








































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

Adjuvant therapy, neoadjuvant therapy, 
vascular endothelial growth factor receptor 
tyrosine kinase inhibitor, immune checkpoint 
inhibitor, renal cell carcinoma

See ”Acknowledgments” for details. Received on July 15, 2022 
Accepted on September 9, 2022 
This article has been peer reviewed.

Soc Int Urol J. 2022;3(6):465–477

DOI: 10.48083/ VSQG7437

2022 WUOF/SIU International Consultation on 
Urological Diseases: Neoadjuvant and Adjuvant 
Therapy for Renal Cell Carcinoma 

Naomi B. Haas,1 Jeffrey Shevach,1 Ian D. Davis,2 Tim Eisen,3 Marine Gross-Goupil,4 Anil Kapoor,5  
Viraj A. Master,6,7 Christopher W. Ryan,8 Manuela Schmidinger9

1Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States 2 Monash University Eastern Health Clinical School, 
Melbourne, Australia 3 University of Cambridge, Cambridge, United Kingdom 4 Département d‘Oncologie Médicale, Hôpital Saint André, CHU de Bordeaux, Bordeaux, 
France 5 McMaster University, Hamilton, Canada 6 Department of Urology, Emory University School of Medicine, Atlanta, United States 7 Winship Cancer Institute of 
Emory University, Atlanta, United States 8 Oregon Health and Science University, Knight Cancer Institute, Portland, United States 9 Department of Urology, Medical 
University of Vienna, Vienna, Austria

Abstract

Patients undergoing definitive surgery or ablative techniques for nonmetastatic kidney cancer have varying degrees 
of risk of recurrent disease post procedure. The ultimate goal of “adjuvant therapy” is to reduce the incidence of 
recurrent disease, and to cure more patients. We summarize the current state of perioperative therapy for kidney 
cancer and explore future directions to develop optimal adjuvant strategies. We define risk and risk of recurrence 
post-definitive therapy, describe the controversies surrounding the trial landscape of adjuvant vascular endothelial 
growth factor receptor tyrosine kinase inhibitors and immune checkpoint inhibitors. We review data on neoadjuvant 
therapy before advanced kidney cancer resection. Radiologic, ethnic, economic, and geographic considerations 
with respect to adjuvant therapy are highlighted, as well as adjuvant therapy issues especially pertinent to patients, 
future directions in adjuvant trial design specifically targeted to biomarkers and patient selection, and sequencing of 
treatment after adjuvant therapy in those patients with recurrence.

Introduction

Patients undergoing definitive surgery or ablative techniques for nonmetastatic kidney cancer have varying degrees 
of risk for recurrent disease post-procedure. The ultimate goal of “adjuvant therapy” is to reduce the incidence of 
recurrent disease, and to cure more patients.

This review summarizes the current state of perioperative therapy for kidney cancer and explores future directions 
to develop optimal adjuvant strategies. We define risk and risk for recurrence post-definitive therapy and describe the 
adjuvant trials landscape of adjuvant vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-
TKI) trials and immune checkpoint inhibitor (IO) trials. We review data on neoadjuvant therapy before advanced 
kidney cancer resection. Radiologic, ethnic, economic, and geographic considerations with regard to adjuvant ther-
apy are highlighted. Also covered are adjuvant therapy issues especially pertinent to patients, future directions in 
adjuvant trial design specifically targeted to biomarkers and patient selection, and sequencing of treatment after adju-
vant therapy in those patients with recurrence.

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SIUJ
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SIUJ
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Defining Risk
Risk for disease recurrence post-nephrectomy for renal 
cell cancer depends largely on the characteristics of 
the primary tumor. This risk can mainly be stratified 
based on stage and grade of the cancer. Patients with 
larger tumors and higher grade are at increased risk 
for recurrence after nephrectomy. Risk for recurrence 
for high-risk patients is greatest early (0–3 years) post-
nephrectomy and plateaus after 4 to 5 years[1].

Some predictive models that have been used for 
survival outcomes post-nephrectomy for renal cell 
carcinoma (RCC) including the UISS (University of 
California LA Integrated Staging System)[2], SSIGN 
(Stage, Size, Grade, Necrosis)[3], Karakiewicz nomo-
gram[4], GRANT (Grade, Age, Node, and Tumor)[5,6], 
and Leibovich[7,8]. The criteria used to determine risk in 
these staging systems can be found in Table 1.

Based on these predictive models, in general, patients 
with resected stage T3 or higher, and high-grade tumors, 
are at the highest risk for recurrent disease, and are 
most likely to benefit from an adjuvant agent that would 
decrease their risk for recurrence and improve overall 
survival (OS). Patients at lower risk (T1 and T2A disease) 
receiving adjuvant therapy for the most part may be 
overtreated, as the risk for recurrence is less than 20%. 
The patient population that would likely benefit the most 
from adjuvant therapy are those with resected metasta-
ses, as demonstrated in KEYNOTE-564[9].

