A Phase III Randomized, Open-label Study to Evaluate Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Axitinib Versus Sunitinib Monotherapy as a First-line Treatment for Locally Advanced or Metastatic Renal Cell Carcinoma (mRCC) (KEYNOTE-426)
Phase: PHASE3
Conditions: Renal Cell Carcinoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02853331
 3-May-2018 
Document Date: 
A Phase III Randomized, Open-label Study to Evaluate 
Efficacy and Safety o f Pembrolizumab (MK-3475) in 
Combination with Axitinib versus Sunitinib Monotherapy as 
a First-line Treatment for Locally Advanced or Metastatic 
Renal Cell Carcinoma (mRCC) (KEYNOTE-426) 

Product:  MK-3475 
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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.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. NJ, U.S.A.
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase III Randomized, Open-label Study to Evaluate Efficacy and Safety of 
Pembrolizumab (MK-3475) in Combination with Axitinib versus Sunitinib Monotherapy as a 
First-line Treatment for Locally Advanced or Metastatic Renal Cell Carcinoma (mRCC) 
(KEYNOTE-426)
IND NUMBER:  122,753
EudraCT NUMBER:  2016-000588-17

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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 17
2.0
TRIAL DESIGN........................................................................................................ 18
Trial Design ........................................................................................................... 18
2.1
Trial Diagram........................................................................................................ 21
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 21
Primary Objective(s) & Hypothesis(es) .............................................................. 21
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 21
3.2
Exploratory Objectives......................................................................................... 22
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 22
Background ........................................................................................................... 22
4.1
Disease Background: Advanced Renal Cell Carcinoma..................................... 22
4.1.1
4.1.1.1
Epidemiology and Disease Characteristics of RCC..................................... 22
4.1.1.2
Current Treatment Options for Advanced RCC .......................................... 23
4.1.1.3
Targeting PD-1 Immune Checkpoints for Cancer Treatments .................... 26
Pharmaceutical and Therapeutic Background .................................................... 26
4.1.2
4.1.2.1
Anti-PD-1 Antibody Pembrolizumab .......................................................... 26
4.1.2.2
Summary of Pembrolizumab Clinical Efficacy and Safety......................... 27
4.1.2.3
Axitinib ........................................................................................................ 28
4.1.2.4
Summary of Clinical Efficacy and Safety of Axitinib in Advanced RCC .. 28
Rationale................................................................................................................ 29
4.2
Rationale for the Trial and Selected Subject Population .................................... 29
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 33
4.2.2
4.2.2.1
Rationale for Dose Selection / Regimen for the Experimental Arm ........... 33
4.2.2.2
Rationale for the Choice of Comparator...................................................... 34
Rationale for Endpoints ...................................................................................... 34
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 34
4.2.3.2
Safety Endpoints.......................................................................................... 35
4.2.3.3
Health-related Quality of Life Endpoints .................................................... 35
4.2.3.4
Rationale for Planned Exploratory Biomarker Research............................. 36

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4.2.3.5
Future Biomedical Research........................................................................ 38
Benefit/Risk ........................................................................................................... 38
4.3
5.0
METHODOLOGY ................................................................................................... 39
Entry Criteria........................................................................................................ 39
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 39
5.1.1
Subject Inclusion Criteria.................................................................................... 39
5.1.2
Subject Exclusion Criteria .................................................................................. 41
5.1.3
Trial Treatment(s) ................................................................................................ 44
5.2
Dose Selection .................................................................................................... 45
5.2.1
Dose Modification .............................................................................................. 45
5.2.2
5.2.2.1
Dose Modification and Toxicity Management Guidelines for Adverse 
Events Potentially Associated with Pembrolizumab Treatment.................. 45
5.2.2.2
Dose Modification Guidelines for Adverse Events Potentially 
Associated with Axitinib Treatment............................................................ 50
5.2.2.3
General Guidance on Evaluation and Management of AEs Potentially 
Associated with Either Pembrolizumab Axitinib or Both in the 
Combination Arm ........................................................................................ 54
5.2.2.3.1
Evaluation and management of ALT/AST elevations during 
axitinib and pembrolizumab combination therapy ............................... 55
5.2.2.4
Dose Modification Guidelines for Adverse Events Potentially 
Associated with Sunitinib Treatment........................................................... 59
Timing of Dose Administration .......................................................................... 61
5.2.3
5.2.3.1
Pembrolizumab Administration................................................................... 62
5.2.3.2
Axitinib Administration............................................................................... 62
5.2.3.3
Sunitinib Administration.............................................................................. 62
5.2.3.4
Dosing Schedules with Study Treatment Interruptions ............................... 63
Trial Blinding...................................................................................................... 64
5.2.4
Randomization ...................................................................................................... 64
5.3
Stratification.......................................................................................................... 64
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 65
5.5
Acceptable Concomitant Medications ................................................................ 65
5.5.1
5.5.1.1
Caution Use of Inhibitors and Inducers of CYP Enzymes (Axitinib) ......... 66
5.5.1.2
Caution Use of Inhibitors and Inducers of CYP Enzymes (Sunitinib)........ 66
5.5.1.3
Hematopoietic Growth Factors.................................................................... 67

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Concomitant Surgery .......................................................................................... 67
5.5.2
5.5.2.1
Axitinib ........................................................................................................ 67
5.5.2.2
Pembrolizumab ............................................................................................ 68
5.5.2.3
Sunitinib....................................................................................................... 68
Prohibited Concomitant Medications.................................................................. 68
5.5.3
Rescue Medications & Supportive Care............................................................. 69
5.6
Management of Treatment-emergent Hypertension ........................................... 69
5.6.1
General Supportive Care Guidelines................................................................... 69
5.6.2
Diet/Activity/Other Considerations..................................................................... 70
5.7
Diet...................................................................................................................... 70
5.7.1
Contraception...................................................................................................... 70
5.7.2
Use in Pregnancy ................................................................................................ 72
5.7.3
Use in Nursing Women....................................................................................... 72
5.7.4
Subject Withdrawal/Discontinuation Criteria................................................... 72
5.8
Discontinuation of Treatment ............................................................................. 72
5.8.1
Withdrawal from the Trial .................................................................................. 73
5.8.2
5.8.2.1
Lost to Follow-up......................................................................................... 73
Second Course Phase (Retreatment)................................................................... 74
5.8.3
Subject Replacement Strategy............................................................................. 75
5.9
Beginning and End of the Trial ........................................................................... 75
5.10
Clinical Criteria for Early Trial Termination ................................................... 75
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 76
Trial Flow Chart (Pembrolizumab in Combination With Axitinib)................ 76
6.1
Trial Flow Chart (Sunitinib)................................................................................ 81
6.2
Trial Flow Chart Second Course Phase (Retreatment) .................................... 86
6.3
7.0
TRIAL PROCEDURES ........................................................................................... 88
Trial Procedures ................................................................................................... 88
7.1
Administrative Procedures.................................................................................. 88
7.1.1
7.1.1.1
Informed Consent......................................................................................... 88
7.1.1.1.1
General Informed Consent.................................................................... 88
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 89
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 89

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7.1.1.3
Subject Identification Card .......................................................................... 89
7.1.1.4
Medical History ........................................................................................... 89
7.1.1.4.1
History of Renal Cell Carcinoma.......................................................... 89
7.1.1.5
Prior and Concomitant Medications Review............................................... 89
7.1.1.5.1
Prior Medications.................................................................................. 89
7.1.1.5.2
Prior Treatment Details for Renal Cell Carcinoma .............................. 90
7.1.1.5.3
Concomitant Medications..................................................................... 90
7.1.1.6
Subsequent Anti-Cancer Therapy Status ..................................................... 90
7.1.1.7
Assignment of Screening Number............................................................... 90
7.1.1.8
Assignment of Treatment/Randomization Number..................................... 90
7.1.1.9
Trial Compliance (Medication).................................................................... 90
Clinical Procedures/Assessments........................................................................ 91
7.1.2
7.1.2.1
Adverse Event Monitoring........................................................................... 91
7.1.2.2
Full Physical Examination........................................................................... 91
7.1.2.3
Directed Physical Exam............................................................................... 91
7.1.2.4
Vital Signs.................................................................................................... 92
7.1.2.5
12-Lead Electrocardiogram ......................................................................... 92
7.1.2.6
Karnofsky Performance Status .................................................................... 92
7.1.2.7
Tumor Imaging and Assessment of Disease................................................ 92
7.1.2.7.1
Tumor Imaging at Screening ................................................................ 93
7.1.2.7.2
Tumor Imaging During the Trial .......................................................... 93
7.1.2.7.3
End of Treatment and Follow-up Tumor Imaging................................ 95
7.1.2.7.4
Second Course (Retreatment) Tumor Imaging..................................... 95
7.1.2.7.5
RECIST 1.1 Assessment of Disease ..................................................... 95
7.1.2.7.6
irRECIST Assessment of Disease......................................................... 96
7.1.2.8
Patient-reported Outcomes........................................................................... 99
7.1.2.8.1
FKSI-DRS........................................................................................... 100
7.1.2.8.2
EORTC-QLQ-C30.............................................................................. 100
7.1.2.8.3
EuroQol EQ-5D-3L ............................................................................ 100
Laboratory Procedures/Assessments ................................................................ 101
7.1.3
7.1.3.1
Urine Pregnancy Test................................................................................. 101
7.1.3.2
Laboratory 
Safety 
Evaluations 
(Hematology, 
Chemistry, 
and 
Urinalysis).................................................................................................. 101

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7.1.3.3
Pharmacokinetic Evaluations/Anti-pembrolizumab Antibodies................ 103
7.1.3.4
Tumor Tissue Collection............................................................................ 103
7.1.3.5
Blood Collections for ctDNA, TCR, RNA, Plasma and Serum 
Biomarker Analyses................................................................................... 104
7.1.3.6
Planned Genetic Analysis Sample Collection............................................ 104
7.1.3.7
Future Biomedical Research Sample Collection ....................................... 104
Other Procedures............................................................................................... 104
7.1.4
7.1.4.1
Withdrawal/Discontinuation...................................................................... 104
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................. 105
7.1.4.2
Blinding/Unblinding .................................................................................. 105
7.1.4.3
Calibration of Equipment........................................................................... 105
Visit Requirements............................................................................................ 105
7.1.5
7.1.5.1
Screening.................................................................................................... 105
7.1.5.2
Treatment Period........................................................................................ 106
7.1.5.2.1
Second Course Phase (Retreatment Period) ....................................... 106
7.1.5.3
Post-Treatment........................................................................................... 106
7.1.5.3.1
End of Treatment ................................................................................ 106
7.1.5.3.2
Safety Follow-up Visit........................................................................ 106
7.1.5.3.3
Imaging Follow-up Visits ................................................................... 107
7.1.5.3.4
Survival Follow-up Visits................................................................... 107
7.1.5.4
Survival Status ........................................................................................... 107
Assessing and Recording Adverse Events ........................................................ 107
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor........................................................................................................ 108
Reporting of Pregnancy and Lactation to the Sponsor ..................................... 109
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................. 109
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................. 109
7.2.3.2
Events of Clinical Interest.......................................................................... 110
7.2.3.3
Protocol-specific Exceptions to Serious Adverse Event Reporting ..... 111
Evaluating Adverse Events ............................................................................... 111
7.2.4
Sponsor Responsibility for Reporting Adverse Events .................................... 114
7.2.5
TRIAL GOVERNANCE AND OVERSIGHT ................................................. 114
7.3
Scientific Advisory Committee......................................................................... 114
7.3.1

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Executive Oversight Committee ....................................................................... 114
7.3.2
Data Monitoring Committee ............................................................................. 114
7.3.3
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 114
Statistical Analysis Plan Summary ................................................................... 115
8.1
Responsibility for Analyses/In-house Blinding ................................................ 116
8.2
Hypotheses/Estimation ....................................................................................... 117
8.3
Analysis Endpoints ............................................................................................. 117
8.4
Efficacy Endpoints............................................................................................ 117
8.4.1
8.4.1.1
Primary....................................................................................................... 117
8.4.1.2
Secondary................................................................................................... 117
Safety Endpoints ............................................................................................... 118
8.4.2
Analysis Population ............................................................................................ 118
8.5
Efficacy Analysis Population............................................................................ 118
8.5.1
Safety Analysis Population ............................................................................... 118
8.5.2
Statistical Methods.............................................................................................. 118
8.6
Statistical Methods for Efficacy Analyses ........................................................ 118
8.6.1
8.6.1.1
Progression-free Survival........................................................................... 119
8.6.1.2
Overall Survival......................................................................................... 120
8.6.1.3
Objective Response Rate ........................................................................... 121
8.6.1.4
Duration of Response................................................................................. 121
8.6.1.5
Disease Control Rate.................................................................................. 121
8.6.1.6
Summary of Statistical Methods for Efficacy............................................ 122
Statistical Methods for Safety Analyses ........................................................... 122
8.6.2
Summaries of Demographic and Baseline Characteristics ............................... 124
8.6.3
Interim Analyses ................................................................................................. 124
8.7
Multiplicity .......................................................................................................... 127
8.8
Sample Size and Power Calculations ................................................................ 128
8.9
Subgroup Analyses and Effect of Baseline Factors.......................................... 129
8.10
Compliance.......................................................................................................... 129
8.11
Extent of Exposure.............................................................................................. 129
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 130
Investigational Product ...................................................................................... 130
9.1

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Packaging and Labeling Information ............................................................... 130
9.2
Clinical Supplies Disclosure............................................................................... 130
9.3
Storage and Handling Requirements................................................................ 130
9.4
Discard/Destruction/Returns and Reconciliation ............................................ 131
9.5
Standard Policies................................................................................................. 131
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 132
Confidentiality..................................................................................................... 132
10.1
Confidentiality of Data ..................................................................................... 132
10.1.1
Confidentiality of Subject Records ................................................................... 132
10.1.2
Confidentiality of Investigator Information...................................................... 132
10.1.3
Confidentiality of IRB/IEC Information........................................................... 133
10.1.4
Compliance with Financial Disclosure Requirements..................................... 133
10.2
Compliance with Law, Audit and Debarment ................................................. 133
10.3
Compliance with Trial Registration and Results Posting Requirements ...... 135
10.4
Quality Management System............................................................................. 135
10.5
Data Management............................................................................................... 135
10.6
Publications ......................................................................................................... 135
10.7
11.0
LIST OF REFERENCES....................................................................................... 138
12.0
APPENDICES......................................................................................................... 142
Merck Code of Conduct for Clinical Trials...................................................... 142
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research............................................................................................................... 144
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 148
Karnofsky Performance Status Scale Definitions Rating (%) Criteria......... 159
12.4
National Cancer Institute Common Terminology Criteria for Adverse 
12.5
Events................................................................................................................... 160
Abbreviations ...................................................................................................... 161
12.6
13.0
SIGNATURES......................................................................................................... 165
Sponsor's Representative ................................................................................... 165
13.1
Investigator.......................................................................................................... 165
13.2

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LIST OF TABLES
Table 1
Summary of Clinical Efficacy from Randomized Phase III Studies in First-line 
Advanced RCC....................................................................................................... 24
Table 2
Summary of Treatment-emergent AEs ≥ 20% (n, %) of All Causality.................. 31
Table 3
Laboratory Results (n, %) by Maximum CTCAE Grade (N = 52)......................... 32
Table 4
Adequate Organ Function....................................................................................... 40
Table 5
Trial Treatments...................................................................................................... 44
Table 6
Dose Modification and Toxicity Management Guidelines for irAEs Associated 
with Pembrolizumab............................................................................................... 46
Table 7
Pembrolizumab-Associated Infusion Reaction Dose Modification and 
Treatment Guidelines ............................................................................................. 49
Table 8
Dose Modification Guidelines for Drug-related AEs Potentially Associated 
with Axitinib Treatment......................................................................................... 51
Table 9
Axitinib Dose Levels .............................................................................................. 54
Table 10 Algorithms of decision on axitinib/ pembrolizumab rechallenge after recovery 
from drug-related ALT/AST elevation................................................................... 57
Table 11 Dose Modification Guidelines for AEs Potentially Associated with Sunitinib 
Treatment................................................................................................................ 59
Table 12 IMDC Risk Evaluation ........................................................................................... 65
Table 13 Imaging and Treatment After First Radiologic Evidence of PD ............................ 98
Table 14 Laboratory Tests ................................................................................................... 102
Table 15 Evaluating Adverse Events................................................................................... 112
Table 16 Censoring Rules for Primary and Sensitivity Analyses of PFS............................ 120
Table 17 Censoring Rules for DOR..................................................................................... 121
Table 18 Analysis Strategy for Key Efficacy Endpoints..................................................... 122
Table 19 Analysis Strategy for Safety Parameters .............................................................. 124
Table 20 Summary of Interim and Final Analyses Strategies ............................................. 125
Table 21 Product Descriptions............................................................................................. 130

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LIST OF FIGURES
Figure 1
Study Schema..................................................................................................... 21
Figure 2
Dose Interruption Scenarios in the Combination Arm ...................................... 63
Figure 3
Dose Interruption Scenarios for Sunitinib ......................................................... 64
Figure 4
Imaging and Treatment for Clinically Stable Subjects after First Radiologic 
Evidence of PD Assessed by the Site ................................................................ 99
Figure 5
Multiplicity Strategy........................................................................................ 127

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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
8.1
8.7
8.8
Statistical Analysis Plan 
Summary
Interim Analyses
Multiplicity
1) Revised assumptions on control arm 
median PFS and OS.
2) Revised IA1 trigger from 50% final 
OS events to once achieving 305 PFS 
events and 7 months of minimum follow 
up.
3) Added one interim analysis for PFS.
4) Initial alpha to PFS and OS changed 
from 0.1% and 2.4% to 0.2% and 2.3% 
respectively.
1) The revised assumptions for median PFS 
and OS on the control arm are based on 
emerging data (see Section 8.9).
2) The trigger for IA1 based on achieving a 
minimum of 305 PFS events and 7 months 
minimum follow up allows relatively 
mature PFS data and the timing is more 
predictable while the accrual of OS events 
is less predictable due to expected 
confounding factors. 
3) Addition of PFS IA is to have earlier 
chance of observing positive efficacy of 
PFS with relatively mature data.
4) Slightly higher alpha is reallocated to PFS 
to ensure adequate power for this important 
primary endpoint without compromising 
the power of OS.

