A Phase 3, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Pembrolizumab (MK-3475) as Monotherapy in the Adjuvant Treatment of Renal Cell Carcinoma Post Nephrectomy (KEYNOTE-564)
Phase: PHASE3
Conditions: Renal Cell Carcinoma
Sponsor: Merck Sharp & Dohme LLC

Product:  MK-3475 
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Protocol/Amendment No.: 564-04 
MK-3475-564-04 Final Protocol
13-Oct-2020
Confidential
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
Protocol Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of 
Pembrolizumab (MK-3475) as Monotherapy in the Adjuvant Treatment of Renal Cell 
Carcinoma Post Nephrectomy (KEYNOTE-564)
Protocol Number: 564-04
Compound Number: MK-3475
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND NUMBER: 122,753
EudraCT NUMBER: 2016-004351-75
NCT NUMBER: NCT03142334
Approval Date: 13 October 2020
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-564-04
13-OCT-2020
To update the censoring rules and remove the PK/ADA sample 
collection.
3475-564-03
11-MAY-2020
Changed the trigger for IA1 timing and total number of targeted events 
for final analysis of DFS by investigator review (IA2) and added 
secondary endpoint to compare event-free survival (EFS) as assessed by 
the blinded independent radiology review for participants treated with 
pembrolizumab versus those receiving placebo.
3475-564-02
04-SEP-2019
Because of the extension of study enrollment from 18 months to 25 
months, there is not sufficient minimum follow-up time if IA1 is 
triggered based on the originally desired number of DFS events 
projected at 3 months after last participant randomized. Thus, IA2 has 
been retooled as IA1 where the trigger is 80% DFS events accrued. This 
will represent roughly a minimum follow-up of 12 months after 
enrollment is finished.
 
 
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Document
Date of Issue
Overall Rationale
3475-564-01
02-NOV-2017
In the global implementation of protocol approved 24-FEB-2017 
deficiencies were noted. The initial intent was to include metachronous 
and synchronous M1 NED postoperative nephrectomy ≤1 year. Since 
study inception, the inclusion of metachronous and synchronous M1 
NED patients was intended; however, during protocol finalization 
metachronous was inadvertently removed. Additionally, minor 
adjustments are incorporated to enhance the clarity of the protocol 
intent, reflect real-time feedback from investigators, and address 
language inconsistencies
3475-564-00
24-FEB-2017
Original
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 04
Overall Rationale for the Amendment:
To update the censoring rules and to remove the sample collection for PK and ADA.
Summary of Changes Table:
Section # and Name
Description of Change
Brief Rationale
2 Schedule of Activities (SoA)
Updated column headers for 
Posttreatment Visits.
Template update to provide clarity, minimize errors, and 
promote consistency.
2 Schedule of Activities (SoA)
Removed PK/ADA sample 
collection.
Correction; the collection of samples for PK/ADA was stopped 
under Amendment 02 of this protocol.
9.6 Pharmacokinetics
9.6.1.1 Blood Collection for PK
9.6.1.2 Blood Collection for Anti-
Pembrolizumab Antibodies
Removed sections on PK and 
ADA sample collection and 
analysis.
Correction; the collection of samples for PK/ADA was stopped 
under Amendment 02 of this protocol.
8.1 Discontinuation of Study 
Treatment
Updated template language to 
include that a participant may 
withdraw from the study after 
discontinuation.
Clarification that continued follow-up after discontinuation is 
not required if a participant chooses to withdraw from the 
study.
9.1.8 Treatment Administration
Updated “administered” to 
“monitored.”
Clarification. The amended language more closely matches 
actual practice at sites and will reduce deviations.
 
 
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Section # and Name
Description of Change
Brief Rationale
9.10.3.3 Follow-up Visits
Added updated template text 
to include participants who 
complete all cycles of 
treatment with those who 
should be followed up for 
efficacy.
To provide clarity, minimize errors, and promote consistency.
10.2 Responsibility for 
Analyses/In-house Blinding
Removed “from a subset” 
from the description of BICR 
review of imaging scans.
All images will be reviewed by BICR, not a subset.
10.6.1.1 Disease-Free Survival
10.6.1.5 Summary of Analysis 
Strategy
Updated censoring rules for 
the primary analysis and the 
sensitivity analysis. The new 
primary analysis is the old 
sensitivity analysis 1 and new 
sensitivity analysis is the old 
primary analysis. The old 
sensitivity analysis 2 is 
removed. Updated Tables 10 
and 11.
Updated the censoring rules per the most recent oncology 
standard for an adjuvant study to follow ITT rule.
10.6.2 Statistical Methods for 
Safety Analyses
Changed “Dose Modification 
due to AE” to “Dose 
Interruption due to AE” in 
Table 12.
Correction: No dose modification was permitted; only 
interruption or discontinuation.
Overall
Minor edits to style and 
formatting to align with 
current Merck style.
To make the document amenable to structured content 
management.
 
 
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Table of Contents
DOCUMENT HISTORY ....................................................................................................... 3
PROTOCOL AMENDMENT SUMMARY OF CHANGES.............................................. 5
1.
Synopsis...................................................................................................................... 16
2.
Schedule of Activities (SoA)..................................................................................... 20
3.
Introduction............................................................................................................... 30
Study Rationale..................................................................................................... 30
Background ........................................................................................................... 31
Pharmaceutical and Therapeutic Background .................................................... 31
Benefit/Risk Assessment....................................................................................... 32
4.
Objectives/Hypotheses and Endpoints.................................................................... 32
5.
Study Design.............................................................................................................. 34
Overall Design....................................................................................................... 34
Trial Diagram...................................................................................................... 36
Number of Participants........................................................................................ 37
Beginning and End of Study Definition.............................................................. 37
Clinical Criteria for Early Trial Termination...................................................... 37
Scientific Rationale for Study Design.................................................................. 37
Rationale for Endpoints ...................................................................................... 43
Efficacy Endpoints....................................................................................... 43
Safety Endpoints.......................................................................................... 44
Pharmacokinetic Endpoints ......................................................................... 44
Patient-Reported Outcomes ......................................................................... 44
Planned Exploratory Biomarker Research................................................... 45
Planned Genetic Analysis ............................................................................ 46
Future Biomedical Research........................................................................ 47
Rationale for the Use of Comparator/Placebo .................................................... 47
Justification for Dose............................................................................................ 47
 
 
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6.
Study Population....................................................................................................... 48
Inclusion Criteria.................................................................................................. 48
Exclusion Criteria................................................................................................. 51
Lifestyle Restrictions ............................................................................................ 53
Meals and Dietary Restrictions........................................................................... 54
Caffeine, Alcohol, and Tobacco ......................................................................... 54
Activity ............................................................................................................... 54
Screen Failures...................................................................................................... 54
Participant Replacement Strategy ...................................................................... 54
7.
Treatments................................................................................................................. 54
Treatments Administered .................................................................................... 54
Dose Modification (Escalation/Titration/Other)................................................ 55
Dose 
Modification 
and 
Toxicity 
Management 
Guidelines 
for 
Pembrolizumab ................................................................................................... 55
Method of Treatment Assignment....................................................................... 60
Stratification........................................................................................................ 61
Blinding.................................................................................................................. 61
Preparation/Handling/Storage/Accountability .................................................. 61
Dose Preparation................................................................................................. 61
Handling, Storage and Accountability................................................................ 61
Treatment Compliance......................................................................................... 62
Concomitant Therapy........................................................................................... 62
Rescue Medications & Supportive Care............................................................. 63
Treatment After the End of the Study................................................................ 64
Clinical Supplies Disclosure................................................................................. 64
8.
Discontinuation/Withdrawal Criteria..................................................................... 64
Discontinuation of Study Treatment................................................................... 64
Withdrawal from the Study................................................................................. 66
Lost to Follow Up.................................................................................................. 66
9.
Study Assessments and Procedures......................................................................... 66
Administrative and General Procedures ............................................................ 67
Informed Consent................................................................................................ 67
 
 
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General Informed Consent........................................................................... 67
Inclusion/Exclusion Criteria ............................................................................... 67
Participant Identification Card............................................................................ 68
Medical History .................................................................................................. 68
History of Renal Cell Carcinoma................................................................. 68
Prior and Concomitant Medications Review ...................................................... 68
Prior Medications......................................................................................... 68
Concomitant Medications............................................................................ 68
9.1.5.2.1
Poststudy Anticancer Therapy.............................................................. 69
Assignment of Screening Number...................................................................... 69
Assignment of Treatment/Randomization Number............................................ 69
Treatment Administration................................................................................... 69
Timing of Dose Administration................................................................... 69
Withdrawal/Discontinuation............................................................................... 70
Withdrawal From Future Biomedical Research .......................................... 70
Participant Blinding/Unblinding......................................................................... 70
Calibration of Critical Equipment....................................................................... 71
Efficacy Assessments ............................................................................................ 72
Tumor Imaging and Assessment of Disease Recurrence.................................... 72
Initial Tumor Imaging at Screening............................................................. 74
Tumor Imaging During Treatment............................................................... 74
End of Treatment and Follow-up Tumor Imaging....................................... 74
Quality of Life Assessments ............................................................................... 75
EuroQoL 5 Dimensions 5 Levels................................................................. 76
European Organization for the Research and Treatment of Cancer 
Quality of Life Questionnaire C30 .............................................................. 76
Functional Assessment of Cancer Therapy Kidney Symptom Index –
Disease-Related Symptoms ......................................................................... 76
Adverse Events, Serious Adverse Events and Other Reportable Safety 
Events..................................................................................................................... 77
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information.................................................................................... 77
Method of Detecting AE and SAE...................................................................... 80
Follow-up of AE, SAE and Other Reportable Safety Event Information........... 80
 
 
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Regulatory Reporting Requirements for SAE .................................................... 80
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying 
as AEs or SAEs................................................................................................... 80
Pregnancy and Exposure During Breastfeeding ................................................. 81
Events of Clinical Interest (ECI)......................................................................... 81
Treatment of Overdose......................................................................................... 81
Safety...................................................................................................................... 82
Physical Examinations........................................................................................ 82
Full Physical Examination........................................................................... 82
Directed Physical Examination.................................................................... 82
Vital Signs........................................................................................................... 82
Electrocardiograms ............................................................................................. 82
Clinical Safety Laboratory Assessments............................................................. 83
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis).................................................................................................... 83
Pregnancy Test............................................................................................. 84
Performance Assessments................................................................................... 84
Eastern Cooperative Oncology Group Performance Status (ECOG PS)..... 84
Pharmacokinetics.................................................................................................. 84
Blood Collection for RNA Analysis and Plasma and Serum Biomarker 
Analysis............................................................................................................... 85
Pharmacodynamics............................................................................................... 85
Tumor Tissue Collection..................................................................................... 85
Future Biomedical Research Sample Collection................................................ 85
Biomarkers ............................................................................................................ 86
Planned Genetic Analysis Sample Collection..................................................... 86
Visit Requirements ............................................................................................... 86
Screening............................................................................................................. 86
Treatment Period Visits ...................................................................................... 87
End of Treatment Visit........................................................................................ 87
Posttreatment Period ........................................................................................... 87
Safety Follow-up Visit................................................................................. 88
Efficacy Follow-up Visits............................................................................ 88
 
 
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Survival Follow-up Contacts ....................................................................... 88
Discontinued Participants Continuing to be Monitored in the Study ................. 88
Survival Status .................................................................................................... 88
Medical Resource Utilization and Health Economics ....................................... 89
10.
Statistical Analysis Plan ........................................................................................... 89
Statistical Analysis Plan Summary ..................................................................... 89
Responsibility for Analyses/In-house Blinding .................................................. 90
Hypotheses/Estimation......................................................................................... 91
Analysis Endpoints ............................................................................................... 92
Efficacy Endpoints.............................................................................................. 92
Primary......................................................................................................... 92
Secondary..................................................................................................... 92
Safety Endpoints ................................................................................................. 92
Analysis Population .............................................................................................. 92
Efficacy Analysis Population.............................................................................. 92
Safety Analysis Population................................................................................. 93
Statistical Methods................................................................................................ 93
Statistical Methods for Efficacy Analyses.......................................................... 93
Disease-Free Survival .................................................................................. 93
Overall Survival........................................................................................... 94
Disease Recurrence-Specific Survival......................................................... 95
Event-Free Survival ..................................................................................... 95
Summary of Analysis Strategy .................................................................... 95
Statistical Methods for Safety Analyses ............................................................. 96
Summaries of Demographic and Baseline Characteristics ................................. 98
Interim Analyses ................................................................................................... 98
Safety Interim Analyses...................................................................................... 98
Efficacy Interim Analyses................................................................................... 99
Multiplicity ............................................................................................................ 99
Multiplicity Control for Efficacy Analyses ........................................................ 99
Multiplicity Control for Safety Analyses.......................................................... 102
Sample Size and Power Calculations ................................................................ 102
 
 
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Subgroup Analyses ............................................................................................. 103
Compliance (Medication Adherence)................................................................ 103
Extent of Exposure.............................................................................................. 103
11.
References................................................................................................................ 104
12.
Appendices............................................................................................................... 114
Appendix 1: Abbreviations and Trademarks .................................................. 114
Appendix 2: Clinical Laboratory Tests ............................................................ 117
Appendix 3: Study Governance Considerations.............................................. 120
Merck Code of Conduct for Clinical Trials .................................................................. 120
Financial Disclosure...................................................................................................... 122
Data Protection.............................................................................................................. 122
Confidentiality of Data ................................................................................................. 122
Confidentiality of Participant Records.......................................................................... 122
Confidentiality of IRB/IEC Information....................................................................... 123
Committees Structure.................................................................................................... 123
Scientific Advisory Committee................................................................................. 123
Executive Oversight Committee............................................................................... 123
Data Monitoring Committee..................................................................................... 123
Publication Policy ......................................................................................................... 124
Compliance with Trial Registration and Results Posting Requirements...................... 124
Compliance with Law, Audit and Debarment .............................................................. 124
Data Quality Assurance ................................................................................................ 125
Source Documents ........................................................................................................ 126
Study and Site Closure.................................................................................................. 126
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................. 127
Definition of AE ........................................................................................................... 127
Definition of SAE ......................................................................................................... 128
Additional Events reported as SAE .............................................................................. 129
Recording AE and SAE ................................................................................................ 129
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor............... 133
Appendix 5: Contraceptive Guidance and Pregnancy Testing ...................... 134
 
 
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Contraception Requirements......................................................................................... 134
Pregnancy...................................................................................................................... 135
Use in Nursing Women................................................................................................. 135
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research........................................................................................... 136
Appendix 7: Poisson Mixture Model................................................................. 140
 
 
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LIST OF TABLES
Table 1
Summary of Clinical Efficacy From Randomized Phase 3 Studies in First-
Line Advanced RCC............................................................................................. 39
Table 2
Completed and Ongoing Targeted Adjuvant Therapies ....................................... 42
Table 3
Adequate Organ Function Laboratory Values...................................................... 51
Table 4
Study Treatments .................................................................................................. 55
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse Events Associated With Pembrolizumab ............................................... 56
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ............................................................................................................. 59
Table 7
Criteria for Determining Recurrence of Disease .................................................. 73
Table 8
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events...................................................................................... 79
Table 9
Eastern Cooperative Oncology Group Performance Status.................................. 84
Table 10
Censoring Rules for Primary and Sensitivity Analysis of Disease-Free 
Survival................................................................................................................. 94
Table 11
Analysis Strategy for Key Efficacy Endpoints..................................................... 96
Table 12
Analysis Strategy for Safety Parameters............................................................... 98
Table 13
Analyses Planned, Endpoints Evaluated, and Drivers of Timing......................... 99
Table 14
Boundary Properties for Planned Interim and Final Analyses for DFS.............. 101
Table 15
Boundary Properties for Planned Interim and Final Analyses for OS................ 101
Table 16
Protocol-Required Safety Laboratory Assessments............................................ 118
 
 
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LIST OF FIGURES
Figure 1
Trial Diagram........................................................................................................ 36
Figure 2
Multiplicity Graph for Type I Error Control of Study Hypotheses .................... 100
Figure 3
Disease-Free Survival Curves Using the Poisson Mixture Model and 
Exponential Model.............................................................................................. 140
 
 
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1. Synopsis
Protocol Title:  
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Pembrolizumab 
(MK-3475) as Monotherapy in the Adjuvant Treatment of Renal Cell Carcinoma Post 
Nephrectomy (KEYNOTE-564)
Short Title: 
Phase 3 Placebo-Controlled Trial of Adjuvant MK-3475 in RCC Post Nephrectomy
Objectives/Hypothesis and Endpoints:
The following objectives will be evaluated in the adjuvant treatment of participants who have 
undergone nephrectomy and have intermediate-high risk, high risk, or M1 NED renal cell 
carcinoma RCC with clear cell component.
Objective/Hypothesis
Endpoint(s)
Primary
●
Objective: To compare DFS as 
assessed by the investigator for 
participants treated with 
pembrolizumab versus those 
receiving placebo 
●
Hypothesis: Pembrolizumab is 
superior to placebo with respect to 
DFS
●
DFS as assessed by the investigator: 
time from randomization to the first 
documented local recurrence, or 
occurrence of distant kidney cancer 
metastasis(es), or death due to any 
cause, whichever occurs first.
Key Secondary
●
Objective: To compare OS for 
participants treated with 
pembrolizumab versus those 
receiving placebo
Hypothesis: Pembrolizumab is 
superior to placebo with respect to 
OS
●
OS: time from randomization to death 
due to any cause
 
 
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Other Secondary
●
To compare the safety and 
tolerability profiles for participants 
treated with pembrolizumab versus 
those receiving placebo
●
AEs, SAEs, AEs leading to 
discontinuation, deaths, laboratory 
values, and vital signs 
●
To compare measures of DRSS, as 
assessed by the investigator, for 
participants treated with 
pembrolizumab versus those 
receiving placebo
●
DRSS1 as assessed by the investigator: 
time from randomization to the first 
documented local recurrence of RCC
●
DRSS2 as assessed by the investigator: 
time from randomization to the first 
documented local recurrence with 
visceral lesion or occurrence of distant 
kidney cancer metastasis(es) with 
visceral lesion, whichever occurs first.
●
To compare EFS as assessed by the 
blinded independent radiology 
review for participants treated with 
pembrolizumab versus those 
receiving placebo 
●
EFS is to be assessed by BICR. EFS is 
defined as time from randomization to 
the first documented local recurrence or 
occurrence of distant kidney cancer 
metastasis(es) among participants, 
which by BICR were considered 
M0/M1 NED; or disease progression 
among participants, which by BICR 
were considered to have M1, or death 
due to any cause, whichever occurs 
first. See Section 9.2.1 for the definition 
of disease progression.
●
To compare DFS and OS according 
to participants’ PD-L1 expression 
status (Positive, Negative) for 
participants treated with 
pembrolizumab versus those 
receiving placebo
●
DFS as assessed by the investigator: 
time from randomization to the first 
documented local recurrence, or 
occurrence of distant kidney cancer 
metastasis(es), or death due to any 
cause, whichever occurs first.
●
OS: time from randomization to death 
due to any cause.
●
To evaluate PROs with the 
EORTC-QLQ-C30 and the 
FKSI-DRS
●
EORTC-QLQ-C30
●
FKSI-DRS
 
 
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Overall Design:
Trial Phase
III
Clinical Indication
Treatment of participants with RCC in the adjuvant 
setting
Population
Post nephrectomy; intermediate-high risk, high risk, and 
M1 NED RCC
Trial Type
Interventional
Type of design
Randomized
Type of control
Placebo
Trial Blinding
Double-blind
Estimated duration 
of trial
The Sponsor estimates that the trial will require 
approximately 50 months to achieve the primary 
objective and 72 months to achieve the key secondary 
objective from the time the first participant signs the 
informed consent until the last participant’s last study-
related phone call or visit.
 
 
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Number of Participants:
Approximately 950 participants will be enrolled.
Treatment Groups and Duration:
Treatment Groups
Placebo or pembrolizumab 200 mg, administered by 
intravenous infusion every 3 weeks. Treatment will be up 
to (approximately) 1 year.
Duration of 
Participation
Each participant will participate in the trial from the time 
the participant signs the informed consent form through 
the final protocol-specified contact. After a screening 
phase of up to 42 days, each participant will be assigned 
to receive trial treatment until disease recurrence, 
unacceptable AEs, intercurrent illness that prevents 
further administration of treatment, investigator’s 
decision to withdraw the participant, noncompliance with 
trial treatment or procedural requirements, administrative 
reasons requiring cessation of treatment, or until the 
participant has received 17 cycles of study treatment
(approximately 1 year). After the end of treatment, each 
participant will be followed for the occurrence of AEs
and spontaneously reported pregnancy as described under 
Section 9.3. Participants who discontinue for reasons 
other than disease recurrence will have posttreatment 
imaging follow-up for disease status until confirmation of 
disease recurrence, initiating a new anticancer treatment, 
withdrawing consent, or becoming lost to follow-up. All 
participants will be followed by telephone for OS until 
death, withdrawal of consent, or the end of the study.
Abbreviations are not spelled out at first use. A list of abbreviations used in this document 
can be found in Appendix 1. Study Governance Considerations are outlined in Appendix 3.
 
 
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2. Schedule of Activities (SoA)
Trial Period:
Screening
Treatment
End of 
Treatment
Posttreatment Period
Notes
Treatment Cycle/Visit
1
2
3
4
5
6
7
8a
9a
Discon
Safety
Efficacy 
Follow-
up
Survival
Follow-
upb
Scheduling Window
(Days)
-42 to -1c
± 3
± 3
± 3
± 3
± 3
± 3
Repeat
±3
Repeat
±3
At time of 
discon
30 days 
post last 
dose
(+7 days)
Every 12, 
16, or 24 
weeks
(±7 days)
Every 12 
weeks
(±7 days)
Cycles 8 and 9 will be 
repeated up to 4 
times, for a total of 17 
doses of study 
treatment.
Administrative Procedures
Informed Consent
X
Consent must be 
obtained prior to 
performing any 
protocol-specified 
procedures.
Informed consent 
may be collected 
outside of the 
42-day Screening 
window (prior to 
randomization).
Informed Consent for 
Future Biomedical 
Research (optional)
X
.
Participant 
Identification Card
X
X
Dispense at
Screening. Add 
randomization 
number at Cycle 1.
Inclusion/Exclusion 
Criteria
X
Demographics and 
Medical History
X
Record RCC history 
separately.
Prior Medication 
Review
X
Record all 
medications taken 
within 30 days prior 
to first dose.
 
 
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Trial Period:
Screening
Treatment
End of 
Treatment
Posttreatment Period
Notes
Treatment Cycle/Visit
1
2
3
4
5
6
7
8a
9a
Discon
Safety
Efficacy 
Follow-
up
Survival
Follow-
upb
Scheduling Window
(Days)
-42 to -1c
± 3
± 3
± 3
± 3
± 3
± 3
Repeat
±3
Repeat
±3
At time of 
discon
30 days 
post last 
dose
(+7 days)
Every 12, 
16, or 24 
weeks
(±7 days)
Every 12 
weeks
(±7 days)
Cycles 8 and 9 will be 
repeated up to 4 
times, for a total of 17 
doses of study 
treatment.
Treatment 
Randomization
X
Randomization 
should occur 
≤3 days prior to 
treatment, but may 
occur the day of 
Cycle 1 treatment.
MK-3475 or Placebo 
Administration
X
X
X
X
X
X
X
X
X
Cycle 1 treatment 
should occur within 
3 days after 
randomization.
Treatment should 
begin after all 
predose trial 
procedures and 
assessments have 
been completed.
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
Record new 
medications started 
during the trial and
up to 30 days after 
last dose. Record all 
medications related 
to reportable SAEs 
and ECIs.
Poststudy Anticancer 
Therapy Status
X
X
X
Survival Status
X
Upon Sponsor 
request, participants 
may be contacted 
for survival status at 
any time during the 
course of the study.
 
 
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Protocol/Amendment No.: 564-04 
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Trial Period:
Screening
Treatment
End of 
Treatment
Posttreatment Period
Notes
Treatment Cycle/Visit
1
2
3
4
5
6
7
8a
9a
Discon
Safety
Efficacy 
Follow-
up
Survival
Follow-
upb
Scheduling Window
(Days)
-42 to -1c
± 3
± 3
± 3
± 3
± 3
± 3
Repeat
±3
Repeat
±3
At time of 
discon
30 days 
post last 
dose
(+7 days)
Every 12, 
16, or 24 
weeks
(±7 days)
Every 12 
weeks
(±7 days)
Cycles 8 and 9 will be 
repeated up to 4 
times, for a total of 17 
doses of study 
treatment.
Efficacy Procedures
Tumor Imaging –
chest, abdomen, pelvis 
(CAP)
X
X
Xd
X
Perform at 
Screening (within 
28 days prior to 
randomization); 
during treatment 
(Q12W from 
randomization) and
during Follow-up 
(Q12W in year 1, 
Q16W in years 2 to 
4, Q24W in years 5 
and beyond).
Follow-up imaging 
should follow 
calendar days from 
the date of 
randomization.
Tumor Imaging – bone 
scan
X
Perform at 
Screening (within 
28 days prior to 
randomization); as 
clinically indicated 
thereafter.
Tumor Imaging – brain 
scan
X
Perform at 
Screening (within 
28 days prior to 
randomization); as 
clinically indicated
thereafter.
 
 
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Protocol/Amendment No.: 564-04 
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Trial Period:
Screening
Treatment
End of 
Treatment
Posttreatment Period
Notes
Treatment Cycle/Visit
1
2
3
4
5
6
7
8a
9a
Discon
Safety
Efficacy 
Follow-
up
Survival
Follow-
upb
Scheduling Window
(Days)
-42 to -1c
± 3
± 3
± 3
± 3
± 3
± 3
Repeat
±3
Repeat
±3
At time of 
discon
30 days 
post last 
dose
(+7 days)
Every 12, 
16, or 24 
weeks
(±7 days)
Every 12 
weeks
(±7 days)
Cycles 8 and 9 will be 
repeated up to 4 
times, for a total of 17 
doses of study 
treatment.
EQ-5D-5L, EORTC-
QLQ-C30, FKSI-DRS
X
X
X
X
X
Xe
Administering
PROs prior to study 
treatment 
administration, AE 
evaluation, and 
disease status 
notification is 
strongly 
recommended. 
PROs should be 
administered at 
Cycles 1, 5, 9, 13, 
and 17, treatment 
discontinuation, 
30 day Follow-up, 
and annually during
posttreatment 
Follow-up until 
disease recurrence
or initiating a new
anticancer 
treatment.
Safety Procedures
Full Physical 
Examination
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
Perform predose.
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
Height at Visit 1 
only.
12-lead ECG (locally 
performed)
X
Perform at 
Screening and as 
clinically indicated 
thereafter.
 
 
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Product:  MK-3475 
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Protocol/Amendment No.: 564-04 
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Trial Period:
Screening
Treatment
End of 
Treatment
Posttreatment Period
Notes
Treatment Cycle/Visit
1
2
3
4
5
6
7
8a
9a
Discon
Safety
Efficacy 
Follow-
up
Survival
Follow-
upb
Scheduling Window
(Days)
-42 to -1c
± 3
± 3
± 3
± 3
± 3
± 3
Repeat
±3
Repeat
±3
At time of 
discon
30 days 
post last 
dose
(+7 days)
Every 12, 
16, or 24 
weeks
(±7 days)
Every 12 
weeks
(±7 days)
Cycles 8 and 9 will be 
repeated up to 4 
times, for a total of 17 
doses of study 
treatment.
Pregnancy Test – Urine 
or Serum 
hCG; WOCBP only)
X
Perform a urine test 
within 72 hours 
prior to 
randomization; if 
positive or not
confirmed as 
negative, perform a 
serum pregnancy 
test. Monthly 
pregnancy testing 
should be conducted 
per local regulations 
where applicable.
PT/INR and aPTT
X
Screening 
assessment should 
be done within 10 
days prior to
randomization. If 
abnormal at 
Screening, then 
perform at each visit 
or as clinically 
indicated thereafter. 
 