Unanswered questions in adjuvant therapy include 
its role in non-clear cell histology. Non-clear cell histol-
ogies can have higher risk for recurrence, but are often 
excluded in adjuvant trials, including the recent land-
mark KEYNOTE-564 adjuvant pembrolizumab trial, 
which required a clear cell component[9].

Abbreviations 
DFS disease-free survival
FDA United States Food and Drug Administration
GRANT Grade, Age, Node, and Tumor
IO immune checkpoint inhibitor
irAEs immune-related adverse events
OS overall survival 
RCC renal cell carcinoma
RFS recurrence-free survival
SSIGN Stage, Size, Grade, Necrosis 
UISS University of California LA Integrated Staging System 
VEGF vascular endothelial growth factor
VEGFR-TKI vascular endothelial growth factor receptor tyrosine 
kinase inhibitor

TABLE 1.  
Predictive models for renal cell carcinoma recurrence and survival 

Risk stratification Criteria used
5-year cancer-specific survival

Low risk Intermediate risk High risk

UISS[2]
T-stage,  

Fuhrman grade, ECOG
91.1% 80.4% 54.7%

SSIGN[3]

TNM stage,  
tumor size,  

Fuhrman grade,  
tumor necrosis

0–2 points 
97.1%

3–4 points 
89.8%

5–6 points  
74.1%

7–9 points 
38.6%

10+ points 
19.2%

GRANT a[5,6]
Age, pT-stage,  

pN-stage,  
Fuhrman grade

0 or 1 risk factors 2 risk factors 3 or 4 risk factors

86%–94% 76% 16%–46%

Karakiewicz[4]
TNM stage,  

Fuhrman grade, 
 tumor size

N/A

Leibovich[7,8]

T-stage, N-stage, 
tumor size,  

Fuhrman grade,  
tumor necrosis

N/A

a 5-year survival outcome for GRANT score is overall survival. 
ECOG: Eastern Cooperative Oncology Group; GRANT: Grade, Age, Node, and Tumor; SSIGN: Stage, Size, Grade, Necrosis; M: metastatic stage; N: node; 
T: tumor; UISS: UCLA integrated staging system.

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Adjuvant Therapy Trials in Renal Cell 
Carcinoma
 Cytokine Era: Several adjuvant trials with cytokines 
or other biologics have been previously completed, and 
summarized elsewhere, and are outside the scope of this 
review[10].

Adjuvant Trials with Targeted Agents
The rationale for testing agents targeting the angiogenic 
pathway in the adjuvant setting is based on multiple 
observations showing that vascular endothelial growth 
factor (VEGF) is involved in the pathogenesis of 
metastasis[11]. Five placebo-controlled, adjuvant, phase 
3 studies investigated the benefit of targeted therapy 
with VEGFR-TKIs versus placebo (Table 2)[12–16]. The 
primary endpoint in all trials was disease-free survival 

(DFS); however, patient populations and study designs 
varied between the trials, with differing agents and 
duration of therapy.

Of these, only S-TRAC[14], which enrolled the highest 
risk group (pT3 and higher) demonstrated an improve-
ment in DFS with sunitinib compared with placebo. 
Patients assigned to sunitinib had a significantly 
improved DFS (6.8 years; 95% CI, 5.8–not reached) when 
compared to patients in the placebo arm (5.6 years; 95% 
CI, 3.8–6.6), though in an updated analysis, there was no 
difference in OS[17]. Notably, the ASSURE[13] trial did 
not identify a significant difference between adjuvant 
sunitinib versus placebo with respect to DFS. The differ-
ences in patient population may have accounted for the 
differences in results between S-TRAC and ASSURE. 
Only patients with clear cell histology were eligible for 

TABLE 2.  
Adjuvant trials with targeted agents in RCC 

Trial N Histology Patient characteristics
Treatment arms 

(vs. placebo)
Duration Endpoint Results

S-TRAC[14] 615 Clear cell
 High-risk RCC patients 

according to UISS
Sunitinib 1 year DFS

HR, 0.76 
95% CI, 0.59–0.98 

(P = 0.03)

ASSURE[13] 1943
Clear cell  

Non-clear cell
Nonmetastatic RCC; disease 
stage II–IV selected by UISS

Sunitinib/ 
Sorafenib

1 year DFS

HR, 1.02 (sunitinib) 
97.5% CI, 0.85–1.23 

(P =0.80) 
HR, 0.97 (sorafenib) 
97.5% CI, 0.80–1.17 

(P = 0.72)

SORCE[12] 1656
Clear cell  

Non-clear cell

Patients with Leibovich 
high- and intermediate-risk 

resected RCC

Sorafenib 
Sorafenib

1 year  
3 years

DFS

HR, 0.94 (1 year 
sorafenib) 95% CI, 
0.77–1.14 (P = 0.51) 
HR, 1.01 (3 years 

sorafenib) 
95% CI, 0.83–1.23 

(P = 0.95)