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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
1.0
Trial Summary
The estimated duration of the trial was 
revised to 44 months.
To align with changes to the SAP.
1.0
Trial Summary
Added additional text to the following 
paragraph:  ‘After study treatment has been 
discontinued, AEs will be collected for 30 
days from the last dose “or until new anti-
cancer therapy is initiated, whichever is 
earlier”..; serious adverse events (SAEs) will 
be collected for … if the subject initiates a 
new anti-cancer therapy “prior to completing 
90 days of follow-up”…
To be consistent with other sections.
2.1
Trial Design 
The 3rd to last paragraph starting with “This 
trial will use a group-sequential design that 
includes…” is revised based on the updated 
statistical design and analysis from 8.1, 8.7,
and 8.8
See rationale provided in the Primary 
Reason for Amendment Table above. 
3.2
Secondary objectives 
Added new Objective (2):  To evaluate PFS 
rate per RECIST 1.1 as assessed by BICR at 
12, 18, and 24 months based on data 
adequacy; to evaluate OS rates at 12, 18, and 
24 months based on data adequacy.
Since 
study 
is 
evaluating 
a 
novel 
combination including immunotherapy, 
landmark analyses on PFS and OS are 
important to compare and characterize the 
tail of the curve.   
4.3
Benefit / risk
The first sentence of the first paragraph is 
updated based on current pembrolizumab 
approved indications and exposures
in 
clinical trials.  
Self-explanatory.

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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.2.2
Dose Modification
Table 6, for the irAE management with 
corticosteroid and/or other therapies for 
hypothyroidism, “liothyroinine” corrected to 
“liothyronine”.
Typographical error correction.
5.5.1.1
Caution Use of 
Inhibitors and Inducers 
of CYP Enzymes 
(Axitinib)
Added text indicating grapefruit or grapefruit 
juice 
increases
axitinib 
plasma 
concentrations and should be avoided.
Added per axitinib label
6.1
Trial Flow Chart 
(Pembrolizumab in 
Combination with 
Axitinib)
Footnote m and Footnote u- added text to 
read that KPS and safety labs would be 
collected at every cycle visit, starting from 
Cycle 2.
Typographical error correction to be 
consistent with the Trial Flow Chart
entries.
6.1, 6.2
2.1
Trial Flow Chart 
(Pembrolizumab in 
Combination With 
Axitinib) and Trial Flow 
Chart (Sunitinib)
Trial Design
Footnote q in both flow charts –added text in 
italics to the final sentence, now it reads: 
Bone scans must be performed for the 
confirmation of Complete Response (CR) for 
subjects with a positive bone scan at 
baseline.
In Section 2.1 8th paragraph, sentence also 
updated to clarify that bone scan for CR 
confirmation is only required for subjects 
with baseline positive bone scan. 
To clarify that for confirmation of 
Complete Response (CR), bone scan is 
only required for subjects who had 
positive bone scan at baseline.

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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
6.3
Trial Flow Chart Second 
Course Phase 
(Retreatment)
Hematology, Chemistry laboratory tests and 
KPS are collected at every cycle. Thyroid 
and urinalysis will continue to be collected at 
every other cycle, starting at Cycle 2, at 
treatment discontinuation and 30 days after 
discontinuation. No footnote changes are 
needed.
Protocol requires that chemistry and 
hematology laboratory test results need to 
be available prior to each pembrolizumab 
dosing.  This change clarifies that these 
are the only safety laboratory tests that 
need to be performed at each cycle visit 
during Second course phase. KPS is also 
added 
to 
have 
a 
complete 
safety 
assessment at each visit. INR is not 
required for every cycle visit as only 
pembrolizumab is administered at Second 
course phase.  
7.1.2.7.2
Tumor Imaging During 
the Trial
In the last sentence of the last paragraph, text 
in italics was added, now it reads: Bone 
scans must also
be performed for the 
confirmation of a CR for those subjects who 
have a positive bone scan at baseline.
See rationale for changes in 6.1 and 6.2 
footnote q. 
7.1.2.7.6
irRECIST Assessment 
of Disease
In Figure 4, timing of 3-5 business days for 
BICR email notice has been removed, now it 
reads: …YES = BICR provides email notice 
of verification of PD.
The timing for BICR email notice can 
only be approximated within 3 to 5 
business 
days 
therefore 
the 
actual 
timeframe is removed.
7.1.4.3
Calibration of 
Equipment
The word ‘critical’ has been removed from 
the title; bullets and text after the first 
paragraph are removed.
It is investigator and site’s responsibility 
for 
calibration 
and 
maintenance 
of 
study/trial equipment, which has already 
been stated in the first paragraph.

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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.2.3.3
Protocol-Specific 
Exceptions to Serious 
Adverse Event 
Reporting
In the first sentence of the first paragraph, 
“The Sponsor” has been changed to “The 
eDMC”, hence the new first sentence reads: 
“The 
eDMC 
will 
monitor 
unblinded 
aggregated efficacy endpoint events and
safety data to ensure the safety of the 
subjects in the trial.”    
Even though this is an open-label 
randomized study, the Sponsor will not 
look at the unblinded aggregated efficacy/ 
safety data until primary endpoints have 
been 
achieved 
or 
study 
has 
been
concluded.  
8.4.1.2
Secondary
For definition of disease control rate, SD has 
been changed to SD of ≥ 6 months.
This is a clinically meaningful SD.
8.5.2
Safety 
Analysis 
Population
Deleted the last sentence: “Details on the 
approach to handling missing data for safety 
analyses are provided in Section 8.6.2
Statistical Methods for Safety Analysis.
The sentence is no longer needed.
8.6.1.1
Progression-free
Survival
Added the estimation for landmark PFS 
rates. 
Updated the censoring rules for primary and 
sensitivity analyses of PFS.
To provide the statistical method for the 
added secondary objective on landmark 
PFS rates.
To be aligned with the recent changes in
the therapeutic standard PFS censoring
rules; the primary analysis closely follows
FDA guidance; and the first sensitivity
analysis closely follows the “intent-to-
treat (ITT) complete follow-up principle”.
8.6.1.2
Overall Survival
Added the estimation for landmark OS rates. To provide the statistical method for the 
added secondary objective on landmark 
OS rates.

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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
8.6.1.4
Duration of Response
Updated the censoring rules for primary and 
sensitivity analyses of DOR.
To be aligned with the updated censoring 
rule for PFS.
8.6.1.6
Summary of Statistical 
Methods for efficacy  
This is a new section header added after the 
first paragraph of previous section 8.6.1.5. 
In Table 18, header of the last column is 
changed from “missing data approach” to 
“missing data / censoring approach
The header was inserted to clarify the 
purpose for the table.  
8.6.2
Statistical Methods for 
Safety Analyses
Updated the criterion for Tier 2 safety events
and updated the list of additional events to be 
considered as Tier 2 or Tier 3 safety events.
Subjects enrolled in this study usually 
experience various adverse events of 
similar types, adverse events reported less 
frequent than in 10% or SAE, Grade 3-5 
events reported in less than 5% of subjects 
would obscure the assessment of overall 
safety profile and add little to meaningful 
interpretation.
8.7
Interim Analyses
Editorial changes in Table 20.
To be more aligned with text in Section 
8.7 and 8.8.
8.9
Sample Size and Power 
Calculations
Power statement is updated for PFS and OS 
endpoints.
Power statement has been changed using 
actual number of randomized subjects
with updated median assumptions in the 
control arm based on emerging data. 
8.10
Subgroup Analyses and 
Effect 
of 
Baseline 
Factors
Pre-specified each subgroup category and 
provided source where PD-L1 cutpoint has 
been selected.
To be more specific and clear.

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1.0 TRIAL SUMMARY
Abbreviated Title
Phase III trial of pembrolizumab plus axitinib vs. sunitinib monotherapy 
in advanced/metastatic renal cell carcinoma (mRCC)
Sponsor Product Identifiers
MK-3475
Pembrolizumab
Trial Phase
Phase III
Clinical Indication
Treatment of subjects with advanced/mRCC
Trial Type
Interventional
Type of control
Active control
Route of administration
Intravenous, oral
Trial Blinding
Unblinded Open-label
Treatment Groups

Pembrolizumab 200 mg every 3 weeks (Q3W) in combination 
with axitinib 5 mg twice daily (BID)

Sunitinib 50 mg once daily (QD) for 4 weeks and then off 
treatment for 2 weeks
Number of trial subjects
Approximately 840 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 
44 months from the time the first subject signs the informed consent 
until the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the informed consent form (ICF) through the final protocol-specified 
contact.  After a screening period of ≤ 28 days, each eligible subject
will first be stratified by the following two factors: 1) International 
mRCC Database Consortium (IMDC) risk categories (favorable vs.
intermediate vs. poor) and 2) geographic regions (North America vs. 
Western Europe vs. “Rest of the World”). After stratification, subjects 
will be randomized 1:1 to one of two treatment arms: Arm 1)
pembrolizumab in combination with axitinib or Arm 2) sunitinib 
monotherapy. 
Study treatments will continue until progressive disease (PD) is 
verified by blinded independent central review (BICR) or further 
confirmed by the investigator, unacceptable adverse events (AEs) or 
intercurrent illness prevents further administration of treatment, death 
or withdrawal of consent.
For the pembrolizumab plus axitinib arm, pembrolizumab will be 
administered for a maximum of 35 doses (approximately 2 years). If a 
subject remains progression-free after 35 doses of pembrolizumab, 
treatment with axitinib will be continued as monotherapy until PD is
BICR verified or further confirmed by the investigator.  In addition, if 1 of 
the 2 compounds needs to be discontinued because of toxicity or 
intolerance, treatment with the other compound as monotherapy will be 
continued until PD is BICR verified or further confirmed by the 
investigator. Subjects who stop pembrolizumab after 35 doses without 
PD or stop pembrolizumab due to having achieved a complete response 
(CR) may be eligible for a second course of pembrolizumab treatment for 
up to 17 additional doses (approximately 1 year) upon experiencing PD.
For both arms, in the event that a CR has been observed in a subject, 
study treatment may be discontinued at the discretion of the 
investigator after CR has been confirmed and after a minimum of 8
cycles (~ 24 weeks) of treatment with pembrolizumab plus axitinib or 
4 cycles (~ 24 weeks) of treatment with sunitinib.

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After study treatment has been discontinued, AEs will be collected for 
30 days from the last dose or until new anti-cancer therapy is initiated, 
whichever is earlier; serious adverse events (SAEs) will be collected 
for 90 days after the last dose of study treatment or for 30 days after 
the last dose of study treatment if the subject initiates a new anti-
cancer therapy prior to completing 90 days of follow up, whichever is 
earlier.
Subjects who discontinue study treatment for reasons other than BICR 
verified PD should continue with imaging assessments per the 
protocol defined schedule until: 1) PD is BICR verified or further 
confirmed by the investigator, 2) initiation of a new anti-cancer 
treatment, 3) death, 4) withdrawal of consent or 5) study conclusion or 
early termination, whichever occurs first.
Following verification or 
confirmation of PD, all subjects will be followed for survival (by 
phone contact or clinic visit) until death, withdrawal of consent, loss 
to follow-up, or until the study is concluded or terminated early, 
whichever comes first. 
A list of abbreviations used in this document can be found in Section 12.6.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a Phase III randomized, open-label, multicenter, global trial to evaluate the efficacy 
and safety of pembrolizumab in combination with axitinib versus sunitinib monotherapy as a 
first-line treatment for advanced/metastatic renal cell carcinoma (mRCC). The trial will be 
conducted in conformance with Good Clinical Practices (GCP). 
The study includes 2 primary objectives: 1) to compare progression-free survival (PFS) 
between the 2 treatment arms per Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST 1.1) [1] as assessed by blinded independent central imaging review (BICR) and 2) 
to compare overall survival (OS) between the 2 treatment arms. Key secondary objectives 
include comparison of objective response rate (ORR), duration of response (DOR), and 
disease control rate (DCR) per RECIST 1.1 as assessed by BICR, patient reported outcomes
(PROs), and safety and tolerability between the two treatment arms.
See Section 3 for a 
complete description of study objectives.  
Approximately 840 subjects will be enrolled into the study. Subjects must have measurable 
disease at baseline as assessed by the investigator/site radiologist per RECIST 1.1 and must 
provide an adequate tumor tissue sample in order to be eligible. See Section 5 for a complete 
list of study inclusion/exclusion criteria.
Randomization Ratio
1:1

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After a screening period of a maximum of 28 days, eligible subjects will first be stratified by
the following 2 factors: 1) the International Metastatic Renal Cell Carcinoma Database 
Consortium (IMDC) risk categories (favorable versus intermediate versus poor) [2, 3] and 2) 
geographic region (North America versus Western Europe versus “Rest of the World”).  
Subjects will then be randomized 1:1 into 1 of the following 2 treatment arms: 
Arm 1)
combination of pembrolizumab 200 mg administered intravenously (IV) 
every 3 weeks (Q3W) and axitinib 5 mg twice daily (BID) taken orally continuously
or 
Arm 2)
sunitinib monotherapy 50 mg daily (QD) taken orally for 4 weeks then off 
treatment for 2 weeks. 
Study treatments will continue until progressive disease (PD) is BICR-verified or further 
confirmed by the investigator, unacceptable adverse events (AEs) or intercurrent illness 
prevents further administration of treatment, death or withdrawal of consent. When a subject 
is first identified with PD by the investigator, the site will request PD to be verified by BICR. 
Subjects who are clinically stable may continue treatment while waiting for BICR 
verification. Progressive disease status may be further confirmed by subsequent scans at the 
site. Detailed descriptions of imaging-based disease assessments, PD verification by BICR, 
and PD confirmation at the site are provided in Section 7.1.2.7.2 and Section 7.1.2.7.6.
For the combination arm, pembrolizumab will be administered for a maximum of 35 doses. 
If a subject remains progression-free after 35 doses of pembrolizumab, treatment with 
axitinib will be continued as monotherapy until PD is verified by BICR or further confirmed
by the investigator.  In addition, if 1 of the 2 compounds needs to be discontinued because of
toxicity or intolerance, treatment with the other compound as monotherapy will be continued 
until PD is verified by BICR or further confirmed by the investigator. For both arms, in the 
event that a complete response (CR) has been observed in a subject, study treatment may be 
discontinued at the discretion of the investigator after the CR has been confirmed and after a 
minimum of 8 cycles of treatment (~24 weeks) in the pembrolizumab plus axitinib arm or 
4 cycles of treatment (~24 weeks) in the sunitinib arm have been received. Detailed criteria 
for study treatment discontinuation and re-treatment are described in Section 5.8.
During the treatment period, subjects will have routine clinical visits for administration of or 
obtaining study treatment, monitoring safety and well-being, and assessing changes in 
disease status. Key study safety assessments include physical examinations, vital signs, 
electrocardiography (ECG), hematology and chemistry laboratories, thyroid function testing
and urinalysis. At each visit, AEs and serious adverse events (SAEs) will be evaluated and 
graded per the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse 
Events (CTCAE), Version 4.0.  The doses of study treatment may be interrupted, reduced 
(only applicable for axitinib and sunitinib), or discontinued upon experiencing severe AEs in 
accordance with the dose modification guidelines for each study treatment (see Section 5.2.2 
for details). 
Study-scheduled imaging assessments for disease status include computed tomography (CT)
and/or magnetic resonance imaging (MRI) for chest, abdomen, and pelvis. These imaging 
assessments will be performed at baseline, after randomization at Week 12, then every 
6 weeks (Q6W) until Week 54, and every 12 weeks (Q12W) thereafter. Bone scans will be 
performed for all subjects at baseline.  If a subject has a positive bone scan at baseline, bone 

