comments and controversies
Evaluating Trials of Adjuvant Therapy: Is
There Benefit for People With Resected
Renal Cancer?
Ian F. Tannock, MD, PhD1,2; Daniel A. Goldstein, MD2,3,4,5; Jonathan Ofer, MD3; Bishal Gyawali, MD6; and Tomer Meirson, MD3
The benefit of any treatment for any disease should be
judged by whether it improves either survival or its quality.
For adjuvant treatment of cancer, effects on overall
survival (OS) are paramount: Patients and their oncol-
ogists are willing to accept substantial toxicity and short-
term deficits in quality of life, if long-term survival can be
improved. Assessment of the validity of randomized
controlled trials (RCTs) evaluating adjuvant therapy re-
quires that several questions about trial design and
analysis be addressed: These factors are shown in
Figure 1. If selection of patients and random assignment
are appropriate, important questions are as follows:
1. If the primary end point is not OS, is it a valid
surrogate for OS? Disease-free survival (DFS) has
been the primary end point in trials of adjuvant
therapy for many types of cancer, but improve-
ment in this end point can occur either because
more patients are cured or because there is a delay
to relapse without change in the probability of long-
term survival; gains in survival for those randomly
assigned to receive adjuvant treatment may be
offset by using similar treatment in control patients
after relapse. In adjuvant trials for women with
breast cancer, 2-year DFS is only moderately
correlated with (smaller) gains in 5-year OS.1 On
the basis of a review of 13 older RCTs with more
than 6,400 participants evaluating adjuvant ther-
apy for renal cell cancer (RCC), Harshman et al2
concluded that there was no strong correlation
Author affiliations
between 5-year DFS and 5-year OS rates or be-
and support
information (if tween treatment effects on these end points. Some
applicable) appear might regard delayed relapse as a benefit, even in
at the end of this the absence of subsequent improvement in OS,
article. but this is offset by the physical and financial
Accepted on February toxicity of the adjuvant treatment that is received by
24, 2023 and
all patients, including those who do not relapse.
published at
ascopubs.org/journal/ 2. Is there evidence of bias in outcomes on the basis of
jco on March 24, the potential surrogate? Specifically, if the primary
2023: DOI https://doi. end point is DFS, is there unequal loss of patients
org/10.1200/JCO.23. between the arms of the trial leading to informative
00280
censoring of patients before disease recurrence is
© 2023 by American
recorded? Informative censoring confounds ran-
Society of Clinical
Oncology dom assignment since one is then comparing
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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
adjuvant treatment and placebo for those patients
who remain on study, which is not a representative
sample of the original randomized groups.3-6
3. Did the patients in the trial receive optimal therapy
after disease recurrence? Agents evaluated as po-
tential adjuvant treatments are usually selected
because they improve OS when used to treat people
with advanced disease. If the patients in the control
arm do not subsequently receive the treatment
evaluated as adjuvant therapy, or a similar agent,
the trial does not prove that earlier use of the agent
as adjuvant therapy (given to all patients) provides
better OS than its selective use after recurrence in
the smaller number of patients who recur.
4. How consistent are the results of the trial with those
of RCTs evaluating identical or similar treatments?
Consistency of results is a far stronger indication of
a true result than an apparently significant P value
in a single trial.7
People who present with RCC should, if possible, un-
dergo surgery to remove all evident disease. A variety of
prognostic models have estimated risk of recurrence
and death on the basis of clinical characteristics of
the tumor8: For patients classified as high-risk (eg, stage
2 [.7 cm] with poor histology or invasion into sur-
rounding tissue, or positive lymph nodes), this risk is
high, with 50% or more of patients eventually dying of
their disease. Thus, there is a substantial need for ef-
fective adjuvant therapy to improve survival. The
Keynote-564 study comparing 1 year of adjuvant
pembrolizumab with placebo has reported significant
improvement in its primary end point of DFS with a
hazard ratio [HR] of 0.63 (95% CI, 0.50 to 0.80) with a
nonsignificant trend to improved survival.9,10 This result
led to rapid approval for registration of adjuvant pem-
brolizumab by the United States Food and Drug Ad-
ministration (FDA) and the European Medicines Agency
and to inclusion in guidelines by the National Com-
prehensive Cancer Network (NCCN), the European
Society of Medical Oncology, and others. After review
of the evidence cited below, we suggest that these
decisions were premature and that no adjuvant therapy
is of proven value for RCC.
1
 Tannock et al

Informative
censoring?

Experimental group

Surrogate outcome
Optimal Consistency
Random assignment with other

OS
postprogression
therapy? studies?

Control group

Appropriate
Valid
control?
surrogate?