EVEREST[20] 1537
Clear cell 

Non-clear cell

Pathological stage 
intermediate or very high-

risk RCC patients with full or 
partial nephrectomy

Everolimus 9 cycles RFS
HR, 0.85 

95% CI, 0.72–1.00  
(P = 0.0246)a

PROTECT[16] 1540 Clear cell

Patients with moderately 
high or high risk after 

nephrectomy of localized 
or locally advanced RCC by 

AJCC TNM v.2010

Pazopanib 1 year DFS
HR, 0.86 

95% CI, 0.70–1.06  
(P = 0.17)

ATLAS[15] 700 Clear cell
High-risk, nonmetastatic 
RCC with nephrectomy by 

AJCC TNM v.2010
Axitinib 3 years DFS

HR, 0.87 
95% CI, 0.66–1.15  

(P = 0.32)

aOne-sided P value, not statistically significant (threshold for significance set at 0.022). 
AJCC TNM: American Joint Commission on Cancer Tumor, Node, Metastasis staging system; CI: confidence interval; DFS: disease-free survival;  
HR: hazard ratio; RCC: renal cell carcinoma; RFS: recurrence-free survival; UISS: UCLA integrated staging system.

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S-TRAC, while clear cell histology accounted for only 
80% of patients in ASSURE. Additionally, the higher 
risk (tumor stage 3 or higher) of patients in S-TRAC 
may have also led to differences in study outcomes. It 
should be noted, however, that in a post-hoc analysis of a 
subpopulation subject to the S-TRAC inclusion criteria, 
DFS was similar between all 3 arms[18]. While this anal-
ysis was underpowered to statistically detect a difference 
between sunitinib and placebo, there was no obvious 
trend in favor of active treatment. It is also possible 

that differences in trial conduct between S-TRAC and 
ASSURE, such as disease imaging intervals (earlier and 
more frequent in S-TRAC), may have contributed to the 
observed differences in DFS, but they would not have 
impact on OS.

While there were differences in outcome of the indi-
vidual VEGFR-TKI studies, a meta-analysis of adjuvant 
VEGFR-TKI trials for patients with RCC did identify a 
DFS benefit (HR, 0.84; 95% CI, 0.76–0.93)[19]. However, 

TABLE 3. 

Ongoing or completed adjuvant trials with immune checkpoint inhibitors in RCC 
 

Trial N Histology
Patient 

characteristics
Treatment arms

Duration 
(months)

Endpoint Result

KEYNOTE-546 
NCT03142334[9,58]

994 Clear cell

pT2, G4/sarcomatoid, 
N0 or 

pT3, G3-4, N0 or 
pT4, any G, N0 or 

pTany, any G, N1 or 
M1 resected

Pembrolizumab 12 DFS
HR, 0.63 
95% CI, 

0.50–0.80

RAMPART 
NCT03288532[59]

1750
Clear cell 

Non-clear cell
Leibovich 3–11

Durvalumab + 
Tremelimumab

12
DFS 
OS

Pending

CheckMate-914 
NCT03138512[24]

1628
Clear cell +/- 
sarcomatoid 

differentiation

pT2a,G3/4, N0 or 
pT2b, any G, N0 or 
pT3, any G, N0 or 
pT4, any G, N0 or 
pTany, any G, N1

Nivolumab + 
Ipilimumab

24 DFS Pendinga

IMmotion010[23] 778

Clear cell 
Non-clear cell 

with sarcomatoid 
differentiation

pT2, G4, or 
pT3a, G3-4 or 
pT3b, any G or 

pTany, any G, N1 or 
M1 resected

Atezolizumab 12 DFS Pendinga

PROSPER[37] 
adjuvant/

neoadjuvant
804

Clear cell 
Non-clear cell

>cT2aN0M0 or 
cTanyN1M0

Nivolumab
1 

neoadjuvant 
9 adjuvant

RFS Pending

LITESPARK-022 1600 Clear cell

pT2, G4/sarcomatoid, 
N0 or 

pT3, any G, N0 or 
pT4, any G, N0 or 

pTany, any G, N1 or 
M1 resected

Pembrolizumab ± 
belzutifan

12 DFS Pending

aPresentations of CheckMate-914 (Arm A), IMmotion-010, and PROSPER (EA8143) at European Society of Medical Oncology meeting 2022  
reported negative results. 
CI: confidence interval; DFS: disease-free survival; HR: hazard ratio; G: tumor grade; N: nodal stage; M: metastatic stage;  
OS: overall survival; pT: pathologic T-stage; RFS: recurrence-free survival.

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the meta-analysis did not identify an OS benefit (nor 
have any of the individual trials), and due to the lack 
of a proven OS benefit, coupled with the high rates of 
unacceptable toxicity and dropout from the treatment 
arms of the VEGFR-TKI trials, adjuvant therapy with 
sunitinib has not achieved widespread adoption, even in 
countries where sunitinib is approved for adjuvant ther-
apy in RCC.

EVEREST is a randomized, placebo-controlled, 
phase 3 trial of everolimus versus placebo for 54 weeks 
in patients with clear and non-clear cell RCC after 
nephrectomy or partial nephrectomy[20]. A total of 
1545 patients with pathological stage intermediate- or 
high-risk status were enrolled. The primary endpoint of 
the trial was recurrence-free survival (RFS), and with 
median follow-up of 76 months, there was improve-
ment in the everolimus arm that did not reach statistical 
significance (HR, 0.85; 95% CI, 0.72–1.00).