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scans after randomization will be performed at Weeks 18, 30, 42, and 54, and then every 
24 weeks (Q24W) thereafter. In addition, a bone scan is also required for confirmation of 
CR for subjects with a positive bone scan at baseline. Additional images for baseline and 
follow-up may be required if lesions outside the aforementioned regions are identified. See 
Sections 7.1.2.7.1 and 7.1.2.7.2 for details. 
Imaging assessments will be performed according to the aforementioned schedule regardless 
of study treatment status until PD is BICR verified or further confirmed by the investigator, 
initiation of another anti-cancer therapy, death, or withdrawal of consent. Subjects who 
discontinue study treatment for reasons other than BICR-verified PD should continue with 
imaging assessments per the protocol-defined schedule until PD is BICR-verified or further 
confirmed by the investigator, initiation of a new anti-cancer treatment, death, withdrawal of 
consent, or study conclusion or early termination, whichever occurs first.   
When a subject is first identified with PD by the investigator, the site will request PD to be 
verified by BICR. Subjects who are clinically stable may continue treatment while waiting 
for BICR verification. Progressive disease status may be further confirmed by subsequent 
scans at the site.  Detailed descriptions of imaging-based disease assessments, PD 
verification by BICR, and PD confirmation at the site are provided in Section 7.1.2.7.2 and 
Section 7.1.2.7.6. Confirmation scans for CR or partial response (PR) will be performed at 
the next scheduled imaging assessment. All disease assessment imaging scans must be 
submitted promptly for BICR review.
After verification or confirmation of PD, subjects may initiate any subsequent anti-cancer
treatment at the discretion of the treating physician and the subject per local standard of care.
Pembrolizumab will not be provided to subjects who progressed on the sunitinib arm. All 
subjects will be followed for survival (by phone contact or clinic visit) until death, 
withdrawal of consent, loss to follow-up, or until the study is concluded or terminated early, 
whichever comes first.
This trial will use a group-sequential design that includes 3 total analyses: 2 planned analyses 
for PFS (1 interim analysis and then final) and 3 planned analyses for OS (2 interim analyses
and final). The first interim analysis (IA1) will be performed after enrollment has been 
completed, once a minimum follow up of 7 months and a minimum of 305 PFS events by 
BICR have been achieved. At IA1, approximately 48% of the final required OS events
(~ 195 death events) are expected. The second interim analysis (IA2) will be performed when 
approximately 74% of the final required OS events (or 299 death events) have accrued. At 
IA2, final PFS analysis will also be performed if statistical significance of PFS has not yet 
achieved at IA1. The final OS analysis will be performed after a total of 404 death events 
have accrued. The study will conclude after the clinical cutoff for the final OS analysis has 
been achieved. Study assumptions, sample size calculations, and details and timing of 
interim and final analyses are described in detail in Section 8.0 – Statistical Analysis Plan 
(SAP).
The study will have an external Data Monitoring Committee (eDMC) to monitor safety 
during the course of the study, to evaluate efficacy and safety data at the interim analyses,
and to provide recommendations for the study in accordance with the eDMC charter and the 
SAP.

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Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Trial Diagram
2.2
The trial design is depicted in Figure 1.
1Subjects who discontinue study treatment for reasons other than BICR-verified PD should continue with 
imaging assessments per the protocol defined schedule until PD is BICR verified or further confirmed by 
investigator, initiation of a new anti-cancer treatment, death, withdrawal of consent or study conclusion or early 
termination, whichever occurs first.
Figure 1
Study Schema
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
In male/female adult subjects (≥18 years of age) with mRCC.
Primary Objective(s) & Hypothesis(es)
3.1
(1) Objective: To evaluate and compare PFS per RECIST 1.1 as assessed by BICR in 
subjects treated with pembrolizumab plus axitinib versus sunitinib monotherapy.
Hypothesis: The combination therapy of pembrolizumab plus axitinib is superior to 
sunitinib monotherapy with respect to PFS as assessed by BICR per RECIST 1.1.
(2) Objective:  To evaluate and compare OS in subjects treated with pembrolizumab plus
axitinib versus sunitinib monotherapy.
Hypothesis: The combination therapy of pembrolizumab plus axitinib is superior to 
sunitinib monotherapy with respect to OS.
Secondary Objective(s) & Hypothesis(es)
3.2
(1) Objective:  To compare ORR and DCR per RECIST 1.1 as assessed by BICR in 
subjects treated with a combination of pembrolizumab plus axitinib versus sunitinib 
monotherapy. DOR will also be evaluated.
Hypothesis: The combination therapy of pembrolizumab plus axitinib is superior to 
sunitinib monotherapy with respect to ORR as assessed by BICR per RECIST 1.1. 

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(2) Objective:  To evaluate PFS rate per RECIST 1.1 as assessed by BICR at 12, 18, and 
24 months based on data adequacy; to evaluate OS rates at 12, 18, and 24 months 
based on data adequacy. 
(3) Objective:  To evaluate and compare safety and tolerability profiles in subjects 
treated with pembrolizumab plus axitinib versus sunitinib monotherapy.
(4) Objective:  To compare time to deterioration (TTD) based on the Functional 
Assessment of Cancer Therapy Kidney Symptom Index—Disease-Related Symptoms 
(FKSI-DRS) scale in subjects treated with pembrolizumab plus axitinib versus 
sunitinib monotherapy.
(5) Objective: To assess the longitudinal score changes from baseline to 42 weeks as 
measured by European Organization for the Research and Treatment of Cancer 
(EORTC) QLQ-C30 global health status/quality of life scale. 
Exploratory Objectives 
3.3
(1) Objective: To evaluate PFS, ORR, DOR, and DCR per immune-related RECIST 
(irRECIST) as assessed by BICR in subjects treated with pembrolizumab plus axitinib 
or sunitinib monotherapy.
(2) Objective: To characterize utility in subjects using the European Quality of Life 
(EuroQol) EQ-5D-3L.
(3) Objective: To characterize the pharmacokinetics (PK) of pembrolizumab in subjects 
treated with pembrolizumab plus axitinib. 
(4) Objective: 
To identify molecular (genomic, metabolic and/or proteomic) 
determinants of response or resistance to pembrolizumab/axitinib treatments in this 
study, so as to define novel predictive and pharmacodynamic biomarkers and 
understand the mechanism of action of the pembrolizumab/axitinib combination.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab (MK-3475). Refer to the approved labeling for detailed 
background information on axitinib and sunitinib.
Disease Background: Advanced Renal Cell Carcinoma
4.1.1
Epidemiology and Disease Characteristics of RCC
4.1.1.1
Renal cell carcinoma accounts for 2% to 3% of all adult malignancies, representing 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 [4]. In the United States (US), the expected number of new cases 
and deaths from kidney and renal pelvis cancer in 2016 is 62,700 and 14,240, respectively 
[5]. 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, 

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translocation, and collecting duct tumors [6]. 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 [6].  
At the initial diagnosis, approximately 65% of patients have localized disease; 16% have
regional spread, and 16% have distant metastasis [5].  Recent epidemiologic data from the 
US indicates that the 5-year survival rate has improved over time. However, the 5-year 
survival rate for patients with distant metastasis is still considerably lower than that of 
localized disease (approximately 12% versus 92% respectively) [5]. The most important 
prognostic factors for survival include tumor stage, grade, degree of local extent, presence of 
regional nodal disease, and distant metastasis [6].
Current Treatment Options for Advanced RCC
4.1.1.2
Advanced RCC has previously been treated with immunotherapies such as interferon alpha 
(IFNα) and interleukin 2 (IL-2) with overall limited clinical activity. 
High-dose IL-2, 
however, had demonstrated durable responses in a small number of highly selected patients
in Phase II non-randomized trials. As a result, it received Food and Drug Administration 
(FDA) approval in 1976 for treating advanced RCC in selected patients [7].
Since 2005, a number of novel anti-cancer agents have been developed, which have
demonstrated significant improvement in clinical efficacy, with acceptable safety profiles in
patients with advanced RCC in large randomized Phase III trials. These agents include the 
vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs)
sunitinib, pazopanib, sorafenib, and axitinib, the anti-vascular endothelial growth factor
(VEGF) monoclonal antibody bevacizumab (given in combination with IFNα), and the 
mammalian target of rapamycin (mTOR) inhibitors, temsirolimus, and everolimus.
Table 1 summarizes the clinical efficacy of systemic treatments in patients with treatment-
naïve advanced RCC from randomized Phase III studies. 
Based on the results of the 
sunitinib versus IFNα trial, the pazopanib versus placebo trial, and the bevacizumab plus 
IFNα versus IFNα trial, sunitinib, pazopanib, and bevacizumab plus IFNα received approval 
from the FDA and European Medicines Agency (EMA) for the treatment of advanced RCC. 
Pazopanib has also demonstrated non-inferiority to sunitinib for PFS and with similar OS in a 
large randomized Phase III study using a non-inferiority design. Temsirolimus received 
regulatory approval as a first-line treatment for poor-risk patients with advanced RCC. 

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Table 1
Summary of Clinical Efficacy from Randomized Phase III 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 et al. NEJM 2007 [8]
Motzer et al. JCO 2009 [9]
Pazopanib vs.
Placebo (N = 233)
11.1 vs. 2.8a
22.9 vs. 20.5 
30 vs. 3a
Sternberg et al. JCO 2010 [10]
Sternberg et al. EJC 2013 [11]
Bevacizumab + IFNα
vs. IFNα (N = 649)
10.2 vs. 5.4a
23.2 vs. 21.3 
31 vs. 13a
Escudier et al. Lancet. 2007 [12]
Escudier et al. JCO 2010 [13]
Sunitinib vs. 
pazopanib (N =
1110)b
9.5 vs. 8.4 
29.3 vs.  28.4
24 vs. 31
Motzer et al. NEJM 2013 [14]
Axitinib vs. sorafenib 
(N = 288; 2:1 
randomization)
10.1 vs. 6.5 
Not reported
32 vs. 15a
Hutson et al. Lancet. 2013 [15]
Temsirolimus vs. 
IFNα (N = 416) c
5.5 vs. 3.1a
10.9 vs. 7.3a
8.6 vs. 4.8
Hudes et al. NEJM 2007 [16]
Abbreviations: EJC = European Journal of Cancer; IFNα = interferon alpha; JCO = Journal of Clinical Oncology;
NEJM = New England Journal of Medicine; ORR = objective response rate; OS = overall survival; PFS = progression-
free survival; RCC = renal cell carcinoma.
a. Results demonstrated statistically significant improvement of the testing arm versus the control arm. 
b. The sunitinib versus pazopanib study used a non-inferiority design which demonstrated that pazopanib was 
noninferior to sunitinib with the primary endpoint PFS meeting the predefined non-inferiority margin
c. OS was the primary endpoint for this study while other trials used PFS as the primary endpoint. This study enrolled 
a poor-risk population while other trials enrolled a majority of subjects with good or intermediate risks. 
Based on the data described above, the current recommendations by the National 
Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology 
(ESMO) for first-line treatment of advanced RCC include sunitinib, pazopanib, and
bevacizumab plus IFNα. Temsirolimus is recommended as a first-line treatment for patients 
with poor prognosis.  High-dose IL-2 and sorafenib are recommended for selected patients. 
In addition, NCCN also included axitinib as a treatment choice based on data from a Phase 
III randomized study of axitinib versus sorafenib in treatment-naïve patients in whom the 
primary endpoint PFS showed no difference between the 2 arms (10.1 months for axitinib 
versus 6.5 months for sorafenib (hazard ratio [HR] = 0.77; 95% confidence interval [CI]: 
0.56 to 1.05; not statistically significant). However, the ORR for axitinib was significantly
higher than that for sorafenib (32% versus 15%; one-sided P = 0.0006) [15]. 
Three TKIs have been evaluated as second- or third-line treatment for patients with advanced 
RCC:
Sorafenib was approved by the FDA for advanced RCC based on a Phase III randomized trial 
demonstrating improvement in PFS compared to placebo in patients having failed prior 
cytokine treatments. The efficacy results for sorafenib compared to placebo were: median
PFS 167 versus 84 days; HR: 0.44; P<0.00001; response rate (RR): 2% versus 0%; median 
OS: 17.8 versus 15.2 months, HR: 0.88; P = 0.146 [17].
Everolimus was approved by the FDA and EMA for the treatment of advanced RCC after 
failure of prior VEGF-targeted therapy based on a Phase III randomized trial demonstrating 
statistically significant improvement in PFS (median 4.9 months for everolimus versus 

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1.9 months for placebo; HR: 0.33 [0.25 to 0.43]; P<0.0001) but no OS benefit (median 
14.8 months for everolimus versus 14.4 months for placebo; HR: 0.87; P= 0.162) [18].  The 
ORR was 2% for everolimus and 0% for placebo [19]. 
Axitinib was evaluated in a phase III randomized study compared to sorafenib in 
advanced/metastatic RCC patients after failure of one prior anti-angiogenic agent. The 
primary endpoint of PFS was significantly improved in axitinib vs. sorafenib (median PFS 
6.7 vs. 4.7 respectively; HR: 0.665, 95% CI, 0.544 to 0.812, P < 0.0001). The secondary 
endpoint of ORR was also significantly higher in axitinib vs. sorafenib (19% vs. 
9% respectively, P = 0.0001). However, the final OS data showed no significant difference 
between the two arms; median OS was 20.1 months for axitinib vs. 19.2 months for sorafenib 
(HR: 0.969, 95% CI, 0.800 to 1.174, one-sided P = 0.3744). Based on these data, axitinib 
gained approval for use in advanced RCC patients after failure of one prior systemic 
treatment (FDA) [22] or after failure of sunitinib or cytokine therapy (EMA).  
Subsequent treatments following the failure of first-line therapy have been divided into
2 categories: 1) treatment choices after prior cytokine therapy and 2) treatment choices after 
prior targeted therapy. Axitinib, sorafenib, sunitinib, and pazopanib have demonstrated 
improved efficacy (PFS) in a cytokine failure population and hence, have been recommended 
by the NCCN and ESMO for use in this population. However, cytokine use in the first-line
setting has been diminishing in favor of the approved anti-angiogenic agents. The following 
treatments are recommended by NCCN and ESMO after prior targeted therapy: axitinib, 
everolimus, sorafenib, sunitinib, pazopanib, bevacizumab plus IFNα, temsirolimus and 
nivolumab.
Recently, nivolumab and cabozantinib have received approval by the FDA to treat patients 
with advanced RCC who have received prior anti-angiogenic therapy. 
Nivolumab is an immune checkpoint inhibitor targeting programmed cell death protein 1 
(PD-1). The approval was based on data from a randomized Phase III open-label study in 
patients with advanced RCC following prior treatment with targeted therapy. Nivolumab 
demonstrated statistically significant improvement in the primary endpoint of OS versus
everolimus during the planned interim analysis (median 25.0 months versus 21.8 months; 
HR: 0.73 (98.5% CI: 0.57 to 0.93; P=.002 met the pre-specified significance P≤.0148). The 
ORR was 25% for nivolumab versus 5% for everolimus (odds ratio 5.98; 95% CI: 3.68 to 
9.72; P<.001). PFS was not significantly improved with a median PFS 4.6 months for 
nivolumab versus 4.4 months for everolimus (HR: 0.88; 95% CI: 0.75 to 1.03; P=.11) [24].
Cabozantinib is a multi-target TKI targeting VEGFR, MET, and AXL. In a randomized 
Phase III trial versus everolimus in patients who failed prior to targeted therapy, cabozantinib
demonstrated significant improvement in the primary endpoint PFS (median 7.4 months
versus 3.8 months; HR: 0.58; 95% CI: 0.45 to 0.75; P<.001) and secondary endpoint ORR 
(21% versus 5%; P<.001). The final OS was significantly improved compared to everolimus 
(median 21.4 vs. 16.5 months; HR: 0.66; 95% CI: 0.53 to 0.83; P=.0003) [25, 26].