 
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Protocol/Amendment No.: 564-04 
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Trial Period:
Screening
Treatment
End of 
Treatment
Posttreatment Period
Notes
Treatment Cycle/Visit
1
2
3
4
5
6
7
8a
9a
Discon
Safety
Efficacy 
Follow-
up
Survival
Follow-
upb
Scheduling Window
(Days)
-42 to -1c
± 3
± 3
± 3
± 3
± 3
± 3
Repeat
±3
Repeat
±3
At time of 
discon
30 days 
post last 
dose
(+7 days)
Every 12, 
16, or 24 
weeks
(±7 days)
Every 12 
weeks
(±7 days)
Cycles 8 and 9 will be 
repeated up to 4 
times, for a total of 17 
doses of study 
treatment.
Chemistry
X
X
X
X
X
X
X
X
X
X
X
Screening 
assessment should 
be done within 10 
days prior to 
randomization. 
After Cycle 1, 
predose laboratory 
safety tests can be 
conducted up to 72 
hours prior to 
dosing.
Hematology
X
X
X
X
X
X
X
X
X
X
X
Screening 
assessment should 
be done within 
10 days prior to
randomization.
After Cycle 1, 
predose laboratory 
safety tests can be 
conducted up to 72 
hours prior to 
dosing.
Urinalysis
X
X
X
X
X
X
X
Screening 
assessment should 
be done within 10 
days prior to
randomization.
After Cycle 1, 
predose laboratory 
safety tests can be 
conducted up to 72 
hours prior to 
dosing.
 
 
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Trial Period:
Screening
Treatment
End of 
Treatment
Posttreatment Period
Notes
Treatment Cycle/Visit
1
2
3
4
5
6
7
8a
9a
Discon
Safety
Efficacy 
Follow-
up
Survival
Follow-
upb
Scheduling Window
(Days)
-42 to -1c
± 3
± 3
± 3
± 3
± 3
± 3
Repeat
±3
Repeat
±3
At time of 
discon
30 days 
post last 
dose
(+7 days)
Every 12, 
16, or 24 
weeks
(±7 days)
Every 12 
weeks
(±7 days)
Cycles 8 and 9 will be 
repeated up to 4 
times, for a total of 17 
doses of study 
treatment.
T3, FT4, and TSH
X
X
X
X
X
X
X
Screening 
assessment should 
be done within 10 
days prior to
randomization.
After Cycle 1, 
predose laboratory 
safety tests can be 
conducted up to 72 
hours prior to 
dosing.
 
 
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Protocol/Amendment No.: 564-04 
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Trial Period:
Screening
Treatment
End of 
Treatment
Posttreatment Period
Notes
Treatment Cycle/Visit
1
2
3
4
5
6
7
8a
9a
Discon
Safety
Efficacy 
Follow-
up
Survival
Follow-
upb
Scheduling Window
(Days)
-42 to -1c
± 3
± 3
± 3
± 3
± 3
± 3
Repeat
±3
Repeat
±3
At time of 
discon
30 days 
post last 
dose
(+7 days)
Every 12, 
16, or 24 
weeks
(±7 days)
Every 12 
weeks
(±7 days)
Cycles 8 and 9 will be 
repeated up to 4 
times, for a total of 17 
doses of study 
treatment.
AE Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
Record all AEs and 
ECIs occurring 
within 30 days after
the last dose of 
study treatment and 
SAEs for 90 days 
after the end of
treatment or 30 days 
after end of 
treatment if the 
participant initiates 
new anticancer 
treatment
(whichever is 
earlier). Participants 
with an AE of 
Grade >1 will be 
followed until the 
resolution of the AE 
to Grade 0-1 or until 
the beginning of a 
new anticancer 
treatment, 
whichever occurs 
first. Report 
treatment-related 
SAEs regardless of 
when they occur.
ECOG PS
X
X
X
X
X
X
X
X
X
X
X
X
Xf
 
 
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Protocol/Amendment No.: 564-04 
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Confidential
Trial Period:
Screening
Treatment
End of 
Treatment
Posttreatment Period
Notes
Treatment Cycle/Visit
1
2
3
4
5
6
7
8a
9a
Discon
Safety
Efficacy 
Follow-
up
Survival
Follow-
upb
Scheduling Window
(Days)
-42 to -1c
± 3
± 3
± 3
± 3
± 3
± 3
Repeat
±3
Repeat
±3
At time of 
discon
30 days 
post last 
dose
(+7 days)
Every 12, 
16, or 24 
weeks
(±7 days)
Every 12 
weeks
(±7 days)
Cycles 8 and 9 will be 
repeated up to 4 
times, for a total of 17 
doses of study 
treatment.
Future Biomedical Research/Biomarkers
Tissue Collection for 
Biomarker Studies
Xg
Submit tumor tissue 
from nephrectomy 
and/or for M1 NED 
participants, tumor 
tissue from resected 
metastatic lesion(s),
as indicated in 
Section 9.7.1. 
Adequacy of the 
sample for 
biomarker analysis
will be evaluated by 
a central laboratory.
Blood for Genetic 
Analysish
X
Collect predose.
Blood for RNA 
Analyses
X
X
X
X
X
Collect predose at 
Cycles 1, 2, and 5, 
at treatment
discontinuation (due 
to any reason), and 
during Follow-up at 
disease recurrence.
Blood for TCR
X
X
X
X
X
Collect predose at 
Cycles 1, 2, and 5, 
at treatment 
discontinuation (due 
to any reason), and 
during Follow-up at 
disease recurrence.
 
 
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Confidential
Trial Period:
Screening
Treatment
End of 
Treatment
Posttreatment Period
Notes
Treatment Cycle/Visit
1
2
3
4
5
6
7
8a
9a
Discon
Safety
Efficacy 
Follow-
up
Survival
Follow-
upb
Scheduling Window
(Days)
-42 to -1c
± 3
± 3
± 3
± 3
± 3
± 3
Repeat
±3
Repeat
±3
At time of 
discon
30 days 
post last 
dose
(+7 days)
Every 12, 
16, or 24 
weeks
(±7 days)
Every 12 
weeks
(±7 days)
Cycles 8 and 9 will be 
repeated up to 4 
times, for a total of 17 
doses of study 
treatment.
Blood for Plasma 
Biomarker Analyses
X
X
X
X
X
Collect predose at 
Cycles 1, 2, and 5, 
at treatment
discontinuation (due 
to any reason), and 
during Follow-up at 
disease recurrence.
Blood for Serum 
Biomarker Analyses
X
X
X
X
X
Collect predose at 
Cycles 1, 2, and 5, 
at treatment 
discontinuation (due 
to any reason), and 
during Follow-up at 
disease recurrence.
a.
The schedule for Cycle 8 will be repeated for Cycles 10, 12, 14, and 16; the schedule for Cycle 9 will be repeated for Cycles 11, 13, 15, and 17, unless otherwise noted.
b.
Participant Survival Follow-up status will be assessed approximately every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of the trial, 
whichever occurs first. For participants who discontinue treatment intervention and who will not enter the Efficacy Follow-up phase, the first Survival Follow-up contact 
will be scheduled 12 weeks after the discontinuation visit and/or Safety Follow-up Visit (whichever is last). For participants who completed assessments in the Efficacy 
Follow-up phase, the first Survival Follow-up contact will be scheduled 12 weeks after the last Efficacy Follow-up Visit has been performed. 
c.
Refer to Section 9.10 for Screening procedures with a window that differs from the 42-day Screening window.
d.
Participants who discontinue from study treatment without documented disease recurrence should have imaging performed at the time of discontinuation if the last 
assessment was more than 28 days prior AND should continue with posttreatment Follow-up procedures until disease recurrence, pregnancy, the start of new anticancer 
treatment, death, withdrawal of consent, or study conclusion (whichever occurs first).
e.
Follow-up PROs will be measured from end of treatment date, have a +14 day window, and will be administered at Week 52 , Week 104, Week 156, Week 208, Week 
260, Week 312, Week 364, Week 416, Week 468, and Week 520 or until disease recurrence or start of a new anticancer treatment.
f.
ECOG PS to be collected only if participants come in for a clinic visit during Follow-up.
g.
Tumor archival tissue may be submitted outside the 42-day screening window (prior to randomization), as long as informed consent was signed prior to submission.
h.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. Sample will not be collected at sites where 
prohibited by local law, local regulation, or IRB/IEC. If the sample is collected, leftover extracted DNA will be stored for future biomedical research if the participant 
signs the future biomedical research consent. If the planned genetic analysis is not approved, but future biomedical research is approved and consent is given, this sample 
will be collected for the purpose of future biomedical research.
 
 
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3. Introduction
Study Rationale 
This is a clinical trial designed to evaluate the efficacy and safety of pembrolizumab in the 
adjuvant setting for participants with RCC with clear cell component that has an 
intermediate-high risk or high risk of disease recurrence or M1 no evidence of disease (M1 
NED).
RCC is the seventh most common cancer in men and the ninth most common cancer in 
women. Worldwide, there are an estimated 209,000 newly diagnosed cases of RCC and an 
estimated 102,000 deaths per year [Escudier, B., et al 2014]. In the United States, the 
expected number of new cases and deaths from kidney and renal pelvis cancer in 2016 is 
62,700 and 14,240, respectively [Siegel, R. L., et al 2016]. Approximately 90% of renal 
tumors are RCC and approximately 80% of these are of clear cell histology. Other less 
common cell types include papillary, chromophobe, translocation, and collecting duct tumors 
[National Comprehensive Cancer Network 2015]. Smoking and obesity are established risk 
factors for RCC. Several hereditary conditions, such as von Hippel-Lindau disease, 
predispose patients to having an increased risk of developing RCC.
The incidence of RCC is increasing continually in recent decades, and approximately two-
thirds of the cases are diagnosed without evidence of metastatic disease [Siegel, R. L., et al 
2016].
These patients are usually managed with a radical surgical approach, but a percentage of 
these patients will have recurrence and eventually die because of the disease. The estimated 
5-year survival of patients with localized RCC patients is approximately 90%, decreasing to 
65% in locally advanced RCC, and only 12% in metastatic RCC [National Cancer Institute 
2016]. Therefore, novel agents with durable clinical benefit and a potential curative effect are 
still needed.
The recently approved immune checkpoint inhibitor nivolumab has demonstrated an overall 
survival (OS) benefit (compared with the standard of care, everolimus), as well as a 
manageable safety profile, in the treatment of patients with advanced RCC whose disease has 
progressed following anti-angiogenic therapy [U.S. Prescribing Information 2016]. Multiple 
studies are currently ongoing or planned to evaluate immune checkpoint inhibitors as 
monotherapy or in combination with selective vascular endothelial growth factor receptor
tyrosine kinase inhibitors or other anti-angiogenic agents (eg, bevacizumab, ipilimumab) in 
the first-line treatment of advanced or metastatic RCC. Preliminary data from Phase 1b, 2, 
and 3 studies (nivolumab/ipilimumab [Checkmate-016 Phase 2; Checkmate-214 Phase 3]; 
bevacizumab/atezolizumab [NCT02420821 Phase 3]; pembrolizumab/axitinib [KN035 
Phase 1b/2]) suggest a promising response pattern, with higher overall response rate and 
progression-free survival rates and tolerable toxicity, as compared with the current standard 
of care, sunitinib or pazopanib.
The safety and antitumor activity of checkpoint inhibitors are also being evaluated in the 
(neo)adjuvant setting for RCC in Phase 1/2 exploratory trials [Pinto, A. 2014], and 
 
 
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preliminary data suggest a possible benefit of treatment on both disease-free survival (DFS)
and OS, with good tolerability in participants who have no current disease burden following 
surgery, but a high risk of recurrence [Ravaud, A., et al 2016].
Background
Pembrolizumab is a potent humanized immunoglobulin (Ig) G4 monoclonal antibody with 
high specificity of binding to the programmed cell death protein 1 (PD-1) receptor, thus 
inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. KEYTRUDA® (pembrolizumab) is 
indicated for the treatment across a number of cancer indications.
Refer to the Investigator’s Brochure/approved labeling for detailed background information, 
including specific indications, for pembrolizumab (MK-3475).
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T cells and the ratio 
of CD8+ effector T cells/FoxP3+ T-regs correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; 
hepatocellular carcinoma; malignant melanoma; and RCC. Tumor-infiltrating lymphocytes 
can be expanded ex vivo and reinfused, inducing durable objective tumor responses in 
cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig variable-type domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 
and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3 zeta, protein kinase C-
theta, and zeta-chain-associated protein kinase, which are involved in the CD3 T-cell 
signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 2004] [Sheppard, K-A, et 
 
 
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al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 downmodulates T-cell responses 
is similar to, but distinct from, that of CTLA-4, because both molecules regulate an 
overlapping set of signaling proteins [Parry, R. V., et al 2005] [Francisco, L. M., et al 2010].
As a consequence, the PD-1/ PD-L1 pathway is an attractive target for therapeutic 
intervention in participants who have undergone nephrectomy and have intermediate-high
risk, high risk, or M1 NED RCC with clear cell component.
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical trials will directly benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Pembrolizumab has been administered to a large number of cancer patients, with a 
well-characterized safety profile, and has received regulatory approval in the US and several 
other countries for advanced melanoma, NSCLC, and head and neck squamous cell 
carcinoma. Overall, pembrolizumab is well tolerated and has demonstrated preliminary 
evidence of anticancer activity in multiple tumor types.
At present, there are no curative systemic treatments for about 35% of primary treated 
patients with intermediate-high risk, high risk, and M1 NED RCC.
Additional details regarding specific benefits and risks for participants participating in this 
clinical trial may be found in the accompanying Investigator’s Brochure and Informed 
Consent documents.
4. Objectives/Hypotheses and Endpoints
The following objectives will be evaluated in the adjuvant treatment of participants who have 
undergone nephrectomy and have intermediate-high risk, high risk, or M1 NED RCC with 
clear cell component.
Objective/Hypothesis
Endpoint(s)
Primary
●
Objective: To compare DFS as assessed by 
the investigator for participants treated 
with pembrolizumab versus those 
receiving placebo
Hypothesis: Pembrolizumab is superior to 
placebo with respect to DFS
●
DFS as assessed by the investigator: 
time from randomization to the first 
documented local recurrence, or 
occurrence of distant kidney cancer 
metastasis(es), or death due to any 
cause, whichever occurs first.
 
 
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Objective/Hypothesis
Endpoint(s)
Secondary
Key Secondary
●
Objective: To compare OS for participants 
treated with pembrolizumab versus those 
receiving placebo
Hypothesis: Pembrolizumab is superior to 
placebo with respect to OS
●
OS: time from randomization to death 
due to any cause.
Other Secondary
●
To compare the safety and tolerability 
profiles for participants treated with 
pembrolizumab versus those receiving 
placebo
●
AEs, SAEs, AEs leading to 
discontinuation, deaths, laboratory
values, and vital signs 
●
To compare measures of DRSS) as 
assessed by the investigator, in participants 
treated with pembrolizumab versus those 
receiving placebo
●
DRSS1 as assessed by the investigator: 
time from randomization to the first 
documented local recurrence of RCC.
●
DRSS2 as assessed by the investigator: 
time from randomization to the first 
documented local recurrence with 
visceral lesion or occurrence of distant 
kidney cancer metastasis(es) with 
visceral lesion, whichever occurs first.
●
To compare EFS as assessed by the 
blinded independent radiology review for 
participants treated with pembrolizumab 
versus those receiving placebo 
●
EFS is to be assessed by BICR. EFS is 
defined as time from randomization to 
the first documented local recurrence or 
occurrence of distant kidney cancer 
metastasis(es) among participants, 
which by BICR were considered 
M0/M1 NED; or disease progression 
among participants, which by BICR 
were considered to have M1, or death 
due to any cause, whichever occurs first. 
See Section 9.2.1 for the definition of 
disease progression.
 
 
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Objective/Hypothesis
Endpoint(s)
●
To compare DFS and OS according to 
participants’ PD-L1 expression status 
(Positive, Negative) for participants treated 
with pembrolizumab versus those 
receiving placebo
●
DFS as assessed by the investigator: 
time from randomization to the first 
documented local recurrence, or 
occurrence of distant kidney cancer 
metastasis(es), or death due to any 
cause, whichever occurs first.
●
OS: time from randomization to death 
due to any cause.
●
To evaluate PROs with the EORTC-QLQ-
C30 and the FKSI-DRS
●
EORTC-QLQ-C30
●
FKSI-DRS 
Tertiary/Exploratory
●
To evaluate PK parameters and the presence 
of ADA
●
PK parameters (clearance and volume of 
distribution)
●
ADA to pembrolizumab
●
To identify molecular (genomic, 
metabolic, and/or proteomic) biomarkers 
that may be indicative of clinical 
response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of pembrolizumab
●
Biomarker analyses may include 
germline genetic variation, genetic 
(DNA) mutations from tumor, tumor 
and blood RNA variation, proteomics 
and IHC, and other blood-derived 
biomarkers
●
To evaluate PROs with the EORTC-QLQ-
C30 and FKSI-DRS and to characterize 
utilities with the EQ-5D-5L
●
All scales, subscales, and single item 
measures for the EORTC-QLQ-C30, 
FKSI-DRS, and EQ-5D-5L
5. Study Design
Overall Design 
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, global trial to 
evaluate the efficacy and safety of pembrolizumab in the adjuvant treatment of RCC post 
nephrectomy. This trial will enroll participants with RCC with clear cell component that is 
intermediate-high risk, high risk, or M1 NED (M1 NED refers to participants who present 
not only with the primary kidney tumor, but also solid, isolated, soft tissue metastases that 
can be completely resected ≤1 year from the time of nephrectomy). See Section 6.1 for a 
definition of the risk categories.
The trial will be conducted in conformance with Good Clinical Practice.
 
 
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The primary objective of the study is to evaluate the efficacy (DFS, as assessed by the 
investigator) of pembrolizumab compared with that of placebo in participants with RCC. 
Screening Period
Individual screening procedures must be performed within the time frames reported in the 
schedule of activities (SoA - Section 2) and procedural details in Section 9. Participants must 
have undergone a nephrectomy and/or metastasectomy ≥28 days prior to signing informed 
consent and ≤12 weeks from randomization. Participants must be tumor-free as assessed by 
the investigator via CT or MRI of the CAP, bone scan, and brain scan. Tumor tissue from the 
participants’ nephrectomy (and metastasectomy for M1 NED) must be submitted to a central 
laboratory for biomarker analysis.
Treatment Period and End of Treatment
Approximately 950 eligible participants will be randomized 1:1 to receive either placebo or 
pembrolizumab 200 mg, administered by IV infusion Q3W.
During the treatment period, participants will have routine clinical visits for administration of 
study treatment and monitoring of safety, wellbeing, and changes in disease status.
Scheduled on-treatment imaging assessments will be performed Q12W from randomization
and should not be adjusted for delays in treatment or cycle starts. Participants will also 
complete QoL questionnaires to assess the impact of treatment on HRQoL.
Key safety assessments include the monitoring of AEs and ECI, physical examinations, vital 
signs, ECGs, as clinically indicated, hematology and chemistry laboratories (including 
thyroid function test), and urinalysis.
Participants may receive study treatment for up to 17 cycles (approximately 1 year) or until 
confirmation of disease recurrence or meeting the criteria for discontinuation of study 
treatment as outlined in Section 8. 
Participants who discontinue from treatment without documented disease recurrence should 
have imaging performed at the time of discontinuation if the last assessment was more than
28 days prior AND should continue with posttreatment Follow-up procedures until disease 
recurrence, pregnancy, the start of new anticancer treatment, death, withdrawal of consent, or 
study conclusion (whichever occurs first).
The End of Treatment Visit should occur at the time study treatment is discontinued for any 
reason (see Section 9.10.4.).
Posttreatment Follow-up Period
After the end of treatment, each participant will undergo a Safety Follow-up Visit at least
30 days (+ 7 days) after the last dose of study treatment or before the initiation of a new 
anticancer treatment, whichever comes first. Participants will be followed for 30 days after 
the last dose of study treatment for AE/ECI monitoring (SAEs will be collected up to 90 days 
 
 
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after the last dose of study treatment or for 30 days following cessation of treatment if the 
participant initiates new anticancer therapy, whichever comes first).
All participants who complete 17 cycles or discontinue from treatment for a reason other than
disease recurrence will undergo radiographic imaging follow-up (Q12W during year 1, 
Q16W during years 2 to 4, then Q24W in years 5 and beyond) for assessment of DFS. 
Imaging during follow-up should continue to be scheduled from the date of randomization. 
QoL questionnaires will continue to be collected once per year during the follow-up period.
Survival Follow-up for survival status and the initiation of subsequent anticancer treatment 
will be assessed Q12W.
Three efficacy interim analyses may be conducted; see Section 10.7 for details.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial SoA - Section 2. Details of each procedure 
are provided in Section 9 – Study Assessments and Procedures.
Trial Diagram
The trial design is depicted in Figure 1.
Figure 1
Trial Diagram
 
 
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Number of Participants
Approximately 950 participants will be randomized 1:1 to pembrolizumab or placebo such 
that approximately 332 DFS events can be observed at the time of the final analysis of the 
study as described in Section 10.9.
Beginning and End of Study Definition
The overall trial begins when the first participant signs the informed consent form (ICF).  
The overall trial ends when the last participant completes the last study-related phone-call or 
visit, withdraws from the trial or is lost to follow-up (i.e. the participant is unable to be 
contacted by the investigator).
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. The trial may be stopped early for safety by the Sponsor
2. Quality or quantity of data recording is inaccurate or incomplete
3. Poor adherence to protocol and regulatory requirements
4. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to participants
5. Plans to modify or discontinue the development of the study treatment
In the event of Sponsor decision to no longer supply study treatment, ample notification will 
be provided so that appropriate adjustments to participant treatment can be made.
Scientific Rationale for Study Design
Selection of Patient Population
RCC has long been considered an immune-reactive malignancy based on anecdotal reports of 
spontaneous remissions in advanced RCC patients with evidence of antigen-specific 
lymphocyte infiltration of tumor tissues [Wierecky, J., et al 2006] and the fact that high-dose 
interleukin-2 (IL-2) could produce durable long-term response in a small subset of advanced 
RCC patients. In RCC, upregulation of the PD-1 receptor on tumor-infiltrating lymphocytes 
and its ligand PD-L1 on tumors is associated with more aggressive disease and poor 
prognosis [Pedoeem, A., et al 2014] [Ahmadzadeh, M., et al 2009]. The rate of PD-L1 
expression in RCC has been reported to be between 10% and 30%, and PD-L2 expression 
has been reported as approximately 50% [Abbas, M., et al 2016] [Shin, S. J., et al 2016] 
[Iacovelli, R., et al 2016]. The evidence above supports targeting RCC with an 
immunotherapeutic approach. Single-agent antitumor activity has been demonstrated by 
another anti-PD-1 antibody, nivolumab, in advanced RCC [Motzer, R. J., et al 2015].
 
 
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Even though vascular endothelial growth factor receptor-targeting antiangiogenic agents, 
such as sunitinib, pazopanib, axitinib, and bevacizumab plus IFNα, have collectively 
improved the outcome of advanced RCC, most patients with intermediate-high risk and high 
risk and most M1 NED patients will progress within 2 to 3 years following nephrectomy 
and/or resection of accessible metastatic lesions for M1 NED patients [Kavolius, J. P., et al 
1998]. Therefore, novel treatments, including in the adjuvant setting, are needed to prevent 
disease recurrence in patients with higher risk RCC.
Watchful waiting or participation in an experimental clinical trial evaluating adjuvant 
treatment are the only options for patients with high risk of recurrence based on the National 
Comprehensive Cancer Network guidelines and current literature.
Other than patients with nodal involvement, the patients with the highest risk of RCC 
recurrence are those that present with not only the primary kidney tumor, but also solid,
isolated, soft tissue metastases that can be completely resected at the time of nephrectomy, 
known as M1 NED. Resection of metastatic disease (metastasectomy) is performed in several 
situations:

Patients with Stage IV disease at presentation, where it is performed with 
nephrectomy

Patients who develop metastatic disease following nephrectomy

Patients who have persistent disease despite systemic therapy
In selected patients with metastatic RCC, surgical resection of metastatic foci is a treatment 
option that can yield long-term DFS. The potential role of surgery is illustrated by the results 
from a series of 278 patients with recurrent RCC, in which 51% of patients underwent 
removal of all of their metastatic disease with curative intent, 25% underwent partial 
resection of their metastatic disease, and 24% were treated without surgery [Kavolius, J. P., 
et al 1998]. Metastases were most frequently resected from the lung, brain, bone, and soft 
tissue. The following findings were noted on multivariate analysis:

The 5-year OS rate was highest in patients treated with metastasectomy with 
curative intent (44% versus 14% for noncurative surgery and 11% for nonsurgical 
intervention). Survival rates after complete resection of a second and third 
metastasis were not different from those after initial metastasectomy.