Adjuvant Trials with Immune Checkpoint 
Inhibitors
Immune checkpoint inhibitors (IOs) targeting the 
programmed cell death protein 1 (PD-1) pathway, or the 
cytotoxic T lymphocyte-associated protein 4 (CTLA-4) 
pathway have revolutionized the treatment of metastatic 
RCC. Their role in the adjuvant setting is currently under 
investigation in multiple clinical trials (Table 3), with 
one phase 3 trial—KEYNOTE-564—having published 
results so far.

KEYNOTE-564[9] is a randomized, double-blind, 
placebo-controlled, phase 3 trial testing the role of the 
PD-1 inhibitor pembrolizumab in patients with interme-
diate-high-risk, high-risk, or M1–no evidence of disease 
(NED) status including intermediate-risk (pT2, grade 4, 
N0M0 or pT3, any grade, N0, M0), high-risk (pT4, any 
grade, any N, M0 or any pT, any grade, N+, M0), and 
also patients who had undergone complete resection 
of metastasis (M1), within a year of primary surgery. 
Patients (n=994) were randomized to receive either 
pembrolizumab or placebo every 3 weeks for 1 year. The 
primary endpoint was investigator-assessed DFS, with 
OS as a secondary endpoint. After a median follow-up 
of 30.1 months, the DFS rate at 30 months was 75.2% 
and 65.5% for pembrolizumab and placebo, respectively 
(HR, 0.63; 95% CI, 0.50–0.80)[21]. OS data is not mature. 
The authors reported grades 3+4 treatment-related 
adverse events (AEs) for pembrolizumab and placebo in 
18.9% and 1.2%, respectively, with no treatment-related 
deaths. In the pembrolizumab group, 22% of patients 
discontinued treatment due to AEs. Based on these 
findings, pembrolizumab has received United States 
Food and Drug Administration (FDA) and European 
Medicines Agency (EMA) approval as an adjuvant treat-
ment in patients with RCC and high risk for relapse.

While data has not yet been presented, recent 
press releases indicate that adjuvant atezolizumab 
(IMmotion010) and ipilimumab and nivolumab combi-
nation therapy (CheckMate-914) have not demon-
strated benefit in the adjuvant setting[22–25]. Once 
full results are published, comparisons in trial design 
and patient selection will need to be carefully exam-
ined to determine why the results are inconsistent with 
KEYNOTE-564. Additional trials evaluating the utility 
of adjuvant IOs are ongoing (Table 3).

Neoadjuvant Therapy in RCC
The standard-of-care management of nonmetastatic 
disease remains surgical resection. Just as combination 
TKI and immunotherapy combinations have come 
to dominate the frontline metastatic space, so too are 
investigators attempting to capitalize on the synergy 
of these agents in the neoadjuvant setting[26–33]. A 
summary of ongoing trials investigating immunotherapy 
in the preoperative setting is found in Table 4.

Neoadjuvant therapy may have several potential 
advantages over adjuvant therapy: First, it may decrease 
tumor burden and improve surgical outcomes, allowing 
for nephron-sparing surgery in select cases, convert-
ing unresectable tumors to resectable, and decreasing 
venous involvement, thereby facilitating ease of surgery. 
Second, response of the primary tumor to therapy can 
predict long-term outcomes to a particular therapy, 
potentially allowing for adaptive adjuvant therapy trials. 
Also, neoadjuvant studies allow for collection of molec-
ular correlative data from peripheral blood as well as 
paired biopsy and resection specimens to aid in response 
evaluation. Lastly, the in situ tumor may provide 
increased priming of the immune system compared 
with micrometastatic disease, leading to a more robust 
immune response[34,35].

The application of immunotherapy in the neoad-
juvant setting is early. Two small phase 2 studies have 
demonstrated that neoadjuvant nivolumab prior to 
nephrectomy was safe and feasible, without delay 
to nephrectomy after receiving at least one dose of 
nivolumab[36,37]. The phase 3 study of neoadjuvant 
nivolumab, PROSPER RCC (NCT03055013), is the only 
phase 3 trial investigating preoperative immunotherapy 
versus observation, with results pending at the European 
Society Medical Oncology (ESMO)[38]. Perioperative 
durvalumab (anti–PD-L1) with or without tremelim-
umab (anti–CTLA-4) was investigated in a multicohort 
phase 1b trial evaluating combined IO[39]. There were 
no treatment-related delays or complications of surgery 
although the addition of tremelimumab was associated 
with excess immune-related AEs (irAEs) and the study 
was suspended.

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Rare instances of irAEs delaying surgery, include 
at least one grade 4 AE, which underscores the need 
for biologic markers of patient susceptibility to irAEs 
[36,39–42]. Notably, there was no signal regarding surgi-
cal complications across the above studies of neoad-
juvant immunotherapy. These data, combined with 
retrospective data, suggest that IO is safe to continue 
through surgery without interruption[43]. Additionally, 
while patients are less likely to have an AE with immu-
notherapy in the adjuvant setting, these AEs can be 

debilitating and permanent, requiring long-term immu-
nosuppression, whereas the AEs seen with VEGFR inhi-
bition typically resolve with drug cessation.