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Targeting PD-1 Immune Checkpoints for Cancer Treatments
4.1.1.3
The adaptive immune system plays a major role in controlling and eradicating cancer via a 
process called cancer immunosurveillance.  Cytotoxic T lymphocytes cells (CTLs, also 
called CD8+ or effector T-cells), which are central to responses within the adaptive 
immunity, can be activated and execute cell killing function upon recognizing tumor-specific 
or tumor-associated antigens presented by antigen presenting cells (APCs) [27, 28, 29].
T-cell activation is tightly controlled by co-stimulatory and co-inhibitory signals which are 
triggered by the interactions between T-cell receptors (TCRs) and their ligands. 
The 
inhibitory pathways, also called immune checkpoints, are crucial for maintaining self-
tolerance and minimizing collateral tissue damage in the event of immune response to 
pathogens. 
Programmed cell death protein 1 (PD-1) is a member of the extended 
CD28/CTLA4 family of T-cell regulators and PD-1-mediated immune checkpoint plays a 
key role in controlling effector T-cell activities within peripheral tissues, including tumors. 
Binding of PD-1 to its ligands programmed death-ligand 1 (PD-L1) and/or programmed 
death-ligand 2 (PD-L2) will trigger downstream signaling inside T-cells leading to decreased 
production of cytokines such as IL-2 and interferon γ, inhibition of cell proliferation, reduced 
T-cell effect or function and survival [27, 30, 31, 32].  PD-L1 was found expressed on the 
surface of many human cancer cells including RCC; and PD-L1 expression by tumor cells 
was found associated with poor prognosis in several cancers including RCC [33].  
Human cancer can exploit immune checkpoint pathways to escape immunosurveillance. 
Restoration of endogenous anti-cancer immunity by immune checkpoint blockade has thus 
become an attractive strategy of cancer immunotherapy. 
The success in the clinical 
development of immune checkpoint inhibitors has significantly changed the landscape of
cancer treatment [28, 29, 30, 34, 35, 36, 37].
Pharmaceutical and Therapeutic Background
4.1.2
Anti-PD-1 Antibody Pembrolizumab 
4.1.2.1
Pembrolizumab is a highly selective and potent humanized monoclonal antibody of the 
IgG4/kappa isotype which is designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2. 
This blockade enhances functional activity of the target 
lymphocytes to facilitate tumor regression and ultimately immune rejection.
As of 
September 2015, the safety and clinical activity of pembrolizumab have been evaluated in 
over 12,000 patients across multiple tumor types via clinical trials and the Melanoma 
Expanded Access Program. Pembrolizumab was generally well tolerated. As of December 
2015, pembrolizumab monotherapy has received full approval from the FDA and EMA for 
the treatment of patients with unresectable or metastatic melanoma, and it has received 
accelerated approval for treating patients with metastatic non-small cell lung cancer 
(NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test and who 
have disease progression on or after platinum-containing chemotherapy. The recommended 
dose for these 2 indications is 2 mg/kg Q3W [38]. 

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Summary of Pembrolizumab Clinical Efficacy and Safety 
4.1.2.2
Refer to the pembrolizumab IB/approved labeling for details regarding pembrolizumab 
preclinical and clinical pharmacology studies as well as clinical safety.
Pembrolizumab clinical activity in advanced melanoma 
In study KEYNOTE-001 (KN001), the Phase I first-time-in-human study, pembrolizumab 
was evaluated in a cohort of 135 subjects with advanced melanoma who were either 
treatment-naïve (31%) or had progressed from prior ipilimumab (69%), at a dosage of 
2 mg/kg Q3W, 10 mg/kg every 2 weeks (Q2W), or 10 mg/kg Q3W. The study showed an 
ORR of 38% (95% CI: 25% to 44%) in the overall population. Response was durable in the 
majority of subjects; median DOR was not reached with median follow up of 11 months [39]. 
In an expansion cohort, 173 subjects with advanced melanoma who had progressed from 
prior ipilimumab were randomly assigned to receive pembrolizumab 2 mg/kg Q3W or 
10 mg/kg Q3W. Similar efficacy results were observed in the 2 arms: ORR was 26% in each 
arm; DCR was 51% and 50%, respectively. With a median follow up of 8 months, 88% of 
responders were still ongoing at the clinical cutoff. 
Even though most responses were 
observed at the first scan, initial response could occur as late as 11 months and CR could 
occur as late as 16 months [40]. 
Clinical efficacy of pembrolizumab in advanced melanoma was further demonstrated in
2 large randomized trials. In study KEYNOTE-002 (KN002) (N = 540), the efficacy and 
safety of pembrolizumab 2 mg/kg Q3W or 10 mg/kg Q3W were compared with 
chemotherapy in subjects refractory to ipilimumab. 
The 6-month PFS rates were 
significantly improved in the 2 pembrolizumab arms compared with the chemotherapy arms. 
The ORR per independent review was 21% in the pembrolizumab 2 mg/kg Q3W arm and
25% in the 10 mg/kg Q3W arm compared to 4% in the chemotherapy arm (P<0.0001 for 
both comparisons). At the time of analysis, median DOR in the pembrolizumab arms was 
not reached; responses were ongoing in 92% and 87% of responders in the 2 pembrolizumab 
arms, respectively, versus 63% in the chemotherapy arm.
There was no statistically 
significant difference in efficacy parameters between the 2 pembrolizumab arms [41]. 
In the Phase III Study KEYNOTE-006 (KN006) (N = 834, unresectable advanced melanoma
population), subjects were randomized in a 1:1:1 ratio to receive pembrolizumab at 10 mg/kg 
Q2W, 10 mg/kg Q3W, or ipilimumab at 3 mg/kg Q3W.  Subjects who received 
pembrolizumab (10 mg/kg Q2W or 10 mg/kg Q3W) showed statistically significant and 
clinically meaningful improvement compared to those who received ipilimumab in the 
estimated 6-month PFS rate (47.3%, 46.4% and 26.5%, respectively), one-year OS rate 
(74.1%, 68.4%,
and 58.2%, respectively), and ORR (33.7%, 32.9%,
and 11.9%, 
respectively). At the time of analysis, median OS was not reached in any treatment group. 
Responses were ongoing in 89.4% and 96.7% of the Q2W and Q3W pembrolizumab-treated 
groups, respectively, and in 87.9% of ipilimumab-treated patients after a median follow up of 
7.9 months [42].
Pembrolizumab clinical activity in advanced NSCLC 
In study KN001, clinical efficacy and safety were evaluated in 495 subjects with NSCLC
after receiving pembrolizumab treatment at 2 mg/kg Q3W, 10 mg/kg Q3W, or 10 mg/kg 
Q2W. The study also evaluated the association between PD-L1 expression in tumor tissue 

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samples and the clinical efficacy by assigning 182 subjects to the training set and 
313 subjects to the validation set.  In the overall population (N = 495), ORR was 19.4% 
(95% CI: 16.0 to 23.2) and median DOR was 12.5 months. In the validation data set, ORR
was 45.2% (95% CI: 33.5 to 57.3) in subjects with ≥ 50% of tumor cells positive for PD-L1 
expression (n = 73); ORR was 16.5% (95% CI: 9.9 to 25.1) in patients with 1% to 49% 
tumor cells positive (n = 103) and 10.7% (95% CI: 2.3 to 28.2) in patients with <1% tumor 
cells positive (n = 28) for PD-L1 expression. These data indicate a potential for PD-L1 to be 
used as a patient enrichment biomarker for better clinical efficacy [43].
Pembrolizumab clinical activity in other advanced cancers 
Study KEYNOTE-012 (KN012) is an ongoing non-randomized, multi-cohort, Phase Ib study 
to evaluate the safety and clinical activity of pembrolizumab 10 mg/kg Q2W in subjects with 
advanced solid tumors that have positive PD-L1 expression either in tumor cells or stroma 
cells. Most of these subjects were heavily pretreated. Subjects with advanced gastric cancer, 
head and neck cancer, urothelial tract cancer, and triple negative breast cancer were enrolled.  
An ORR of 31% was observed in subjects with advanced gastric cancers (N = 39) [44]; an 
ORR of 27.6% (95% CI: 12.7 to 47.2%) was observed in subjects with advanced urothelial 
tract cancer (N = 33) [45]; an ORR of 24.8% (95% CI: 17.3 to 33.6%) was observed in 
subjects with advanced head and neck cancer (N = 132) [46]. Impressive responses have also 
been reported by Nanda et al., in triple negative breast cancer at the 2014 San Antonio Breast 
Cancer Symposium [47]. In all these cohorts, durable responses were observed in those who 
responded including some durable stable diseases (SDs). Higher PD-L1 expression seemed 
to be associated with higher response.  
Axitinib 
4.1.2.3
Axitinib (INLYTA, AG-013736) is an oral, small molecule, TKI selective for VEGFRs 1, 2 
and 3 and is approved multinationally for the treatment of advanced RCC after failure of 1
prior systemic therapy (actual indication varies according to region/country). 
Axitinib is an ATP-competitive inhibitor that binds to the unphosphorylated (non-activated) 
“DFG-out” conformation of the catalytic domain of a receptor tyrosine kinase.  In enzymatic 
assays, axitinib was found to be highly potent (Ki = 28 picomolar) against the kinase activity 
of juxta-membrane domain containing human VEGFR 2 recombinant protein. In additional
kinase assays, axitinib showed potent and ATP-competitive inhibition of the VEGFRs 1, 2, 3 
and PDGFR-, but not other closely-related family kinases.  Receptor binding studies and 
cell-based assays, confirmed that axitinib is a potent and selective inhibitor of VEGFRs 1, 2 
and 3.  Axitinib was shown to have antiangiogenic activity in a number of models, including 
a spontaneous pancreatic islet-cell tumor of RIP-TAG-2 transgenic mice model, and 
demonstrated anti-tumor efficacy including marked cyto-reductive anti-tumor activity in 
multiple tumor models implanted in athymic mice. 
Summary of Clinical Efficacy and Safety of Axitinib in Advanced RCC  
4.1.2.4
Axitinib monotherapy has been evaluated in advanced RCC in 2 randomized Phase III trials. 
The Phase III study of axitinib versus sorafenib in advanced RCC patients who failed prior 
systemic treatments demonstrated a statistically significant advantage for axitinib over 
sorafenib for the primary PFS endpoint (median PFS 6.7 months versus 4.7 months; HR: 

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0.67; 95% CI: 0.54 to 0.81; P<.0001) but not OS (median 20.1 months for axitinib vs.
19.2 months for sorafenib; HR: 0.969; 95% CI: 0.800 to 1.174; one-sided P=.3744) and has 
been approved by the FDA and EMA for treating advanced RCC after failure of prior 
treatment [20, 21]. The most common (20%) adverse reactions observed in this study 
following treatment with axitinib were diarrhea, hypertension, fatigue, decreased appetite, 
nausea, dysphonia, hand-foot syndrome, decreased
weight, vomiting, asthenia, and 
constipation [20].
The Phase III study of axitinib vs. sorafenib in treatment-naïve advanced clear cell RCC had 
a 2:1 randomization (axitinib N=192, sorafenib N=96).  There was no significant difference 
in median PFS between subjects treated with axitinib or sorafenib; 10.1 months (95% CI 7.2,
12.1) vs. 6.5 months (95% CI 4.7, 8.3), respectively, with stratified hazard ratio 0.77, (95% 
CI 0.56, 1.05).  The ORR in the axitinib arm (32%) was statistically significant compared to 
the sorafenib arm (15%) as assessed by an Independent Review Committee, with a risk ratio
of 2.21, (95% CI 1.31, 3.75, stratified one sided P=0.0006) [15].  Based on this data, axitinib 
was recommended by NCCN as a first-line treatment choice for advanced RCC [6]. The most 
common AEs (≥20%) observed with axitinib were diarrhea, hypertension, weight decrease, 
fatigue, decreased appetite, hand-foot syndrome, dysphonia, asthenia, hypothyroidism and 
nausea [15].  
Overall, the AEs reported for axitinib in clinical studies were considered manageable and 
generally reversible.  Further details on clinical pharmacology and safety can be found in the 
axitinib label [22, 23].
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
In this study, we will evaluate a novel drug combination including an effective 
anti-angiogenic agent axitinib and a PD-1 immune checkpoint inhibitor pembrolizumab in as 
a first-line treatment for advanced RCC. The rationale is as follows: 
1. Advanced RCC remains an area with unmet medical need. Even though 
VEGF/VEGFR targeting anti-angiogenic agents, such as sunitinib, pazopanib, 
axitinib, and bevacizumab plus IFNα, have collectively made substantial 
improvement in the outcome of advanced RCC patients, most patients will progress 
within 2 years following a standard first-line treatment.  As of now, the best median 
OS seen with first-line advanced RCC treatments in a population with good and 
intermediate prognosis was approximately 28 to 29 months as shown in the Phase III 
sunitinib versus pazopanib trial [14].  In a meta-analysis by Heng et al. [2] on 
645 patients who received first-line anti-VEGF/VEGFR agents including sunitinib, 
sorafenib, and bevacizumab within the US and Canada, the median survival was 
22 months. Based on Surveillance, Epidemiology, and End Results (SEER) data 
from 2004-2010, the 5-year survival rate of advanced RCC was only 12% [5]. 
Therefore, further development of novel agents with durable clinical benefit and 
curative effects is still highly needed for advanced RCC.  

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2. Axitinib, a potent VEGFR TKI, has established single agent clinical efficacy in 
advanced RCC.
Even though the Phase III randomized study of axitinib versus
sorafenib in the first-line setting did not demonstrate statistically significant 
improvement in the primary endpoint of PFS for axitinib compared to sorafenib, the 
efficacy results of axitinib (PFS of 10.1 months and ORR of 32%) were comparable 
to that of other standard-of-care first-line agents (see Table 1). Therefore, axitinib 
has been listed as a choice of treatment by NCCN for treatment-naïve advanced RCC 
patients. Axitinib is an approved agent for advanced RCC patients who have failed a 
prior therapy [6].
3. RCC has long been considered an immune-reactive tumor based on anecdotal 
reports of spontaneous remissions in advanced RCC patients with evidence of 
antigen-specific lymphocyte infiltration of tumor tissues [48] and the fact that 
high-dose IL-2 could produce durable long-term response in a small subset of 
advanced RCC patients. In RCC, upregulation of PD-1 receptor on tumor-infiltrating 
lymphocytes and its ligand PD-L1 on tumors is associated with more aggressive 
disease and poor prognosis [32, 49]. The evidence above supports targeting RCC 
with an immunotherapeutic approach. Even though pembrolizumab monotherapy has 
not been evaluated in advanced RCC, single agent anti-tumor activity has been 
demonstrated by another anti-PD-1 antibody, nivolumab, in advanced RCC. In a 
Phase I study that included 33 heavily pretreated advanced RCC patients, ORR was 
achieved in 9/33 (27%) of patients with another 9 patients (27%) achieving stable 
disease at the 24-week follow-up. Five patients had durable responses longer than 
1 year [50]. 
4. Preliminary results from a Phase 1b study of pembrolizumab in combination 
with axitinib has shown promising efficacy results and an acceptable safety 
profile. Study KN035 (A4061079) is a Phase Ib study evaluating safety, PK and 
pharmacodynamics of axitinib in combination with pembrolizumab in treatment-
naïve advanced RCC patients. The study enrolled a total number of 52 subjects.  
Eleven subjects were enrolled in the initial dose finding phase in which axitinib 5 mg 
BID (administered orally) plus pembrolizumab 2 mg/kg Q3W (administered 
intravenously) were evaluated as the target dose level. Of these 11 subjects, the 
median age was 63 years, 8 were male and 9 had an Eastern Cooperative Oncology 
Group (ECOG) performance status of 0. Three dose-limiting toxicities (DLTs) were 
reported: transient ischemic attack in 1 subject and reduction in the dose of axitinib to 
<75% the target dose level in 2 subjects because of treatment-related toxicity. 
Axitinib 5 mg BID plus pembrolizumab 2 mg/kg Q3W were identified as the 
recommended doses for the expansion phase.
Following the dose finding stage, an additional 41 treatment-naïve advanced RCC patients 
were enrolled (last subject enrolled in September 2015). The safety of the entire study 
population (N = 52) is summarized here based on a data cutoff of March 2016 (data not 
published). The demographic features are typical for that of an advanced RCC population: 
median age was 63 years, 78.8% male and 86.5% white. All had an ECOG performance 
status of 0 and 1. Of the 52 patients, 12 had discontinued pembrolizumab treatment: 
7 (13.5%) due to AE, 4 (7.7%) due to PD, and 1 (1.9%) for other reasons; 14 had 
discontinued axitinib treatment: 8 (15.4%) due to AEs, 4 (7.7%) due to PD, 1 (1.9%) of each 