The strongest predictors of prolonged survival were a disease-free interval from 
nephrectomy to detection of metastases of greater than 1 year (55% 5-year OS versus 
9% 5-year OS for patients with a disease-free interval of a year or less); a single site 
of metastasis (54% 5-year OS for a single site versus 29% 5-year OS for multiple 
sites), especially if the site was the lung; and age younger than 60 years (49% 5-year 
OS versus 35% 5-year OS for age 60 years or older).
While patients after nephrectomy with a lower risk evaluation may be well served with no 
initiation of Follow-up treatment, in accordance with international guidelines such as those of 
the European Association of Urology, patients with intermediate-high risk and high risk of 
 
 
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recurrence within 6 to 36 months after primary treatment represent a population with a 
significant unmet medical need. Almost all patients with recurrence after primary 
nephrectomy and M1 NED patients after primary resection develop distant metastasis and 
require first-line metastatic treatment; a summary of Phase 3 studies of first-line treatments 
for RCC and their associated survival rates is shown in Table 1.
Therefore, reduction in the risk for recurrence through appropriate adjuvant treatment could 
be valuable in patients at a higher risk of recurrence, but to date no agent has proven to be 
useful in this setting. Immune therapies, hormonal therapies, and finally targeted therapy, 
effective in the advanced setting, have been tested for this indication, without success for this 
unmet medical need [Pinto, A. 2014].
Table 1
Summary of Clinical Efficacy From Randomized Phase 3 Studies in First-Line 
Advanced RCC
Study (N)
Median 
PFS 
(months)
Median OS 
(months)
ORR (%)
Reference
Sunitinib vs. IFNα 
(N=750)
11.0 vs. 5a
26.4 vs. 21.8 
31 vs. 6a
[Motzer, R. J., et al 2007]
[Motzer, R. J., et al 2009]
Pazopanib vs. 
placebo (N=233)
11.1 vs. 
2.8a
22.9 vs. 20.5 
30 vs. 3a
[Sternberg, C. N., et al 2010]
[Sternberg, C. N., et al 2013]
Bevacizumab + 
IFNα vs. IFNα 
(N=649)
10.2 vs. 
5.4a
23.3 vs. 21.3 
31 vs. 13a
[Escudier, B., et al 2007]
[Escudier, B., et al 2010]
Sunitinib vs. 
pazopanib 
(N=1110) b
9.5 vs. 8.4 
29.3 vs. 28.4
25 vs. 31
[Motzer, R. J., et al 2013]
Axitinib vs. 
sorafenib (N=288; 
2:1 randomization)
10.1 vs. 6.5 
Not reported
32 vs. 15a
[Hutson, T. E., et al 2013]
Temsirolimus vs. 
IFNα (N=416) c
5.5 vs. 3.1a
10.9 vs. 7.3a
8.6 vs. 4.8
[Hudes, G., et al 2007]
EJC = European Journal of Cancer; IFNα = interferon-alpha; JCO = Journal of Clinical Oncology; NEJM = New England 
Journal of Medicine; ORR = overall response rate; PFS = progression-free survival.
a. Results demonstrated statistically significant improvement of the testing arm versus the control arm. 
b. The sunitinib versus pazopanib study used a noninferiority design, which demonstrated that pazopanib was noninferior 
to sunitinib with the primary endpoint PFS meeting the predefined noninferiority margin.
c. OS was the primary endpoint for this study while other trials used PFS as the primary endpoint. This study enrolled a 
high-risk population while other trials enrolled a majority of participants with good or intermediate risks.
Rationale for Adjuvant Setting
When considering adjuvant therapy, it is very important to select patients who are at a higher 
risk of recurrence, as these patients will be the ones more likely to have any benefit from 
treatment. As stated previously, patients with no evidence of metastatic disease at diagnosis 
 
 
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might have a risk of recurrence up to 35% or 40% after surgery [Haas, N. B., et al 2016] 
[National Cancer Institute 2016] [Pinto, A. 2014].
For patients with a partial or radical nephrectomy, the risk of recurrence largely depends on 
tumor size, grade, stage, histology, performance status, and completeness of resection 
[Eggener, S. E., et al 2006] [Stephenson, A. J., et al 2004] [Leibovich, B. C., et al 2003].
Currently, pathologic tumor stage is the single most important prognostic factor in resected 
RCC, but does not fully explain disparities in survival among stages [Frank, I., et al 2005].
Some other histologic features, such as histologic subtype, and presence of necrosis or 
sarcomatoid component have been linked with a poorer prognosis [Kunkle, D. A., et al 2007].
Regarding histologic subtypes, chromophobe and papillary type I seem to have a more 
indolent clinical course, and papillary type II and clear cell RCC show a more aggressive 
behavior [Leibovich, B. C., et al 2003]. The most common form of RCC is clear cell disease, 
so named because the high lipid content in the cytoplasm is dissolved during histological 
preparation methods leaving a clear cytoplasm. A 4-tiered grading (Fuhrman) system based 
on nuclear morphology is also an important prognostic factor in clear cell RCC [Kunkle, D. 
A., et al 2007] [Rini, B. I., et al 2009] [Fuhrman, S. A., et al 1982].
A systematic review with meta-analysis of adjuvant therapies for locally advanced RCC was 
published in 2011 [Scherr, A. J., et al 2011]; it concluded that there was no support for using 
systemic therapy in the adjuvant setting, as there was no evidence of any benefit and there 
was evidence of substantial toxicity. The therapeutic modalities included in this study were 
mainly chemotherapy, immune therapies, and hormonal treatments, since no trial with 
targeted therapies had been completed at that time.
Immunotherapy was one of the standard options for metastatic RCC before the advent of 
targeted therapies. IL-2 and IFN were commonly used in that setting, but with poor results, 
achieving a response rate of 6% to 10% and some durable responses, and a median OS of 12 
to 15 months [Gleave, M. E., et al 1998]. Nevertheless, none of the adjuvant trials with 
immune therapies has been successful. Two trials compared IFN with placebo in T3 to T4 
and/or node-positive participants, without improvements in DFS or OS [Pizzocaro, G., et al
2001] [Messing, E. M., et al 2003]. Two other small trials that explored the role of IL-2, 
whether in monotherapy as a single-dose treatment [Clark, J. I., et al 2003] or combined with 
IFN [Passalacqua, R., et al 2014], also had negative results. A triple combination of IL-2, 
IFN, and 5-fluorouracil also failed to show an improvement in DFS compared with placebo 
and was associated with significant toxicity [Aitchison, M., et al 2014]. This same schedule 
was tested in a different trial, showing no differences in DFS, but a worse OS for the 
treatment arm [Atzpodien, J., et al 2005]. Some other trials have explored the potential role 
in the adjuvant setting of therapeutic vaccines [Patel, D. N., et al 2016].
The use of radiotherapy in an adjuvant setting has not been established as a standard for this 
indication. In a trial published in 1987, a total of 72 participants with Stage II to III kidney 
cancer were randomized to adjuvant radiation therapy (50 Gy in the tumor bed and both 
ipsilateral and contralateral nodes) or no further treatment. This trial was closed early 
because of unacceptable toxicity, and no differences in recurrence rate or survival were seen 
between the arms [Kjaer, M., et al ]. A similar trial performed even earlier, in the 1970s, also 
did not find a benefit from postoperative radiation therapy [Finney, R. 1973].
 
 
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Some other studies explored the role of hormone therapies, with disappointing results. One 
prospective multicenter study compared medroxyprogesterone acetate treatment for 1 year 
versus no treatment after radical nephrectomy and failed to demonstrate any benefit in 
survival [Scherr, A. J., et al 2011]. Another trial testing chemotherapy with adjuvant tegafur 
and uracil was also unsuccessful [Naito, S., et al 1997].
Until recently, a number of Phase 2/3 clinical studies failed to demonstrate substantial and 
consistent benefit in the adjuvant setting for RCC, whether using immunotherapy, 
radiotherapy, hormonal therapy, or chemotherapy. Trials testing targeted therapies such as 
sunitinib, sorafenib, pazopanib, and axitinib have either failed (eg, ASSURE – ECOG2805)
or are ongoing, dealing with significant toxicities in participants with no existing disease 
burden during treatment (Table 2; [Haas, N. B., et al 2016] [Pinto, A. 2014]).
 
 
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Table 2
Completed and Ongoing Targeted Adjuvant Therapies
Trial (Sponsor)
Random-
ization
Treatment Details
N
Status
Inclusion Criteria
(Stage/Grade)
Inclusion
Criteria
(Histology)
Results
ASSURE
(ECOG)51
Sorafenib
400 mg BID × 54
Wk Amendment: 
startingdose reduced
to 400 mg daily with
dose escalation
1943
Completed
pT1b N0 M0
(Grade 3-4),
pT2-pT4 N0 M0,
pT(any) N1 M0
Any
histologya
DFS: 97.5%;
HR,
0.97 (CI,
0.80-1.17) vs
placebo
Sunitinib
50 mg daily (4 wk
on/2wkoff)
Amendment: 
startingdose
reducedto
37.5 mgdaily with
dose escalation
DFS:
97.5%; HR,
1.02 (CI,
0.85-1.23) vs
placebo
S-TRAC
(Pfizer)2
Sunitinib
50 mg daily (4 
wk on/2 wk off),
9 cycles
615
Completed
pT3 N0 M0
(Grades 2-4),
pT4 N0 M0,
pT(any) N1 M0
ccRCConly
DFS:6.8y
vs5.6y for
placebo;HR,
0.76 (CI,
0.59-0.98;
P=.03)
ATLAS
(Pfizer)
Axitinib
5 mg BID × 3 y
592
Enrolling
pT2-4 N0 M0,
pT(any) N1 M0
ccRCConly
PROTECT
(GlaxoSmith-
Kline)
Pazopanib
800 mg daily × 1 y
Amendment: starting
dosereduction to
600 mg daily with dose 
escalation
1500
In
follow-up
pT2 N0 M0
(Grades 3-
4), pT3-4
N0 M0,
pT(any) N1 M0
ccRCConly
SORCE
(Medical
Research
Council)
Sorafenib
400 mg BID × 1 y or
400 mg BID × 3 y
Amendment: 
startingdose
reduction to
400 mg daily in 
botharmswithdose
escalation
1420
In
follow-up
pT1a N0 M0
(Grade 4),
pT1b N0 M0
(Grades 3-4), 
pT2-4 N0
M0, pT1b-4
N1 M0
Any
histology
EVEREST
(SWOG)
Everolimus
10mgdaily
1218
Enrolling
pT1b N0 M0
(Grades 3-
4), pT2-4
N0 M0
pT(any) N1 M0
Any
histologya
ASSURE, Sunitinib Malate or Sorafenib Tosylate in Treating Patients With Kidney Cancer That Was Removed by Surgery; ATLAS, 
Adjuvant Axitinib Therapy of Renal Cell Cancer in High Risk Patients; BID, twice a day; ccRCC, clear cell renal cell carcinoma; DFS, 
disease-free survival; EVEREST, Everolimus in Treating Patients With Kidney Cancer Who Have Undergone Surgery; HR, hazard ratio; 
PROTECT, A Study to Evaluate Pazopanib as an Adjuvant Treatment for Localized Renal Cell Carcinoma; SORCE, Sorafenib in Treating 
Patients at Risk of Relapse After Undergoing Surgery to Remove Kidney Cancer; S-TRAC, A Clinical Trial Comparing Efficacy and 
Safety of Sunitinib Versus Placebo for the Treatment of Patients at High Risk of Recurrent Renal Cell Cancer; TNM, tumor, node, 
metastasis; wk, week/weeks; y, year/years.
a duct-Bellini RCC excluded
Source: [Patel, D. N., et al 2016]
In October 2016, results from a Phase 3 randomized, placebo-controlled study of sunitinib 
(S-TRAC) showed a median duration of DFS that was significantly longer in the sunitinib 
group (6.8 years; 95% CI: 5.8) to not reached compared with the placebo group (5.6 years;
95% CI: 3.8 to 6.6), with a HR of 0.76 for independent radiologic review, at the cost of a 
higher rate of toxic events. There were no statistically significant differences in OS data at 
the reported data cutoff. Dose reductions due to AEs were more frequent in the sunitinib 
group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 
13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 and 4 AEs were more frequent in the 
 
 
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sunitinib group (48.4% and 12.1%, respectively) than in the placebo group (15.8% and 3.6%, 
respectively). The incidence of SAEs in the groups was similar (21.9% for sunitinib vs. 
17.1% for placebo); no deaths were attributed to toxic effects related to study treatment 
[Ravaud, A., et al 2016].
These recent data are encouraging, as this is the first study to show a positive DFS in this 
patient population; however, the treatment discontinuation rate was high and the AEs created
a meaningful burden for participants. Additionally, the study did not include those at the
highest risk of recurrence, M1 NED, in the investigated patient population. Globally, there is 
no current treatment standard in the adjuvant setting for RCC after nephrectomy.
Rationale for Stratification
In previous studies [Haas, N. B., et al 2016] [Ravaud, A., et al 2016] and ongoing adjuvant 
RCC trials, stratification for ECOG 0 versus 1+ is considered an important strategy to 
equally distribute participants. Participants with an initial diagnosis of RCC and an ECOG 
status greater than 0 typically have underlying comorbidities and are clinically considered to 
have a worse long-term outcome when compared to participants with an initial diagnosis of 
RCC and an ECOG status of 0. 
The stratification of US over rest of world addresses the potential significant treatment 
paradigm shift in first and second-line metastatic RCC due to early adoption of new 
treatment regimens and broader availability of treatments in the US over other regions of the 
world. This stratification factor does not impact the primary endpoint of DFS. Instead it 
addresses equal distribution of participants having differential access to new treatment 
regimens during OS Follow-up.
Rationale for Endpoints
Efficacy Endpoints
Primary Efficacy Endpoint
The primary efficacy endpoint, DFS as assessed by the investigator, is considered an 
appropriate clinical endpoint for an adjuvant trial that will evaluate the study treatment’s 
impact on disease recurrence and has been explored in a number of ongoing pivotal Phase 3
studies serving as a surrogate for OS assessment [Ravaud, A., et al 2016] [Haas, N. B., et al 
2016]. DFS has been accepted as a surrogate endpoint to support drug approval for adjuvant 
settings in which participants are expected to experience cancer symptoms upon recurrence 
(eg, adjuvant breast cancer hormonal therapy, adjuvant colon cancer, and adjuvant cytotoxic 
breast cancer therapy). In the proposed patient population, participants are entering the trial 
tumor free. In the adjuvant setting, an investigator determines the absolute recurrence of 
disease. This assessment is equally appropriate to an independent reviewer determination 
since it does not involve tumor burden level grading expected with existing advanced 
metastatic disease.
 
 
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While OS has been recognized as the gold standard for the demonstration of superiority of a 
new antineoplastic therapy in randomized clinical studies, in some oncology indications such 
as RCC, survival may be prolonged. In such instances where a survival endpoint would be 
difficult to achieve, DFS may represent a measure of clinical benefit, especially if the 
magnitude of the effect is large and the therapy has an acceptable risk/benefit profile.
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs; and changes in vital signs and laboratory values. AEs
will be assessed as defined by CTCA), Version 4.0.
Pharmacokinetic Endpoints
THIS BLOOD WORK WILL NO LONGER BE COLLECTED WITH THE 
IMPLEMENTATION OF AMENDMENT 2.
Blood samples will be obtained to measure the PK of pembrolizumab.
PK parameters (clearance, volume of distribution) will be characterized and the effect of 
extrinsic and intrinsic factors will be evaluated to support the proposed dosing regimen. PK 
data will also be used to explore the exposure-response relationships for pembrolizumab 
antitumor activity/efficacy, as well as safety in the proposed patient population, if feasible.
Patient-Reported Outcomes
Symptomatic improvement is considered a clinical benefit. As part of the analyses for this 
trial, participants will provide information regarding their HRQoL via EORTC-QLQ-C30 
and EQ-5D-5L. These PROs are not pure efficacy or safety endpoints because they are 
affected by both disease recurrence and treatment tolerability. Clinical experts have indicated 
that the FKSI-DRS instrument primarily captures disease-related, as opposed to treatment-
related, changes in HRQoL.
Rationale for the EORTC-QLQ-C30 
The EORTC-QLQ-C30 is the most widely used cancer-specific HRQoL instrument, which 
contains 30 items and measures 5 functional dimensions (physical, role, emotional, cognitive, 
and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, 
sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global 
health and QoL scale. Thus, secondary objectives are to assess mean changes from baseline 
in the global health status/QoL scale from the EORTC-QLQ-C30.
Rationale for the FKSI-DRS
The FKSI-DRS is a patient-reported instrument that measures whether the participant has 
experienced any of the following 9 kidney cancer-related symptoms: lack of energy, fatigue, 
weight loss, pain, bone pain, shortness of breath, cough, fever, or blood in the urine. 
Responses to all FKSI-DRS items are summed to generate a summary symptom score 
 
 
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ranging from 0 to 36, with higher scores indicating improved (more favorable) symptom 
status. The FKSI-DRS is a reliable, valid, and responsive brief index of the most important 
symptoms associated with advanced kidney cancer.
Rationale for the EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcomes and will 
provide data for use in economic models and analyses including developing health utilities or 
quality-adjusted life-years. The 5 health state dimensions in this instrument include the 
following: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each 
dimension is rated on a 5-point scale from 1 (no problem) to 5 (extreme problem). The EQ-
5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the participant
rates his or her general state of health at the time of the assessment. This instrument has been 
used extensively in cancer studies, and published results from these studies support its 
validity and reliability.
Planned Exploratory Biomarker Research
 
 
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Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, and 
severity and progression of disease. Variable response to therapy may be due to genetic 
determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease 
being treated. Therefore, where local regulations and IRB/IEC allow, a sample will be 
collected for DNA analysis from consenting participants.
DNA samples will be used for research related to the study treatment(s), the disease under 
study and related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to the disease under study, related diseases and study drug(s). Genetic 
research may consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome [or analysis of the entire genome] (as appropriate).
 
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DNA samples will be analyzed for variation across the entire genome. Analyses may be 
conducted if it is hypothesized that this may help further understand the clinical data. 
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
Future Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time.  The 
details of Future Biomedical Research are presented in Appendix 6 – Collection and 
Management of Specimens for Future Biomedical Research.
Rationale for the Use of Comparator/Placebo
The use of a placebo control for this trial is considered appropriate in this patient population 
because such a patient would have no disease burden following nephrectomy; these 
participants would then be followed without further treatment until disease recurrence, as no 
other regimens are yet approved for RCC in the adjuvant setting.
Justification for Dose
The planned dose of pembrolizumab for this trial is 200 mg Q3W. The initial dose approved 
by the United States Food and Drug Administration (FDA) for treatment of melanoma 
patients was 2 mg/kg Q3W. Currently, clinical trials evaluating pembrolizumab are using a 
fixed dose of 200 mg Q3W. The use of a fixed dose is based on PK findings summarized 
below.
The PK profile of pembrolizumab is consistent with that of other humanized monoclonal 
antibodies, which typically have a low clearance and a limited volume of distribution. A 
population PK model, which characterized the influence of body weight and other participant
covariates on exposure using available data from 1139 participants (from Keynote 001 and 
Keynote 002), has been performed. The majority of these participants (1077; 94.6%) had 
advanced melanoma. The distribution of exposures from the 200 mg fixed dose were 
predicted to considerably overlap those obtained with the 2 mg/kg dose and importantly 
maintained individual participant exposures within the exposure range established in 
 
 
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melanoma as associated with maximal clinical response. This comparison also demonstrated 
that the 200 mg Q3W regimen provided no substantive differences in PK variability (range of 
the distribution of individual exposures) as seen with weight-based dosing.
In translating to other solid tumor indications, similarly flat exposure-response relationships 
for efficacy and safety as observed in participants with melanoma can be expected, as the 
antitumor effect of pembrolizumab is driven through immune system activation rather than 
through a direct interaction with tumor cells, rendering it independent of the specific tumor 
type. In addition, available PK results in participants with melanoma, NSCLC, and other 
solid tumor types support a lack of meaningful difference in PK exposures obtained at tested 
doses among tumor types.
A fixed-dose regimen is expected to simplify the dosing regimen (potentially reducing dosing 
errors), as well as be more convenient for physicians. A fixed dosing scheme will also reduce 
complexity in the logistical chain at treatment facilities, as well as reducing waste.
6. Study Population
Male and female participants with intermediate-high risk, high risk and M1 NED RCC of at 
least 18 years of age will be enrolled in this trial.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Must have histologically confirmed diagnosis of RCC with clear cell component with 
or without sarcomatoid features. Diagnosis of RCC with clear cell component is to be 
made by the investigator and does not require central histology review.
Demographics
2. Be ≥18 years of age on day of signing informed consent.
Female Participants:
3. Female participants of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to randomization. If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.
4. Female participants of childbearing potential must be willing to use an adequate 
method of contraception as outlined in Appendix 5, for the course of the trial through 
120 days after the last dose of trial drug.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the participant.
 
 
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Male Participants:
5. Male participants of childbearing potential must agree to use an adequate method of 
contraception as outlined in Appendix 5, starting with the first dose of trial therapy 
through 120 days after the last dose of trial therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the participant.
Informed Consent
6. The participant provides written informed consent/assent for the trial. The participant
may also provide consent/assent for Future Biomedical Research; however, the 
participant may participate in the main trial without participating in Future 
Biomedical Research.
Other Inclusion Criteria
7. Have intermediate-high risk, high risk, or M1 NED RCC as defined by the following
pathological tumor-node-metastasis and Fuhrman grading status [Leibovich, B. C., et 
al 2003] [Rini, B. I., et al 2009] [Fuhrman, S. A., et al 1982]:
a) Intermediate-high risk RCC

pT2, Gr. 4 or sarcomatoid, N0, M0

pT3, Any Gr., N0, M0
b) High risk RCC

pT4, Any Gr. N0, M0

pT Any stage, Any Gr., N+, M0
c) M1 NED RCC -participants who present not only with the primary kidney tumor, 
but also solid, isolated, soft tissue metastases that can be completely resected at 
one of the following: 

the time of nephrectomy (synchronous) or,

≤1 year from nephrectomy (metachronous)
8. Have received no prior systemic therapy for advanced RCC.
9. Have undergone a partial nephroprotective or radical complete nephrectomy (and 
complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED 
participants) with negative surgical margins. 
10. Must have undergone a nephrectomy and/or metastasectomy ≥28 days prior to 
signing informed consent and ≤12 weeks prior to randomization.
11. Must be tumor free as assessed by the investigator and validated by either CT or MRI 
scan of the brain and CAP and a bone scan ≤28 days from randomization. All 
baseline scans must be sent to the central imaging vendor and receipt must be 
confirmed prior to randomization. 
 
 
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12. Must have provided adequate tissue per the following:

Nephrectomy only: tissue from nephrectomy (required).

Synchronous M1 NED: tissue from nephrectomy (required) AND, 
metastasectomy tissue (if available).

Metachronous M1 NED: tissue from metastasectomy (required) AND, 
nephrectomy tissue (if available).
Adequacy of the samples for biomarker analysis will be evaluated by a central 
laboratory. 
Note: If submitting unstained cut slides, newly cut slides should be submitted to the 
testing laboratory within 14 days from the date the slides are cut (details pertaining to 
tumor tissue submission and guidelines for tissue adequacy can be found in the 
Procedure Manual).
13. Have an ECOG PS of 0 or 1.
 
 
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14. Specimens must be collected within 10 days prior to randomization. Have adequate 
organ function as defined in the following table:
Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine OR
Measured or calculatedb creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥30 mL/min for participants with creatinine 
levels >1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN
Coagulation
International normalized ratio (INR) OR
prothrombin time (PT)
≤1.5 × ULN 
unless participant is receiving anticoagulant 
therapy as long as INR or PT is within 
therapeutic range of intended use of 
anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal.
a. Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
b Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for treatments.
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has had major surgery, other than nephrectomy and/or resection of preexisting
metastases for M1 NED participants, within 12 weeks prior to randomization.
 
 
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Note: If participants received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting study 
treatment.
2. Has received prior radiotherapy for RCC.
3. Has preexisting brain or bone metastatic lesions.
4. Has residual thrombus post nephrectomy in the vena renalis or vena cava.
5. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study treatment.
6. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids, or immunosuppressive 
drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a form of 
systemic treatment and is allowed.
7. Has a known additional malignancy that is progressing or required active treatment
≤3 years ago. Exceptions include early stage cancers (carcinoma in situ or Stage 1)
treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma 
of the skin, in situ cervical cancer, in situ prostate cancer, or in situ breast cancer that 
has undergone potentially curative therapy.
8. Has a history of (noninfectious) pneumonitis that required steroids or has current 
pneumonitis.
9. Has an active infection requiring systemic therapy.
10. Has a history of, or is currently on, dialysis.
11. Has a known history of human immunodeficiency virus infection. No human 
immunodeficiency virus testing is required unless mandated by local health authority.
12. Has a known active hepatitis B (hepatitis B surface antigen reactive) or HCV (eg, 
HCV RNA [qualitative] is detected).
Note: HCV RNA testing is not required in those countries where local standard of 
care uses only hepatitis C antibody testing as evidence of status of hepatitis C.
13. Has a known history of active tuberculosis (Bacillus tuberculosis).
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the participant’s 
participation for the full duration of the trial, or is not in the best interest of the 
participant to participate, in the opinion of the treating investigator.
15. Has a known psychiatric or substance abuse disorder that would interfere with the 
cooperation with the requirements of the trial in the opinion of the investigator.
16. Has had a prior solid organ transplant.
17. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
(refer to Investigator’s Brochure for further details on excipients).
 
 
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18. A WOCBP who has a positive urine pregnancy test within 72 hours before 
randomization. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. Participants must be excluded/discontinued 
from the trial in the event of a positive or borderline positive test result.
19. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the Screening visit through 120 days after 
the last dose of study treatment.
Prior/Concomitant Therapy
20. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or 
with an agent directed to another coinhibitory T-cell receptor (ie, CTLA-4, OX-40, 
CD137) or has previously participated in a Merck pembrolizumab (MK-3475) clinical 
trial.
21. Has received prior anticancer therapy, monoclonal antibody, chemotherapy, or an 
investigational agent or device within 4 weeks or 5 half-lives (whichever is longer) 
before first dose of study treatment or not recovered (ie, must be ≤Grade 1 or at 
baseline) from AEs due to previously administered agents.
Note: Upon consultation with the Sponsor, denosumab may be allowed for bone 
protective purposes if dosing has been stable for ≥2 weeks before screening.
Note: Participants with ≤Grade 2 neuropathy are an exception and may qualify for the 
trial.
22. Has received a live vaccine within 30 days prior to the first dose of study treatment. 
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus 
Calmette-Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza 
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
Prior/Concurrent Clinical Study Experience
23. Is currently participating in or has participated in a trial of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study
treatment.
Note: Participants who have entered the Follow-up phase of an investigational trial 
may participate as long as it has been 4 weeks or 5 half-lives after the last dose of the 
previous investigational agent.
Lifestyle Restrictions
No lifestyle restrictions are required, apart from those mentioned in the inclusion and 
exclusion criteria.
 
 
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Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
Caffeine, Alcohol, and Tobacco
There are no restrictions on caffeine, alcohol, or tobacco intake while a participant is enrolled 
in this trial.
Activity
There are no restrictions on the participant’s level of activity while they are enrolled in this 
trial.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any adverse events or SAE meeting reporting requirements as outlined 
in the entry guidelines.
Participant Replacement Strategy
A participant who discontinues from study treatment or withdraws from the trial will not be 
replaced.
7. Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
Clinical supplies [study treatment(s) provided by the Sponsor] will be packaged to support 
enrollment.  Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
Treatments Administered
The study treatments to be used in this trial are outlined below in Table 4.
 
 
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Table 4
Study Treatments
Study Treatment Name:
Pembrolizumab (MK-3475)
Placebo
Dosage Formulation:
Solution for infusion
Saline solution for 
infusion
Unit Dose Strength(s):
25 mg/mL (100 mg/4 mL)
0 mg
Dosage Level(s):
200 mg Q3W
0 mg Q3W
Route of Administration:
IV infusion
IV infusion
Sourcing:
Provided centrally by the 
Sponsor
Provided locally by the 
trial site
All trial treatments will be administered on an outpatient basis.
All supplies indicated in Table 4 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements.  Every attempt should be made to source these 
supplies from a single lot/batch number. The trial site is responsible for recording the lot 
number, manufacturer, and expiry date for any locally purchased product as per local 
guidelines unless otherwise instructed by the Sponsor.
Refer to section 9.1.8 for details regarding administration of the study treatment.
Dose Modification (Escalation/Titration/Other)
Dose Modification and Toxicity Management Guidelines for Pembrolizumab
Dose Modification and Toxicity Management for Immune-related Adverse Events 
Associated With Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications.
Based on existing clinical trial data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids, and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, or skin biopsy may 
be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 5.
 
 
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Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated With 
Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroids should be initiated first, followed by oral steroids. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and 
symptoms of pneumonitis

Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation (ie,
peritoneal signs and ileus).

Participants with ≥Grade 2 diarrhea 
suspecting colitis should consider 
gastrointestinal consultation and performing 
endoscopy to rule out colitis.

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up 
AST / ALT 
elevation or 
increased 
bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5-1 mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable)
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
T1DM or 
hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement 
therapy for participants with 
T1DM 

Administer antihyperglycemic in 
participants with hyperglycemia

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinuea
Hyperthyroidism 
Grade 2
Continue 

Treat with nonselective 
beta-blockers (eg, propranolol) or 
thionamides as appropriate

Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4 
Withhold or 
Permanently 
discontinuea
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up 
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All Other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold

Based on severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event. Events that 
require 
discontinuation 
include and not 
limited to:
Guillain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; 
irAE=immune-related adverse event; IV=intravenous; T1DM= Type 1 diabetes mellitus.
a.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.
NOTE: For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be 
resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).
 