Regulatory Issues
Uptake of new therapies into routine clinical practice is 
based on published peer-reviewed evidence, influenced 
by international guidelines and recommendations, and 
tailored to the needs of each specific patient based on 
their circumstances and comorbidities. The “real-world” 

TABLE 4. 

Ongoing clinical trials investigating neoadjuvant therapy (± adjuvant component) in locally advanced or metastatic  
(with planned cytoreductive nephrectomy) RCC 

Immunotherapy or immunotherapy combinations

NCT Trial # Phase Arm Drug Dose

NCT04393350 2 Single Lenvatinib and pembrolizumab
 Len:18 mg daily 

Pembro: 200 mg q3w

NCT03680521 2 Single Sitravatinib and nivolumab
Sitravatinib: oral capsule daily 

Nivolumab: 24 mg IV q2w

NCT04385654 2 Single Toripalimab and axitinib
Toripalimab: 240 mg IV q3w 

Axitinib: 5 mg PO BID

NCT04118855 2 Single Toripalimab and axitinib
Toripalimab: 240 mg IV q3w 

Axitinib: 5 mg PO BID

NCT04995016 
PANDORA

2 Single Pembrolizumab and axitinib
Pembrolizumab: 200 mg q3w 

Axitinib: 5 mg PO BID

NCT05024318 
NAPSTER

2 Randomized
SABR (arm 1) vs. pembrolizumab 

and SABR (arm 2)

Arm 1: 
SABR: 42 Gy in 3 fractions 

Arm 2: 
Pembrolizumab 200 mg q3w x 3 cycles  
with SABR administered after cycle 1

NCT03341845 
NeoAvAx

2 Single Axitinib and avelumab
Axitinib: 5mg BID 

Avelumab: 10mg/kg q2w

NCT04028245 
SPARC-1

2 Single Spartalizumab and canakinumab
Spartalizumab: 400 mg q4w 
Canakinumab: 300 mg q4w

NCT03055013 
PROSPER RCC

3 Randomized
Perioperative nivolumab vs. 

observation

Nivolumab: 480 mg every 14 days x 1 
neoadjuvant cycle and up to 9 cycles 

adjuvantly

NCT04322955 
Cyto-KIK

2 Single
Preoperative nivolumab and 

cabozantinib
Nivolumab: 480 mg every 4 weeks 

Cabozantinib: 40 mg daily

aOr deemed unresectable by surgeon. bClear cell must be predominant histology ( > 50%). cBegins 2 weeks prior to nivolumab. dClear cell component. 
eIncluding rhabdoid and sarcomatoid differentiation. fFeasibility if > 85% proceed. gFirst 3 to 6 subjects will hold cabozantinib for 3 weeks prior to 
surgery; if safe, all others will hold for only 2 weeks prior. 

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TABLE 4. 

Ongoing clinical trials investigating neoadjuvant therapy (± adjuvant component) in locally advanced or metastatic  
(with planned cytoreductive nephrectomy) RCC 

Immunotherapy or immunotherapy combinations

NCT Trial # Phase Arm Drug Dose

NCT04393350 2 Single Lenvatinib and pembrolizumab
 Len:18 mg daily 

Pembro: 200 mg q3w

NCT03680521 2 Single Sitravatinib and nivolumab
Sitravatinib: oral capsule daily 

Nivolumab: 24 mg IV q2w

NCT04385654 2 Single Toripalimab and axitinib
Toripalimab: 240 mg IV q3w 

Axitinib: 5 mg PO BID

NCT04118855 2 Single Toripalimab and axitinib
Toripalimab: 240 mg IV q3w 

Axitinib: 5 mg PO BID

NCT04995016 
PANDORA

2 Single Pembrolizumab and axitinib
Pembrolizumab: 200 mg q3w 

Axitinib: 5 mg PO BID

NCT05024318 
NAPSTER

2 Randomized
SABR (arm 1) vs. pembrolizumab 

and SABR (arm 2)

Arm 1: 
SABR: 42 Gy in 3 fractions 

Arm 2: 
Pembrolizumab 200 mg q3w x 3 cycles  
with SABR administered after cycle 1

NCT03341845 
NeoAvAx

2 Single Axitinib and avelumab
Axitinib: 5mg BID 

Avelumab: 10mg/kg q2w

NCT04028245 
SPARC-1

2 Single Spartalizumab and canakinumab
Spartalizumab: 400 mg q4w 
Canakinumab: 300 mg q4w

NCT03055013 
PROSPER RCC

3 Randomized
Perioperative nivolumab vs. 

observation

Nivolumab: 480 mg every 14 days x 1 
neoadjuvant cycle and up to 9 cycles 

adjuvantly

NCT04322955 
Cyto-KIK

2 Single
Preoperative nivolumab and 

cabozantinib
Nivolumab: 480 mg every 4 weeks 

Cabozantinib: 40 mg daily

aOr deemed unresectable by surgeon. bClear cell must be predominant histology ( > 50%). cBegins 2 weeks prior to nivolumab. dClear cell component. 
eIncluding rhabdoid and sarcomatoid differentiation. fFeasibility if > 85% proceed. gFirst 3 to 6 subjects will hold cabozantinib for 3 weeks prior to 
surgery; if safe, all others will hold for only 2 weeks prior. 