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due to patient refusal and other reasons. The median days on treatment by cutoff date was 
211 days. The incidences of AEs due to all causalities were: all-grade, 100%; Grade 4, 3.8%; 
Grade 3, 53.8%; Grade 2, 32.7% and Grade 1, 9.6%. There were no Grade 5 AEs. All-grade 
AEs ≥ 20% are displayed in Table 2. Most laboratory abnormalities were Grade 1 or 2 
(Table 3).
Table 2
Summary of Treatment-emergent AEs ≥20% (n, %) of All Causality
AE terms 
All Grades
Grade 1
Grade 2
Grade 3
Grade 4
Any AEs
52 (100)
5 (9.6)
17 (32.7)
28 (53.8)
2 (3.8)
Diarrhea 
37 (71.2)
26 (50.0)
8 (15.4)
3 (5.8)
0
Fatigue 
37 (71.2)
19 (36.5)
16 (30.8)
2 (3.8)
0
Dysphonia
22 (42.3)
20 (38.5)
2 (3.8)
0
0
Hypertension
19 (36.5)
2 (3.8)
7 (13.5)
10 (19.2)
0
Hypothyroidism
19 (36.5)
8 (15.4)
11 (21.2)
0
0
ALT increased
18 (34.6)
8 (15.4)
7 (13.5)
3 (5.8)
0
Decreased appetite
18 (34.6)
13 (25.0)
4 (7.7)
1 (1.9)
0
Hand-foot syndrome
18 (34.6)
5 (9.6)
12 (23.1)
1 (1.9)
0
Cough 
17 (32.7)
16 (30.8)
1 (1.9)
0
0
Nausea
17 (32.7)
12 (23.1)
4 (7.7)
1 (1.9)
0
AST increased
16 (30.8)
8 (15.4)
5 (9.6)
3 (5.8)
0
Arthralgia
14 (26.9)
9 (17.3)
5 (9.6)
0
0
Dizziness
12 (23.1)
11 (21.2)
0
1 (1.9)
0
Dyspnea
12 (23.1)
7 (13.5)
3 (5.8)
1 (1.9)
1 (1.9)
Headache
12 (23.1)
5 (9.6)
4 (7.7)
3 (5.8)
0
Oral pain
11 (21.2)
9 (17.3)
1 (1.9)
1 (1.9)
0
Proteinuria 
11 (21.2)
5 (9.6)
6 (11.5)
0
0
Weight decreased
11 (21.2)
7 (13.5)
2 (3.8)
3.8
0
Abbreviations: 
AE=adverse 
event; 
ALT=alanine 
aminotransferase; 
AST=aspartate 
aminotransferase.
Percentage is based on the number of patients receiving at least 1 dose of study treatment.

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Table 3
Laboratory Results (n, %) by Maximum CTCAE Grade (N = 52)
Lab parameters 
All grades
Grade 1
Grade 2
Grade 3
Grade 4
Hematology
Anemia
25 (48.1)
25 (48.1) 0
0
0
Hemoglobin 
increased
9 (17.3)
6 (11.5)
1 (1.9)
2 (3.8)
0
Lymphocyte 
count 
increased
3 (5.8)
0
1 (1.9)
2 (3.8)
0
Lymphopenia
25 (48.1)
8 (15.4)
13 (25.0)
4 (7.7)
0
Neutrophils 
count 
decreased
4 (7.7)
3 (5.8)
1 (1.9)
0
0
Platelets 
count 
decreased
13 (25.0)
11 (21.2) 2 (3.8)
0
0
White Blood Cells 
count decreased
6 (11.5)
5 (9.6)
1 (1.9)
0
0
Chemistry
ALT increased
27 (51.9)
19 (36.5)
6 (11.5)
2 (3.8)
0
Alkaline 
Phosphatase 
increased
16 (30.8)
16 (30.8)
0
0
0
AST increased
27 (51.9)
22 (42.3)
5 (9.6)
0
0
Bilirubin 
(Total) 
increased
10 (19.2)
5 (9.6)
2 (3.8)
3 (5.8)
0
Creatinine increased
45 (86.5)
38 (73.1)
5 (9.6)
0
2 (3.8)
Hypercalcemia
12 (23.1)
11 (21.2)
0
0
1 (1.9)
Hyperglycemia
45 (86.5)
30 (57.7)
14 (26.9)
1 (1.9)
0
Hyperkalemia
14 (26.9)
8 (15.4)
4 (7.7)
1 (1.9)
1 (1.9)
Hypermagnesemia
5 (9.6)
3 (5.8)
0
2 (3.8)
0
Hypernatremia
0
0
0
0
0
Hypoalbuminemia
12 (23.1)
12 (23.1)
0
0
0
Hypocalcemia
7 (13.5)
5 (9.6)
2 (3.8)
0
0
Hypoglycemia
6 (11.5)
5 (9.6)
1 (1.9)
0
0
Hypokalemia
8 (15.4)
7 (13.5)
0
1 (1.9)
0
Hypomagnesemia
4 (7.7)
3 (5.8)
1 (1.9)
0
0
Hyponatremia
23 (44.2)
19 (36.5)
0
4 (7.7)
0
Hypophosphatemia
12 (23.1)
1 (2.0)
8 (16.0)
3 (6.0)
0

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Preliminary unpublished efficacy data from these 52 patients showed an ORR of 67.3% 
(CR = 3.8%, PR = 63.5%); SD of 21.2%; PD of 3.8%, and 4 subjects (7.7%) with best 
response indeterminate.  
Based on the scientific rationale of targeting angiogenesis and immune-check point 
pathways, as well as the promising data from these 52 patients, further evaluation of the 
combination regimen of axitinib plus pembrolizumab is warranted. We expect that this novel 
combination may provide additional clinical benefit in advanced RCC compared to the 
current standard of care in the first-line setting.
Rationale for Dose Selection/Regimen/Modification
4.2.2
Rationale for Dose Selection / Regimen for the Experimental Arm
4.2.2.1
The following dose regimen is selected for the axitinib/pembrolizumab combination: 

Axitinib 5 mg BID dosed continuously 

Pembrolizumab 200 mg Q3W 
In the Phase Ib study KN035 (A4061079) that evaluated the combination of axitinib and 
pembrolizumab, axitinib 5 mg BID continuous dosing and pembrolizumab 2 mg/kg Q3W 
was determined as the recommended combination regimen (see Section 4.2.1). However, 
based on collective evidence, a flat dose of 200 mg Q3W has been determined for 
pembrolizumab used either as monotherapy or in combination regimens. 
Rationale for using 200 mg Q3W dose for pembrolizumab
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W.  The dose 
recently approved in the US and several other countries for treatment of melanoma is 
2 mg/kg Q3W.  Information on the rationale for selecting a 200 mg Q3W dose is summarized 
below.
An integrated body of evidence suggests that 200 mg Q3W is expected to provide similar 
response to 2 mg/kg Q3W, 10 mg/kg Q3W, and 10 mg/kg Q2W.  Previously, a flat 
pembrolizumab exposure-response relationship for efficacy and safety has been found in 
subjects with melanoma and NSCLC in the range of doses between 2 mg/kg and 10 mg/kg.  
Exposures for 200 mg Q3W are expected to lie within this range and will be close to those 
obtained with the 2 mg/kg Q3W dose.
A population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed.  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.  The distribution of exposures from the 200 mg fixed 
dose are predicted to considerably overlap with those obtained from the 2 mg/kg dose and 
importantly will maintain individual patient exposures within the exposure range established 
in melanoma and NSCLC as associated with maximal clinical response.  
In translating to other solid tumor indications, similarly flat exposure-response relationships 
for efficacy and safety as observed in subjects with melanoma and NSCLC can be expected, 
as the anti-tumor effect of pembrolizumab is driven through immune system activation rather 
than through a direct interaction with tumor cells, rendering it independent of the specific 

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tumor type.  In addition, available PK results in subjects 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 will simplify the dosing regimen to be more convenient for physicians 
and will reduce the potential for dosing errors.  A fixed dosing scheme will also reduce 
complexity in the logistical chain at treatment facilities and reduce wastage.  The existing 
data suggest that 200 mg Q3W is the appropriate dose for pembrolizumab.
Rationale for the Choice of Comparator
4.2.2.2
This study will evaluate the efficacy and safety of a novel combination of a VEGFR TKI 
axitinib and a PD-1 immune checkpoint inhibitor pembrolizumab in treatment-naïve 
advanced RCC. The NCCN and ESMO recommended standard treatment in this setting 
includes sunitinib, pazopanib, bevacizumab plus IFNα based on highly significant results 
from large Phase III randomized trials. Sunitinib is the most frequently used first-line 
treatment in advanced RCC and has a well characterized safety profile therefore sunitinib is 
selected as a control for the study. 
Rationale for Endpoints
4.2.3
Efficacy Endpoints
4.2.3.1
This is a pivotal Phase III randomized open-label study to evaluate the efficacy and safety of 
the combination of pembrolizumab plus axitinib compared with sunitinib monotherapy. The 
study includes dual primary efficacy endpoints: 1) PFS per RECIST 1.1 as assessed by BICR
and 2) overall survival.  
Progression-free survival has been used as an acceptable primary endpoint in randomized 
Phase III trials to support regulatory approval for new treatments in advanced RCC in both 
the first-line setting and in subjects who have failed prior treatments. In the first-line setting, 
all current approvals including sunitinib, pazopanib, and bevacizumab plus IFNα, but not
temsirolimus, were based on demonstrating a statistically significant and clinically 
meaningful improvement in PFS without demonstrating survival benefit. Temsirolimus was 
approved only for the poor risk group based on demonstrating survival benefit in this subset 
of patients. Agents approved for subsequent treatments in advanced RCC were also based on 
PFS, including axitinib, sorafenib, and everolimus. Therefore, PFS is included as a primary 
endpoint for the study. 
The primary analysis of PFS will be based on BICR in order to limit bias. Since this is an 
open-label study, measures have been taken to ensure that the central radiologist will be 
blinded to the treatment assignments of the subjects. In order to avoid PD being determined
prematurely by the investigator, subjects with suspected radiologic progression first 
identified at the site will have all scans submitted for BICR verification of PD. The results of 
central PD verification will be communicated to the site promptly.
Overall survival is the ultimate gold standard endpoint to demonstrate superiority of 
anti-cancer therapy. Given the list of available therapies for advanced RCC for treatment 
beyond first-line and that the study allows subjects to select any subsequent anti-cancer 
treatment upon progression, the OS assessment is likely to be confounded by subsequent 

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treatments. The Sponsor will ensure that adequate information on subsequent therapies is 
collected and analyses are included to evaluate the confounding issues. 
Secondary endpoints consist of ORR, DOR, and DCR per RECIST 1.1 as assessed by BICR.
Durable response has been demonstrated with pembrolizumab and other immune checkpoint 
inhibitors in subsets of patients in multiple tumor types and provides meaningful supportive 
evidence for clinical efficacy. 
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may 
produce antitumor effects by potentiating endogenous cancer-specific immune responses.  
The response patterns seen with such an approach may extend beyond the typical time course 
of responses seen with cytotoxic agents, and subjects may manifest a clinical response after 
an initial increase in tumor burden or even the appearance of new lesions.  Standard RECIST
1.1 may, thus, not provide an accurate response assessment of immunotherapeutic agents 
such as pembrolizumab. 
Based on an analysis of patients with melanoma enrolled in 
KEYNOTE-001, 7% of evaluable patients experienced delayed or early tumor 
pseudoprogression.  Of note, patients who had progressive disease by RECIST 1.1 but not by 
irRECIST had longer OS than patients with progressive disease by both criteria.  
Additionally, the data suggest that RECIST 1.1 may underestimate the benefit of 
pembrolizumab in approximately 15% of patients.  These findings support the need to apply 
a modification to RECIST 1.1 that takes into account the unique patterns of atypical response 
in immunotherapy and enables treatment beyond initial radiographic progression. 
irRECIST is RECIST 1.1 adapted to account for the unique tumor response seen with 
immuno-therapeutics as described in Nishino et al [51]. The assessment of unidimensional 
target lesions and response categories per irRECIST are identical to RECIST 1.1.  However, 
Merck has implemented an adaptation related to new lesions, non-target lesions, and tumor 
burden assessment in order to confirm radiographic progression. irRECIST will be used by 
local site investigators to assess tumor response and progression, and to make treatment 
decisions as well as by the BICR in support of the PFS, ORR, DOR, and DCR endpoints.
Safety Endpoints
4.2.3.2
The safety objective is to characterize the safety and tolerability of pembrolizumab in 
combination with axitinib in subjects with advanced mRCC as a first-line treatment.  The 
following safety parameters will be analyzed: AEs and SAEs graded per NCI CTCAE, 
Version 4.0 criteria with time to onset/recovery, causality and outcome; changes in 
laboratory values, vital signs since baseline, treatment discontinuations and reason for 
discontinuation, death and cause of death, etc.  Concomitant medications will be collected 
with time and reasons for use. These are routine safety parameters collected and analyzed in 
Phase II/III oncology trials. 
Health-related Quality of Life Endpoints
4.2.3.3
FKSI-DRS, EORTC-QLQ-C30, and EuroQol EQ-5D-3L are not pure efficacy or safety 
endpoints because they are affected by both disease progression and treatment tolerability. 

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The FKSI-DRS scale and global health status/quality of life scale from EORTC-QLQC30 are 
the key PRO endpoints. Although no formal hypothesis was formulated, the p-value on 
treatment comparisons will be provided. No multiplicity adjustment was performed.
The 9 items of the FKSI-DRS are summarized into a symptom scale ranging in score from 
zero (0) to thirty-six (36), with zero being the worst possible score and 36 being the best 
possible score [52]. The minimum important change in the FKSI-DRS used to define 
symptom progression is approximately a change of 2 points and that definition has been used 
for this mRCC symptom scale in other mRCC trials [19, 52, 53]. The Time-to-Deterioration 
of FKSI-DRS is defined as: 

The time to first onset of 2 or more decreases from baseline.

The time to first onset of 2 or more decrease from baseline and confirmed by the 
second adjacent 2 or more decrease from baseline.