FIG 1. Important questions to ask of RCTs evaluating adjuvant therapy. A poor surrogate end point, informative
censoring, suboptimal treatment of controls at relapse, and inconsistency with the results of similar RCTs
confound the results of the Keynote-564 trial evaluating adjuvant pembrolizumab for renal cell carcinoma2,3 and
of the S-TRAC trial evaluating adjuvant sunitinib.4 OS, overall survival; RCTs, randomized controlled trials.

Unfortunately, results of the Keynote-564 trial are subject to
each of the concerns illustrated in Figure 1.11 There is
uneven dropout between the arms of the study during the
early follow-up period suggesting missing data for reasons
other than patients remaining on their assigned treatment
at time of the data lock. We lack information about re-
currence for these censored patients, but in a sensitivity
analysis, we have constructed curves for modified time to
treatment failure (mTTF),5 where excess censoring, in
addition to disease recurrence or death are regarded as
events (Fig 2A): the HR for mTTF is 0.81 (95% CI, 0.65 to
1.00) and not significant (P 5 .056). The authors of the
study undertook sensitivity tests for the primary end point of
DFS, which still provided significant results for differences
in the HR for DFS but they did not reproduce the mTTF test,
where only disproportionally censored patients in the
pembrolizumab group were considered events.12
Second, the subsequent treatment received by participants
who relapsed in the Keynote-564 trial was suboptimal: Only
36% of the 166 patients in the control group who relapsed
received any form of immunotherapy, despite consistent
evidence that such treatment improves survival for people
with metastatic RCC.13-17 The authors have defended this
management by stating that the standard treatment for
patients who relapse after nephrectomy is varied and might
consist of close surveillance, local ablative therapies, sur-
gery, or targeted therapy.12 Although some patients might
be managed initially in this way, participants in the trial had
intermediate or high-risk disease and 84% of control pa-
tients who recurred had metastases.10 With a median
follow-up of 30 months, there would have been few re-
lapsing patients with slowly progressive disease, and for
most relapsing patients, optimal treatment would have in-
cluded immunotherapy. In some countries immunotherapy
for advanced disease might not be available because of cost,
and sponsors of adjuvant trials should be required to provide
such treatment to relapsing control patients without cost. If
the small apparent difference in OS in the Keynote-546 study
becomes stronger with further follow-up, this might be due to
inferior treatment of controls at relapse rather than superior
treatment of those randomly assigned to receive adjuvant
pembrolizumab.
Finally, the results of three other trials evaluating adjuvant
immunotherapy for RCC with nivolumab 6 ipilumumab or
with atezolizumab have been published or presented, and
each of these trials failed to show significant differences in
DFS or OS.18-20 Some might argue that pembrolizumab is a
more effective drug, but this is not supported by the totality of
experience with immunotherapy, especially when compar-
ing the PD-1 inhibitors pembrolizumab and nivolumab.
Labaki and Choueiri21 have proposed that these different
results might be due to differences in trial design, such as
inclusion or not of patients whose tumors had sarcomatoid
differentiation, duration of adjuvant treatment, and inclusion
or not of patients who had no evident disease after meta-
stectomy. As shown in their Forest plot, the 8.7% of patients
who were randomly assigned after metastectomy in the
Keynote-564 trial seemed to have better than average im-
provement in DFS with pembrolizumab, consistent with
known benefits of the drug to improve outcomes in those
with metastatic disease. In general, the differences in pa-
tients between the trials were minor, and most patients had
clear cell RCC and received adjuvant treatment after ne-
phrectomy for localized disease. Inspection of the essentially

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 No Evidence to Support Adjuvant Therapy for Renal Cancer

A 1.00

Pembrolizumab
Placebo
0.75

Adjusted DFS (%)

0.50

0.25 HR, 0.81 (95% CI, 0.65 to 1.0)

P = .056

0 5 10 15 20 25 30 35 40 45 50

Time (months)
No. at risk:
Placebo 498 437 389 356 325 235 125 74 35 1 0
Pembrolizumab 496 458 416 396 361 260 135 77 39 19 0

B 1.00

Sunitinib
Placebo
0.75
Adjusted DFS (%)

0.50

0.25 HR, 1.0 (95% CI, 0.83 to 1.3)

P = .71

0 12 24 36 48 60 72 84 96

Time (months)
No. at risk:
Placebo 306 220 181 150 135 102 37 10 2
Sunitinib 309 225 173 153 144 119 53 10 3

FIG 2. Modified time to treatment failure curves derived from published DFS curves for (A) the Keynote 546 trial
comparing adjuvant pembrolizumab (red) with placebo (blue) and (B) the S-TRAC trial comparing adjuvant
sunitinib (red) with placebo (blue). Tumor recurrence, death, and excess censoring are regarded as events. Note
that unlike the original published curves, these adjusted DFS curves (corrected for informative censoring) do not
indicate significant differences between the randomized groups. DFS, disease-free survival; HR, hazard ratio.