access to and uptake of new therapies is inf luenced 
primarily by what is approved and, more importantly, 
reimbursed in each region or available to those with 
financial resources. The impact of heterogeneous 
regulatory approval processes was clearly illustrated 
with sunitinib. While sunitinib was granted approval 
as adjuvant therapy for patients with risk for RCC 
recurrence by the United States FDA, counterparts 
in the European Union and United Kingdom did not 
grant approval for an adjuvant indication. Additionally, 
the Kidney Cancer Research Network of Canada 

issued a consensus statement that did not support the 
use of VEGFR-TKI in the adjuvant setting following a 
systematic review and meta-analysis of trials in this 
space[44].

In November 2021, the FDA approved adjuvant 
pembrolizumab for patients who are at intermedi-
ate-high or high risk for recurrence after surgery based 
on the KEYNOTE-564 study results using investi-
gator-assessed DFS as the major efficacy outcome[9]. 
The review of the pembrolizumab submission was 

Duration Goal N Stage Histology Primary endpoint Status

12 weeks 17
≥cT3Nx or 
T any N+a

ccb ORR Recruiting

Sitravatinib: 6–8 weeksc 
Nivolumab: 4–6 weeks

25 Locally advanced RCC cc
ORR and point in 

treatment course of ORR
Active, not recruiting

6 weeks 40 cT ≥ 2 or cN+ non-cc MPR, pCR, pNR Not yet recruiting

Up to 12 weeks 30 T2-3, N0, M0 cc ORR Not yet recruiting

12 weeks 18
≥T3Nx or 
T any N+f

ccd MPR Not yet recruiting

9 weeks 26
T1b-3, N0-1, M0 or low volume 
M1 planned for nephrectomy

cce MPR Not yet recruiting

12 weeks 40
“nonmetastatic, completely 
resectable primary tumor of 
intermediate to high risk”

cc Rate of partial response
Results: 

30% partial response 
rate

8 weeks 14 ≥ cT2Nx or cTanyN1 ccb
% of patients who 
proceed to radical 

nephrectomyf
Not yet recruiting

7-28 days preoperative,  
up to 9 months  

post-operatively
766 ≥ cT2Nx or cTanyN1 any EFS Completed

Up to 12 weeksg 45 Metastatic ccb CR rate Recruiting

cc: clear cell; EFS: event-free survival; Gy: Gray; Len: lenvatinib; M: metastatic stage; MPR: major pathologic response; N: nodal stage;  
ORR: objective response rate; pCR: pathologic complete response; Pembro: pembrolizumab; pNR: pathologic nodal response; RCC: renal cell carcinoma;  
SABR: stereotactic ablative radiotherapy; T: tumor stage.

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also conducted under Project Orbis, which facilitates 
concurrent review of oncology products among inter-
national partners, allowing for simultaneous decisions 
in all countries. The Australian Therapeutic Goods 
Administration, Health Canada, and Swissmedic partic-
ipated in this review. The approval of pembrolizumab 
redemonstrated the FDA’s acceptance of DFS as a regu-
latory endpoint for adjuvant RCC trials. In the UK, the 
appraisal of pembrolizumab in the adjuvant setting has 
started, the EMA has approved, and publication of the 
results from the National Institute for Health and Care 
Excellence (NICE) are pending[45].

Issues Important to Patients
Adjuvant and Neoadjuvant Therapy
Adjuvant therapy given after curative intent therapy 
can be likened to life insurance: “a bet you do not want 
to win.” A life insurance policy is essentially saying to 
a company, “I bet I die,” and the company saying, “We 
bet you don’t.” A decision to undertake adjuvant therapy 
employs similar thinking. Patients with no apparent 
residual disease will be offered adjuvant therapy to 
reduce their theoretical risk for recurrence and death 
from cancer. Most patients who receive adjuvant 
therapy cannot benefit from it, and are therefore only 
exposed to possible harms, which is evident in the high 
discontinuation rate seen in the above adjuvant studies. 
However, it may be possible to increase the proportion 
of patients who may benefit through careful patient 
selection.

Conversely, neoadjuvant therapy is “a bet you want to 
win”—an investment in treatment now, while cancer is 
still detectable, to try to improve outcomes from defin-
itive treatment such as surgery. Currently for patients 
with renal cell cancer, this approach is nearly always in 
the context of a clinical trial, as its benefit is unproven.