The time to first onset of 2 or more decrease from previous nadir and confirmed 
by the second adjacent 2 or more decrease from nadir.
The longitudinal score changes of the EORTC QLQ-C30 global health status/quality of life 
scale 
(i.e., 
items 
29 
and 
30) 
from 
baseline 
and 
the 
proportions 
of 
deterioration/stable/improvement at 42 weeks (i.e., based on expected median PFS of 
11 months in the control group) into the study will be described. A 10-point decrease is often 
considered as the minimal clinical meaningful difference. Other supportive analyses include 
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 quality of life 
scale.
EuroQol EQ-5D-3L is another set of endpoints as a measure of health outcome. The EuroQol 
EQ-5D-3L will provide data for use in economic models and analyses including developing 
health utilities or quality-adjusted life years (QALYs).
Electronic patient-reported outcomes (PROs), in the order of FKSI-DRS, EORTC QLQ-C30 
and EuroQol EQ-5D-3L, will be completed by the patient prior to all other study procedures.
See the Trial Flow Chart (Section 6.0) as well as Section 7.1.2.8 for details on PRO 
administration and timepoints.
Rationale for Planned Exploratory Biomarker Research
4.2.3.4
CCI

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CCI

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Future Biomedical Research
4.2.3.5
The Sponsor will conduct Future Biomedical Research on specimens collected 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.
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 subjects. The objective of collecting 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 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of this Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
4.3
Pembrolizumab has received regulatory approval for multiple advanced cancer indications 
with more than 20,000 cancer participants having received pembrolizumab treatment in the 
clinical trial program as of 30-MAR-2017 [refer to pembrolizumab IB for up-to-date 
information]. Pembrolizumab has been established with a well-characterized safety profile.  
Pembrolizumab is well tolerated at doses up to 10 mg/kg Q2W and has demonstrated anti-
cancer clinical activity and efficacy in a broad range of cancer indications (see Summary in 
Section 4.1.2.2).  Axitinib is a VEGFR-TK inhibitor agent that has been approved for 
advanced RCC after a prior targeted therapy and has also been studied in treatment-naïve 
subjects with advanced RCC and shown acceptable efficacy (see Section 4.1.2.4).  The 
combination of pembrolizumab 2 mg/kg Q3W and axitinib 5 mg BID continuous dosing has 
demonstrated promising preliminary efficacy with an ORR of 67% and a safety profile 
consistent with a combined safety profile from each agent based on data from 52 treatment-
naïve advanced RCC patients (see Section 4.2.1 for further details).  As the efficacy and 
safety profile of the pembrolizumab plus axitinib combination has not yet been characterized 
in a larger data set, participating subjects may experience side effects not yet observed or 
they may not respond to the combination. However, such risks exist with current standard of 
care treatments. At present, there are no curative systemic treatments for advanced or 
metastatic RCC and only approximately 30% of patients develop objective responses to the 
CCI

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current standard of care treatments (see summary in Section 4.1.1.2 and Table 1), all of 
which may cause severe side effects as described in the label for each drug.
Sunitinib has been approved by regulatory agencies globally for the treatment of advanced 
RCC and has been recommended as a choice of first-line treatment for advanced RCC by 
NCCN and ESMO guidelines (see Section 4.1.1.2). 
Additional details regarding specific benefits and risks for subjects participating 
pembrolizumab clinical trial may be found in the accompanying IB and Informed Consent 
documents.  Efficacy and safety risk information for using sunitinib and axitinib can also 
been found in the current label of each drug.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/female adult (≥18 years) subjects with mRCC will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial.  The subject 
may also provide consent for future biomedical research.  However, the subject may 
participate in the main trial without participating in future biomedical research.
2. Be ≥18 years of age on day of signing informed consent.
3. Have histologically confirmed diagnosis of RCC with clear cell component with or 
without sarcomatoid features.
4. Have locally advanced/metastatic disease, ie, newly diagnosed Stage IV RCC per 
American Joint Committee on Cancer or have recurrent disease. 
5. Have measurable disease per RECIST 1.1 as assessed by the investigator /site 
radiologist.  Lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.
6. Have received no prior systemic therapy for advanced RCC.
7. Have provided archival tumor tissue sample or newly obtained core or excisional 
biopsy of a tumor lesion as required. 
Lesions cannot be previously irradiated. 
Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.
Note: Tumor blocks are preferred over cut slides. Please refer to the Study Procedures 
Manual for important details regarding tumor tissue submission time window and 
process.
8. Have Karnofsky performance status (KPS) ≥70% as assessed within 10 days prior to 
randomization (see Section 12.4 for KPS description). 

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9. Subjects receiving bone resorptive therapy (including but not limited to 
bisphosphonate or RANK-L inhibitor) must have therapy initiated at least 2 weeks 
prior to randomization.
10. Demonstrate adequate organ function as defined in Table 4 and all screening 
laboratory tests should be performed within 10 days prior to randomization. 
Table 4
Adequate Organ Function 
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mm3 or ≥ 1.5 × 109 / L 
Platelets
≥100,000 / mm3 or ≥ 100 ×109 / L
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L– without a red blood 
cell transfusion within 2 weeks of the 
screening test
Renal
Serum creatinine 
OR
calculated creatinine clearance
(CrCl)a Note: GFR can also be used 
in place of creatinine or CrCl
≤1.5 × upper limit of normal (ULN) 
OR
≥40 mL/min for subjects with creatinine 
levels > 1.5 ×institutional ULN
Urine protein 
< 2+ by dipstick urinalysis 
If dipstick is ≥2+, then 24 hr urine protein 
must be < 2 g, or urine protein creatinine 
ratio (UPC) must be  < 2 
Hepatic
Serum total bilirubin
≤ 1.5 × ULN OR
Direct bilirubin ≤ ULN for subjects 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 subject 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;.
a Creatinine clearance should be calculated per institutional standard.
11. Female subjects of childbearing/reproductive 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.
Note, in the event that 72 hours have elapsed between the screening pregnancy test 
and the first dose of study treatment, another pregnancy test (urine or serum) must be 
performed and must be negative in order for subject to start receiving study 
medication.

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12. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception, for 
the course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
13. Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 5.7.2- Contraception, starting with the first dose 
of study therapy through 120 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating in or has participated in a study of an investigational agent 
or has used an investigational device within 4 weeks prior to randomization.
2. Has had major surgery within 4 weeks, received radiation therapy within 2 weeks
prior to randomization, or has not recovered (i.e., ≤Grade 1 or at baseline) from AEs
due to prior treatment.
3. Has had prior treatment with any anti-PD-1, or PD-L1, or PD-L2 agent or an antibody 
targeting any other immune-regulatory receptors or mechanisms. Examples of such 
antibodies include (but are not limited to) antibodies against IDO, PD-L1, IL-2R, and 
GITR.
4. Has received prior systemic anti-cancer therapy for RCC (e.g., VEGF/VEGFR, 
chemotherapy or mTOR-targeting agents). 
Note: 
Prior neoadjuvant/adjuvant therapy for RCC is acceptable if completed 
> 12 months prior to randomization.
5. Has a history of severe hypersensitivity reaction (e.g., generalized rash/erythema, 
hypotension, bronchospasm, angioedema, or anaphylaxis) to axitinib or sunitinib.
6. Has a diagnosis of immunodeficiency OR is receiving a systemic steroid therapy
exceeding physiologic corticosteroid dose or any other form of immunosuppressive 
therapy within 7 days prior to randomization, except in the case of central nervous 
system (CNS) metastases (see exclusion 9).  
7. Has an active autoimmune disease requiring systemic treatment within the past 
2 years
(i.e., 
with 
use 
of 
disease-modifying 
agents, 
corticosteroids,
or 
immunosuppressive drugs) OR with a documented history of clinically severe 
autoimmune disease.

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Note: Subjects with vitiligo, Sjögren’s syndrome, Type 1 diabetes, or resolved 
childhood asthma/atopy will not be excluded from the study.  Subjects requiring
intermittent use of bronchodilators, inhaled steroids, or local steroid injections will 
not be excluded from the study.  Subjects with hypothyroidism, or adrenal or pituitary 
insufficiency who are stable on hormone replacement will not be excluded from the 
study. 
8. Has a known additional malignancy that has progressed or has required active 
treatment in the last 3 years.  
Note:  Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
superficial bladder cancer, or carcinoma in situ such as breast cancer in situ are 
acceptable if they have undergone potentially curative therapy. 
9. Has known active CNS metastases and/or carcinomatous meningitis. Subjects with 
previously treated brain metastases may participate provided they are radiologically
stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging 
(note that the repeat imaging should be performed during study screening), clinically 
stable and without requirement of steroid treatment for at least 14 days prior to 
randomization.
10. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has a known history of Human Immunodeficiency Virus (HIV) infection (HIV 1
and/or 2 antibodies).  
Note: HIV 1 and/or 2 antibodies testing is required when the investigator has reason 
to suspect the subject has HIV infection or is otherwise mandated per local guidance.
13. Has a known history of Hepatitis B (eg, Hepatitis B surface antigen [HBsAg]
reactive) or known active Hepatitis C virus (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.
14. Has received a live virus vaccine within 30 days of randomization (See Section 5.5.3
for further detail).
15. Has a clinically significant gastrointestinal (GI) abnormality including:

Malabsorption, total gastric resection, or any other condition that might affect 
the absorption of orally taken medication 

Active GI bleeding, as evidenced by hematemesis, hematochezia or melena in 
the past 3 months without evidence of resolution documented by endoscopy or 
colonoscopy

Intraluminal metastatic lesion with suspected bleeding, inflammatory bowel 
disease, ulcerative colitis or other GI condition associated with increased risk 
of perforation

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16. Has QT interval corrected for heart rate (QTc) ≥ 480 msec.
17. Has a history of any of the following cardiovascular conditions within 12 months of 
randomization:

Myocardial infarction

Unstable angina pectoris

Cardiac angioplasty or stenting

Coronary/peripheral artery bypass graft

Class III or IV congestive heart failure per New York Heart Association 

Cerebrovascular accident or transient ischemic attack 
18. Has a history of deep vein thrombosis or pulmonary embolism within 6 months of 
screening.
19. Has poorly controlled hypertension defined as systolic blood pressure (SBP)
≥150 mm Hg and/or diastolic blood pressure (DBP) ≥ 90 mm Hg.
Note: measurement of screening blood pressure (BP) reading is based on an average 
of 3 readings at least 2 minutes apart. Subjects with initial screening BP ≥150/90 mm 
Hg can be treated with anti-hypertensive medication to achieve a well-controlled 
status and are eligible with reassessed SBP/DBP of < 150/90 mm Hg.
20. Has evidence of inadequate wound healing.
21. Has active bleeding disorder or other history of significant bleeding episodes within 
30 days of randomization. 
22. Has hemoptysis within 6 weeks prior to randomization.
23. Has current use (within 7 days of randomization) or anticipated need for treatment 
with drugs or foods that are known strong cytochrome P450 (CYP3A4/5) inhibitors 
including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, 
ketoconazole, 
nefazodone, 
nelfinavir, 
ritonavir, 
saquinavir, 
telithromycin, 
troleandomycin, voriconazole, and grapefruit or grapefruit juice.  
NOTE: The topical use of these medications, such as 2% ketoconazole cream, is 
allowed.
24. Has current use (within 7 days of randomization) or anticipated need for treatment 
with drugs that are known strong CYP3A4/5 inducers, including but not limited to 
carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s wort; or 
drugs that are known with proarrhythmic potential (see Section 5.5.3 for list of 
drugs).
25. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.

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26. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
27. Has had a prior solid organ transplant.
28. 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 trial treatment.
Trial Treatment(s)
5.2
The treatments to be used in this trial are outlined below in Table 5.  
Table 5
Trial Treatments
Treatment
Regimen
Route of 
Administration
Duration of treatment
Use in Study
Pembrolizumab/Axitinib Combination Arm
Pembrolizumab
200 mg every 
3 weeks (Q3W)
IV infusion
Up to 35 doses (about 24 
months) or until PD is BICR 
verified 
or 
further 
confirmed 
by 
the 
investigatora
Experimental
Axitinib
5 
mg 
twice 
daily (BID)
Orally (PO)
Continued treatment until 
PD
is BICR verified or 
further confirmed by the 
investigator
Experimental
Sunitinib Monotherapy Arm
Sunitinib
50 
mg 
daily 
(QD)
4 weeks on, 2 
weeks off
PO
Continued treatment until 
PD
is BICR verified or 
further confirmed by the 
investigator
Comparator 
(standard of care)
Abbreviations: BICR=blinded independent central review; BID=twice daily; IV=intravenous; PD=progressive 
disease; PO=per os/by mouth; Q3W=every 3 weeks.
a
Subjects in the pembrolizumab+axitinib arm may receive a second course of treatment with additional 17 
doses. Details are described in Section 5.8.2.  
Trial Treatment should begin within 3 days of randomization.
All supplies indicated in Table 5 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will 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.
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.

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Dose Selection
5.2.1
The rationale for selection of the doses for the pembrolizumab plus axitinib combination and 
the sunitinib monotherapy to be used in this trial is provided in Section 4.0, Background and 
Rationale.  Details on the preparation and administration of pembrolizumab are in the 
Pharmacy Manual.
Dose Modification
5.2.2
Every effort should be made to administer study treatments per the planned dosing schedule.
Dose modification guidelines for a particular study treatment are to be followed if AEs are 
assessed as associated or potentially associated with that study treatment. 
Dose Modification and Toxicity Management Guidelines for Adverse Events
5.2.2.1
Potentially Associated with Pembrolizumab Treatment
Dose modification and toxicity management for immune-related AEs (irAEs) associated 
with pembrolizumab
Adverse events 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 6.

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Table 6
Dose Modification and Toxicity Management Guidelines for irAEs 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 corticosteroid should be initiated first followed by oral steroid. 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 
GI 
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
Type 1 diabetes 
mellitus (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 anti-hyperglycemic 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 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers 
(eg, 
propranolol) 
or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
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 type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/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
1.
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 for 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 the
infusion. 
Dose 
modification 
and 
toxicity 
management 
guidelines 
on 
pembrolizumab-associated infusion reactions are provided in Table 7. 
Table 7
Pembrolizumab-Associated 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 subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires 
therapy 
or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); 
prophylactic 
medications 
indicated 
for ≤24 hrs
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 subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping the 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 
100 mL/hr to 50 mL/hr).  Otherwise, dosing will 
be held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate 
premedication 
should 
be 
permanently 
discontinued 
from 
further 
treatment with pembrolizumab
Subject 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 
(i.e., 
not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption 
of 
infusion); recurrence of 
symptoms 
following 
initial 
improvement; 
hospitalization 
indicated 
for 
other 
clinical sequelae (e.g., 
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 subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further treatment with pembrolizumab.
No subsequent dosing
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 reasons other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy.  Subjects should be 
placed back on pembrolizumab within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor.  The reason for interruption should be documented in 
subject's study record. 
Dose Modification Guidelines for Adverse Events Potentially Associated with 
5.2.2.2
Axitinib Treatment
Dose modification guidelines for treatment-related AEs that are potentially associated with 
axitinib are provided in Table 8. If a subject has a dose reduction due to treatment-related 
toxicity and the AEs resolve, the axitinib dose can be re-escalated to the previous dose if the 
subject can tolerate it and the AE does not recur. 

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Table 8
Dose Modification Guidelines for Drug-related AEs Potentially Associated with 
Axitinib Treatment
Toxicity 
NCI CTCAE grade
Axitinib
Hypertension 
See Section 5.6.2 for 
monitoring/
management 
of 
axitinib-related 
hypertension
SBP 150 mm Hg and 
/ or 
DBP 100 mm Hg
Continue at the same dose level
Antihypertensive treatment maybe initiated
SBP >150 mm Hg but 
<160 mm Hg
and / or 
DBP >100 mm Hg but 
<105 mm Hg  
Continue at the same dose level, and institute new or 
additional antihypertensive medication if not on maximal 
antihypertensive treatment, or 
Reduce by 1 dose level if on maximal antihypertensive 
treatment.
SBP >160 mm Hg and 
/ or 
DBP >105 mm Hg
Hold and adjust antihypertensive medication to achieve BP 
controlled to SBP 150 mm Hg and DBP 100 mm Hg. 
Resume at the same dose level or 1 level reduced.  
Note: If axitinib dosing is temporarily interrupted, subjects
receiving antihypertensive medications should be monitored
closely for hypotension.  The plasma half-life of axitinib is 
2-4 hours and BP usually decreases within 1-2 days 
following dose interruption.
Recurrent 
hypertension 
following 
previous 
dose reduction 
Repeat dose interruption and/or dose reduction.
Permanently discontinue if hypertension is severe and 
persistent despite anti-hypertensive treatments and dose 
reduction, or experiencing hypertensive crisis, transient or 
permanent neurological deficit related to uncontrolled 
hypertension.
Proteinuria
Dipstick negative or 
1+ 
Continue at the same dose level.
If dipstick shows ≥2+, perform 24-hour urine protein or UPC.  Dosing may continue 
while waiting for test results.
Urine 
protein 
<3 g/24 hr or UPC <3 
Continue at the same dose level.
Urine 
protein 
3 g/24 hr or UPC ≥3  
Hold until urine protein is <3 g/24 hr or UPC<3.
Restart with 1 dose level lower
Permanently discontinue if urine protein cannot reduce to 
< 3 g/24 hr or UPC <3 after dose reduced to 2 mg BID
Diarrhea
Grade 1 – 2 
Continue at the same does level
Grade 3
Follow the guidelines as in non-hematologic toxicities
Grade 4
Follow the guidelines as in non-hematologic toxicities 

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Toxicity 
NCI CTCAE grade
Axitinib
Hemorrhage 
/Bleeding 
Grade 1
For hemoptysis, interrupt study treatment and evaluate 
underlying causes. Resume at the discretion of the 
investigator. 
For other Grade 1 hemorrhage/bleeding events, continue at 
the current dose; monitor as clinically indicated.
Grade 2
For pulmonary or GI bleed (other than hemorrhoidal 
bleeding), 
Permanently discontinue and follow-up per protocol.
For other Grade 2 hemorrhage/bleeding events, interrupt 
study treatment until the AE resolves to Grade 1. Restart at 
1 dose level lower
Grade 3 or 4
Permanently discontinue and follow-up per protocol.
AST/ALT with total 
bilirubin 
<2xULN 
and 
PT/INR 
<1.5xULN
Grade 1
Continue at the same dose level
Grade 2
Hold until recovery to <2xULN or BL.  
Restart at same dose level.
Grade 3 or 4
Hold until recovery to <2xULN or BL.  
Restart at 1 dose level lower.
AST/ALT Elevation 
with 
clinically 
significant 
hepatic 
dysfunction 
(i.e. 
total 
bilirubin 
≥2xULN excluding 
biliary 
obstruction 
or 
PT/INR 
≥1.5xULN)
Permanently discontinue and follow-up per protocol.
See Section 5.2.2.3.1 for details in evaluating and managing 
ALT/AST 
elevations 
during 
axitinib/pembrolizumab 
combination treatment
Hyperthyroidism
Grades 1-2
Continue at the same dose level
Grade 3
If 
symptoms 
can 
be 
controlled
with 
symptomatic 
medications, or if asymptomatic: may continue at the same 
dose level or dose reduced by 1 dose level per Investigator 
judgment
Grade 4
Hold until recovery to Grade 1 or BL.  
Restart at 1 dose level lower.
Hypothyroidism 
All grades 
Axitinib can be continued while thyroid replacement therapy 
is instituted
Renal 
Failure 
or 
Nephritis
Grade 1-2
Continue at the same dose level
Grade 3 -4
Hold until recovery to Grade < 2.  
Restart at 1 dose level lower.