 
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab-associated 
infusion reaction are provided in Table 6. 
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption, 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 h
Stop Infusion.
Additional appropriate medical therapy may 
include, but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (eg, from 
100 mL/h to 50 mL/h). Otherwise dosing will be 
held until symptoms resolve and the participant
should be premedicated for the next scheduled 
dose.
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
treatment
Participant may be 
premedicated 1.5 h 
(±30 minutes) prior to infusion 
of pembrolizumab with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include, but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Participant is permanently discontinued from 
further study treatment.
No subsequent dosing
IV=intravenous; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; 
NSAID=nonsteroidal anti-inflammatory drug; po=per os (orally).
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study treatment. Participants
should be placed back on study treatment within 3 weeks of the scheduled interruption, 
unless otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the participant’s study record.
Method of Treatment Assignment 
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization.  Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
 
 
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Treatment allocation/randomization will occur centrally using the IVRS/IWRS.  There are 2
study treatment arms.  Participants will be assigned randomly in a 1:1 ratio to either:

Pembrolizumab monotherapy

Placebo (carrier solution only)
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
Metastasis status (M0 versus M1 NED) 
Within M0 group, there will be 2 stratification factors: 
a.
ECOG PS (0 versus 1)
b. US participant (YES versus NO)
Blinding 
A double-blinding technique will be used.  MK-3475 and placebo will be prepared and/or 
dispensed in a blinded fashion by an unblinded pharmacist or qualified trial site personnel. 
The participant and the investigator who is involved in the study treatment administration or 
clinical evaluation of the participants are unaware of the group assignments.
See Section 9.1.10 for a description of the method of unblinding a participant during the trial, 
should such action be warranted.
Preparation/Handling/Storage/Accountability
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual.
The rationale for selection of doses to be used in this trial is provided in Section 5.5. There 
are no specific calculations or evaluations required to be performed in order to administer the
proper dose to each participant.
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
 
 
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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all trial sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate.  Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The trial site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of study 
treatments in accordance with the protocol and any applicable laws and regulations.
Treatment Compliance
Study intervention will be administered by the investigator and/or study staff according to the 
specifications within the Pharmacy Manual.
Interruptions from the protocol specified treatment plan for greater than 3 weeks between 
study treatments for situations other than treatment-related AEs such as medical / surgical 
events or logistical reasons not related to study treatment require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to continue 
the participant on study treatment requires the mutual agreement of the investigator, the 
Sponsor and the participant.
Listed below are specific restrictions for concomitant therapy during the course of the trial:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab
 
 
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
Radiation therapy

Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, 
rabies, Bacillus Calmette-Guérin, and typhoid vaccine. Seasonal influenza vaccines 
for injection are generally killed virus vaccines and are allowed; however, intranasal
influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
AE that is suspected to have an immunologic etiology. The use of physiologic doses 
of corticosteroids may be approved after consultation with the Sponsor.
Note: Use of prophylactic corticosteroids to avoid allergic reactions (eg, IV contrast 
dye or transfusions) is permitted.
Note: The use of intermittent inhaled steroids or intranasal or local injection of 
corticosteroids is permitted.
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments (excluding the exceptions noted above) for clinical management 
should be removed from the trial. Participants may receive other medications that the 
investigator deems to be medically necessary.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, over-the-counter products, herbal supplements, and IV medications and fluids. 
If changes occur during the trial period, documentation of drug dosage, frequency, route, and 
date should also be included on the eCRF.
All concomitant medications received within 30 days prior to the first dose of study treatment 
and up to 30 days after the last dose of study treatment should be recorded. Concomitant 
medications administered 30 days after the last dose of study treatment should be recorded 
for SAEs and ECIs as defined in Section 9.3.
Medications intended solely for supportive care (ie, antiemetics, analgesics, megestrol 
acetate for anorexia) are allowed. The exclusion criteria describe other medications that are 
prohibited in this trial. There are no prohibited therapies during the posttreatment Follow-up 
phase.
Rescue Medications & Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 7.2, Table 5 and Table 6. Where appropriate, these guidelines include the use of oral 
or IV treatment with corticosteroids, as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids. Note that several courses of 
steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
 
 
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decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care. The treatment guidelines are intended to be applied when the investigator determines 
the events to be related to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 5 and Table 6
in Section 7.2 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Treatment After the End of the Study 
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
This trial is blinded but supplies are provided open label; therefore, an unblinded pharmacist 
or qualified trial site personnel will be used to blind supplies.  Study treatment identity (name, 
strength or potency) is included in the label text; random code/disclosure envelopes or lists 
are not provided.
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind participants and to unmask study treatment identity. In the event that the 
emergency unblinding call center is not available for a given site in this trial, the central 
electronic treatment allocation/randomization system (IVRS/IWRS) should be used in order 
to unblind participants and to unmask study treatment identity.  The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
See Section 9.1.10, Participant Blinding/Unblinding, for a description of the method of 
unblinding a participant during the trial, should such action be warranted.
8. Discontinuation/Withdrawal Criteria 
Discontinuation of Study Treatment 
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment discontinuation may be important 
to the study, they must be collected through the participant’s last scheduled follow-up, even 
if the participant has discontinued study treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
will still continue to participate in the study as specified in Section 2 - SoA and Section 
9.10.4 – Discontinued Participants Continuing to be Monitored in the Study, unless the 
participant withdraws from the study.
 
 
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Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 9.1.9 – Withdrawal/Discontinuation.
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:
○
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment.
o
Participants with AEs meeting discontinuation criteria as described in Section 9.
o
The participant has a medical condition or personal circumstance or is noncompliant to 
study treatments or procedures, which, in the opinion of the investigator and/or Sponsor, 
place the participant at unnecessary risk from continued administration of study 
treatment.
o
The participant has a confirmed positive serum pregnancy test.
o
The participant has received 17 cycles of study treatment.
o
Any progression or recurrence of the malignancy under study.
NOTE: All scans for the participant must be submitted to the central imaging vendor 
according to the Procedures Manual. Clinically stable participants that are first identified 
with disease recurrence may remain on study treatment while waiting for confirmation of 
recurrence by the investigator (Section 9.2.1).
o
A new malignancy requiring active treatment.
NOTE: In the event that a new malignancy is diagnosed and requires active treatment, the 
Sponsor should be consulted as to whether the participant should be discontinued from 
study treatment.
o
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment.
o
Recurrent Grade 2 pneumonitis.
o
Investigator’s decision to discontinue participant.
For information about the End of Treatment Visit and Safety Follow-up Visit, please refer to 
Section 9.10.3.
For participants who are discontinued from study treatment but continue to be monitored in 
the trial, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study treatment is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study treatment. 
 
 
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Withdrawal from the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study including the procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant, as well as 
specific details regarding withdrawal from Future Biomedical Research are outlined in 
Section 9.1.9 – Withdrawal/Discontinuation.
Lost to Follow Up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
o
The site must attempt to contact the participant and reschedule the missed visit.  If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
o
The investigator or designee must make every effort to regain contact with the
participant at each missed visit (e.g. phone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
o
Note:  A participant is not considered lost to follow up until the last scheduled visit 
for the individual participant.  The amount of missing data for the participant will be 
managed via the pre-specified data handling and analysis guidelines.
9. Study Assessments and Procedures
●
Study procedures and their timing are summarized in the SoA. 
●
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
●
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
Repeat or unscheduled samples and images may be taken for safety reasons or for technical 
issues with the samples.
 
 
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Administrative and General Procedures
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
participant or each participant’s legally acceptable representative prior to participating in a 
clinical trial or Future Biomedical Research. If there are changes to the participant’s status 
during the trial (eg, health or age of majority requirements), the investigator or qualified 
designee must ensure the appropriate consent is in place. 
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the participant before 
participation in the trial.
The initial ICF, any subsequent revised written ICF and any written information provided to 
the participant must receive the IRB/IEC’s approval/favorable opinion in advance of use.  
The participant or his/her legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the participant’s 
willingness to continue participation in the trial.  The communication of this information will 
be provided and documented via a revised consent form or addendum to the original consent 
form that captures the participant’s dated signature or by the participant’s legally acceptable 
representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements.
Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the participant, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to Future Biomedical Research.  A copy of the informed 
consent will be given to the participant.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial.
 
 
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Participant Identification Card
All participants will be given a Participant Identification Card identifying them as 
participants in a research trial. The card will contain trial site contact information (including 
direct telephone numbers) to be utilized in the event of an emergency. The investigator or 
qualified designee will provide the participant with a Participant Identification Card 
immediately after the participant provides written informed consent. At the time of treatment 
allocation/randomization, site personnel will add the treatment/randomization number to the 
Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically significant. Details regarding the 
disease for which the participant has enrolled in this trial will be recorded separately and not 
listed as medical history.
History of Renal Cell Carcinoma
The investigator or qualified designee will obtain information regarding the participants’ 
RCC. This information will include, but is not limited to, the presentation and stage at initial
diagnosis, date of initial diagnosis, date of nephrectomy (and metastasectomy for M1 NED), 
surgical outcome and location of metastases (if applicable).
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant
within 30 days before the first dose of study treatment. Treatment for the disease for which 
the participant has enrolled in this trial will be recorded separately and not listed as a prior 
medication.
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant
during the trial through the Safety Follow-up Visit.
All medications related to reportable SAEs and ECI should be recorded as defined in 
Section 9.3.
 
 
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9.1.5.2.1 Poststudy Anticancer Therapy
If a participant initiates a new anticancer therapy while receiving study treatment, study
treatment must be discontinued and the participant will move into the Survival Follow-up 
phase. If a participant initiates a new anticancer therapy within 30 days after the last dose of 
study treatment, the End of Treatment Visit and the 30-day Safety Follow-up Visit must 
occur before the first dose of the new therapy. All new anticancer therapy initiated after the 
study start must be recorded in the poststudy anticancer therapy eCRF.
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization.  Each participant
will be assigned only one screening number.  Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the Screening Visit requirements (screening/rescreening) are provided in 
Section 9.10.1.
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization.  Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Treatment Administration
Study intervention will be monitored by the investigator and/or study staff according to the 
specifications within the Pharmacy Manual.
Study Treatment should begin within 3 days of randomization.
Timing of Dose Administration
Cycle 1 Day 1 denotes the first dose of study treatment administered. Subsequent doses of 
study treatment will be administered on Day 1 of each 21-day cycle (±3 days). Treatment 
should begin after all predose study procedures and assessments have been completed as 
specified in the SoA (Section 2).
Study treatment will be administered as a 30-minute IV infusion Q3W. Sites should make 
every effort to target infusion timing to be as close to 30 minutes as possible. However, given 
 
 
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the variability of infusion pumps from site to site, a window of - 5 minutes and + 10 minutes 
is permitted (ie, infusion time is 25 to 40 minutes).
The Pharmacy Manual contains specific instructions for the preparation and administration of 
the study treatment infusion solution.
Withdrawal/Discontinuation
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant discontinues/withdraws from participation in the trial, all applicable 
activities scheduled for the End of Treatment Visit should be performed at the time of 
discontinuation.  Any adverse events which are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 9.3 - Adverse Events, Serious Adverse Events, and Other Reportable 
Safety Events. Participants who complete 17 cycles of study treatment (approximately 
1 year) must discontinue treatment. After discontinuing treatment period, all participants 
should return to the site for the End of Treatment Visit and Safety Follow-up visit and then 
proceed to Efficacy Follow-up (described in Section 9.10.3).
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the principal investigator for the main trial.  If 
medical records for the main trial are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com).  Subsequently, 
the participant's consent for Future Biomedical Research will be withdrawn.  A letter will be 
sent from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of 
the investigator to inform the participant of completion of withdrawal.  Any analyses in 
progress at the time of request for withdrawal or already performed prior to the request being 
received by the Sponsor will continue to be used as part of the overall research trial data and 
results.  No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
 
 
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dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
toxicity grade of the AEs observed, the relation to study intervention, the reason thereof, etc., 
in the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
For studies that require nonemergency unblinding as part of the study design (eg, disease 
progression) to support treatment decisions, instructions in the IVRS/IWRS Unblinded Site 
User Manual should be followed.
Once an emergency unblinding or a nonemergency unblinding that is part of the study design 
has taken place, the investigator, site personnel, and Sponsor personnel may be unblinded so 
that the appropriate follow-up medical care can be provided to the participant.
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device 
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Laboratory equipment – as required for inclusion laboratory results and trial 
assessments

Imaging equipment – as required for trial objectives

Infusion equipment – as required for administering drug product.
 
 
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Efficacy Assessments 
Tumor Imaging and Assessment of Disease Recurrence
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual. All baseline, on-treatment, and follow-up scans must be 
sent to the central imaging vendor. Acceptable modalities for each anatomic region are as 
follows: 

For imaging of the CAP, CT is the strongly preferred modality and should be 
acquired with IV and oral contrast. An MRI with IV contrast should only be used 
when CT is contraindicated.

For brain imaging MRI is preferred; however, CT imaging will be acceptable, if an 
MRI is medically contraindicated.

For imaging of bone, bone scintillation or the local standard of care modality should 
be used. X-rays may also be taken for symptomatic sites even if a bone scan is 
negative.
The same imaging technique regarding modality and contrast should be used in a participant 
throughout the trial to optimize the visualization of existing and new tumor burden.
The investigator will verify that each participant is tumor free at baseline and will make the 
determination that a participant has met the criteria for recurrence of RCC. 
To assess the adequacy of DFS as assessed by the investigator, a blinded audit for a subset of 
participants will be conducted as outlined in the supplemental Statistical Analysis Plan 
(sSAP).
Criteria for Determination of Disease Recurrence
Disease recurrence is defined as local recurrence of RCC, or occurrence of distant kidney 
cancer metastasis(es) and is to be determined according to the clinical, pathologic, and 
radiographic criteria in Table 7. Radiographic evidence for disease recurrence is required, 
while confirmation of recurrence by biopsy or cytology is strongly encouraged, when safely 
feasible. The date of disease recurrence (eg, RCC) should be the date the first radiographic 
image with evidence of disease recurrence was obtained even if additional confirmatory 
procedures (eg, repeat imaging, biopsy, and/or cytology) are performed later.
 
 
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Table 7
Criteria for Determining Recurrence of Disease
Anatomic Location
Acceptable Recurrence Criteria
(Must meet radiographic evidence of disease recurrence. 
Confirmation of recurrence by biopsy or cytology strongly 
encouraged when safely feasible.)
Lung

Positive cytology or biopsy in the presence of a solitary 
lesion

Radiologic evidence of lesion(s) determined to be 
consistent with metastases

Neoplastic pleural effusion should be established by 
cytology or pleural biopsy
Liver

Positive cytology or biopsy

Multiple new focal defects on MRI, CT, or ultrasound 
that are enlarging in size as documented by repeat scans

Proof of neoplastic abdominal ascites should be 
established by cytology or pleural biopsy
Central Nervous System

Positive brain CT or MRI scan or cerebral spinal fluid 
cytology
Subcutaneous and Lymph Node 
Recurrence

Positive biopsy

Progressively enlarging solid mass or node(s) as 
evidenced by repeat CT or MRI

Ureteral obstruction in the presence of a mass as 
documented on CT or MRI
Other Organs

Positive radiographic study 

Positive biopsy/aspiration cytology

Progressively enlarging solid mass or node(s) as 
evidenced by repeat CT or MRI
Renal Bed

Positive radiographic study 

Positive biopsy/aspiration cytology

Progressively enlarging solid mass or node(s) as 
evidenced by 2 CT or MRI scans separated by at least a 
4-week interval
Skeletal

Positive radiographic study such as bone scan

For a solitary lesion, unequivocal finding on scan or
biopsy is required to demonstrate recurrence

MRI or CT of solitary or equivocal lesion seen on bone 
scan that confirms metastasis is also acceptable
CT = computed tomography; MRI = magnetic resonance imaging.
Criteria for Determination of Disease Progression
Participants, which by BICR were considered to have baseline disease (M1 by BICR), 
disease progression is defined as either unequivocal progression of baseline disease or 
appearance of new lesions as assessed by BICR.
 
 
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Initial Tumor Imaging at Screening
Initial tumor imaging during Screening (baseline) must be performed for all participants as 
follows:

CT (or MRI) of CAP (within 28 days prior to date of randomization)

A brain scan (within 28 days prior to date of randomization)

A bone scan (within 28 days prior to date of randomization)
Scans performed as part of routine clinical management are acceptable for use as screening 
tumor imaging if they are of diagnostic quality, performed within timeframe specified above 
and are able to be assessed by the central imaging vendor. 
All screening images must be submitted to the central imaging vendor prior to 
randomization. The central imaging vendor will verify that all scans are received and of 
diagnostic quality prior to randomization. Tumor-free status at baseline will be confirmed by 
the investigator for enrollment.
Tumor Imaging During Treatment
The timing of on-treatment imaging assessments should follow calendar days from the date 
of randomization and should not be adjusted for dose delays or cycle starts.
Postrandomization, on-treatment imaging assessments of CAP should be performed at the 
following time points:
Week 12 (± 7 days)
Week 24 (± 7 days)
Week 36 (± 7 days)
Week 48 (± 7 days)
On-treatment bone scans will be performed as clinically indicated. A bone scan may be 
obtained if there are new symptoms of bone pain in participants with negative bone scans at 
Screening. X-ray evaluation may be obtained for symptomatic sites in participants with 
negative bone scan evaluations.
On-treatment brain scans will be performed at Screening and as clinically indicated thereafter.
End of Treatment and Follow-up Tumor Imaging
Participants who complete all 17 cycles of study treatment or discontinue study treatment due 
to a reason other than disease recurrence should continue to be monitored for disease status 
per the follow-up imaging schedule. Imaging should continue until disease recurrence, 
pregnancy, the start of a new anticancer treatment, withdrawal of consent, death, or the end 
of the trial, whichever occurs first. Follow-up imaging should follow calendar days from the 
date of randomization. 
 
 
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For participants who discontinue study treatment for reasons other than disease recurrence, 
tumor imaging should be performed at the time of treatment discontinuation. If a previous 
scan was obtained within 28 days prior to the date of discontinuation, then a scan at treatment 
discontinuation is not mandatory. These participants should continue to be monitored for 
disease status per the follow-up imaging schedule. Imaging should continue until disease 
recurrence, pregnancy, the start of a new anticancer treatment, withdrawal of consent, death, 
or the end of the trial, whichever occurs first. If a discontinuation scan is performed and the 
next scheduled time point is fewer than 28 days later, this scheduled time point may be 
skipped. In this case, the imaging should resume with the subsequent scheduled time point. 
For participants who discontinue study treatment due to disease recurrence, the initial 
imaging demonstrating recurrence is the final required imaging, unless recurrence is 
confirmed with a repeat scan. In this case, the confirmatory scan is the final required imaging.
The timing of follow-up imaging assessments should follow calendar days from the date of 
randomization. Imaging should be performed according to the following schedule (all 
timepoints are from the date of randomization):
Follow-up Year 1 (Q12W)
Week 60 (± 7 days)
Week 72 (± 7 days) 
Week 84 (± 7 days)
Week 96 (± 7 days)
Follow-up Years 2 to 4 (Q16W)
Week 112 (± 7 days)
Week 192 (± 7 days)
Week 128 (± 7 days)
Week 208 (± 7 days)
Week 144 (± 7 days)
Week 224 (± 7 days)
Week 160 (± 7 days)
Week 240 (± 7 days)
Week 176 (± 7 days)
Week 256 (± 7 days)
Follow-up Years 5 and Beyond (Q24W)
Week 280 (± 7 days)
Week 304 (± 7 days)
Week 328 (± 7 days)
(continue at Q24W ± 7 days)
Quality of Life Assessments
The EORTC-QLQ-C30, FKSI-DRS, and EQ-5D-5L PROs are to be completed electronically 
by study participants at various time points as specified in the SoA (Section 2), beginning 
 
 
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with the baseline assessment and continuing until disease recurrence or start of a new 
anticancer treatment. 
The PROs will be administered in the following order: (1) EQ-5D-5L, (2) EORTC-QLQ-C30, 
and (3) FKSI-DRS. It is strongly recommended that PROs be administered prior to AE 
evaluation, disease notification status, and study treatment administration.
EuroQoL 5 Dimensions 5 Levels
The EQ-5D-5L is a standardized instrument for use as a measure of health outcomes. The 
EQ-5D-5L will provide data for use in economic models and analyses including developing 
health utilities or quality-adjusted life-years. The 5 health state dimensions in this instrument 
include the following: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression [Rabin, R. 2001] [Pickard, A. S., et al 2007]. Each dimension is rated on a 
5-point scale from 1 (no problem) to 5 (extreme problem). The EQ-5D-5L also assesses the 
general state of health using a visual analog scale (0 to 100). The EQ-5D-5L will always be 
completed by participants first, prior to completing any other PRO.
European Organization for the Research and Treatment of Cancer Quality of 
Life Questionnaire C30
The EORTC-QLQ-C30 was developed to assess the QoL of patients with cancer. It has been 
translated and validated into 81 languages and used in more than 3,000 studies worldwide. It 
consists of 5 functioning scales (physical, role, cognitive, emotional, and social), 3 symptom 
scales (fatigue, nausea/vomiting, pain), and additional single-symptom items. It is scored on 
a 4-point scale (1 = not at all, 2 = a little, 3 = quite a bit, 4 = very much). The EORTC-QLQ-
C30 instrument also contains 2 global scales that use a 7-point scale scoring with anchors 
(the scores range from 1 = very poor to 7 = excellent) [Aaronson, N. K., et al 1993].
Functional Assessment of Cancer Therapy Kidney Symptom Index – Disease-
Related Symptoms
The FKSI-DRS is a patient-reported instrument that measures whether the participant has 
experienced any of the following 9 kidney cancer-related symptoms: lack of energy, fatigue, 
weight loss, pain, bone pain, shortness of breath, cough, fever, or blood in the urine [Cella, 
D., et al 2007]. Each item is scored by using the following 5 response categories: 0, not at all; 
1, a little bit; 2, somewhat; 3, quite a bit; and 4, very much. Responses to all FKSI-DRS 
items are summed to generate a summary symptom score ranging from 0 to 36, with higher 
scores indicating improved (more favorable) symptom status. The FKSI-DRS is a reliable, 
valid, and responsive brief index of the most important symptoms associated with advanced 
kidney cancer [Cella, D., et al 2007].
If, at the time of first dose of study treatment, the translated version of the FKSI-DRS – one 
of the PRO measures – is not available for that language/country, and it cannot be completed 
by the participant at Cycle 1, Day 1, then the FKSI-DRS will not be required for this 
participant at any point of the study. The other study PRO measures must be completed as 
scheduled.
 
 
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Note: For some sites, the translated FKSI-DRS might become available after study startup 
and should be administered to participants at their time of first dose of study treatment; for 
some sites, the FKSI-DRS translation might not be available for the entire duration of the 
study. Missing FKSI-DRS for such a reason will not be considered a protocol deviation.
Adverse Events, Serious Adverse Events and Other Reportable Safety Events
The definitions of an adverse event (AE) or serious adverse event (SAE), as well as the 
method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting AE, SAE and other reportable safety event reports can be 
found in Appendix 4.
Progression of the cancer under study is not considered an adverse event as described in 
Section 9.3.5 – Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs, and Appendix 4.
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE as well as other reportable safety events. Investigators remain responsible for following 
up AE, SAEs and other reportable safety events for outcome according to Section 9.3.3.
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure. 
●
All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study treatment must be reported by the investigator. 
●
All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following cessation of 
study treatment if the participant initiates new anticancer therapy, whichever is earlier 
must be reported by the investigator. 
●
All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 30 
days following cessation of study treatment if the participant initiates new anticancer 
therapy must be reported by the investigator. 
●
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered to be drug-related.
 
 
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Investigators are not obligated to actively seek AE or SAE in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator must 
promptly notify the sponsor.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the sponsor or designee within the timeframes as indicated in Table 8.
 
 
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Table 8
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
Specified Follow-
up Period
Reporting Time Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Serious Adverse 
Event (SAE)
including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- Potential DILI
- Require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 days 
of learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously 
reported 
–
Follow 
to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
 
 
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Method of Detecting AE and SAE
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrence.
Follow-up of AE, SAE and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE and other reportable safety events 
including pregnancy and exposure during breastfeeding, ECI, Cancer and Overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 8.3). In addition, the investigator will 
make every attempt to follow all non-serious AEs that occur in randomized participants for 
outcome.  Further information on follow-up procedures is given in Appendix 4.
Regulatory Reporting Requirements for SAE

Prompt notification (within 24 hours) by the investigator to the sponsor of SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. All Adverse Events will be reported to regulatory authorities, IRB/IECs 
and investigators in accordance with all applicable global laws and regulations, i.e., 
per ICH Topic E6 (R1) Guidelines for Good Clinical Practice.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will file 
it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs
or SAEs
Progression/recurrence of the cancer under study is not considered a reportable event.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the trial. Any suspected endpoint which upon review is 
not progression/recurrence of the cancer under study will be forwarded to Global Safety as an
SAE within 24 hours of determination that the event is not progression/recurrence of the 
cancer under study.
 
 
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Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
reported to the investigator or their designee), including the pregnancy of a male participant's 
female partner, that occurs during the trial are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events).  If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
Events of Clinical Interest (ECI)
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
Events of clinical interest for this trial include: 
1. an overdose of Sponsor's product, as defined in Section 9.4 – Treatment of Overdose, 
that is not associated with clinical symptoms or abnormal laboratory results.
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed
with additional evaluation will be made through consultation between the study investigators
and the Sponsor Clinical Director; however, abnormalities of liver blood tests that do not
meet the criteria noted above are not ECIs for this trial.
Treatment of Overdose
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab (200 mg) by 5 times (ie, any dose higher than 1000 mg) in a 3-week
time period. No specific information is available on the treatment of overdose of
pembrolizumab. In the event of overdose, pembrolizumab should be discontinued and the 
 
 
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participant should be observed closely for signs of toxicity.  Appropriate supportive 
treatment should be provided if clinically indicated.
Safety 
Details regarding specific safety procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pretrial to posttrial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Procedure 
Manual.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
Full Physical Examination
The investigator or qualified designee will perform a full physical examination during the 
Screening period and at the End of Treatment Visit. Clinically significant abnormal findings
at Screening should be recorded as medical history. The time points for full physical 
examinations are described in Section 2. After the first dose of study treatment, new 
clinically significant abnormal findings should be recorded as AEs.
Directed Physical Examination
For cycles that do not require a full physical examination as defined in Section 2, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated prior to the administration of the study treatment. New clinically significant 
abnormal findings should be recorded as AEs.
Vital Signs
Vital signs include temperature, pulse, respiratory rate, weight, and blood pressure. The 
investigator or qualified designee will take vital signs at Screening, prior to the 
administration of each dose of trial treatment, and during the End of Treatment Visit as 
specified in the SoA (Section 2). Height will be measured at Visit 1 only. Vital signs are to 
be taken before blood collection for laboratory tests and measured once the participant has 
been in a seated position for 5 minutes. Due to site logistics, blood draw prior to vital signs 
may be approved after consultation with the Sponsor
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures once at 
Screening and as clinically indicated thereafter. Clinically significant abnormal findings at 
Screening should be recorded in the medical history.
 
 
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Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in study 
participant management or are considered clinically significant by the investigator 
(eg, SAE or AE or dose modification), then the results must be recorded in the 
appropriate CRF (eg, SLAB).

For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 30 days (or until the initiation of a new 
anticancer treatment, whichever occurs first) after the last dose of study treatment, 
every attempt should be made to perform repeat assessments until the values 
return to normal or baseline or if a new baseline is established as determined by 
the investigator. 
There may be instances when sites are unable to obtain the thyroid function testing results 
prior to scheduled dosing. Review of thyroid function tests (FT3, FT4 and TSH) results after 
dosing is acceptable.
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn over the course of the trial 
(from pretrial to posttrial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Procedure 
Manual. Refer to the SoA (Section 2) for the timing of laboratory assessments.
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2. All 
safety laboratory tests must be performed by a central laboratory. After Cycle 1, predose
safety laboratory tests may be collected up to 72 hours prior to study treatment administration. 
If central laboratory results are not expected prior to study treatment administration the 
investigator may also perform laboratory tests locally. Note: local laboratory may not be used 
in lieu of central laboratory.
 