Patient Preferences
Clinicians and patients often have different goals for 
treatment and expectations of outcomes. A patient 
preference substudy in the SORCE clinical trial[12] used 
a validated questionnaire aiming to understand what 
degree of improvement in survival would be judged by 
participants and investigators as sufficient to justify their 
participation and potential side effects from treatment 
with sorafenib[46]. Investigators judged that larger 
survival benefits were required than their patients to 
make adjuvant treatment worthwhile[46,47]. Patients 
and clinicians also perceive and report adverse events 
differently. Clinician assessment through the NCI 
Common Terminology Criteria for Adverse Events 
(CTCAE) is not always concordant with patient-reported 
outcomes (PRO)[48]. Owing to the differences between 
patient and clinician perspectives, it is imperative to 
work with community partners in the design of adjuvant 

clinical trials in RCC to ensure the outcomes align with 
community expectations and needs[49].

Unmet Needs
The most obvious unmet need in the context of 
clinical trials for RCC is for effective therapies. None 
of the trials so far have demonstrated a survival 
advantage, including the data with pembrolizumab in 
KEYNOTE-564[9]. It is therefore reasonable to advise 
patients that the standard of care remains observation, 
with access to life-prolonging therapies in the event of 
relapse. Patients want better treatments and outcomes 
with quicker results[50–53], and they want trials that 
examine and report the patient experience. These are all 
considerations for future trial designs but also apply to 
everyday treatment decision-making.

Future Directions
Several issues need to be considered when designing 
clinical trials of adjuvant therapy in RCC.

Statistical Designs for the Trials
There is equipoise in arguments for randomized control 
trials (RCTs) versus multi-arm multistage (MAMS) 
designs for adjuvant trials. RCTs are preferred in 
industry and ask well-defined controlled questions. This 
approach gives confidence that the trial will be delivered 
in the projected timescale and the simple design is easy 
for patients and physicians to understand. MAMS trials 
are ideal for academic consortia and can ask multiple 
questions simultaneously and in sequence and adapt to 
new data. Rapid advancements in prostate cancer have 
been made using this approach via STAMPEDE and 
in kidney cancer via RAMPART. This model allows 
adaptions that include adding arms, dropping arms, and 
changing control arms in light of new data. Although 
initially less attractive for commercial support, this 
approach, which demonstrated speed and quality of data 
at low cost, could be compelling.

Trial Endpoints
The aim of adjuvant treatment is to improve the cure rate 
or at least to prolong healthy life. OS remains the gold 
standard but in event-driven trials, this will either take 
a long time (generally 3 to 4 years to accrue and 3 to 7 
years for maturity) or will require very large numbers 
of patients. This massively increases costs and slows 
potential progress. Moreover, there is expenditure 
of patients who may not need therapy and perhaps 
undertreatment of very high-risk patients. Thus, DFS 
has become a de facto approach and was an accepted 
endpoint for S-TRAC and KEYNOTE-564. However, 
in a recent meta-analysis encompassing 13 studies and 
more than 6400 patients treated with adjuvant therapies 
for RCC, correlation between 5-year DFS and OS rates 
was modest, suggesting DFS is not a good surrogate 

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marker of OS[54]. These results underline the difficulty 
of choosing the good primary objective in designing an 
adjuvant clinical trial in RCC.

Essential requirements for future trials include 
cost-effectiveness: need for innovation in therapies to 
reduce health care costs, including the medium (such as 
oral checkpoint inhibitors instead of intravenous), the 
duration of therapy, and access to care. Finally, quality of 
life remains underappreciated: the diarrhea and dysgeu-
sia and fatigue experienced from VEGFR-TKIs continue 
to have poor remedy, and the autoimmune side effects 
from immunotherapy can be permanent. The risk/
benefit ratio for adjuvant therapy must outweigh that of 
reserving treatment only for metastatic disease.

Biomarkers Needed
Contemporar y metastatic clear cell cancer tria l 
designs have failed to address whether both IO and 
antiangiogenic therapy are necessary for individual 
patients. Both pure antiangiogenic trials and pure IO 
monotherapy trials have been applied to the adjuvant 
setting with continued uncertainty as to whom would 
benefit from adjuvant therapy or neoadjuvant therapy 
and for how long. With the availability of molecular 
signatures, which could improve prognostication, there 
is opportunity to design smarter trials. Transcriptomics, 
which appear to indicate sensitivity or resistance of 
some metastatic renal cancers to IO or antiangiogenic 
therapy[55], need validation and could be used to 
select treatments when indicated, or could be used in 
the development of adaptive, biomarker-driven basket 
trials similar to I-SPY2 in breast cancer (NCT01042379). 
The PROSPER trial is undergoing such analysis 
retrospectively. Specimens from the ASSURE trial are 
undergoing whole-exome RNA sequencing, which likely 
will provide further insight into which patients are more 

likely to relapse and have worse prognosis. Furthermore, 
analysis of kidney injury molecule-1 (KIM-1) from 
blood correlates with detection of recurrence[56] and 
plasma DNA methylation immunoprecipitation analysis 
are being retrospectively validated to predict recurrence 
in this population[57]. If validated, these tools could be 
applied to future trials to guide patient populations to be 
offered or spared adjuvant therapy.