superimposable DFS curves for the three negative trials
discloses no significant differences in rates of censoring
between the randomized groups, so unlike Keynote-564,
these trials appear free of the bias of informative censoring.
Even without inherent biases, trials evaluating similar strat-
egies can give different results because of statistical vari-
ability. As stated succinctly by Ioannidis7(p0696): “the high rate
of non-replication (lack of confirmation) of research dis-
coveries is a consequence of the convenient, yet ill-founded
strategy of claiming conclusive research findings solely on
the basis of a single study assessed by formal statistical
significance, typically for a P ,.05.”
The above experience with immunotherapy is reminiscent of
the evaluation of adjuvant sunitinib for RCC that was approved
by the FDA in 2017 (but not by the European Medicines
Agency) on the basis of statistical improvement in the primary
end point of DFS in the S-TRAC trial,22 despite superim-
posable OS curves (shown only in the appendix of the original
paper). The larger ASSURE trial evaluating both adjuvant
sunitinib and sorafenib was negative,23 as were two trials

Journal of Clinical Oncology 3

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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 Tannock et al

evaluating adjuvant therapy using the related drugs axitinib
and pazopanib.24,25 The S-TRAC trial suffers from each of the
limitations outlined in Figure 1 (informative censoring, where
corrected DFS curves are no longer significant, see Fig 2B,
suboptimal treatment of controls at relapse, and inconsistent
results with other trials). The treatment is toxic with four
sunitinib treatment-related deaths in the ASSURE trial23 and
reduces quality-of-life; although referred to as double-blind,
oncologists who manage patients taking sunitinib will rec-
ognize that its side effects do not allow effective concealment
of allocation. Although it is used rarely, adjuvant sunitinib
remains FDA-approved and still appears in NCCN and other
guidelines. With adjustment for the bias of inadequate
treatment of relapsing controls, OS might be shorter in patients
receiving adjuvant sunitinib. FDA approval should be
rescinded, and it should not be prescribed.
Recommendation of adjuvant pembrolizumab for high-
risk RCC is now included in several guidelines, including
those of the NCCN and European Society of Medical
Oncology, but the European Association of Urology
regards (appropriately) the evidence of benefit as weak.
On the basis of the above critical review, we suggest that
there is no proven role for adjuvant therapy with pem-
brolizumab or any other drug after nephrectomy for pa-
tients with high-risk RCC. Recommendations might
change if follow-up of current trials reveals substantial
improvement in OS, with assurance that most control
patients received optimal therapy after relapse. Future
trials of adjuvant therapy should avoid the problems
summarized in Figure 1 by specifying OS as the primary
end point and providing optimal treatment free of charge
to control patients who relapse.

AFFILIATIONS AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF

1
Division of Medical Oncology, Princess Margaret Cancer Centre, INTEREST
Toronto, Ontario, Canada Disclosures provided by the authors are available with this article at DOI
2
Optimal Cancer Care Alliance, Ann Arbor, MI https://doi.org/10.1200/JCO.23.00280.
3
Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel
4
Clalit Health Service, Tel Aviv, Israel
5
Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
AUTHOR CONTRIBUTIONS
6
Division of Cancer Care and Epidemiology, Departments of Oncology and Administrative support: Ian F. Tannock
Public Health Sciences, Queen’s University Cancer Research Institute, Manuscript writing: All authors
Kingston, Ontario, Canada Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

CORRESPONDING AUTHOR
Ian F. Tannock, MD, PhD, Division of Medical Oncology, Princess
Margaret Cancer Centre, 610 University Avenue, Toronto, ON M5G 2M9,
Canada; e-mail: ian.tannock@uhn.ca.

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 No Evidence to Support Adjuvant Therapy for Renal Cancer

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n n n

Journal of Clinical Oncology 5

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 Tannock et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Evaluating Trials of Adjuvant Therapy: Is There Benefit for People With Resected Renal Cancer?
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted.
Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript.
For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
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Ian F. Tannock Bishal Gyawali

Consulting or Advisory Role: Roche/Genentech, Bayer (Inst)
Daniel A. Goldstein
Stock and Other Ownership Interests: TailorMed, Vivio Health
Consulting or Advisory Role: Vivio Health
Research Funding: MSD (Inst), BMS (Inst), Janssen (Inst)
Consulting or Advisory Role: Vivio Health
Tomer Meirson
Consulting or Advisory Role: Purple Biotech
No other potential conflicts of interest were reported.

© 2023 by American Society of Clinical Oncology

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