 
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Pregnancy Test
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal (refer to Appendix 5 for definitions), must be tested for 
pregnancy within 72 hours of randomization. If a urine test is positive or not evaluable, a 
serum test will be required. Participants must be excluded/discontinued from the trial in the 
event of a positive or borderline-positive test result.
Monthly pregnancy testing should be conducted per local regulations where applicable.
Performance Assessments
Eastern Cooperative Oncology Group Performance Status (ECOG PS)
The investigator or qualified designee will assess ECOG PS (see Table 9) at Screening, prior 
to dosing on Day 1 of each treatment cycle through Cycle 17, at treatment discontinuation, at 
the Safety Follow-up Visit as specified in the SoA (Section 2). During the Follow-up period,
ECOG PS is to be collected only if participants come in for a clinic visit (ie, during Follow-
up).
Table 9
Eastern Cooperative Oncology Group Performance Status
GRADE
Eastern Cooperative Oncology Group Performance Status
0
Fully active, able to carry on all predisease performance without restriction.
1
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light sedentary nature, eg, light housework, office work.
2
Ambulatory and capable of all self-care, but unable to carry out any work 
activities; up and about more than 50% of waking hours.
3
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair.
5
Dead.
Oken M, Creech R, Tomey et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5:649-55.[Oken, M. M., et al 1982]
http://www.ecog-acrin.org/resources/ecog-performance-status
Pharmacokinetics
Blood samples for PK and ADA analysis are no longer being collected under this protocol.
 
 
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Blood Collection for RNA Analysis and Plasma and Serum Biomarker Analysis
Blood should be collected predose for Cycles 1, 2, and 5, at the time of discontinuation, and 
if the participant has disease recurrence during the Follow-up period. Leftover RNA, plasma, 
and serum will be stored at the end of the trial for Future Biomedical Research if the 
participant has consented (see Section 9.8).
Further details are provided in the Procedure Manual.
Pharmacodynamics
Tumor Tissue Collection
Tissue should be obtained from participants per the following parameters:

Nephrectomy only: tissue from nephrectomy required for predominant analysis.

Synchronous M1 NED: tissue from nephrectomy required for predominant analysis 
AND, when available, metastasectomy tissue for secondary analysis.

Metachronous M1 NED: tissue from metastasectomy required for predominant 
analysis AND, when available, nephrectomy tissue for secondary analysis.
At disease recurrence, if a new core or excisional biopsy of a tumor is obtained as part of 
standard practice, information from the pathology report should be entered into the eCRF. If 
the participant signs the Future Biomedical Research consent, any leftover tissue that would 
ordinarily be discarded at the end of the main study will be retained for Future Biomedical 
Research. Details regarding time points for collection of tumor tissue are outlined in the SoA 
– Section 2. Include a copy of the local pathology report with the tissue for biomarker 
analysis.
Detailed instructions for tissue collection, processing, and shipment are provided in the 
Procedure Manual.
Future Biomedical Research Sample Collection 
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research

Leftover plasma and serum from biomarker analysis

Leftover RNA

Leftover main trial tumor tissue
 
 
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Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants in this 
study as specified in the SoA (Section 2):
●
Blood for genetic analysis
●
Blood for RNA analysis
●
Blood for TCR
●
Plasma for biomarker analysis
●
Blood for serum biomarker analysis
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedure Manual.
Samples should be collected for planned analysis of associations between genetic variants in 
germline/tumor DNA and drug response. If a documented law or regulation prohibits (or 
local IRB/Independent Ethics Committee [IEC] does not approve) sample collection for these 
purposes, then such samples should not be collected at the corresponding sites.
Leftover DNA extracted from planned genetic analysis samples will be stored for future 
biomedical research only if participant signs the Future Biomedical Research consent.
Visit Requirements
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA). Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
Screening
Within 42 days prior to treatment randomization, potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 6.1 and Section 6.2.
Visit requirements are outlined in the SoA (Section 2). Screening procedures may be 
repeated after consultation with the Sponsor.
 
 
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Written consent must be obtained prior to performing any protocol-specific procedure.
Results of a test performed prior to the participant signing consent as part of routine clinical 
management are acceptable in lieu of a Screening test if performed within the specified time 
frame. Screening procedures are to be completed within 42 days prior to randomization, 
except for the following:

Laboratory tests are to be performed within 10 days prior to randomization.

For WOCBP, a urine pregnancy test will be performed within 72 hours prior to 
randomization. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required (performed by the local study site laboratory).

CAP, bone, and brain imaging will be performed 28 days before randomization.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial Screening period are acceptable in lieu of a repeat 
Screening test if performed within the specified time frame and the corresponding
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
Treatment Period Visits
Visit requirements are outlined in the SoA (Section 2). Specific procedure-related details are 
provided in Section 9.1.
Participants who discontinue study treatment for a reason other than disease recurrence will 
be considered as on study and should continue with regularly scheduled assessments, (also 
refer to Section 9.10.3), including collecting participant information on the start of new 
anticancer therapy, disease recurrence, and death.
End of Treatment Visit
The End of Treatment Visit should occur at the time study treatment is discontinued for any 
reason. If the End of Treatment Visit occurs at the same time as the mandatory Safety 
Follow-up Visit, the End of Treatment Visit procedures and any additional Safety Follow-up 
procedures should be performed. Visit requirements are outlined in the SoA (Section 2).
Posttreatment Period
Participants who complete study treatment, and participants who discontinue for a reason 
other than disease recurrence, will move to Follow-up phase.
All participants who complete study treatment and who discontinue for any reason will 
complete an End of Treatment Visit and a Safety Follow-up Visit. The End of Treatment 
Visit and Safety Follow-up Visit may occur simultaneously to accommodate the participant.
 
 
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Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted at least 30 days (+7 days) after 
the last dose of study treatment or before the initiation of a new anticancer treatment, 
whichever comes first.
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study treatment for a reason other than disease recurrence will continue to 
receive scans according to Section 9.2.1.3. At Week 60, participants will move into the 
Efficacy Follow-up period and should be assessed Q12W in year 1, Q16W in years 2, 3, and 
4, and Q24W in year 5 and beyond to monitor disease status as outlined in the SoA 
(Section 2) and annually to collect quality of life data. Every effort should be made to collect 
information regarding disease status until the start of new anticancer therapy, disease 
recurrence, death, or end of trial. Information regarding posttrial anticancer treatment will be 
collected if new treatment is initiated. Participants who completed all efficacy assessments 
and/or will not have further efficacy assessments must enter the Survival Follow-up Phase.
Survival Follow-up Contacts
Participant Survival Follow-up status will be assessed approximately every 12 weeks to 
assess for survival status until death, withdrawal of consent, or the end of the trial, whichever 
occurs first.
The first Survival Follow-up contact should be scheduled as described below: 
•
For participants who discontinue treatment intervention and who will not enter the 
Efficacy Follow-up phase, the first Survival Follow-up contact will be scheduled 
12 weeks after the discontinuation visit and/or Safety Follow-up Visit (whichever is 
last).  
•
For participants who completed assessments in the Efficacy Follow-up phase, the first 
Survival Follow-up contact will be scheduled 12 weeks after the last Efficacy Follow-
up visit has been performed.
Discontinued Participants Continuing to be Monitored in the Study
Participants who discontinue study treatment for a reason other than disease recurrence will 
be considered as on study and should continue with regularly scheduled assessments (also 
refer to Section 9.10.3), including collecting participant information on the start of new 
anticancer treatment, disease recurrence, and death.
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to, but not limited to an external 
 
 
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Data Monitoring Committee (eDMC) review, interim and/or final analysis. Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact 
during the Sponsor defined time period will be contacted for their survival status (excluding 
participants that have a previously recorded death event in the collection tool).
Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency department visits must be reported in the eCRF, 
from the time of treatment allocation/randomization through 90 days following cessation of 
study treatment, or 30 days following cessation of study treatment, if the participant initiates 
new anticancer therapy, whichever is earlier.
10. Statistical Analysis Plan
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E9). Changes to exploratory or other nonconfirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analysis, will be 
documented in a sSAP and referenced in the Clinical Study Report for the study. Separate 
analysis plans may be developed for PK/modeling analysis, biomarker analysis, and genetic 
data analysis. Post hoc exploratory analyses will be clearly identified in the Clinical Study 
Report. The PRO analysis plan will be included in the sSAP.
Statistical Analysis Plan Summary
Key elements of the Statistical Analysis Plan are summarized below; the comprehensive plan 
is provided in Section 10.2 through Section 10.12.
Study Design Overview
This is a randomized, double-blind, multicenter Phase 3 trial to evaluate the 
efficacy and safety of pembrolizumab versus placebo as an adjuvant treatment 
for RCC post nephrectomy. 
Treatment Assignment
Approximately 950 participants will be randomized 1:1 into the following 
2 treatment arms: pembrolizumab 200 mg or matching placebo (saline 200 mg 
infusion) administered IV Q3W. Stratification factors are provided in 
Section 7.3.1.
Analysis Populations
Efficacy: Intention-to-Treat
Safety: All Participants as Treated
Primary Endpoints
DFS as assessed by the investigator
Key Secondary 
Endpoints
OS
Statistical Methods for
Key Efficacy Analyses
The primary and secondary hypotheses addressing DFS and OS will be evaluated 
by comparing pembrolizumab to placebo using a stratified log-rank test.
Estimation of the hazard ratio will be done using a stratified Cox regression 
model. Event rates over time will be estimated within each treatment group using
the Kaplan-Meier method.
 
 
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Statistical Methods for
Key Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers differ with 
respect to the analyses that will be performed. There are no Tier 1 events in this 
trial. Tier 2 parameters will be assessed via point estimates with 95% CIs
provided for between-group comparisons; only point estimates by treatment 
group are provided for Tier 3 safety parameters. The 95% CI for the between-
treatment differences in percentages will be provided using the Miettinen and 
Nurminen method.
Interim and Final 
Analyses
Three interim analyses are planned for the study (one interim analysis for DFS 
and 3 interim analyses for OS). Results will be reviewed by an external data 
monitoring committee. Details are provided in Section 10.7.
IA1
o
Purpose: Interim analysis for DFS and OS. 
o
Timing: When at least 265 disease recurrence events by 
investigator assessment have accrued and a minimum follow-up 
(time from last participant randomized to IA1) of 12 months is 
achieved. Approximately 94 OS events are expected at this time.
IA2
o
Purpose: Final analysis for DFS and interim analysis for OS 
o
Timing: Final analysis of DFS when approximately 332 DFS 
events by investigator assessment have accrued if DFS is not 
rejected at IA1, Approximately 132 OS events are expected at 
this time.
IA3
o
Purpose: Interim analysis for OS 
o
Timing: When approximately 172 OS events have accrued, 
Final analysis (FA)
o
Purpose: Final analysis for OS 
o
Timing: When approximately 200 OS events have accrued, 
Multiplicity
The overall Type I error rate is strongly controlled at 2.5% (1-sided) with a fixed 
sequence testing procedure to test DFS at alpha level of 2.5% (1-sided) first and 
pass the alpha to OS if the hypothesis test of DFS is declared successful. A group 
sequential approach will be used to allocate alpha between the interim and final 
analyses. The study will be considered a success if DFS is demonstrated to be 
statistically significant under multiplicity control. Note that if the statistical 
criterion for success for DFS is met at an IA, a regulatory application may be 
submitted based on DFS for a full approval consideration and the study could 
still continue for OS.
Sample Size and Power
The sample size was planned for 950, but the following power calculations are
based on 990, which is a number more in line with the actual final number of 
randomized subjects. DFS is the primary endpoint for this study. The expected 
median DFS time in the control group is 45 months; based on 332 events and a 
Poisson mixture cure rate model with assumed cure rate of 0.3, the study has 
95% power to detect a hazard ratio of 0.67 (pembrolizumab versus placebo) at 
alpha = 2.5% (1-sided). 
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
 
 
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The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment. Randomization will be implemented in IVRS/IWRS.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete. In addition, blinded independent central imaging review will be performed on 
imaging scans without knowledge of the treatment group assignments of participants.
Planned interim analyses are described in Section 10.7. Blinding to treatment assignment will 
be maintained at all investigational sites. The results of interim analyses will not be shared 
with the investigators prior to the completion of the study. Participant-level unblinding will 
be restricted to an external unblinded statistician and external unblinded scientific 
programmer performing the interim analysis, who will have no other responsibilities 
associated with the study.
Treatment-level results of the interim analysis will be provided by the unblinded statistician 
to the external data monitoring committee (eDMC). Limited additional Sponsor personnel 
may be unblinded to the treatment-level results of the interim analysis (analyses), if required, 
in order to act on the recommendations of the eDMC. The extent to which individuals are 
unblinded with respect to results of interim analyses will be documented by the unblinded 
statistician.
The eDMC will serve as the primary reviewer of the unblinded results of the DFS and OS at 
interim analyses and will make recommendations for discontinuation of the study or 
modification to an EOC of the Sponsor. Depending on the recommendations of the eDMC, 
the Sponsor may prepare a regulatory submission. If the eDMC recommends modifications 
to the design of the protocol or discontinuation of the study, the EOC may be unblinded to 
results at the treatment level in order to evaluate and direct the Sponsor protocol team as to 
the appropriate actions to be taken on these recommendations. Additional logistical details, 
revisions to the above plan, and data monitoring guidance will be provided in the DMC 
Charter.
Prior to final study unblinding, the unblinded statistician and unblinded scientific 
programmer will not be involved in any discussions regarding modifications to the protocol, 
statistical methods, identification of protocol deviations, or data validation efforts after the 
interim analyses.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 4.
 
 
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Analysis Endpoints
Efficacy Endpoints
Primary
Disease-Free Survival
DFS, as assessed by the investigator, is defined as the time from randomization to the first 
documented local recurrence, or occurrence of distant kidney cancer metastasis(es), or death 
due to any cause, whichever occurs first. See Section 10.6.1 for the censoring rules.
Secondary
Overall Survival
OS is defined as the time from randomization to death due to any cause. Participants without
documented death at the time of the final analysis will be censored at the date of the last
follow-up.
Disease Recurrence-Specific Survival

DRSS1 is defined as the time from randomization to the first documented local 
recurrence of RCC as assessed by the investigator.

DRSS2 is defined as the time from randomization to the first documented local 
recurrence with visceral lesion or occurrence of distant kidney cancer metastasis(es) 
with visceral lesion, whichever occurs first, as assessed by the investigator.
Event-Free Survival
EFS is to be assessed by BICR. EFS is defined as time from randomization to the first 
documented local recurrence or occurrence of distant kidney cancer metastasis(es) among 
participants, which by BICR were considered disease-free at baseline (M0/M1 NED); or 
disease progression among participants, which by BICR were considered to have baseline
disease (M1), or death due to any cause, whichever occurs first. See Section 9.2.1 for the 
definition of disease progression.
Safety Endpoints
Safety endpoints are described in Section 5.4.1.2.
Analysis Population
Efficacy Analysis Population
The Intention-to-Treat population will serve as the population for the primary and key 
secondary efficacy analyses. All randomized participants will be included in this population. 
Participants will be analyzed in the treatment group to which they are randomized. 
 
 
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Safety Analysis Population
The All Participants as Treated (APaT) population will be used for the analysis of safety data 
in this study. The APaT population consists of all randomized participants who received at 
least 1 dose of study treatment. Participants will be analyzed in the treatment group 
corresponding to the study treatment they actually received for the analysis of safety data 
using the APaT population. For most participants this will be the treatment group to which 
they are randomized. Participants who take incorrect study treatment for the entire treatment 
period will be included in the treatment group corresponding to the study treatment actually 
received. Any participant who receives the incorrect study treatment for one cycle, but
receives the correct treatment for all other cycles will be analyzed according to the correct 
treatment group and a narrative will be provided for any events that occur during the cycle 
for which the participant is incorrectly dosed.
At least 1 laboratory measurement obtained subsequent to at least 1 dose of study treatment 
is required for inclusion in the analysis of each specific parameter. To assess change from 
baseline, a baseline measurement is also required.
Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives on OS and disease recurrence-specific survival. Methods related to the secondary 
objective, PROs, as well as exploratory objectives will be described in the sSAP.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 10.8 – Multiplicity. Nominal p values 
may be computed for other efficacy analyses, but should be interpreted with caution due to 
potential issues of multiplicity.
Disease-Free Survival
The nonparametric Kaplan-Meier method will be used to estimate the DFS curve in each 
treatment group. The hypotheses addressing a treatment difference in DFS will be tested 
by the stratified log-rank test. A stratified Cox proportional hazard model with Efron's
method of tie handling will be used to estimate the magnitude of the treatment difference (ie,
hazard ratio [HR]) between the treatment arms. The HR and its 95% CI from the
stratified Cox model with Efron's method of tie handling and with a single treatment
covariate will be reported. The stratification factors used for randomization (see 
Section 7.3.1) will be applied to both the stratified log-rank test and the stratified Cox model.
Since participants enrolled with baseline disease by BICR could have a different time to 
event distribution compared to participants who were disease-free at baseline by BICR, a 
sensitivity analysis will be performed using the stratified Cox model and stratified log-rank 
test with stratification factors used for randomization with baseline disease status by BICR 
as an additional stratum. 
 
 
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Since disease recurrence is assessed periodically, disease recurrence can occur any time in
the time interval between the last assessment when disease recurrence was not documented
and the assessment when disease recurrence is documented. For the primary analysis, for the 
participants who have disease recurrence (local recurrence or occurrence of distant kidney 
cancer metastasis(es)) as assessed by the investigator’s review, the true date of disease 
recurrence will be approximated by the date of the first assessment at which disease 
recurrence is objectively documented, regardless of discontinuation of study treatment. Death 
is always considered as a confirmed disease recurrence event.
In order to evaluate the robustness of the DFS endpoint, a sensitivity analysis with a different 
set of censoring rules may be performed. The sensitivity analysis is the same as the primary 
analysis except that events after 2 consecutive missed disease assessments or after new 
anticancer therapy, if any, should be censored at last disease assessment prior to the earlier 
date of ≥2 consecutive missed disease assessments and new anticancer therapy.
The censoring rules for primary and sensitivity analysis are summarized in Table 10.
Table 10
Censoring Rules for Primary and Sensitivity Analysis of Disease-Free Survival
Situation
Primary Analysis
Sensitivity Analysis
No recurrence and no death; new
anticancer treatment is not initiated
Censored at last
disease assessment
Censored at last disease
assessment
No recurrence and no death; new
anticancer treatment is initiated
Censored at last
disease assessment
Censored at last disease
assessment before new anticancer
treatment
Recurrence or death documented after ≤1 
missed disease assessment and before new 
anticancer treatment, if any
Event at date of
documented recurrence 
or death
Event at date of documented
recurrence or death
Recurrence or death documented 
immediately after ≥2 consecutive missed
disease assessments, or after new 
anticancer treatment, if any
Event at date of
documented recurrence 
or death
Censored at the last disease 
assessment prior to the earlier date 
of ≥2 consecutive missed disease 
assessments and new anticancer
treatment, if any
The proportional hazards assumption on DFS will be examined using both graphical and 
analytical methods if warranted. The log [-log] of the survival function versus time for DFS 
will be plotted for the comparison between pembrolizumab and the placebo arm. If the 
curves are not parallel, indicating that hazards are not proportional, supportive analyses may 
be conducted to account for the possible nonproportional hazards effect associated with 
immunotherapies: for example, using the Restricted Mean Survival Time method [Uno, H., et 
al 2014] and parametric method [Odell, P. M., et al 1994]. Further details of sensitivity 
analyses will be described in the sSAP.
Overall Survival
The nonparametric Kaplan-Meier method will be used to estimate the survival curves. The 
hypotheses of treatment difference in survival will be tested by the stratified log -rank test.
 
 
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A stratified Cox proportional hazard model with Efron's method of tie handling will be used
to estimate the magnitude of the treatment difference (ie, the HR). The HR and its 95% CI
from the stratified Cox model with a single treatment covariate will be reported. The
stratification factors used for randomization will be applied to both the stratified log-rank test
and the stratified Cox model.
The OS analysis will be conducted according to the hypothesis testing plan as described in 
Section 10.7 and Section 10.8.
Disease Recurrence-Specific Survival
The nonparametric cumulative incidence estimator will be used to estimate the DRSS1 and 
DRSS2 curves in each treatment group. For DRSS1, only local recurrence is counted as an 
event. Death, or occurrence of distant kidney cancer metastasis(es) will be censored at 
documented date of disease metastasis or death, whichever occurs first. For DRSS2, only 
disease recurrence with visceral lesion is counted as an event. Death, local recurrence 
without visceral lesion, distant metastasis without visceral lesion will be censored at 
documented date of disease recurrence or death, whichever occurs first.
Event-Free Survival
The nonparametric Kaplan-Meier method will be used to estimate the EFS curve in each 
treatment group. Although no formal hypothesis will be performed for testing the treatment 
difference in EFS, nominal p-value from stratified log-rank test will be provided to serve as a 
sensitivity analysis for the primary endpoint of DFS by investigator. A stratified Cox
proportional hazard model with Efron's method of tie handling will be used to estimate the 
magnitude of the treatment difference (ie, hazard ratio [HR]) between the treatment arms.
The HR and its 95% CI from the stratified Cox model with Efron's method of tie handling
and with a single treatment covariate will be reported. The stratification factors used for
randomization (see Section 7.3.1) with baseline disease status by BICR as an additional 
stratum will be applied to both the stratified log-rank test and the stratified Cox model.
Summary of Analysis Strategy
Table 11 summarizes the primary analysis approach for primary and key secondary efficacy 
endpoints. Sensitivity analysis methods are described above for DFS.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, 
multiple populations, and interim analyses is described in Section 10.7 - Interim Analyses
and in Section 10.8 - Multiplicity.
 
 
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Table 11
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical 
Methoda
Analysis Population
Missing Data
Approach
Primary Hypothesis
DFS as assessed by the 
investigator
Test: Stratified Log-
rank test Estimation: 
Stratified Cox model 
with Efron’s tie 
handling method
ITT 

Primary 
censoring rule

Sensitivity 
analysis
Key Secondary Hypothesis
OS
Test: Stratified Log-
rank test Estimation: 
Stratified Cox model 
with Efron’s tie 
handling method
ITT
Censored at the last 
date the participant
was known to be alive 
ITT = Intention-to-Treat; OS = overall survival; DFS = disease-free survival
.aStatistical models are described in further detail in the text. For stratified analyses, the stratification factors used for
randomization (see Section 7.3.1) will be applied to the analysis model.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and laboratory tests.
Tiered Approach
The analysis of safety results will follow a tiered approach (Table 12). The tiers differ with 
respect to the analyses that will be performed. Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p values and 95% CI provided for 
between-group comparisons. Other safety parameters will be considered Tier 2 or Tier 3. 
There is no expectation of enhanced safety signal in this adjuvant study other than safety 
signals of which we are already aware from past studies. Participants do not have tumor
burden and their existing safety profile might be less intensive. Hence, we do not expect any 
new safety signals. Therefore there are no events of interest that will be analyzed as Tier 1
safety endpoints in this study.
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for 
between-group comparisons; only point estimates by treatment group are provided for Tier 3 
safety parameters.
AEs (specific terms as well as system organ class terms) will be classified as belonging to 
"Tier 2" or "Tier 3," based on the number of events observed. Membership in Tier 2 requires 
that at least 10% of the subjects in any treatment group exhibit the event; all other AEs and 
predefined limits of change will belong to Tier 3.
 
 
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The threshold of at least 10% of subjects with events was chosen because the incidence rate 
would allow meaningful statistical assessments; events reported in less frequent than 10% of 
subjects would obscure the assessment of overall safety profile and add little to the 
meaningful interpretation. Because many 95% CIs may be provided without adjustment for
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in
review, not a formal method for assessing the statistical significance of the between-group
differences in AEs and predefined limits of change.
Continuous measures such as changes from baseline in laboratory values that are not 
prespecified as Tier 1 safety parameters will be considered Tier 3 safety parameters. 
Summary statistics for baseline, on-treatment, and change from baseline values will be 
provided by treatment group in table format.
In addition, the broad clinical and laboratory AE categories consisting of the percentage of 
participants with Grade 3-5 AE (incidence ≥5% of subjects in one of the treatment groups) 
and SAE (incidence ≥5% of subjects in one of the treatment groups) will be considered Tier 
2 endpoints.
The threshold of at least 5% of subjects with events was chosen for Tier 2 Grade 3-5 AEs and 
SAEs because the incidence rate would allow meaningful statistical assessments; those AEs 
are expected to happen less frequent than specific AEs/SOCs, but important for overall safety 
profile assessment.
The broad clinical and laboratory AE categories consisting of the percentage of subjects with 
any AE, any Grade 3-5 AE, any SAE, any drug-related AE, any AE that is both drug-related 
and Grade 3-5, any AE that is both serious and drug-related, dose modification due to AE, 
discontinuation due to an AE, death, and specific AEs or SOCs with incidence <10% of 
subjects in all of the treatment groups will be considered Tier 3 endpoints. 
Note that 95% CIs will be provided for between-treatment differences in the percentage of 
participants with Tier 2 events; these analyses will be performed using the Miettinen and 
Nurminen method, an unconditional, asymptotic method.
 
 
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Table 12
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Specific Serious AE (incidence ≥5% of subjects in 
one of the treatment groups)
X
X
Specific Grade 3-5 AE (incidence ≥5% of subjects in 
one of the treatment groups)
X
X
Specific AEs or SOCs (incidence ≥10% of subjects in 
one of the treatment groups)
X
X
Tier 3
Any AE
X
Any Serious AE 
X
Any Grade 3-5 AE 
X
Any drug-related AE
Any Serious and Drug-related AE
X
X
Any Grade 3-5 and Drug-related AE
X
Dose Interruption due to AE
Discontinuation due to AE
Death
X
X
X
Specific AEs or SOCs (incidence <10% of subjects in 
all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, Vital 
Signs)
X
Abbreviations: AE = adverse event; CI = confidence interval; ECG = electrocardiogram; PDLC = 
predefined limit of change; SOC = system organ class.
Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of participants screened and randomized, and the
primary reasons for screening failure and discontinuation will be displayed. Demographic 
variables (eg, age), baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized by treatment either by descriptive statistics or 
categorical tables.
Interim Analyses
Safety Interim Analyses
The eDMC has responsibility for assessment of overall risk:benefit. The eDMC will review 
safety periodically with reviews about every 6 months in the first year and every 12 months 
thereafter. When prompted by safety concerns, the eDMC can request corresponding efficacy 
data. eDMC review of efficacy data to assess the overall risk:benefit to trial participants will 
 
 
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not require multiplicity assessment typically associated with a planned efficacy interim 
analysis. Any eDMC recommendation will be communicated to the Sponsor as agreed to in 
the eDMC charter.
Efficacy Interim Analyses
Three interim analyses are planned in addition to the final analysis for this trial. Results of 
the interim analyses (IA) will be reviewed by an eDMC. If both DFS and OS null hypotheses 
are rejected prior to the final analysis, the eDMC may recommend stopping the trial early for 
efficacy. At each IA, the eDMC may also recommend stopping the trial early for futility. 
Details on how the above planned analyses are incorporated into establishing statistical 
significance and the boundaries with regard to efficacy and futility are discussed further in 
Section 10.8, Multiplicity.
The analyses planned, endpoints evaluated and drivers of the timing are summarized in 
Table 13. 
Table 13
Analyses Planned, Endpoints Evaluated, and Drivers of Timing
Analysis
Endpoint(s)
Timing
IA1
DFS, OS
Enrollment complete and at least 265 DFS events by 
investigator assessment have occurred and a minimum 
follow-up (time from last participant randomized to IA1) of 
12 months is achieved.
IA2
DFS, OS
332 DFS events; if DFS rejected before IA2, timing driven 
by 132 OS events
IA3
OS
172 OS events
FA
OS
200 OS events
Abbreviations: DFS = disease-free survival; FA = Final analysis; IA1 – first interim analysis; IA2 = second 
interim analysis; IA3 = third interim analysis; OS = overall survival
Multiplicity
Multiplicity Control for Efficacy Analyses
The trial uses the method of Maurer and Bretz (2013)[Maurer, W. 2013] to provide strong 
multiplicity control for multiple hypotheses as well as interim analyses. Figure 2 shows the 
initial one-sided α-allocation for each hypothesis in the ellipse representing the hypothesis. 
The weights for reallocation from each hypothesis to the others are represented in the boxes 
on the lines connecting hypotheses. This is further explained below.
 