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Toxicity 
NCI CTCAE grade
Axitinib
Non-hematologic
Toxicities, 
Laboratory 
Abnormalities and/or 
Other Drug Related 
Toxicities suspected 
to be contributed to 
axitinib 
and 
not 
considered immune-
related
Grade 1 - 2
Continue axitinib at the same dose level
Grade 3 - 4
Grade 3 toxicities controlled with symptomatic medications, 
or Grade 3 asymptomatic biochemistry (other than abnormal 
liver test) laboratory abnormalities may continue axitinib at 
the same dose level per Investigator judgment. 
Other Grade 3 toxicities may continue axitinib dose reduced 
by 1 dose level.
Grade 4 asymptomatic biochemistry laboratory (other than 
abnormal liver test) abnormality may continue axitinib 
without interruption per Investigator’s judgment. 
Other 
Grade 
4 
non-hematologic/laboratory 
and 
non-laboratory abnormalities hold treatment until recovery to 
Grade <2 then, then restart axitinib dose reduced by 1 dose 
level. 
Grade 
3-
4 
discontinuation criteria 
Permanently discontinue axitinib for: 

Severe or Grade 3 drug-related AEs that recur

Any life-threatening AEs. 

Subjects with the following events will be 
permanently 
discontinued: 
RPLS, 
arterial 
thrombosis/ischemia, 
Hematologic 
Laboratory 
Abnormalities
Grade 1-3
Continue axitinib at the same dose level.
Grade 4
Hold axitinib until recovery to Grade 2.
Restart axitinib dose reduced by 1 dose level.
Note: Grade 4 lymphopenia not associated with clinical 
events, (e.g., opportunistic infection) may continue on with 
axitinib.
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BID=twice daily; BL=baseline; BP=blood pressure; DBP=diastolic blood pressure; GI=gastrointestinal; NCI 
CTCAE= National Cancer Institute Common Terminology Criteria for Adverse Events; SBP=systolic blood 
pressure; UPC=urine protein creatinine
Allowed Dose Reduction, Interruption and Escalation Levels for Axitinib
The starting dose of axitinib is 5 mg BID. The axitinib dose may be adjusted by a dosing 
interruption with or without dose reduction as indicated.  The dose modification can occur 
independently for the 2 drugs used in the pembrolizumab plus axitinib arm.  If axitinib dose 
reduction from 5 mg BID is required, the next recommended dose level is 3 mg BID. If 
further dose reduction is required, the next dose level will be 2 mg BID. Axitinib should be 
permanently discontinued if subjects cannot tolerate 2 mg BID.  The axitinib dose can also be 
interrupted due to toxicity. 
Consult with the Sponsor if dose has been interrupted 
consecutively for more than 3 weeks to determine whether subject may resume axitinib 
treatment.
Subjects who have tolerated axitinib 5 mg BID for 2 consecutive treatment cycles (i.e. 
6 weeks) with no > Grade 2 treatment-related AEs to axitinib and with BP well controlled to 
≤150/90 mm Hg may have axitinib dose increased to 7 mg BID. Axitinib dose may be 
further increased to 10 mg BID using the same criteria. Particular attention should be 

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provided to a subject’s overall safety profile prior to implementing intra-subject dose 
increase for axitinib. See Table 9 for axitinib dose levels. 
Table 9
Axitinib Dose Levels
Dose Level
Dose
+2
10 mg BID
+1
7 mg BID
Starting 
dose
5 mg BID
-1
3 mg BID
-2
2 mg BID
General Guidance on Evaluation and Management of AEs Potentially 
5.2.2.3
Associated with Either Pembrolizumab Axitinib or Both in the Combination 
Arm
Based on the known toxicity profiles of pembrolizumab and axitinib, certain treatment-
related AEs are uniquely associated with one drug versus the other. 
For example,
hypertension, arterial thrombotic events, proteinuria, and hemorrhagic events are known risks 
for axitinib treatment, while immune-related AEs are risks for pembrolizumab treatment. 
However, certain AEs may be initially considered attributed to either study drugs, such as 
diarrhea, hypothyroidism, and liver enzyme elevation. Therefore, evaluation of attribution is 
important for determining the study drug most likely related to the AE, or an alternative 
etiology, and subsequently proper clinical management. The following aspects should be 
considered: 
1. Timing of AE onset: 
Since axitinib is dosed BID continuously due to a short half-life, and pembrolizumab 
is dosed Q3W due to a long half-life, axitinib can be interrupted to assess whether an 
AE improves/resolves with dechallenge (i.e., interruption of treatment) based on the 
following two scenarios.
o
If an AE occurs during a treatment cycle (i.e., between 2 pembrolizumab 
doses), only axitinib dose interruption is needed.
o
If an AE occurs at the beginning of a treatment cycle, axitinib can be 
interrupted and dosing of pembrolizumab should be held. 
If a subject recovers from an AE in response to axitinib interruption (i.e., positive 
dechallenge), the event is more likely to be attributed to axitinib. Otherwise, after 
excluding other alternative explanations,
an
immune-related
AE should be 
considered. 
2. Severity of AE: 
If an AE is suspected to be treatment related and is severe/life threatening at the time 
of onset or is rapidly worsened, action including interrupting or holding both drugs 
and initiating treatment with a corticosteroid (with exception of hypothyroidism, 
TIDM) and other supportive care should be taken promptly. 

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5.2.2.3.1 Evaluation and management of ALT/AST elevations during axitinib and 
pembrolizumab combination therapy
Based on the existing data from clinical trials, ALT/AST elevations have been observed in 
advanced cancer patients who received axitinib or pembrolizumab monotherapy treatment. In 
the Phase 3 study that compared axitinib versus sorafenib in treatment-naïve advanced RCC 
patients [15], laboratory data showed that the rate of ALT elevation was 40.4% for all grade, 
29.8% for Grade 1, 6.7% for Grade 2, 3.9% for Grade 3, and zero for Grade 4. The AE data 
showed that reported ALT elevation regardless of causality was 10.6% for all grade, 4.8% for 
Grade 1, 2.6% for Grade 2, 3.2% for Grade 3, and zero for Grade 4. Similar results were 
observed for AST [unpublished data provided by Pfizer]. 
Based on data from 2799 subjects with either advanced melanoma or NSCLC treated with 
pembrolizumab monotherapy, the incidence of immune-mediated hepatitis was 0.7% for all 
grade, 0.4% for Grade 3, and no Grade 4 or 5 events [Pembrolizumab IB]. In the updated 
data from an ongoing Phase 1/2 study of axitinib plus pembrolizumab in treatment-naïve 
advanced RCC, 4 out of 52 subjects had Grade 3 and another 4 had Grade 2 treatment-related 
ALT/AST elevations or hepatic dysfunction.  
Differentiation of whether ALT/AST elevations are attributable to axitinib or pembrolizumab 
or both may be challenging, as no specific clinical picture or laboratory markers are 
available. In addition, alternative causes (e.g., viral hepatitis and other severe infections, liver 
metastasis, ischemia, alcohol intake, etc.) should be excluded before more definitively 
concluding the attribution of ALT/AST elevation by the study drugs.
For assessing drug-induced liver injury (DILI), the Roussel Uclaf Causality Assessment 
Method (RUCAM) can be used as a valid tool in which factors like time to onset of 
ALT/AST elevation, response to drug dechallenge, response to drug rechallenge, evaluation 
of alternative causes etc. are collectively evaluated and scored to determine the possibility of 
attribution to ALT/AST elevation [54]. For axitinib, early-onset, prompt recovery from 
ALT/AST
elevation in response to axitinib interruption without confounding by 
corticosteroid treatment, suggests the event is likely associated with axitinib after excluding 
other alternative explanations). A positive rechallenge, i.e., ALT/AST recurrence following 
retreatment will provide further support for its attribution. The determination of immune-
related hepatitis mostly relies on the exclusion of other causes including axitinib. If the initial 
ALT/AST elevation does not respond rapidly to axitinib interruption but responds to 
subsequent corticosteroid treatment, it suggests a potential for immune-mediated hepatitis by 
pembrolizumab. It should be borne in mind that not all immune-mediated hepatitis will 
respond to corticosteroid treatment.

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Guidelines on causality evaluation and management for ALT/AST elevations of > 3xULN 
during axitinib / pembrolizumab combination treatment are outlined in the following:
1. Promptly interrupt both study drugs and any other suspected concomitant 
medications. Note, concomitant medications include over-the-counter (OTC) and 
herbal medications and supplements.
2. Adequately monitor liver enzymes and liver function changes - Liver enzyme 
tests should include ALT, AST, and ALP; liver function tests should include total 
bilirubin, and PT or INR. Bilirubin fractionation should be performed if total bilirubin 
is ≥ 2xULN or is clinically significant as elevated conjugated bilirubin (i.e., direct 
bilirubin) reflects liver dysfunction.  Liver enzyme tests and liver function tests will 
be referred, collectively, as liver tests for the rest of this section.
a.
Repeat liver tests within 24 to 72 hours to confirm the initial observation.
b. Continue to monitor liver tests twice weekly, while evaluating other causes, 
until ALT/AST values are trending down (>10% decrease between sequential 
assessments) and then monitored weekly until recovered to ≤ 2xULN or 
values are back to baseline. 
3. Decision on initiation of corticosteroid treatment - While corticosteroid is essential 
for managing immune-mediated hepatitis, administration of steroids prior to 
identifying the most likely causes of ALT/AST elevation will confound the causality 
assessment and impact proper management of the event. Hence the followings are 
recommended:  
a.
Hold steroid initiation for ALT/AST elevations that are not associated with 
signs of clinically significant hepatic dysfunction (i.e., total bilirubin <2xULN 
and PT/INR <1.5xULN). Continue to monitor with liver tests and clinical 
symptoms. 
b. Steroid therapy should be initiated if: 
i. ALT/AST elevation is associated with signs of clinically significant 
hepatic dysfunction (i.e., ALT/AST > 3 x ULN concurrent with total 
bilirubin ≥2xULN (excluding biliary obstruction) and/or PT/INR 
≥1.5xULN) OR, 
ii. ALT/AST elevation has been persistent (ie, no prompt improvement 
after axitinib dechallenge) or further increased and without alternative 
causes identified.  Consider observing liver enzyme and function 
changes for approximately 3 to 7 days prior to making a decision, if 
subject is clinically stable.
4. Thoroughly evaluate alternative causes – The following includes a list of potential 
alternative causes that should be evaluated and excluded:  
a.
Medical history relevant to the liver event
b. History of alcohol use and recent alcohol use  
c.
Serology for hepatitis A, B, C, and E; serology for CMV, EBV

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d. Obstructive hepatic disease  
e.
Cardiac or vascular etiology (e.g., any cause of severe hypoperfusion of the 
liver, severe cardiac failure)
f.
Severe systemic infection
g. Exposure to other drugs including OTC and herbal medications that are 
potentially associated to DILI (e.g., statins, acetaminophen etc.)
h. Evaluating other causes as appropriate 
5. Decision on axitinib/ pembrolizumab rechallenge – If initial ALT/AST elevation 
event is assessed as related to study treatment (i.e., alternative causes were excluded), 
the decision on rechallenge with one or both study treatments should be based on the 
outcome of causality assessments (as described above) and the severity of the initial 
ALT/AST
elevation event. Prior to rechallenge with either axitinib or 
pembrolizumab, initial ALT/AST elevations must recover to ≤ 2 × ULN or to 
baseline values without signs and symptoms of hepatic dysfunction. See Table 10 for 
algorithms of decision on axitinib/ pembrolizumab rechallenge after recovery from 
drug-related ALT/AST elevation. 
6. Severe hepatic events should be promptly managed, including hospital admission and 
seeking hepatic consultation as appropriate.
Table 10
Algorithms of decision on axitinib/ pembrolizumab rechallenge after recovery 
from drug-related ALT/AST elevation
Initial ALT/AST elevation 
scenario
Rechallenge decision
Scenario 1: ALT/AST > 3 x ULN 
concurrent 
with 
total 
bilirubin 
≥2xULN 
(excluding 
biliary 
obstruction) 
and/or 
PT/INR 
>1.5xULN (i.e., ALT/AST elevation 
with clinically significant signs of 
hepatic dysfunction)

No rechallenge with either axitinib or pembrolizumab is allowed. 
Subject should be followed with liver tests until recovery..  
Scenario 2: ALT/AST  >3-5 x ULN 
without clinically significant signs 
of hepatic dysfunction (i.e. total 
bilirubin < 2xULN and PT/INR 
<1.5xULN)

Axitinib and pembrolizumab combination can be resumed 
sequentially with axitinib (at the  previous dose) resumed first for 
2-3 weeks with weekly liver test monitoring: 
o
If no recurrence, consider adding pembrolizumab 
o
If with ALT/AST recurrence is >5xULN (i.e., Grade 3 or 
4), 
discontinue 
axitinib 
and 
rechallenge 
with 
pembrolizumab
o
If ALT/AST recurrence is >3-5xULN (i.e., Grade 2), dose 
reduce axitinib then rechallenge or discontinue axitinib 
and rechallenge with pembrolizumab

Permanently discontinue pembrolizumab if ALT/AST recurrence is 
>5× ULN or interrupt pembrolizumab if ALT/AST recurrence is >3
to 5× ULN after its rechallenge and manage per Section 5.2.2.1. 

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Initial ALT/AST elevation 
scenario
Rechallenge decision
Scenario 3: ALT/AST >5 to 10×
ULN without clinically significant 
signs of hepatic dysfunction (i.e.,
total bilirubin < 2× ULN and 
PT/INR <1.5× ULN). Consultation 
with Sponsor medical monitor is 
required prior to rechallenge.

If initial event is likely to be immune-mediated by pembrolizumab 
(i.e., no prompt decrease in ALT/AST after axitinib interruption
and required initiation of steroid treatment as described in item 3b 
of this section, responded to steroid treatment, and no alternative 
explanations):
o
discontinue pembrolizumab and rechallenge with axitinib 
as monotherapy (at same dose)

If initial event is likely related to axitinib (e.g. prompt recovery 
after axitinib interruption without confounding by steroid 
treatment), first rechallenge with axitinib (at reduced dose) for 2 to 
3 weeks with weekly liver test monitoring:
o
If no recurrence, add pembrolizumab 
o
If ALT/AST recurrence is >5× ULN, permanently 
discontinue axitinib and rechallenge with pembrolizumab
o
If ALT/AST recurrence is >3 to 5× ULN, dose reduce 
axitinib 
then 
rechallenge 
or 
discontinue 
axitinib, 
depending on the reoccurrence of the events and 
rechallenge with pembrolizumab

Permanently discontinue pembrolizumab if ALT/AST recurrence is 
>5× ULN or interrupt pembrolizumab if ALT/AST recurrence is >3
to 5× ULN after its rechallenge and manage per Section 5.2.2.1.
Scenario 4: ALT/AST > 10 × ULN 
without clinically significant signs 
of hepatic dysfunction
Consultation 
with 
Sponsor 
medical monitor is required prior 
to rechallenge

If initial event is likely to be immune-mediated by pembrolizumab:
o
discontinue pembrolizumab and rechallenge with axitinib 
as monotherapy

If initial event is likely related to axitinib and unlikely due to 
pembrolizumab:
o
Rechallenge with pembrolizumab monotherapy

If event is potentially related to a contribution of both drugs (such 
as upfront steroid use with improvement along with axitinib 
interruption), subject may be rechallenged with axitinib at reduced 
dose:
o
If no recurrence, continue with axitinib monotherapy
o
If ALT/AST elevation recurs, discontinue axitinib and 
may be rechallenged with pembrolizumab  

Permanently discontinue pembrolizumab if ALT/AST recurrence is 
>5× ULN or interrupt pembrolizumab if ALT/AST recurrence is >3
to 5× ULN after its rechallenge and manage per Section 5.2.2.1.

