, Astra Zeneca, Pfizer, 
Amgen, BMS, Pharmacyclics, SeaGen, Calithera, QED 
Therapeutics, Eisai, Aveo, Eli Lilly, Aravive, Astellas, 
MJH Associates, Vaniam, Aptitude Health, PeerView.

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15. Grimm M-O, Esteban E, Barthélémy P, Schmidinger M, Busch J, 
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of a tailored approach in advanced renal cell carcinoma (TITAN-
RCC). J Clin Oncol.2021;39(15_suppl):4576-4576. doi: 10.1200/
JCO.2021.39.15_suppl.4576.

16. McKay RR, McGregor BA, Xie W, Braun DA, Wei X, Kyriakopoulos CE, 
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483 SIUJ  •  Volume 3, Number 6  •  November 2022 SIUJ.ORG

2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES

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