 
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Figure 2
Multiplicity Graph for Type I Error Control of Study Hypotheses
Abbreviations: DFS = disease-free survival; OS = overall survival
If the DFS null hypothesis is rejected at the 2.5% level, then the OS null hypothesis may be 
formally evaluated for statistical significance at the 2.5% level. For each endpoint, group 
sequential methods will be used to adjust for the interim and final analyses planned. If the 
DFS null hypothesis is rejected at an interim or final analysis, each OS interim and final 
analysis test may be compared to its rejection boundary for formal testing. For instance, the 
OS hypothesis will not be formally evaluated for statistical significance until the DFS null 
hypothesis is rejected. 
For DFS, the information fraction at each analysis will be based on the final planned number 
of 332 events. A Lan-DeMets O’Brien-Fleming spending approximation -spending function 
is used to set efficacy bounds. Nonbinding futility spending is done by controlling the 
probability of crossing the futility bound under the null hypothesis (total of 1-α=97.5%); a
HSD spending function with = -6 is used to set testing boundaries at each analysis.
For OS, the information fraction at each analysis will be based on the final planned number 
of 200 deaths. A Lan-DeMets O’Brien-Fleming spending approximation -spending function 
is used to set efficacy bounds. As with DFS, nonbinding futility spending is done by 
controlling the probability of crossing the futility bound under the null hypothesis (total of 
1-α=97.5%); an HSD spending function with = -6 is used to set testing boundaries at each 
analysis.
Bounds at the expected number of events for each hypothesis at each analysis of DFS and OS 
are shown in Table 14 and Table 15, respectively. Bounds will be adjusted according to the 
actual number of events at each analysis.
 
 
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Table 14
Boundary Properties for Planned Interim and Final Analyses for DFS 
Analysis
Value
Efficacy
Futilitya
IA1: 80% (First Interim for DFS)
Z
2.2504
-0.5476
N: 990
p (1-sided)
0.0122
0.7080
Events: 265
HR at bound
0.7584
1.0696
Month: 39
P(Cross) if HR=1
0.0122
0.2920
P(Cross) if HR=0.67
0.8402
0.0001
IA2: (Final Analysis for DFS)
Z
2.0249
2.0249
N: 990
p (1-sided)
0.0214
0.0214
Events: 332
HR at bound
0.8005
0.8005
Month: 50
P(Cross) if HR=1
0.0250
0.9750
P(Cross) if HR=0.67
0.9490
0.0510
Abbreviations: DFS = disease-free survival; FA = Final analysis; HR = hazard ratio; IA1 – first interim analysis; IA2 = second 
interim analysis; OS = overall survival
a Futility boundary is nonbinding.
Table 15
Boundary Properties for Planned Interim and Final Analyses for OS
Analysis
Value
Efficacy
Futilitya
IA1: 47% (First Interim for OS)
Z
3.0679
-1.7717
N: 990
p (1-sided)
0.0011
0.9618
Events: 94
HR at bound
0.5305
1.4421
Month: 39
P(Cross) if HR=1
0.0011
0.0382
P(Cross) if HR=0.67
0.1280
0.0001
IA2: 66% (Second Interim for OS)
Z
2.5455
-1.1786
N: 990
p (1-sided)
0.0055
0.8807
Events: 132
HR at bound
0.6416
1.2281
Month: 50
P(Cross) if HR=1
0.0058
0.1247
P(Cross) if HR=0.67
0.4033
0.0003
IA3: 86% (Third Interim for OS)
Z
2.2023
-0.2090
N: 990
p (1-sided)
0.0138
0.5828
Events: 172
HR at bound
0.7143
1.0324
Month: 63
P(Cross) if HR=1
0.0157
0.4195
P(Cross) if HR=0.67
0.6688
0.0025
Final
Z
2.0534
2.0534
N: 990
p (1-sided)
0.0200
0.0200
Events: 200
HR at bound
0.7476
0.7476
Month: 72
P(Cross) if HR=1
0.0250
0.9750
P(Cross) if HR=0.67
0.7930
0.2070
Abbreviations: DFS = disease-free survival; FA = Final analysis; HR = hazard ratio; IA1 – first interim analysis; IA2 = second 
interim analysis; IA3 = third interim analysis; OS = overall survival
a Futility boundary is nonbinding.
 
 
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Multiplicity Control for Safety Analyses
To account for any multiplicity concerns raised by the DMC review of unplanned efficacy 
data when prompted by safety concerns, a sensitivity analysis for DFS and OS will be 
pre-specified in the sSAP. This analysis will be performed if requested by the eDMC. 
However, eDMC review of DFS and OS data beyond the planned efficacy analysis to assess 
the overall risk:benefit to trial participants will not require multiplicity assessment typically 
associated with a planned efficacy IA because these analyses are not to declare a positive 
efficacy finding.
Sample Size and Power Calculations
The study will randomize participants in a 1:1 ratio into the pembrolizumab and placebo 
arms. DFS and OS are the primary endpoint and key secondary endpoint, respectively. The 
sample size was planned for 950, but the following power calculations are based on 990, 
which is a number more in line with the actual final number of randomized participants.
For the DFS endpoint, based on a target number of 332 events and one IA at approximately 
80% of the target number of events, the study has approximately 95% power to detect a HR
of 0.67 at an overall alpha level of 2.5% (1-sided). 
For the OS endpoint, the power is conditional on the null hypothesis of DFS being rejected, 
based on a target number of 200 events and 3 interim analyses at approximately 47%, 66%,
and 86% of the target number of events, the study has approximately 79% power to detect a 
HR of 0.67 or approximately 88% power to detect a HR of 0.635 at an overall alpha level of 
2.5% (1-sided).
The above sample size and power calculations for DFS and OS assume the following:

DFS follow a Poisson mixture cure rate model [de Castro, M., et al 2010] with 
assumed cure rate of 0.3. The cure rate of 0.3 is estimated based on historical data 
[Leibovich, B. C., et al 2003]. 

The median DFS is assumed to be 45 months for those not cured in the control group.

OS follows an exponential distribution with a median of 145 months for the control 
group. 

Enrollment period of 27 months with monthly accrual of 20 participants during the 
first 5 months and monthly accrual of 30 participants from month 6 to month 21, and 
monthly accrual of 1 participant for the last month.

A yearly drop-out rate of 2% for DFS and 1% for OS.
Technical details on the Poisson mixture cure rate model are in Appendix 7. The sample size 
and power calculation were performed using R (package “gsDesign”).
 
 
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Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoint will be estimated and plotted within each category of the following classification 
variables:
•
ECOG PS (0, 1) 
•
Metastasis status (M0, M1 NED)
•
Type of nephrectomy (Radical, Partial)
•
Geographic region (US, Non-US)
•
PD-L1 status (Positive, Negative)
•
Age (<65, ≥65 years)
•
Sex (Female, Male)
•
Race (white, non-white)
•
Baseline disease status by BICR (M0/M1 NED, M1)
Country-specific populations may also be analyzed per local regulatory requirements.
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles. Summary 
statistics will be provided on extent of exposure for the APaT population.
 
 
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C, George JA, Wooters J, et al. PD-1 
inhibits 
T-cell 
receptor 
induced 
phosphorylation of the ZAP70/CD3zeta 
signalosome and downstream signaling to 
PKCtheta. FEBS Lett. 2004;574:37-41.
[00VMQC]
[Shin, S. J., et al 2016]
Shin SJ, Jeon YK, Kim PJ, Cho YM, Koh J, 
Chung DH, et al. Clinicopathologic Analysis 
of PD-L1 and PD-L2 Expression in Renal 
Cell 
Carcinoma: 
Association 
with 
Oncogenic Proteins Status. Ann Surg Oncol. 
2016 Feb;23(2):694-702.
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[Siegel, R. L., et al 2016]
Siegel RL, Miller KD, Jemal A. Cancer 
statistics, 2016. CA Cancer J Clin. 2016 
Jan;66(1):7-30.
[04CMDP]
[Stephenson, A. J., et al 2004]
Stephenson AJ, Chetner MP, Rourke K, 
Gleave ME, Signaevsky M, Palmer B, et al. 
Guidelines for the surveillance of localized 
renal cell carcinoma based on the patterns of 
relapse after nephrectomy. J Urol. 2004 
Jul;172(1):58-62.
[04J9KR]
[Sternberg, C. N., et al 2010]
Sternberg CN, Davis ID, Mardiak J, 
Szczylik C, Lee E, Wagstaff J, et al. 
Pazopanib in locally advanced or metastatic 
renal cell carcinoma: results of a randomized 
phase III trial. J Clin Oncol. 2010 Feb 
20;28(6):1061-8.
[04CMHW]
[Sternberg, C. N., et al 2013]
Sternberg CN, Hawkins RE, Wagstaff J, 
Salman P, Mardiak J, Barrios CH. et al. A 
randomised, double-blind phase III study of 
pazopanib in patients with advanced and/or 
metastatic renal cell carcinoma: final overall 
survival results and safety update. Eur J 
Cancer. 2013 Apr;49(6):1287-96.
[04CQH7]
[U.S. Prescribing Information 
2016]
U.S. Prescribing Information: OPDIVO 
(nivolumab) injection, for intravenous use: 
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[Uno, H., et al 2014]
Uno H, Claggett B, Tian L, Inoue E, Gallo 
P, Miyata T, et al. Moving beyond the 
hazard ratio in quantifying the between-
group difference in survival analysis. J Clin 
Oncol. 2014 Aug 1;32(22):2380-5.
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[Wierecky, J., et al 2006]
Wierecky J, Muller MR, Wirths S, Halder-
Oehler E, Dorfel D, Schmidt SM, et al. 
Immunologic and clinical responses after 
vaccinations with peptide-pulsed dendritic 
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[Zhang, X., et al 2004]
Zhang X, Schwartz J-CD, Guo X, Bhatia S, 
Cao E, Chen L, et al. Structural and 
functional analysis of the costimulatory 
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12. Appendices
Appendix 1: Abbreviations and Trademarks
Abbreviation
Definition
ADA
antidrug antibodies
AE
adverse event
APaT
All Participants as Treated
aPTT
activated partial thrombin time
β-hCG
β-human chorionic gonadotropin
BICR
blinded independent central review
CAP
chest, abdomen, and pelvis
CD28
cluster of differentiation 28
CI
confidence interval
CRF
case report form
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T lymphocyte protein 4
DFS
disease-free survival
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DRSS
disease recurrence-specific survival
ECG
electrocardiogram
ECI
events of clinical interest
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
electronic case report form
EDC
electronic data collection
eDMC
external data monitoring committee
EFS
event-free survival
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EORTC-QLQ-C30
European Organization for the Research and Treatment of 
Cancer Quality of Life Questionnaire C30
EQ-5D-5L
EuroQoL 5 Dimensions 5 Levels
FDA
United States Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FKSI-DRS
Functional Assessment of Cancer Therapy Kidney Symptom 
Index - Disease-Related Symptoms
FSH
follicle-stimulating hormone
FT4
free thyroxine
GEP
gene expression profiling
HCV
hepatitis C virus
HR
hazard ratio
HRQoL
health-related quality of life
HSD
Hwang-Shih-DeCani
 
 
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Abbreviation
Definition
IA1
first interim analysis
IA2
second interim analysis
ICF
informed consent form
IEC
Independent Ethics Committee
IFN
interferon
IFNα
interferon-alpha
IFNγ
interferon-gamma
Ig
immunoglobulin
IHC
immunohistochemistry
IL-2
interleukin-2
INR
international normalized ratio
irAE
immune-related AE
IRB
Institutional Review Board
IUD
intrauterine device
IV
intravenous
IVRS
interactive voice response system
IWRS
integrated web response system
M
distant metastasis
M1 NED
M1 no evidence of disease
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NSAID
Nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
OS
overall survival
PD-1
programmed cell death protein 1
PD-L1/PD-L2
programmed cell death ligand 1/2
PK
pharmacokinetic
PRO
patient-reported outcome
PT
prothrombin time
Q3W
every 3 weeks
Q12W
every 3 months
Q16W
every 4 months
Q24W
every 6 months
QoL
quality of life
RCC
renal cell carcinoma
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reactions
T1DM
Type 1 diabetes mellitus
T3
triiodothyronine
TCR
T cell repertoire
 
 
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Abbreviation
Definition
TSH
thyroid-stimulating hormone
US
United States
WOCBP
woman of childbearing potential
 
 
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Appendix 2: Clinical Laboratory Tests 
Table 16 will be performed by the central laboratory. 
o
Use of central laboratory is required.
o
Clinical laboratory tests may be performed by a local laboratory if the investigator 
deems it necessary, or if the central laboratory results are not expected in time to 
make a study treatment decision (eg, central laboratory specimen was drawn 
predose on Day 1 of infusion).
o
If a significant difference (e.g. one lab results report normal labs and the other lab 
results report an AE for the same timepoint) is noted between local and central 
labs the discordant lab result(s) must be entered into the eCRF.
o
If local laboratory specimens are drawn for scheduled timepoints, duplicate 
specimens MUST also be submitted to central laboratory.
o
If the local laboratory results are used for a response evaluation, adverse event
assessment, or other reason as directed by Sponsor (eg. Central lab was unable to 
perform a test, but the local lab has results for the same timepoint) the results 
must be entered into the eCRF.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
 
 
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Table 16
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Bicarbonatea
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)
Total Protein
Glucose
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis

Specific gravity

Glucose, protein, blood, by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening Tests

Serum or urine β human chorionic gonadotropin (β-hCG) pregnancy test (as 
needed for WOCBP)b

Serology (human immunodeficiency virus antibody)d

PT/INR

aPTT

Total T3 or free T3, FT4, and TSHc

All study-required laboratory assessments will be performed by a central 
laboratory, with the exception of: pregnancy testing
aPTT=activated partial thrombin time; FT4=free thyroxine; INR=international normalized ratio; MCH=mean corpuscular 
hemoglobin; MCV=mean corpuscular volume; PT=prothrombin time; RBC=red blood cells; T3=triiodothyronine; 
TSH=thyroid-stimulating hormone (thyrotropin); WBC=white blood cells
NOTES:
a
If this test is not done as part of local standard of care, this test does not need to be performed.
b
Perform on women of childbearing potential within 72 hours prior to randomization. Pregnancy tests must be repeated 
prior to every cycle or monthly, as required or as specified per local regulatory guidance.
c
T3 is preferred; if not available free T3 may be tested.
d
Only if mandated by local health authority. If the local laboratory is unable to perform these tests, the site should 
submit the sample to the central laboratory for testing. Details are provided in the Procedure Manual.
NOTE:
Report % or absolute results per standard of practice. Report the results in the same manner throughout the 
trial.
.
 
 
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Laboratory tests for Screening should be performed within 10 days prior to randomization. 
After Cycle 1, predose laboratory safety tests can be conducted up to 72 hours prior to dosing 
unless otherwise noted on the flow charts. 
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each dose of study treatment. Unresolved 
abnormal laboratory values that are drug-related AEs should be followed until resolution. 
Laboratory tests do not need to be repeated after the end of treatment if laboratory results are 
within the normal range.
Investigators must document their review of each laboratory safety report.
 
 
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Appendix 3: Study Governance Considerations
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participant safety is the overriding concern 
in the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (eg, contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
participant preferences, etc.  
The design (ie, participant population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial 
initiation, sites are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Participant Protection
A. IRB/IEC review
All clinical trials will be reviewed and approved by an independent IRB/IEC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/IEC prior to implementation, except that 
changes required urgently to protect participant safety and well-being may be enacted in anticipation of IRB/IEC
approval. For each site, the IRB/IEC and Merck will approve the participant informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance.  
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care.  Participants are never denied access to 
appropriate medical care based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Participants are enrolled only after providing informed consent 
for participation.  Participants may withdraw from a Merck trial at any time, without any influence on their access to, 
or receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding participant confidentiality, to the greatest extent possible.  Unless required by 
law, only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential 
medical records that might identify the research participant by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.  Merck does not pay incentives to 
enroll participants in its trials.  However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
Merck does not pay for participant referrals.  However, Merck may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/IEC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/IEC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the participant
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the participant will be identified by unique code 
only; full names/initials will be masked prior to transmission to the Sponsor.
 
 
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By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this trial in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Committees Structure
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
eDMC regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (eg, they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both participant
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 10.7 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
 
 
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Publication Policy
The results of this study may be published or presented at scientific meetings. The sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before submission.  This allows the sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are 
participant to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow participants to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in this appendix 
under the Merck Code of Conduct for Clinical Trials.
 
 
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The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the trial 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
The Investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection, and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator or 
qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or regulatory authority as a result of an audit or inspection to cure 
deficiencies in the trial documentation and worksheets/case report forms.
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
 
 
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study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Study and Site Closure
The sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
 
 
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the sponsor for human use.
Events Meeting the AE Definition 
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in 
the medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.
●
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
●
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, the AE term should reflect the clinical symptoms or abnormal test 
result.  An overdose without any associated clinical symptoms or abnormal laboratory 
results is reported using the terminology “accidental or intentional overdose without 
adverse effect.”
●
Any new cancer (that is not a condition of the study). 
Note: Progression of the cancer under study is not a reportable event. Refer to 
Section 9.3.5 for additional details.
 
 
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Events NOT Meeting the AE Definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has 
not worsened.
●
Refer to section 9.3.5 for protocol specific exceptions
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation.  (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition 
that is diagnosed prior to the use of a Merck product and is documented in the patient’s 
medical history.
d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
 
 
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e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
f.
Other important medical events:
●
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Additional Events reported as SAE
Additional Events which require reporting in the same manner as SAE
●
In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Recording AE and SAE
AE and SAE Recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.
●
The investigator will record all relevant AE/SAE information on the Adverse Event 
case report forms/worksheets at each examination.
●
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the AE CRF page.
 
 
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●
There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all participant identifiers, with the exception of 
the participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.
●
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and 
other reportable safety event) according to the NCI Common Terminology for 
Adverse Events (CTCAE), version 4.0. Any adverse event which changes CTCAE 
grade over the course of a given episode will have each change of grade recorded on 
the adverse event case report forms/worksheets.
●
Grade 1: Mild; asymptomatic or mid symptoms; clinical or diagnostic 
observations only; intervention not indicated.
●
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
●
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation or hospitalization indicated; disabling; limiting 
self-care ADL.
●
Grade 4: Life threatening consequences; urgent intervention indicated.
●
Grade 5: Death related to AE.
Assessment of Causality
●
Did the Sponsor's product cause the adverse event?
●
The determination of the likelihood that the Sponsor's product caused the adverse 
event will be provided by an investigator who is a qualified physician.  The 
investigator’s signed/dated initials on the source document or worksheet that 
supports the causality noted on the AE form, ensures that a medically qualified 
assessment of causality was done.  This initialed document must be retained for 
the required regulatory time frame.  The criteria below are intended as reference 
guidelines to assist the investigator in assessing the likelihood of a relationship 
between the test product and the adverse event based upon the available 
information
●
The following components are to be used to assess the relationship between 
the Sponsor's product and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more 
likely the Sponsor's product caused the adverse event:
 
 
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●
Exposure:  Is there evidence that the participant was actually exposed to the 
Sponsor's product such as:  reliable history, acceptable compliance assessment 
(pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
●
Time Course:  Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor's product? Is the time of onset of the AE 
compatible with a drug-induced effect (applies to trials with investigational 
medicinal product)?
●
Likely Cause:  Is the AE not reasonably explained by another etiology such 
as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
●
Dechallenge: Was the Sponsor's product discontinued or 
dose/exposure/frequency reduced?
●
If yes, did the AE resolve or improve?
●
If yes, this is a positive dechallenge. 
●
If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's 
product(s) is/are only used one time.)
●
Rechallenge:  Was the participant re-exposed to the Sponsor's product in this 
trial?
●
If yes, did the AE recur or worsen?
●
If yes, this is a positive rechallenge. 
●
If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death 
or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH 
WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S 
PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN 
THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE 
PROTOCOL, AND IF REQUIRED, THE INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study treatment Profile:Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the 
Sponsor's product or drug class pharmacology or toxicology?
 
 
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●
The assessment of relationship will be reported on the case report forms /worksheets 
by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements.
●
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor's product relationship).
●
Yes, there is a reasonable possibility of Sponsor's product relationship:
There is evidence of exposure to the Sponsor's product.  The temporal sequence 
of the AE onset relative to the administration of the Sponsor's product is 
reasonable.  The AE is more likely explained by the Sponsor's product than by 
another cause. 
●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor's product OR temporal sequence of the AE 
onset relative to administration of the Sponsor's product is not reasonable OR the 
AE is more likely explained by another cause than the Sponsor’s product.  (Also 
entered for a participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
Follow-up of AE and SAE
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
●
New or updated information will be recorded in the CRF.
●
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
 
 
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Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor
AE, SAE, and Other Reportable Safety Event Reporting to Sponsor via Electronic 
Data Collection Tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool.  
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.  
●
Reference section 9.3.1 – Time Period and Frequency for Collecting AE and 
SAE and Other Reportable Safety Event Information for reporting time 
requirements 
●
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
●
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.
●
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form or by 
telephone (see next section).
●
Contacts for SAE reporting can be found in the Investigator Trial File Binder (or 
equivalent).
SAE Reporting to the Sponsor via Paper CRF
●
If the electronic data collection tool is not operational, facsimile transmission or 
secure e-mail of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
 
 
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Appendix 5: Contraceptive Guidance and Pregnancy Testing
Contraception Requirements
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.
For this trial, male participants will be considered to be of nonreproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).
Female participants will be considered of nonreproductive potential if they meet 1 of the 
following criteria: 

She is postmenopausal, defined as at least 12 months with no menses without an 
alternative medical cause. In women <45 years of age who are not using hormonal 
contraception or hormonal replacement therapy, a high follicle-stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a postmenopausal
state. In the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.

She had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to Screening.

She has a congenital or an acquired condition that prevents childbearing.
Female and male participants of reproductive potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, while receiving trial drug and for 120 days 
after the last dose of trial drug by complying with 1 of the following: 

Practice abstinence from heterosexual activity.
Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the participant’s preferred and usual lifestyle and if 
considered acceptable by local regulatory agencies and IRBs/IECs. Periodic abstinence (eg, 
calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not 
acceptable methods of contraception. 

Use (or have their partner use) acceptable contraception during heterosexual activity.
Acceptable methods of contraception area:

Single method (1 of the following is acceptable):
o
Intrauterine device (IUD)
o
Vasectomy of a female participant’s male partner 
o
Contraceptive rod implanted into the skin

Combination method (requires use of 2 of the following):
o
Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
o
Cervical cap with spermicide (nulliparous women only)
 
 
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o
Contraceptive sponge (nulliparous women only) 
o
Male condom or female condom (cannot be used together)
o
Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection
aIf a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for participants participating at 
sites in this country/region.
Participants should be informed that taking the trial medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the trial. In order to participate 
in the trial, participants of childbearing potential must adhere to the contraception 
requirement (described above) from the day of trial medication initiation (or 14 days prior to 
the initiation of trial medication for oral contraception) throughout the trial period up to 120 
days after the last dose of trial medication. If there is any question that a participant of 
childbearing potential will not reliably comply with the requirements for contraception, that 
participant should not be entered into the trial. 
Pregnancy
If a female participant inadvertently becomes pregnant while on treatment with 
pembrolizumab, the participant will be immediately discontinued from trial treatment. The 
site will contact the participant at least monthly and document the participant’s status until 
the pregnancy has been completed or terminated. The outcome of the pregnancy will be 
reported to the Sponsor without delay and within 24 hours if the outcome is a serious adverse 
experience (eg, death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). The trial investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the 
fetus or newborn to the Sponsor. If a male participant impregnates his female partner, the 
trial personnel at the site must be informed immediately and the pregnancy must be reported 
to the Sponsor and followed as described in Section 9.3.1 (Table 8).
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, participants who are breastfeeding are not eligible for enrollment.
 
 
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Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this trial as outlined in Section 9.8 – Future 
Biomedical Research Sample Collection will be used in various experiments to 
understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Participants for Enrollment
All participants enrolled in the clinical trial will be considered for enrollment in 
Future Biomedical Research.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
trial visit by the investigator or his or her designate.  Informed consent for Future 
 
 
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Biomedical Research should be presented to the participants on the visit designated in 
the trial flow chart.  If delayed, present consent at next possible Participant Visit.  
Consent forms signed by the participant will be kept at the clinical trial site under 
secure storage for regulatory reasons.  
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for Future Biomedical Research will be 
captured in the electronic Case Report Forms (eCRFs). Any specimens for which 
such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the participant is having blood drawn for other trial purposes.
4. Confidential Participant Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing participant
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens.  This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant
identifiers and this unique code will be held at the trial site.  No personal identifiers will 
appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in the future biomedical research 
protocol and consent. Future Biomedical Research specimens remaining with the third 
party after specific analysis is performed will be reported to the Sponsor.
 