Sequencing of Treatments Postadjuvant Therapy
The new approval and future use of IO adjuvant therapy 
in some patients affects the design of first-line metastatic 
renal cancer trials. The timing of relapse may be 
important, as it is untested whether patients who relapse 
while receiving adjuvant therapy might still benefit 
from VEGFR-TKI monotherapy or VEGFR-TKI /IO 
or IO/IO. Furthermore, should patients who relapse 6 
months after IO therapy be considered differently than 
those who relapse later post-therapy? For now, these are 
unanswered questions. The application of molecular 
typing becomes essential in this era, and tools such as 
KIM-1, DNA methylation, or circulating tumor DNA 
(ctDNA) if sensitive enough, could be used for cancer 
screening, as is in process in GRAIL[58], to identify 
earlier cancers and thereby obviate the use of adjuvant 
therapy in many patients.

Conclusions
While IO shows promise for the adjuvant treatment of 
high-risk clear cell RCC, there is still much to learn from 
ongoing clinical trials and longer follow-up data in this 
space, and the lessons learned from adjuvant targeted 
therapy trials must now be applied to this era. We must 
await and properly weigh OS data from trials of adjuvant 
IO, and we should strive to identify readily scalable 
biomarkers that can be used to hone patient selection 
criteria in future prospective therapeutic trials.

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Acknowledgments
N. Haas: Participation on a data safety monitoring 
board or advisory board: Merck; Eisai, Exilexis, Aveo, 
Roche (all paid to me). Leadership or fiduciary role in 
other board, society, committee or advocacy group, 
paid or unpaid: Co-Chair Genitourinary Committee 
ECOG-ACRIN, Member NCI GU Steering Committee, 
ECOG-ACRIN representative to NCI Renal Task Force. 
Funding: DOD Kidney Cancer Consortium.

J. Shevach: T32HG009495 funding support.

I. Davis: Participation on a data safety monitoring 
board or advisory board: Ipsen; Eisai, BMS, Merck/
Pfizer avelumab, AztraZeneca IO (all advisory boards 
unpaid; honoraria paid directly to ANZUP). Leadership 
or fiduciary role in other board, society, committee or 
advocacy group, paid or unpaid: Director and Board 
Chair, ANZUP Cancer Trials Group (unpaid).

Other financial or non-financial interests: Institutional 
payments to support kidney cancer trials: ANZUP 
Cancer Trials Group, MSD, AstraZeneca, Exelixis, 
Merck, Pfizer, Eisai.

T. Eisen: Employment: AstraZeneca (to March 2020); 
Employment as VP Oncology Early Clinical Dev Roche 
(from March 2020); Employment as VP GU Oncology 
Late Clin Dev AstraZeneca Research support. Stock 
options AstraZeneca and Roche. Leadership or fiduciary 
role in other board, society, committee or advocacy 
group, paid or unpaid: Macmillan Cancer Support 
Trustee for 10 years to 2021; Cambridge University 
Health Partners non-executive director

Travel Support to Genitourinary Symposiums ASCO 
2020 Roche.

M. Gross-Goupil: Participation on a data safety 
monitoring board or advisory board: MSD, BMS, Pfizer, 
Ipsen. Leadership or fiduciary role in other board, 
society, committee or advocacy group, paid or unpaid: 
Member of the GETUG. Support for attending meetings 
and/or travel: MSD, Ipsen, BMS, Pfizer.

A. Kapoor: Participation on a data safety monitoring 
board or advisory board: Ipsen, Eisai, Merck, BMS, 
Janssen, Bayer, Abbvie (Advisory Boards). Leadership 
or fiduciary role in other board, society, committee or 
advocacy group, paid or unpaid: Chair, Kidney Cancer 
Research Network of Canada (KCRNC). Stock options: 
Verity Pharma.

V. Master: Participation on a data safety monitoring 
board or advisory board: Merck, Pfizer, BMS, Exilexis.

Support for attending meetings and/or travel: American 
College of Surgeons.

C. Ryan: Grants or contracts from any entity: Ayala, 
Bristol Meyer Squibb, Daiichi-Sankyo, Deciphera, 
Exelixis, Genentech, Novartis, Karyopharm, Merck, 
Nektar, Pfizer, Xynomic, Shasqi, Monopar, Boehringer 
Ingelheim, PTC Therapeutics, Trillium Therapeutic 
(to my institution for all). Consulting Fees: Exelixis (all 
payments to me) Aveo, Daiichi, Sankyo, Synox, Bristol 
Meyer Squibb, Astra Zeneca, Janssen.

M. Schmidinger: Consulting fees and honoraria: BMS, 
MSD, Ipsen, Exelixis, EISAI. Support for attending 
meetings and/or travel: MSD Ipsen BMS. Participation 
on a data safety monitoring board or advisory board: 
BMS MSD, Ipsen, EISAI.

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476SIUJ.ORG SIUJ  •  Volume 3, Number 6  •  November 2022

Neoadjuvant and Adjuvant Therapy for Renal Cell Carcinoma

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