 
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6. Withdrawal From Future Biomedical Research 
Participants may withdraw their consent for Future Biomedical Research and ask that 
their biospecimens not be used for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the principal investigator for the main trial. If 
medical records for the main trial are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for Future Biomedical Research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable.  
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research trial data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
 
 
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participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants.  Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the participant have been minimized. No 
additional risks to the participant have been identified as no additional specimens are 
being collected for Future Biomedical Research (ie, only leftover samples are being 
retained). 
The Sponsor has developed strict security, policies and procedures to address participant
data privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA AND SAMPLE CODING CATEGORIES - E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
 
 
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Confidential
Appendix 7: Poisson Mixture Model
The Poisson mixture model is applied to account for the failure rates decreasing over time in 
a trial in which the patient population is a mixture of participants who are susceptible to
disease recurrence and participants who would not have a disease recurrence event after 
long-term follow-up. The latter participants are called long-term survivors. The Poisson 
mixture model assumes a survival function [de Castro, M., et al 2010] for a control group (c) 
as a function of time (t), as follows:
where θ = –log(Cure_Rate), λ is a constant hazard rate, and t ≥0.
In the adjuvant setting, according to the published literature [Leibovich, B. C., et al 2003]
and study assumptions, ~30% participants will be long-term survivors or will be cured in the
long-term (ie, Cure_Rate=0.3), and it is more likely that after approximately 5 to 6 years after
study initiation there will be minimal accumulation of DFS events. 
According to the published literature [Leibovich, B. C., et al 2003], it is assumed that DFS 
follows a Poisson mixture model distribution with median DFS of 45 months in the placebo 
group. Figure 3 below shows the DFS curves using the Poisson mixture model and 
exponential model. Compared to the curve from the exponential model, the curve from the 
Poisson mixture model looks more similar to the curve in the published literature.
Figure 3
Disease-Free Survival Curves Using the Poisson Mixture Model and Exponential 
Model
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Supplemental SAP  
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Supplemental Statistical Analysis Plan (sSAP)
 
 
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Supplemental SAP  
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TABLE OF CONTENTS
TABLE OF CONTENTS.....................................................................................................2
LIST OF TABLES...............................................................................................................4
LIST OF FIGURES .............................................................................................................5
1. INTRODUCTION .........................................................................................................6
2. SUMMARY OF CHANGES.........................................................................................6
3. ANALYTICAL AND METHODOLOGICAL DETAILS............................................9
3.1 STATISTICAL ANALYSIS PLAN SUMMARY .........................................9
3.2 RESPONSIBILITY FOR ANALYSES/IN-HOUSE BLINDING ...............10
3.3 HYPOTHESES/ESTIMATION ...................................................................11
3.4 ANALYSIS ENDPOINTS ...........................................................................13
3.4.1
Efficacy Endpoints............................................................................13
3.4.1.1
Primary..................................................................................13
3.4.1.2
Secondary..............................................................................13
3.4.2
Safety Endpoints...............................................................................14
3.4.3
Patient Reported Outcome (PRO) Endpoints ...................................14
3.4.3.1
Secondary..............................................................................14
3.4.3.2
Exploratory ...........................................................................14
3.5 ANALYSIS POPULATIONS ......................................................................15
3.5.1
Efficacy Analysis Populations..........................................................15
3.5.2
Safety Analysis Populations .............................................................15
3.5.3
PRO Analysis Population .................................................................16
3.6 STATISTICAL METHODS.........................................................................16
3.6.1
Statistical Methods for Efficacy Analyses........................................16
3.6.1.1
Disease-Free Survival (DFS)................................................16
3.6.1.2
Overall Survival (OS)...........................................................18
3.6.1.3
Disease Recurrence Specific Survival..................................19
3.6.1.4
Event-Free Survival ..............................................................19
3.6.1.5
Analysis Strategy for Key Efficacy Variables......................19
3.6.2
Statistical Methods for Safety Analyses...........................................20
3.6.3
Summaries of Baseline Characteristics and 
Demographics .........................................................................................22
3.6.4
Patient Reported Outcomes (PRO) Analysis....................................22
3.6.4.1
PRO compliance summary ...................................................22
3.6.4.2
Mean change from baseline..................................................23
3.6.4.3
Overall Improvement and Overall 
Improvement/Stability ......................................................................24
3.6.4.4
Analysis Strategy for Key PRO Endpoints...........................24
3.7 INTERIM ANALYSES................................................................................25
3.7.1
Safety Interim Analyses....................................................................25
 
 
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3.7.2
Efficacy Interim Analyses ................................................................25
3.8 MULTIPLICITY ..........................................................................................26
3.8.1
Multiplicity Control for Efficacy Analyses ......................................26
3.8.2
Multiplicity Control for Safety Analyses..........................................28
3.9 SAMPLE SIZE AND POWER CALCULATIONS.....................................28
3.10
SUBGROUP ANALYSES AND EFFECT OF BASELINE 
FACTORS ....................................................................................................30
3.11
COMPLIANCE (MEDICATION ADHERENCE) ................................31
3.12
EXTENT OF EXPOSURE.....................................................................31
4
REFERENCES ............................................................................................................31
 
 
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LIST OF TABLES
Table 1
Censoring Rules for Primary and Sensitivity Analysis of Disease-Free Survival.
........................................................................................................................... 17
Table 2
Analysis Strategy for Key Efficacy Endpoints.................................................. 19
Table 3
Analysis Strategy for Safety Parameters ........................................................... 21
Table 4
PRO Data Collection Schedule and Mapping of Study visit to Analysis Visit. 23
Table 5
Analyses Planned, Endpoints Evaluated and Drivers of Timing....................... 26
Table 6
Boundary Properties for Planned Interim and Final Analyses for DFS ............ 27
Table 7
Boundary Properties for Planned Interim and Final Analyses for OS............... 28
 
 
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LIST OF FIGURES
Figure 1
Multiplicity Graph for Type I Error Control of Study Hypotheses ................... 26
Figure 2
Disease-Free Survival Curves Using the Poisson Mixture Model and Exponential 
Model
........................................................................................................................... 30
 
 
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1. INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of 
confirmatory analyses for this trial, this supplemental SAP provides additional statistical 
analysis details/data derivations and documents modifications or additions to the analysis plan 
that are not “principal” in nature and result from information that was not available at the time 
of protocol finalization.  
2. SUMMARY OF CHANGES
Section # and 
Name
Description of Change
Brief Rationale
3.1 Statistical 
Analysis Plan 
Summary
3.7.2 Efficacy 
Interim Analyses
3.8.1
Multiplicity 
Control for Efficacy 
Analyses
Per protocol amendment 
3 and 4
(1) Changed the timing of 
interim analyses and final 
analysis.
(2) Changed α-spending 
function for primary DFS
from Hwang-Shih-
DeCani (HSD) spending 
function with = -15 to 
Lan-DeMets O’Brien-
Fleming spending 
approximation α-
spending function.
(1) IA1 will be triggered by achieving 
approximately 265 DFS events by 
investigator and 12 months minimum 
follow up to ensure data maturity for 
the first IA; The trigger for IA2 is 
updated based on an increased total 
number of 332 DFS events by 
investigator to allow more mature DFS 
data and increased probability of 
success at the final analysis of DFS to 
align with the extended enrollment 
period and the actual number of 
randomized subjects. Replaced the 
wording of ‘at least 265 DFS events’ 
by ‘approximately 265 DFS events’ to 
allow some flexibility in the IA1 
timing for this event-driven study.   
(2) To apply a more commonly used 
alpha spending function that is relative 
but not too conservative to ensure 
adequate power for the primary 
endpoint at IA1. 
3.4.1.2 Secondary
Per protocol amendment 
3,
Defined event-free 
survival.
To define an endpoint that better 
represents the events to be expected in 
the RCC adjuvant setting for patients 
with or without baseline disease by 
BICR.
 
 
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Section # and 
Name
Description of Change
Brief Rationale
3.6.1.4 Event-Free 
Survival
Per protocol amendment 
3, provided the analysis 
method for evaluating 
event-free survival.
To provide an appropriate statistical 
method for the analysis of EFS.
3.9 Sample Size and 
Power Calculations
Per protocol amendment 
3 and 4, power statement 
is updated for DFS and 
OS endpoints.
To update the power statement due to 
the following changes:
(1) Increased total number of DFS 
events at IA2 due to the 
increased actual number of 
randomized subjects during an 
extended accrual period and 
correspondent to an increased 
targeted power
(2) Updated alpha spending 
function for DFS that is more 
commonly used
(3) Updated enrollment rates that 
are more in line with the actual 
enrollment rates
(4) Updated the yearly drop-out 
rate for DFS that is more in line 
with the actual drop-out rate 
3.6.1.1 Disease-Free 
Survival
Per protocol amendment 
3 and 4, added two
sensitivity analyses:
(1) One for primary DFS
by investigator 
assessment with 
participants with baseline 
disease by BICR as an 
additional stratum.
(2) One for DFS by BICR 
with participants with 
baseline disease by BICR 
censored at baseline
To evaluate the robustness of the 
results from the primary analysis 
method after adjusting the potential 
confounding effect of baseline disease 
status
 
 
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Section # and 
Name
Description of Change
Brief Rationale
3.6.1.1 Disease-Free 
Survival
Added one potential 
sensitivity analysis 
considering COVID-19 
impact
To evaluate the impact of COVID-19 
on primary DFS analysis if there are 
more than 5% of randomized 
participants censored due to COVID-
19
3.6.1.1 Disease-Free 
Survival
3.6.1.2 Overall 
Survival (OS)
Added one potential 
sensitivity analysis for 
MaxCombo test
To account for the potential loss of 
power with logrank test when the 
proportional hazard assumption is 
violated
3.10
Subgroup 
Analyses
Per protocol amendment 
3 and 4, added following 
subgroup analyses:
Baseline disease status by 
BICR (NED, Non-NED)
Added a requirement for 
subgroup analysis that 
number of participants in 
subgroup must greater 
than or equal to 5% of the 
ITT population.
To study whether the treatment effect 
is consistent across subgroups defined 
by baseline disease status by BICR.
To predefine the threshold for number 
of participants to perform subgroup 
analysis to allow more meaningful 
estimate within subgroup and avoid 
potential model convergence issue due 
to small sample size in the subgroup. 
3.6.1
Statistical 
Methods for 
Efficacy Analyses
Per protocol amendment 
4, updated censoring rules 
for the primary analysis 
and the sensitivity 
analysis. The new 
primary analysis is the 
old sensitivity analysis 1 
and new sensitivity 
analysis is the old 
primary analysis. The old 
sensitivity analysis 2 is 
removed.
Updated the censoring rules per the 
most recent oncology standard for an 
adjuvant study to follow ITT rule to 
produce more unbiased estimate.
 
 
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Section # and 
Name
Description of Change
Brief Rationale
3.4.3 PRO 
Endpoints
3.5.3 PRO Analysis 
Population
3.6.4 PRO Analysis
Added PRO analysis 
endpoints, analysis 
population and statistical 
methods.
To provide details on endpoint 
definition, analysis population and 
analysis method for PRO endpoints.
3. ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
STATISTICAL ANALYSIS PLAN SUMMARY
Key elements of the statistical analysis plan are summarized below; the comprehensive 
plan is provided in Section 3.2 through Section 3.12.
Study Design Overview
This is a randomized, double-blind, multicenter Phase III trial to evaluate the 
efficacy and safety of pembrolizumab versus placebo as an adjuvant treatment 
for renal cell carcinoma (RCC) post nephrectomy. 
Treatment Assignment
Approximately 950 participants will be randomized 1:1 into the following two 
treatment arms: pembrolizumab 200 mg or matching placebo (saline 200 mg 
infusion) administered intravenously (IV) every 3 weeks (Q3W). Stratification 
factors are provided in protocol Section 7.3.1. 
Analysis Populations
Efficacy: Intention-to-Treat
Safety: All Participants as Treated
Primary Endpoints
Disease-free survival (DFS) as assessed by the investigator
Key Secondary 
Endpoints
Overall survival (OS)
Statistical Methods for
Key Efficacy Analyses
The primary and secondary hypotheses addressing DFS and OS will be 
evaluated by comparing pembrolizumab to placebo using a stratified log-rank 
test. Estimation of the hazard ratio will be done using a stratified Cox 
regression model. Event rates over time will be estimated within each 
treatment group using the Kaplan-Meier method. 
Statistical Methods for
Key Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers differ 
with respect to the analyses that will be performed. There are no Tier 1 events 
in this trial. Tier 2 parameters will be assessed via point estimates with 95% 
confidence intervals (CI) provided for between-group comparisons; only point 
estimates by treatment group are provided for Tier 3 safety parameters. The
95% CI for the between-treatment differences in percentages will be provided
using the Miettinen and Nurminen method.
 
 
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Interim and Final 
Analyses
Three interim analyses are planned for the study (one interim analysis for 
DFS and three interim analyses for OS). Results will be reviewed by an 
external data monitoring committee. Details are provided in Section 10.7.
First Interim Analysis (IA1) 
o
Purpose: Interim analysis for DFS and OS. 
o
Timing: When approximately 265 disease recurrence events by 
investigator assessment have accrued and a minimum follow-
up (time from last participant randomized to IA1) of 12 months 
is achieved. Approximately 94 OS events are expected at this 
time.
Second Interim Analysis (IA2)
o
Purpose: Final analysis for DFS and interim analysis for OS 
o
Timing: Final analysis of DFS when approximately 332
DFS events by investigator assessment have accrued if DFS 
is not rejected at IA1, Approximately 132 OS events are 
expected at this time.
Third Interim Analysis (IA3) 
o
Purpose: Interim analysis for OS 
o
Timing: When approximately 172 OS events have accrued, 
Final analysis (FA) 
o
Purpose: Final analysis for OS 
o
Timing: When approximately 200 OS events have accrued, 
Multiplicity
The overall Type I error rate is strongly controlled at 2.5% (1-sided) with a 
fixed sequence testing procedure to test DFS at alpha level of 2.5% (1-sided) 
first and pass the alpha to OS if the hypothesis test of DFS is declared 
successful. A group sequential approach will be used to allocate alpha between 
the interim and final analyses. The study will be considered a success if DFS is 
demonstrated to be statistically significant under multiplicity control. Note that 
if the statistical criterion for success for DFS is met at an IA, a regulatory 
application may be submitted based on DFS for a full approval consideration 
and the study could still continue for OS.
Sample Size and Power
The sample size was planned for 950 but the following power calculations are
based on 990 which is a number more in line with the actual final number of 
randomized subjects. DFS is the primary endpoint for this study. The expected 
median DFS time for those not cured in the control group is 45 months; based 
on 332 events and a Poisson mixture cure rate model with assumed cure rate of 
0.3, the study has 95% power to detect a hazard ratio of 0.67 (pembrolizumab 
versus placebo) at alpha = 2.5% (1-sided). 
3.2
RESPONSIBILITY FOR ANALYSES/IN-HOUSE BLINDING
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment. Randomization will be implemented in IVRS/IWRS.
This study will be conducted as a double-blind study under in-house blinding procedures. The 
official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
 
 
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complete. In addition, blinded independent central imaging review will be performed on 
imaging scans without knowledge of the treatment group assignments of participants.
Planned interim analyses are described in Section 3.7. Blinding to treatment assignment will 
be maintained at all investigational sites. The results of interim analyses will not be shared 
with the investigators prior to the completion of the study. Participant-level unblinding will be 
restricted to an external unblinded statistician and external unblinded scientific programmer 
performing the interim analysis, who will have no other responsibilities associated with the 
study.
Blinding issues related to the planned interim analyses are described in Section 3.7.
3.3
HYPOTHESES/ESTIMATION
Objective/Hypothesis
Endpoint(s)
Primary
●
Objective: To compare DFS as assessed 
by the investigator for participants treated 
with pembrolizumab versus those 
receiving placebo
Hypothesis: Pembrolizumab is superior 
to placebo with respect to DFS
●
DFS as assessed by the investigator: 
time from randomization to the first 
documented local recurrence, or 
occurrence of distant kidney cancer 
metastasis(es), or death due to any 
cause, whichever occurs first.
Secondary
Key Secondary
●
Objective: To compare OS for 
participants treated with pembrolizumab 
versus those receiving placebo
Hypothesis: Pembrolizumab is superior 
to placebo with respect to OS
●
OS: time from randomization to death 
due to any cause.
Other Secondary
●
To compare the safety and tolerability 
profiles for participants treated with 
pembrolizumab versus those receiving 
placebo
●
Adverse events (AEs), serious AEs 
(SAEs), AEs leading to 
discontinuation, deaths, laboratory 
values, and vital signs 
●
To compare measures of disease 
recurrence-specific survival (DRSS), as 
assessed by the investigator, in 
participants treated with pembrolizumab 
versus those receiving placebo
●
DRSS1 as assessed by the investigator: 
time from randomization to the first 
documented local recurrence of RCC.
●
DRSS2 as assessed by the investigator: 
time from randomization to the first 
documented local recurrence with 
visceral lesion or occurrence of distant 
 
 
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Objective/Hypothesis
Endpoint(s)
kidney cancer metastasis(es) with 
visceral lesion, whichever occurs first.
●
To compare event-free survival (EFS) as 
assessed by the blinded independent 
radiology review for participants treated 
with pembrolizumab versus those 
receiving placebo 
●
EFS as assessed by the blinded 
independent radiology review (BICR): 
time from randomization to the first 
documented local recurrence or 
occurrence of distant kidney cancer 
metastasis(es) among participants 
disease free at baseline (M0/M1-NED)
by BICR; or disease progression 
among participants with baseline 
disease (M1) by BICR, or death due to 
any cause, whichever occurs first.
●
To compare DFS and OS according to 
participants’ PD-L1 expression status 
(Positive, Negative) for participants 
treated with pembrolizumab versus those 
receiving placebo
●
DFS as assessed by the investigator: 
time from randomization to the first 
documented local recurrence, or 
occurrence of distant kidney cancer 
metastasis(es), or death due to any 
cause, whichever occurs first.
●
OS: time from randomization to death 
due to any cause.
●
To evaluate patient-reported outcomes 
(PROs) with the European Organization 
for the Research and Treatment of Cancer 
Quality of Life Questionnaire C30 
(EORTC-QLQ-C30) and the Functional 
Assessment of Cancer Therapy Kidney 
Symptom Index – Disease Related 
Symptoms (FKSI-DRS)
●
EORTC-QLQ-C30
●
FKSI-DRS 
Tertiary/Exploratory
●
To evaluate pharmacokinetic (PK) 
parameters and the presence of antidrug 
antibodies (ADA)
●
PK parameters (clearance and volume 
of distribution)
●
ADA to pembrolizumab
●
To identify molecular (genomic, 
metabolic, and/or proteomic) biomarkers 
that may be indicative of clinical 
response/resistance, safety, 
●
Biomarker analyses may include 
germline genetic variation, genetic 
(DNA) mutations from tumor, tumor 
and blood RNA variation, proteomics 
 
 
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Objective/Hypothesis
Endpoint(s)
pharmacodynamic activity, and/or the 
mechanism of action of pembrolizumab
and IHC, and other blood-derived 
biomarkers
●
To evaluate PROs with the EORTC-
QLQ-C30 and FKSI-DRS and to 
characterize utilities with the EuroQol 5 
Dimensions 5 Levels (EQ-5D-5L)
●
All scales, sub-scales, and single item 
measures for the EORTC-QLQ-C30, 
FKSI-DRS, and EQ-5D-5L
3.4
ANALYSIS ENDPOINTS
3.4.1
Efficacy Endpoints
3.4.1.1 Primary
Disease-Free Survival
DFS, as assessed by the investigator, is defined as the time from randomization to the first 
documented local recurrence, or occurrence of distant kidney cancer metastasis(es), or death 
due to any cause, whichever occurs first. See Section 3.6.1 for the censoring rules.
3.4.1.2 Secondary
Overall Survival
OS is defined as the time from randomization to death due to any cause. Participants without
documented death at the time of the final analysis will be censored at the date of the last follow-
up.
Disease Recurrence Specific Survival

DRSS1 is defined as the time from randomization to the first documented local recurrence 
of RCC as assessed by the investigator.

DRSS2 is defined as the time from randomization to the first documented local recurrence 
with visceral lesion or occurrence of distant kidney cancer metastasis(es) with visceral 
lesion, whichever occurs first, as assessed by the investigator.
Event-Free Survival

EFS is to be assessed by BICR. EFS is defined as time from randomization to the first 
documented local recurrence or occurrence of distant kidney cancer metastasis(es) among 
participants which by BICR were considered disease free at baseline (M0/M1 NED); or 
disease progression among participants which by BICR were considered to have baseline 
 
 
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disease (M1), or death due to any cause, whichever occurs first. See protocol Section 9.2.1 
for the definition of disease progression.
3.4.2
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs; and changes in laboratory values. AEs will be assessed 
as defined by Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0.
3.4.3
Patient Reported Outcome (PRO) Endpoints
3.4.3.1 Secondary
•
Mean change from baseline in EORTC QLQ-C30 global health status/quality of life 
scores.
•
Mean change from baseline in EORTC QLQ-C30 functional subscales: physical 
functioning.
•
Mean change from baseline in FKSI-DRS score.
3.4.3.2 Exploratory
Following are the PRO endpoints which are going to be used for exploratory analyses:
•
Mean change from baseline in EORTC QLQ-C30 symptom subscales: nausea and 
vomiting symptom, diarrhea symptom.  
•
Mean change from baseline in EQ-5D-5L Health State Score using visual analogue 
scale (VAS).
•
3roportions of deterioration / stability / improvement / stability + improvement in 
EORTC QLQ-C30 global health status / QoL, its functional (physical functioning) 
where 
o
Improvement is defined as a 10 points or more increase in score (in the positive 
direction) from baseline at any time during the study and confirmed by a 10 
points or more improvement at the next consecutive visit.
o
Stability is defined as, when the criteria for improvement are not met, a less 
than 10 points worsening in score from baseline at any time during the study 
and confirmed by a less than 10 points worsening at the next consecutive visit.
o
Stability + improvement is defined as an improvement or less than 10 points 
worsening in score from baseline at any time during the trial and confirmed by 
an improvement or less than 10 points worsening in score at the next 
consecutive visit.
o
Deterioration is defined as, when the criteria for improvement or stability are 
not met, a 10 points or greater worsening from baseline at any time during the 
study.

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
Proportions of deterioration / stability / improvement / stability + improvement in 
FKSI-DRS score where 
o
Improvement is defined as a 3-points or more increase in score (in the positive 
direction) from baseline at any time during the study and confirmed by a 3-
points or more improvement at the next consecutive visit.
o
Stability is defined as, when the criteria for improvement are not met, a less 
than 3 points worsening in score from baseline at any time during the study and 
confirmed by a less than 3 points worsening at the next consecutive visit.
o
Stability + improvement is defined as an improvement or less than 3 points 
worsening in score from baseline at any time during the trial and confirmed by 
an improvement or less than 3 points worsening in score at the next consecutive 
visit.
o
Deterioration is defined as, when the criteria for improvement or stability are 
not met, a 3 points or greater worsening from baseline at any time during the 
study.
3.5 ANALYSIS POPULATIONS
3.5.1
Efficacy Analysis Populations
The Intention-to-Treat population will serve as the population for the primary and key 
secondary efficacy analyses. All randomized participants will be included in this population. 
Participants will be analyzed in the treatment group to which they are randomized. Details on 
the approach to handling missing data are provided in Section 3.6.1 – Statistical Methods for 
Efficacy Analyses.
3.5.2
Safety Analysis Populations
The All Participants as Treated (APaT) population will be used for the analysis of safety data 
in this study. The APaT population consists of all randomized participants who received at 
least 1 dose of study treatment. Participants will be analyzed in the treatment group 
corresponding to the study treatment they actually received for the analysis of safety data using 
the APaT population. For most participants this will be the treatment group to which they are 
randomized. Participants who take incorrect study treatment for the entire treatment period will 
be included in the treatment group corresponding to the study treatment actually received. Any 
participant who receives the incorrect study treatment for one cycle but receives the correct 
treatment for all other cycles will be analyzed according to the correct treatment group and a 
narrative will be provided for any events that occur during the cycle for which the participant 
is incorrectly dosed.
At least 1 laboratory measurement obtained subsequent to at least 1 dose of study treatment is 
required for inclusion in the analysis of specific parameter. To assess change from baseline, a 
baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
3.6.2–Statistical Methods for Safety Analysis.
 
 
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3.5.3
PRO Analysis Population
The PRO analyses are based on the PRO full analysis set (FAS) population, defined as subjects 
who have at least one PRO assessment available and have received at least one dose of the 
study medication. Participants will be analyzed in the treatment group to which they are 
randomized.
3.6 STATISTICAL METHODS
3.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary objectives 
on OS and disease recurrence specific survival. Separate analysis plans may be developed for 
PK/ADA modeling analysis, biomarker analysis, and genetic data analysis.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 3.8 – Multiplicity. Nominal p values may 
be computed for other efficacy analyses, but should be interpreted with caution due to potential 
issues of multiplicity.
3.6.1.1 Disease-Free Survival (DFS)
The non-parametric Kaplan-Meier method will be used to estimate the DFS curve in each 
treatment group. The hypotheses addressing a treatment difference in DFS will be tested 
by the stratified log-rank test. A stratified Cox proportional hazard model with Efron's method
of tie handling will be used to estimate the magnitude of the treatment difference (ie, hazard 
ratio [HR]) between the treatment arms. The HR and its 95% CI from the stratified Cox 
model with Efron's method of tie handling and with a single treatment covariate will be 
reported. The stratification factors including Metastasis status (M0 versus M1 NED), ECOG 
PS (0 versus 1) and US participant (YES versus NO) will be applied to both the stratified log-
rank test and the stratified Cox model. 
Since participants enrolled with baseline disease by BICR could have a different time to event 
distribution compared to participants who were disease free at baseline by BICR, a sensitivity 
analysis will be performed using the stratified Cox model and stratified log-rank test with
stratification factors used for randomization with baseline disease status by BICR as an 
additional stratum. Specifically, a total of six strata will be used: M0 + ECOG PS 0 + US 
participant vs. M0 + ECOG PS 0 + Non-US participant vs. M0 + ECOG PS 1 + US participant 
vs. M0 + ECOG PS 1 + Non-US participant vs. M1 NED vs. M1 by BICR. In addition, DFS 
by BICR will be analyzed as a sensitivity analysis in which participants enrolled with baseline 
disease by BICR will be censored at randomization date. 
Since the trial was ongoing during the outbreak of COVID-19, sensitivity analyses are planned 
to evaluate the impact of COVID-19 on primary DFS analysis if there are more than 5% of
randomized participants who were censored at last disease assessment due to COVID-19
resulted missing imaging scans. In order to stress-test the assumption of censored at random 
with an assumption that favors the placebo group over the experimental treatment group, we 
will assume COVID-19 related censoring in the experimental treatment group is informative 
of impending DFS event, while the censoring in the placebo group is non-informative. 
 
 
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Specifically, we will randomly select a certain percentage (δ) of COVID-19 related censoring 
and count them as events at the censoring time in the experimental group, while keep all 
COVID-19 related censoring as censored in placebo group. A series of sensitivity analyses 
could be performed with increasing values of δ to assess whether the primary DFS analysis 
results are robust to the deviations from censored at random assumption for the COVID-19 
related censoring.
Since disease recurrence is assessed periodically, disease recurrence can occur any time in the
time interval between the last assessment when disease recurrence was not documented and
the assessment when disease recurrence is documented. For the primary analysis, for the 
participants who have disease recurrence (local recurrence or occurrence of distant kidney 
cancer metastasis(es)) as assessed by the investigator’s review, the true date of disease 
recurrence will be approximated by the date of the first assessment at which disease recurrence 
is objectively documented, regardless of discontinuation of study treatment. Death is always 
considered as a confirmed disease recurrence event. In order to evaluate the robustness of the 
DFS endpoint, a sensitivity analysis with a different set of censoring rules may be performed. 
The sensitivity analysis is the same as the primary analysis except that events after 2 
consecutive missed disease assessments or after new anti-cancer therapy, if any, should be 
censored at last disease assessment prior to the earlier date of ≥2 consecutive missed disease 
assessments and new anti-cancer therapy.
The censoring rules for primary and sensitivity analysis are summarized in Table 1.
Table 1
Censoring Rules for Primary and Sensitivity Analysis of Disease-Free 
Survival
Situation
Primary Analysis
Sensitivity Analysis
No recurrence and no death; new
anticancer treatment is not initiated
Censored at last
disease assessment
Censored at last disease
assessment
No recurrence and no death; new
anticancer treatment is initiated
Censored at last
disease assessment
Censored at last disease
assessment before new anti-cancer 
treatment
Recurrence or death documented after ≤1 
missed disease assessment and before 
new anti-cancer treatment, if any
Event at date of
documented recurrence 
or death
Event at date of documented
recurrence or death
Recurrence or death documented 
immediately after ≥2 consecutive missed
disease assessments, or after new anti-
cancer treatment, if any
Event at date of
documented recurrence 
or death
Censored at the last disease 
assessment prior to the earlier date 
of ≥2 consecutive missed disease 
assessments and new anti-cancer 
treatment, if any
The proportional hazards assumption on DFS will be examined using both graphical and 
analytical methods if warranted. The log [-log] of the survival function versus time for DFS 
will be plotted for the comparison between pembrolizumab and the placebo arm. If the curves 
are not parallel, indicating that hazards are not proportional, supportive analyses may be
conducted to account for the possible non-proportional hazards effect associated with 
immunotherapies: for example, using the Restricted Mean Survival Time method [1] and 
 
 
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parametric method [2]. The RMST is simply the population average of the amount of event-
free survival time experienced during a fixed study follow-up time. This quantity can be 
estimated by the area under the Kaplan-Meier curve up to the follow-up time. The clinical 
relevance and feasibility should be taken into account in the choice of follow-up time to define 
RMST (e.g., near the last observed event time assuming that the period of clinical interest in 
the survival experience is the whole observed follow-up time for the trial, but avoiding the 
very end of the tail where variability may be high); a description of the RMST as a function of 
the cutoff time may be of interest. The difference between two RMSTs for the two treatment 
groups will be estimated and 95% CI will be provided.
A sensitivity analysis may be performed based on the MaxCombo test with logrank FH (0, 1), 
FH (1, 1) at the final analysis of DFS to account for the potential loss of power with logrank 
test when the proportional hazard assumption is violated.
3.6.1.2 Overall Survival (OS)
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
hypotheses of treatment difference in survival will be tested by the stratified log -rank test. A 
stratified Cox proportional hazard model with Efron's method of tie handling will be used to 
estimate the magnitude of the treatment difference (ie, the HR). The HR and its 95% CI from 
the stratified Cox model with a single treatment covariate will be reported. The stratification 
factors used for randomization will be applied to both the stratified log-rank test and the 
stratified Cox model. 
The proportional hazards assumption on OS may be examined using both graphical and 
analytical methods if warranted.  The log [-log] of the survival function vs. time for OS will 
be plotted for the comparison between pembrolizumab and the placebo arm. If the curves are 
not parallel, indicating that hazards are not proportional, supportive analyses may be conducted 
to account for the possible non-proportional hazards effect associated with immunotherapies: 
for example, using the Restricted Mean Survival Time method [1], parametric method [2], etc. 
The RMST is simply the population average of the amount of event-free survival time 
experienced during a fixed study follow-up time. This quantity can be estimated by the area 
under the Kaplan-Meier curve up to the follow-up time. The clinical relevance and feasibility 
should be taken into account in the choice of follow-up time to define RMST (e.g., near the 
last observed event time assuming that the period of clinical interest in the survival experience 
is the whole observed follow-up time for the study, but avoiding the very end of the tail where 
variability may be high); a description of the RMST as a function of the cutoff time may be of 
interest. The difference between two RMSTs for the two treatment groups will be estimated 
and 95% CI will be provided.
A sensitivity analysis may be performed based on the MaxCombo test with logrank FH (0, 1), 
FH (1, 1) at the final analysis of OS to account for the potential loss of power with logrank test 
when the proportional hazard assumption is violated.
The OS analysis will be conducted according to the hypothesis testing plan as described in 
Section 3.7 and Section 3.8.
 
 
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3.6.1.3 Disease Recurrence Specific Survival
The non-parametric cumulative incidence estimator will be used to estimate the DRSS1 and 
DRSS2 curves in each treatment group. For DRSS1, only local recurrence is counted as an 
event. Death, or occurrence of distant kidney cancer metastasis(es) will be censored at 
documented date of disease metastasis or death, whichever occurs first. For DRSS2, only 
disease recurrence with visceral lesion is counted as an event. Death, local recurrence without
visceral lesion, distant metastasis without visceral lesion will be censored at documented date 
of disease recurrence or death, whichever occurs first.
3.6.1.4
Event-Free Survival
The non-parametric Kaplan-Meier method will be used to estimate the EFS curve in each 
treatment group. The hypotheses addressing a treatment difference in EFS will be tested by
the stratified log-rank test. A stratified Cox proportional hazard model with Efron's method of
tie handling will be used to estimate the magnitude of the treatment difference (ie, hazard ratio 
[HR]) between the treatment arms. The HR and its 95% CI from the stratified Cox model
with Efron's method of tie handling and with a single treatment covariate will be reported.
The stratification factors used for randomization (see Section 7.3.1 in protocol) with baseline 
disease status by BICR as an additional stratum will be applied to both the stratified log-rank
test and the stratified Cox model.
3.6.1.5
Analysis Strategy for Key Efficacy Variables
Table 2 summarizes the primary analysis approach for primary and key secondary efficacy 
endpoints. Sensitivity analysis methods are described above for DFS.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, multiple 
populations, and interim analyses is described in Section 3.7 - Interim Analyses and in Section 
3.8 - Multiplicity.
Table 2
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
†
Statistical Method
Analysis Population
Missing Data
Approach
Primary Hypothesis #1
DFS as assessed by the 
investigator
Test: Stratified Log-
rank test Estimation: 
Stratified Cox model 
with Efron’s tie 
handling method
ITT 

Primary 
censoring rule

Sensitivity 
analysis
Key Secondary Hypothesis
OS
Test: Stratified Log-
rank test Estimation: 
Stratified Cox model 
with Efron’s tie 
handling method
ITT
Censored at the last 
date the participant was 
known to be alive 
†Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for randomization
will be applied to the analysis model.
ITT = intention-to-treat; OS = overall survival; DFS = disease-free survival.
 
 
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3.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests.
Tiered Approach
The analysis of safety results will follow a tiered approach (Table 3). The tiers differ with 
respect to the analyses that will be performed. Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p values and 95% CI provided for 
between-group comparisons. Other safety parameters will be considered Tier 2 or Tier 3. There 
is no expectation of enhanced safety signal in this adjuvant study other than safety signals of 
which we are already aware from past studies. Participants do not have tumor burden and their 
existing safety profile might be less intensive. Hence, we do not expect any new safety signals. 
Therefore there are no events of interest that will be analyzed as Tier 1 safety endpoints in this 
study.
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for 
between-group comparisons; only point estimates by treatment group are provided for Tier 3 
safety parameters.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method, an 
unconditional, asymptotic method [3].
Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the event; all other AEs and predefined limits of change will belong to Tier 3. The threshold 
of at least 10% of participants was chosen for Tier 2 events because the population enrolled in 
this study is in critical condition and usually experiences various AEs of similar types 
regardless of treatment; events reported less frequently than 10% of participants would obscure 
the assessment of the overall safety profile and add little to the interpretation of potentially 
meaningful treatment differences. In addition, Grade 3 to 5 AEs (≥5% of participants in 1 of 
the treatment groups) and SAEs (≥5% of participants in 1 of the treatment groups) will be 
considered Tier 2 endpoints. Because many 95% CIs may be provided without adjustment for 
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in safety 
review, not as a formal method for assessing the statistical significance of the between-group 
differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. The broad AE 
categories consisting of the proportion of participants with any AE, a drug related AE, a serious 
AE, an AE which is both drug-related and serious, a Grade 3-5 AE, a drug-related Grade 3-5 
AE, and discontinuation due to an AE will be considered Tier 3 endpoints. Only point estimates 
by treatment group are provided for Tier 3 safety parameters.
 
 
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Continuous measures such as changes from baseline in laboratory that are not pre-specified as 
Tier-1 endpoints will be considered Tier 3 safety parameters. Summary statistics for baseline, 
on-treatment, and change from baseline values will be provided by treatment group in table 
format.
Table 3
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Grade 3-5 AE (incidence ≥5% of participants in one of the 
treatment groups)
X
X
Serious AE (incidence ≥5% of participants in one of the 
treatment groups)
X
X
AEs (incidence ≥10% of participants in one of the treatment 
groups)
X
X
Tier 3
Any AE
X
Any Grade 3-5 AE
X
Any Serious AE 
X
Any Drug-Related AE
X
Any Serious and Drug-Related AE
X
Any Grade 3-5 and Drug-Related AE
X
Discontinuation due to AE
X
Dose Interruption due to AE
X
Death
X
Specific AEs, SOCs (incidence <10% of participants in all 
of the treatment groups)
X
Change from Baseline Results (lab toxicity shift)
X
Abbreviations: AE = adverse event; CI = confidence interval; SOC = system organ class.
Frequency of AE by time period from first dose (e.g., 0-3, 3-6, 6-9, 9-12 and beyond 12
months) may also be provided.  In each time interval, the denominator is the number of 
participants at risk for the event during the particular time period, defined as participants who 
are event-free up until the start of the interval.  
To properly account for the potential difference in follow-up time between the study arms, 
which is expected to be longer in the pembrolizumab arm, AE incidence adjusted for treatment 
exposure analyses may be performed as appropriate.  
Time to Grade 3-5 AE
In addition to the tiered approach, exploratory analysis may be performed on the time to the 
first Grade 3-5 AE. The time to the first Grade 3-5 AE is defined as the time from the first day 
of study drug to the first event of a Grade 3-5 AE. Summary statistics will be provided.  
 
 
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3.6.3
Summaries of Baseline Characteristics and Demographics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of participants screened and randomized, and the
primary reasons for screening failure and discontinuation will be displayed. Demographic 
variables (eg, age), baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized by treatment either by descriptive statistics or 
categorical tables.
3.6.4
Patient Reported Outcomes (PRO) Analysis
This section describes the planned analyses for the key PRO endpoints. As there is no formal 
hypothesis testing for PRO endpoints, nominal p-values will be provided for treatment 
comparisons of pembrolizumab vs. placebo. No multiplicity adjustment will be performed. 
3.6.4.1 PRO compliance summary
Completion and compliance of EORTC QLQ-C30, FKSI-DRS and EQ-5D by visit and by 
treatment will be described. Numbers and percentages of complete and missing data at each 
visit will be summarized.  An instrument is considered complete if at least one valid score is 
available according to the missing item rules outlined in the scoring manual for the instrument. 
Completion rate of treated participants (CR-T) at a specific time point is defined as the number 
of treated participants who complete at least one item over the number of treated participants 
in the PRO analysis population.
CR-T ൌ ܰݑܾ݉݁ݎ ݋݂ ݐݎ݁ܽݐ݁݀ ݌ܽݎݐ݅ܿ݅݌ܽ݊ݐݏ ݓ݄݋ ܿ݋݉݌݈݁ݐ݁ ܽݐ ݈݁ܽݏݐ ݋݊݁ ݅ݐ݁݉
ܰݑܾ݉݁ݎ ݋݂ ݐݎ݁ܽݐ݁݀ ݌ܽݎݐ݅ܿ݅݌ܽ݊ݐݏ ݅݊ ݐ݄݁ ܴܱܲ ݈ܽ݊ܽݕݏ݅ݏ ݌݋݌ݑ݈ܽݐ݅݋݊ 
The completion rate is expected to shrink in the later visit during study period due to the 
participants who discontinued early. Therefore, another measurement, compliance rate of 
eligible participants (CR-E) will also be employed as the support for completion rate.  CR-E 
is defined as the number of treated participants who complete at least one item over number of 
eligible participants who are expected to complete the PRO assessment, not including the 
participants missing by design such as death, discontinuation, translation not available. 
CR-E ൌ ܰݑܾ݉݁ݎ ݋݂ ݐݎ݁ܽݐ݁݀ ݌ܽݎݐ݅ܿ݅݌ܽ݊ݐݏ ݓ݄݋ ܿ݋݉݌݈݁ݐ݁ ܽݐ ݈݁ܽݏݐ ݋݊݁ ݅ݐ݁݉
ܰݑܾ݉݁ݎ ݋݂ ݈ܾ݈݁݅݃݅݁ ݌ܽݎݐ݅ܿ݅݌ܽ݊ݐݏ ݓ݄݋ ܽݎ݁ ݁ݔ݌݁ܿݐ݁݀ ݐ݋ ܿ݋݉݌݈݁ݐ݁
The reasons of non-completion and non-compliance will be provided in supplementary table:
–
Completed as scheduled
–
Not completed as scheduled
–
Off-study: not scheduled to be completed.
In addition, reasons for non-completion as scheduled of these measures will be collected using 
“miss_mode” forms filled by site personnel and will be summarized in table format.  The 
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schedule (study visits and estimated study times) and mapping of study visit to analysis visit 
for PRO data collection is provided in Table 4.
Table 4
PRO Data Collection Schedule and Mapping of Study visit to Analysis Visit
Study Week
Week 
0 
(Baseline)
Week 
12
Week 24 to Week 
36
(Every 
12 
weeks)
Week 
48
Week 52
Week 104 to Week 
520 
(Every 
52
weeks)
Study Day
1
85
Week number 
*7+1
337
365
Week number *7+1
Day Range 
<=1
[2, 
126]
[Week number*7-
41, week 
number*7+42]
[295, 
351]
[352, 
546]
[Week number*7-
181, week 
number*7+182]
3.6.4.2 Mean change from baseline
The time point for the mean change from baseline is defined as the latest time point at which 
CR-T ≥ 60% and CR-E ≥80% and week 52 was selected based on blinded data review prior 
to the database lock for any PRO analysis.
To assess the treatment effects on the PRO score change from baseline in the global health 
status/QoL and its physical functioning, nausea and vomiting symptom, diarrhea symptom, 
FKSI-DRS, EQ-5D-5L VAS outcome a constrained longitudinal data analysis (cLDA) model 
proposed by Liang and Zeger [4] will be applied, with the PRO score as the response variable,
and treatment by time interaction and stratification factors used for randomization (See Section
7.3.1) as covariates.  The treatment difference in terms of least square (LS) mean change from 
baseline will be estimated from this model together with 95% CI.  Model-based LS mean with 
95% CI will be provided by treatment group for PRO scores at baseline and post-baseline time 
point. 
The cLDA model assumes a common mean across treatment groups at baseline and a different 
mean for each treatment at each of the post-baseline time points. In this model, the response 
vector consists of baseline and the values observed at each post-baseline time point. Time is 
treated as a categorical variable so that no restriction is imposed on the trajectory of the means 
over time. The cLDA model is specified as follows:
ܧ൫ܻ௜௝௧൯ൌߛ଴൅ߛ௝௧ܫሺݐ൐0ሻ൅ߚܺ௜, ݆ൌ1,2;  ݐൌ0,1,2,3, . . ݇
where Yijt is the PRO score for participant i, with treatment assignment j at visit t; γ0 is the 
baseline mean for all treatment groups, γjt is the mean change from baseline for treatment group 
j at time t; Xi is the stratification factor (binary) vector for this participant, and β is the 
coefficient vector for stratification factors. An unstructured covariance matrix will be used to 
model the correlation among repeated measurements. If the unstructured covariance model 
fails to converge with the default algorithm, then Fisher scoring algorithm or other appropriate 
methods can be used to provide initial values of the covariance parameters. In the rare event 
that none of the above methods yield convergence, a structured covariance such as Toeplitz 
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can be used to model the correlation among repeated measurements. In this case, the 
asymptotically unbiased sandwich variance estimator will be used. The cLDA model implicitly 
treats missing data as missing at random (MAR).
Line plots for the empirical mean change from baseline in EORTC QLQ-C30 global health 
status/QoL, its physical functioning and FKSI-DRS will be provided across time points till 
Week 52 as a supportive analysis.
In addition, the model-based LS mean change from baseline to the specified post-baseline time 
point together with 95% CI will be plotted in bar charts for EORTC QLQ-C30 global health 
status/QoL and its each functioning scale, symptom scale and FKSI-DRS score.   
3.6.4.3 Overall Improvement and Overall Improvement/Stability
Overall improvement rate will be analyzed, which is defined as the proportion of participants 
who have achieved an improvement as defined in Section 3.4.3 PRO Endpoints. Stratified 
Miettinen and Nurminen’s method will be used for comparison of the overall improvement 
rate between the treatment groups. The difference in overall improvement rate and its 95% CI 
from the stratified Miettinen and Nurminen’s method with strata weighting by sample size will 
be provided. The stratification factors used for randomization (See Section 7.3.1 in protocol) 
will be applied to the analysis.  
The point estimate of overall improvement rate will be provided by treatment group, together 
with 95% CI using exact binomial method by Clopper and Pearson [5]. The same method will 
be used to analyze overall improvement/stability rate, which is defined as the proportion of 
participants who have achieved improvement/stability as defined in Section 3.4.3 PRO 
Endpoints.
3.6.4.4 Analysis Strategy for Key PRO Endpoints
Endpoint/Variable
Statistical Method
Analysis Population
Missing Data 
Approach
Mean change from baseline in 
– EORTC QLQ-C30
Global health status/QoL
Functioning scale
Symptom scale
– FKSI-DRS 
– EQ-5D VAS
cLDA model
FAS
Model-based.
Overall improvement and overall 
improvement/stability in 
– EORTC QLQ-C30
Global health status/QoL
Physical functioning
– FKSI-DRS 
Stratified 
Miettinen 
and Nurminen method
FAS
Participants 
with 
missing 
data 
are 
considered 
not 
achieving 
improvement/stability
.
Abbreviations: cLDA = constrained longitudinal data analysis, FAS = full analysis set, QoL = quality of life.
 
 
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3.7 INTERIM ANALYSES
Treatment-level results of the interim analysis will be provided by the unblinded statistician to 
the external data monitoring committee (eDMC). Limited additional Sponsor personnel may 
be unblinded to the treatment level results of the interim analysis (analyses), if required, in 
order to act on the recommendations of the eDMC. The extent to which individuals are 
unblinded with respect to results of interim analyses will be documented by the unblinded 
statistician.
The eDMC will serve as the primary reviewer of the unblinded results of the DFS and OS at 
interim analyses and will make recommendations for discontinuation of the study or 
modification to an Executive Oversight Committee (EOC) of the Sponsor. Depending on the 
recommendations of the eDMC, the Sponsor may prepare a regulatory submission. If the 
eDMC recommends modifications to the design of the protocol or discontinuation of the study, 
the EOC may be unblinded to results at the treatment level in order to evaluate and direct the 
Sponsor protocol team as to the appropriate actions to be taken on these recommendations. 
Additional logistical details, revisions to the above plan, and data monitoring guidance will be 
provided in the DMC Charter. 
Prior to final study unblinding, the unblinded statistician and unblinded scientific programmer 
will not be involved in any discussions regarding modifications to the protocol, statistical 
methods, identification of protocol deviations, or data validation efforts after the interim 
analyses.
If the trial is positive at an interim analysis for primary endpoint DFS, additional analyses,
including but not limited to the protocol-specified final analysis, may be carried out for
exploratory purpose or upon regulatory request.
3.7.1
Safety Interim Analyses
The eDMC has responsibility for assessment of overall risk:benefit. Periodic safety monitoring 
will be specified in the eDMC charter with input from the eDMC members.  When prompted 
by safety concerns, the eDMC can request efficacy data to assess the overall risk: benefit to 
study participants. Any eDMC recommendation will be communicated to the Executive 
Oversight Committee (EOC) as agreed to in the eDMC charter.
3.7.2
Efficacy Interim Analyses
Three interim analyses are planned in addition to the final analysis for this trial. In this study, 
the futility bounds are non-binding. Results of the interim analyses (IA) will be reviewed by 
an eDMC. If both DFS and OS null hypotheses are rejected prior to the final analysis, the 
eDMC may recommend stopping the trial early for efficacy. At each IA, the eDMC may also 
recommend stopping the trial early for futility. Details on how the above planned analyses are 
incorporated into establishing statistical significance and the boundaries with regard to efficacy 
and futility are discussed further in Section 3.8, Multiplicity.
The analyses planned, endpoints evaluated and drivers of the timing are summarized in 
Table 5.
 
 
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Table 5
Analyses Planned, Endpoints Evaluated and Drivers of Timing
Analysis
Endpoint(s)
Timing
IA1
DFS, OS
Enrollment complete and approximately 265 DFS events by 
investigator assessment have occurred and a minimum 
follow-up (time from last participant randomized to IA1) of 
12 months is achieved.
IA2
DFS, OS
332 DFS events by investigator assessment; if DFS rejected 
before IA2, timing driven by 132 OS events
IA3
OS
172 OS events
FA
OS
200 OS events
3.8 MULTIPLICITY
3.8.1
Multiplicity Control for Efficacy Analyses
The trial uses the method of Maurer and Bretz [6] to provide strong multiplicity control for 
multiple hypotheses as well as interim analyses. Figure 1 shows the initial one-sided α-
allocation for each hypothesis in the ellipse representing the hypothesis. The weights for 
reallocation from each hypothesis to the others are represented in the boxes on the lines 
connecting hypotheses. This is further explained below.
Figure 1
Multiplicity Graph for Type I Error Control of Study Hypotheses
If the DFS null hypothesis is rejected at the 2.5% level, then the OS null hypothesis may be 
formally evaluated for statistical significance at the 2.5% level. For each endpoint, group 
sequential methods will be used to adjust for the interim and final analyses planned. If the DFS 
null hypothesis is rejected at an interim or final analysis, each OS interim and final analysis 
test may be compared to its rejection boundary for formal testing. For instance, the OS 
hypothesis will not be formally evaluated for statistical significance until the DFS null 
hypothesis is rejected.   
For DFS, the information fraction at each analysis will be based on the final planned number 
of 332 events. A Lan-DeMets O’Brien-Fleming spending approximation -spending function 
is used to set efficacy bounds. Non-binding futility spending is done by controlling the 
 
 
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probability of crossing the futility bound under the null hypothesis (total of 1-α=97.5%); a 
Hwang-Shih-DeCani (HSD) spending function with = -6 is used to set testing boundaries at 
each analysis.
For OS, the information fraction at each analysis will be based on the final planned number of 
200 deaths. A Lan-DeMets O’Brien-Fleming spending approximation -spending function is 
used to set efficacy bounds. As with DFS, non-binding futility spending is done by controlling 
the probability of crossing the futility bound under the null hypothesis (total of 1-α=97.5%); 
an HSD spending function with = -6 is used to set testing boundaries at each analysis.
Bounds at the expected number of events for each hypothesis at each analysis of DFS and OS 
are shown in Table 6 and Table 7, respectively. If the actual number of DFS or OS events at 
the interim and final analyses differs from those specified in the table, the bounds will be 
updated using this spending function evaluated at the observed information fraction (fraction 
of observed over expected final events) at each analysis.
Table 6
Boundary Properties for Planned Interim and Final Analyses for DFS 
Analysis
Value
Efficacy
Futility†
IA1: 80% (First Interim for DFS)
Z
2.2504
-0.5476
N: 990
p (1-sided)
0.0122
0.7080
Events: 265
HR at bound
0.7584
1.0696
Month: 39
P(Cross) if HR=1
0.0122
0.2920
P(Cross) if HR=0.67
0.8402
0.0001
IA2: (Final Analysis for DFS)
Z
2.0249
2.0249
N: 990
p (1-sided)
0.0214
0.0214
Events: 332
HR at bound
0.8005
0.8005
Month: 50
P(Cross) if HR=1
0.0250
0.9750
P(Cross) if HR=0.67
0.9490
0.0510
IA = Interim Analysis.
†: Futility boundary is non-binding.
 
 
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Table 7
Boundary Properties for Planned Interim and Final Analyses for OS
Analysis
Value
Efficacy
Futility†
IA1: 47% (First Interim for OS)
Z
3.0679
-1.7717
N: 990
p (1-sided)
0.0011
0.9618
Events: 94
HR at bound
0.5305
1.4421
Month: 39
P(Cross) if HR=1
0.0011
0.0382
P(Cross) if HR=0.67
0.1280
0.0001
IA2: 66% (Second Interim for OS)
Z
2.5455
-1.1786
N: 990
p (1-sided)
0.0055
0.8807
Events: 132
HR at bound
0.6416
1.2281
Month: 50
P(Cross) if HR=1
0.0058
0.1247
P(Cross) if HR=0.67
0.4033
0.0003
IA3: 86% (Third Interim for OS)
Z
2.2023
-0.2090
N: 990
p (1-sided)
0.0138
0.5828
Events: 172
HR at bound
0.7143
1.0324
Month: 63
P(Cross) if HR=1
0.0157
0.4195
P(Cross) if HR=0.67
0.6688
0.0025
Final
Z
2.0534
2.0534
N: 990
p (1-sided)
0.0200
0.0200
Events: 200
HR at bound
0.7476
0.7476
Month: 72
P(Cross) if HR=1
0.0250
0.9750
P(Cross) if HR=0.67
0.7930
0.2070
IA = Interim Analysis.
†: Futility boundary is non-binding.
3.8.2
Multiplicity Control for Safety Analyses
To account for any multiplicity concerns raised by the DMC review of unplanned efficacy data 
when prompted by safety concerns, a sensitivity analysis for DFS and OS may be considered.
This analysis will be performed if requested by the eDMC. However, eDMC review of DFS 
and OS data beyond the planned efficacy analysis to assess the overall risk:benefit to trial 
participants will not require multiplicity assessment typically associated with a planned 
efficacy IA because these analyses are not to declare a positive efficacy finding.
3.9 SAMPLE SIZE AND POWER CALCULATIONS
The study will randomize participants in a 1:1 ratio into the pembrolizumab and placebo arms. 
DFS and OS are the primary endpoint and key secondary endpoint, respectively. The sample 
size was planned for 950 but the following power calculations are based on 990 which is a 
number more in line with the actual final number of randomized participants.
For the DFS endpoint, based on a target number of 332 events and one IA at approximately 
80% of the target number of events, the study has approximately 95% power to detect a HR of 
0.67 at an overall alpha level of 2.5% (1-sided). 
For the OS endpoint, the power is conditional on the null hypothesis of DFS being rejected, 
based on a target number of 200 events and three interim analyses at approximately 47%, 66%, 
and 86% of the target number of events, the study has approximately 79% power to detect a 
HR of 0.67 or approximately 88% power to detect a HR of 0.635 at an overall alpha level of 
2.5% (1-sided).
 
 
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The above sample size and power calculations for DFS and OS assume the following:
•
DFS follow a Poisson mixture cure rate model [7] with assumed cure rate of 0.3. The 
cure rate of 0.3 is estimated based on historical data [8]. 
•
The median DFS is assumed to be 45 months for those not cured in the control group.
•
OS follows an exponential distribution with a median of 145 months for the control 
group. 
•
Enrollment period of 27 months with monthly accrual of 20 participants during the first 
5 months and monthly accrual of 30 participants from month 6 to month 21, and 
monthly accrual of 1 patient for the last month. 
•
A yearly drop-out rate of 2% for DFS and 1% for OS. 
The Poisson mixture model is applied to account for the failure rates decreasing over time in a 
trial in which the patient population is a mixture of patients who are susceptible to disease 
recurrence and patients who would not have a disease recurrence event after long-term follow-
up. The latter patients are called long-term survivors. The Poisson mixture model assumes a 
survival function [5] for a control group (c) as a function of time t, as follows:
Sሺtሻൌexp ሺെθሺ1 െexpሺെλtሻሻሻ, 
where 
)
_
log(
Rate
Cure
−
=
θ
, λ is a constant hazard rate, and
0
≥
t
.
In the adjuvant setting, according to the published literature [8] and study assumptions, ~30% 
participants will be long-term survivors or will be cured in the long-term (ie, Cure_Rate=0.3), 
and it is more likely that after approximately 5 to 6 years after study initiation there will be 
minimal accumulation of DFS events. 
According to the published literature [8], it is assumed that DFS follows a Poisson mixture 
model distribution with median DFS of 45 months for those not cured in the placebo group.  
Figure 2 below shows the DFS curves using the Poisson mixture model and exponential model. 
Compared to the curve from the exponential model, the curve from the Poisson mixture model 
looks more similar to the curve in the published literature.


3.4
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Figure 2
Disease-Free Survival Curves Using the Poisson Mixture Model and 
Exponential Model
The sample size and power calculation were performed using R (package “gsDesign”).
3.10 SUBGROUP ANALYSES AND EFFECT OF BASELINE FACTORS
To determine whether the treatment effect is consistent across various subgroups, the estimate 
of the between-group treatment effect (with a nominal 95% CI) for the primary endpoint will 
be estimated and plotted within each category of the following classification variables:
•
ECOG PS (0, 1) 
•
Metastasis status (M0, M1 NED)
•
Type of nephrectomy (Radical, Partial)
•
Geographic region (US, Non-US)
•
PD-L1 status (Positive, Negative)
•
Age (<65, ≥65 years)
•
Sex (Female, Male)
•
Race (White, non-White)
•
Baseline disease status by BICR (NED, Non-NED)
 
 
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Country-specific populations may also be analyzed per local regulatory requirements. The 
consistency of the treatment effect will be assessed using descriptive statistics for each 
category of the subgroup variables listed above. If the number of participants in a category of 
a subgroup variable is less than 5% of the ITT population, the subgroup analysis will not be 
performed for this category of the subgroup variable. The subgroup analyses will be conducted 
using an unstratified Cox model.
3.11 COMPLIANCE (MEDICATION ADHERENCE)
Drug accountability data for study treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
3.12 EXTENT OF EXPOSURE
The extent of exposure will be summarized as duration of treatment in cycles. Summary 
statistics will be provided on extent of exposure for the APaT population.
4
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2.
Anderson KM. A nonproportional Hazards Weibull Accelerated Failure Time Regression 
Model.  Biometrics 1991; 47: 281-288.
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Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985;4:213-26.
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Liang KY, Zeger SL. Longitudinal data analysis of continuous and discrete responses for pre-
post designs. Sankhya—The Indian Journal of Statistics Series B 2000; 62:134–148.
5.
Clopper CJ, Pearson ES: The use of confidence of fiducial limits illustrated in the case of the 
binomial. Biometrika 26::404,1934-413.
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Maurer W, Bretz F. Multiple testing in group sequential trials using graphical approaches. Stat 
Biopharm Res 2013; 5(4):311-20.
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de Castro M, Cancho VG, Rodrigues J. A hands-on approach for fitting long-term survival 
models under the GAMLSS framework. Comput Methods Programs Biomed. 2010  Feb;
97(2):168-77.
8.
Leibovich BC, Blute ML, Cheville JC, Lohse CM, Frank I, Kwon ED, et al. Prediction of 
progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a 
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