Permanently discontinue axitinib if ALT/AST recurrence is 
>5× ULN or interrupt axitinib if ALT/AST recurrence is >3 to 5× 
ULN and rechallenge with reduced dose. 
Note: 1. Subject should have weekly monitoring with liver tests (i.e., liver enzyme and function tests) for 2-3 
weeks after each drug rechallenge. 2. If both study drugs are discontinued due to a hepatic event, subjects 
should be monitored until AE resolution as per protocol and continue imaging and survival follow-up as per 
protocol. 3. Events under Scenario 1, 3, and 4 must be reported to the Sponsor as Events of Clinical Interest 
(see Section 7.2.3.2 for details). 4. Liver tests include liver enzyme (ALT, AST, and ALP) and liver function 
(bilirubin and PT/INR) tests. 
Abbreviations: ALP =
alkaline phosphatase; ALT
=
alanine aminotransferase; AST
=
aspartate 
aminotransferase; INR = international normalized ratio; PT = prothrombin time.

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Dose Modification Guidelines for Adverse Events Potentially Associated with 
5.2.2.4
Sunitinib Treatment
The study is using the label-recommended dose and schedule for RCC (50 mg QD 4 weeks 
on, 2 weeks off).  Dose interruption and/or dose modification in 12.5-mg increments or 
decrements is recommended based on individual safety and tolerability, as per label 
recommendations. If 50 mg QD cannot be tolerated, the next dose level is 37.5 mg QD. 
Dose can be further reduced to 25 mg QD. Once toxicity has been alleviated, doses should 
be re-escalated stepwise to 37.5 mg and then 50 mg. Subjects requiring a dose below 25 mg 
QD should be permanently discontinued from study treatment. During each 6-week cycle, 
subjects will be off of treatment for 2 weeks. If an additional dose interruption for more than 
2 weeks is required, the Sponsor should be consulted (Table 11). 
Table 11
Dose Modification Guidelines for AEs Potentially Associated with Sunitinib 
Treatment
Toxicity 
NCI CTCAE 
Grade
Sunitinib
Hypertension
See Section 5.6.2 for 
monitoring/management 
of 
treatment-related 
hypertension.
SBP 150 mm Hg
and 
/ 
or 
DBP 
100 mm Hg
Continue at the same dose level
Antihypertensive treatment maybe initiated
SBP >150 mm Hg
but < 160 mm Hg
and / or 
DBP >100 mm Hg
but < 105 mm Hg  
Continue at the same dose level, and institute new or 
additional antihypertensive medication if not on maximal 
antihypertensive treatment, or
Reduce by 1 dose level if on maximal antihypertensive 
treatment.
SBP >160 mm Hg
and / or 
DBP > 105 mm Hg
Hold dose and adjust antihypertensive medication to achieve 
BP controlled to SBP 150 mm Hg and DBP 100 mm Hg. 
Resume at the same dose level or 1 level reduced.  
Note: If sunitinib dosing is temporarily interrupted, subjects 
receiving antihypertensive medications should be monitored 
closely for hypotension.  
Recurrent 
hypertensions 
following previous 
dose reduction 
Repeat dose interruption and/or dose reduction by one lower 
dose level. 
Permanently discontinue if hypertension is severe and 
persistent despite antihypertensive treatment and dose 
interruption, or experience hypertensive crisis, transient or 
permanent neurological deficit related to uncontrolled 
hypertension.

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Toxicity 
NCI CTCAE 
Grade
Sunitinib
Proteinuria
Dipstick 
negative 
or 1+ 
Continue at the same dose level.
If dipstick shows ≥ 2+, perform 24-hour urine protein or UPC.  Dosing may 
continue while waiting for test results
Urine protein 
< 3 g/24 hr or 
UPC < 3 
Continue at the same dose level.
Urine 
protein 
3 g/24 hr 
or 
UPC ≥3  
Hold until urine protein is < 3 g/24 hr or UPC <3.
Restart with 1 dose level lower
Permanently discontinue if urine protein cannot reduce to 
< 3 g/24 hr or UPC <3 after dose reduced to 25 mg daily
Prolongation 
of 
QTc 
Interval: 
480 < QTc 
< 500 msec
Continue study treatment; monitor as clinically indicated.
QTc 500 msec
Permanently discontinue and follow-up per protocol.
Diarrhea/Colitis
Grade 1-2
Continue at the same does level
Grade 3
Continue and dose reduce by 1 dose level 
Follow the guidelines as in non-hematologic toxicities
Grade 4
Follow the guidelines as in non-hematologic toxicities 
Hemorrhage 
/Bleeding: 
Investigate and document 
underlying etiology of the 
bleeding
Grade 1
For hemoptysis, interrupt study treatment and evaluate 
underlying causes. Resume at the discretion of the investigator. 
For other Grade 1 hemorrhage/bleeding events, continue at the 
current dose; monitor as clinically indicated.
Grade 2
For pulmonary or GI bleed (other than hemorrhoidal bleeding), 
Permanently discontinue and follow-up per protocol.
For other Grade 2 hemorrhage/bleeding events, interrupt study 
treatment until the AE resolved to Grade 1. Restart at 1 dose 
level lower
Grade 3 or 4
Permanently discontinue and follow-up per protocol.
Hyperthyroidism
Grades 1-2
Continue at the same dose level
Grade 3
Grade 3 toxicities controlled with symptomatic medications, or 
Grade 3 asymptomatic biochemistry (other than abnormal liver 
tests) laboratory abnormalities: may continue at the same dose 
level or reduce by one dose level per Investigator judgment
Grade 4
Hold until recovery to Grade 1 or BL.  
Restart at 1 dose level lower.
Hypothyroidism 
All grades 
Dose can be continued while thyroid replacement therapy is 
instituted
Isolated AST/ ALT or 
bilirubin elevation
Grade 1
Continue at the same dose level
Grade 2
Hold until recovery to Grade 1 or BL.  
Restart at same dose level.
Grade 3 or 4
Hold until recovery to Grade 1 or BL.  
Restart at 1 dose level lower.
ALT/AST >3xULN 
concurrent 
with 
total 
bilirubin 
> 2xULN 
(excluding Gilbert 
syndrome)
Permanently discontinue and perform virology and serology 
tests to evaluate the causes  

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Toxicity 
NCI CTCAE 
Grade
Sunitinib
Non-hematologic
Toxicities, 
Laboratory 
Abnormalities 
and/or 
Other 
Drug 
Related 
Toxicities suspected to be 
contributed to sunitinib
Grade 1 - 2
Continue at the same dose level
Grade 
3 
or 
intolerable grade 2
Withhold dose until toxicity is Grade ≤1 or has returned to BL
Resume treatment at the same dose level.a
If the toxicity recurs with Grade 3 severity (or intolerable 
Grade 2) at the discretion of the investigator, reduce the dose 
by 1 level. 
Grade 4
Withhold dose until toxicity is Grade ≤1 or has returned to BL, 
then reduce the dose by 1 level and resume treatment, or 
discontinue at the discretion of the investigator.a
Permanently discontinue sunitinib for: 

Any life-threatening adverse event.

Subjects 
with 
the 
following 
events: 
CHF,b
pancreatitis, necrotizing fasciitis, nephrotic syndrome 
and thrombotic microangiopathy), RPLS, and arterial 
thrombosis/ ischemia 

Nausea, vomiting, or diarrhea persist at Grade 3 or 4 
despite maximal medical therapy.  
Hematologic Laboratory 
Abnormalities
Grade 1-2
Continue at the same dose level.
Grade 3
Withhold dose until toxicity is Grade ≤2 or has returned to BL, 
then resume treatment at the same dose level.c
If the toxicity recurs with Grade 3 severity, at the discretion of 
the investigator, reduce the dose by 1 level.
Grade 4
Withhold dose until toxicity is Grade ≤2 or has returned to BL
Restart with 1 dose level lower.c
a Subjects who develop Grade 3 hypophosphatemia or Grade 4 hyperuricemia without clinical symptoms may continue study 
treatment without interruption at the discretion of the investigator.  
b Subjects should be carefully monitored for clinical signs and symptoms of CHF while receiving sunitinib. Assessment of 
LVEF should be considered as clinically indicated per sunitinib label and standard of care. 
c Subjects who develop Grade 3 or 4 lymphopenia may continue study treatment without interruption.  Complicated 
neutropenia includes duration of Grade 4 longer than 7 days or concurrent fever or infection.
Timing of Dose Administration
5.2.3
Study treatments should begin on the day of randomization or within 3 days of randomization
in both treatment arms. Study treatments and relevant safety assessments are cycle based. 
The day that the first dose of study treatment is received by each subject denotes Cycle 1 Day 
1 (C1D1).
For the combination arm, each treatment cycle is 21 days, which is based on a Q3W dosing 
schedule of pembrolizumab. C1D1 of the combination arm should start when the subject can 
receive the first dose of pembrolizumab. The first dose of axitinib should start on the same 
day when first dose of pembrolizumab is administered, if possible, or start on the following 
day. For the sunitinib arm, each treatment cycle is 42 days. Study treatment will continue in 
21-day or 42-day cycles, for the combination arm and sunitinib arm, respectively, until study 
treatments are permanently discontinued for the subject. The clinical visits and assessments 
are detailed in Section 6 – Trial Flow Chart.  

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Pembrolizumab Administration 
5.2.3.1
Pembrolizumab will be administered on Day 1 of each 21-day cycle (± 3 days) starting on 
C1D1.
Pembrolizumab should be administered after all pre-dose study procedures and 
assessments have been completed as detailed on the Trial Flow Charts in Section 6.  
Pembrolizumab should be administered as a 30-minute IV infusion.  Sites should make every 
effort to target infusion timing to be as close to 30 minutes as possible.  However, given the 
variability of infusion pumps from site to site, a window of –5 min and +10 min is permitted 
(i.e., infusion time is 30 minutes: –5 min/+10 min). The Pharmacy Manual contains specific 
instructions for the preparation and administration of pembrolizumab.  
Axitinib Administration
5.2.3.2
Axitinib will be taken orally BID, at approximately the same time in the morning and 
evening each day with approximately 12 hours between the 2 doses.  Axitinib should be 
taken continuously with exception of dose interruptions due to drug-related AEs or 
intolerance (see Section 5.2.2).
Axitinib tablets may be administered with or without food.  Tablets must not be crushed, split 
or dissolved and subjects should be instructed to swallow the study medication whole 
without manipulation or chewing of the medication prior to swallowing. 
Subjects must be instructed that if they miss a dose or vomit any time after taking a dose, 
they must not “make it up” with an extra dose, but instead resume subsequent doses as 
prescribed.  Any missed dose may be taken later up to 3 hours before the next scheduled 
dose, otherwise, it should be skipped and dosing should resume with subsequent doses as 
prescribed.  Subjects must be instructed to record all doses (missed or vomited doses) in a 
dosing diary supplied by the site.  If doses are missed or vomited, this must be indicated in 
the source documents and case report forms (CRFs).  If a subject inadvertently takes 1 extra 
dose during a day, the subject should not take the next dose. A dosing diary will be provided 
to subjects to record dosing details for axitinib. 
Sunitinib Administration
5.2.3.3
The first dose of sunitinib administration denotes C1D1 for each subject.  Each treatment 
cycle of sunitinib is 42 days ± a 3-day window. Within each treatment cycle, sunitinib will 
be administered orally once daily for 4 weeks and then off treatment for 2 weeks.   
Sunitinib can be administered with or without food.  Capsules must not be crushed, split, or 
dissolved and subjects should be instructed to swallow the study medication whole without 
manipulation or chewing of the medication prior to swallowing. 
Subjects must be instructed that if they miss a dose or vomit any time after taking a dose, 
they must not “make it up” with an extra dose, but instead resume subsequent doses as 
prescribed.  Subjects must be instructed to record all doses (missed or vomited doses) in a 
dosing diary supplied by the site.  If doses are missed or vomited, this must be indicated in 
the source documents and CRFs.
A dosing diary will be provided to subjects to record 
dosing details for sunitinib. 

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Dosing Schedules with Study Treatment Interruptions
5.2.3.4
In general, subjects in the combination arm should be maintained on an every 21-day (Q21D) 
treatment and assessment schedule from C1D1 until both treatment(s) are permanently 
discontinued. 
In the events that treatment-related AEs require dose interruption or 
discontinuation of one study drug only, the other study drug should be continued as 
scheduled, so as the safety assessments. Sometimes, both drugs need to be withheld for a 
treatment-related AE until causality is clear or until AE improves. Figure 2 depicts a few 
dose interruption scenarios that may be encountered in the combination arm. 
Figure 2
Dose Interruption Scenarios in the Combination Arm
Scenario (A), at C2D1 visit, an immune-related AE is identified that requires pembrolizumab 
to be on hold but not axitinib, axitinib is then continued. A worsening of hypertension led to 
brief dose interruption of axitinib during cycle 1 and Cycle 3. Scenario (B), axitinib was 
interrupted from C1D10 for an axitinib-specific toxicity, subject still comes for C2D1 visit 
for safety assessment and received Cycle 2 dose of pembrolizumab on schedule. Scenario 
(C), pembrolizumab has been on hold after Cycle 1 due to a drug-related AE, pembrolizumab 
can be resumed on C3D10, and the subject may start C4D1 ahead of time and continue the 
Q21D treatment and safety assessment cycle with this new starting point.  
Similarly, subjects who are randomized to the sunitinib arm should be maintained on a 
42-day treatment and assessment schedule as much as possible. Figure 3 depicts a few dose 
interruption scenarios for the sunitinib arm. 

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Figure 3
Dose Interruption Scenarios for Sunitinib
(A), if a dose interruption is required within the 28-day treatment period of a cycle, the 
remaining doses should be completed followed by 2-weeks’ off treatment period. (B) If dose 
interruption extends to the off treatment period and AE resolved, subject should complete the 
remaining off treatment period and resume treatment at the next cycle per schedule. (C) If 
dose interruption extends to the treatment period of the following cycle, subject should 
resume with a new 42-day cycle and continue the 4 weeks on treatment and 2 weeks off 
treatment schedule and the required assessments.  
Trial Blinding 
5.2.4
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization
5.3
Treatment randomization will occur centrally using an interactive voice response system / 
integrated web response system (IVRS/IWRS). There are 2 treatment arms.  Subjects will be 
assigned randomly in a 1:1 ratio to the pembrolizumab plus axitinib combination arm or the
sunitinib monotherapy arm.
Stratification
5.4
Prior to randomization subjects will be stratified according to the following factors:
1. International Metastatic RCC Database Consortium (IMDC) risk group: favorable 
versus intermediate versus poor risk groups [2, 3]
2. Geographic region: North America versus Western Europe versus “Rest of the 
World.”  
IMDC risk category for each subject is determined first by assessing 6 risk factors as shown 
in Table 12.

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Table 12
IMDC Risk Evaluation
Assessments
Risk Factor
Baseline Karnofsky Performance Status
< 80%
Interval between initial diagnosis of RCC to start of first-line systemic 
treatment for advanced disease 
(note for this study, date of randomization will be used as the start of first-
line systemic treatment)
< 1year
Baseline Hemoglobin
< Lower limit of normal
Baseline Platelet Count
> Upper limit of normal
Baseline Corrected Calcium1
> Upper limit of normal
Baseline Neutrophil
> Upper limit of normal
The IMDC risk group is determined by totaling the existing risk factors per subject.
IMDC Risk Group
IMDC Category
Favorable
No risk factors
Intermediate
1 or 2 risk factors
Poor
3 or more risk factors
1.
Corrected 
calcium 
can 
be 
calculated 
based 
on 
the 
following 
formula:
Corrected calcium (mg/dl) = 0.8 × [4.0 - subject’s albumin (g/dl)] + subject’s calcium (mg/dl).
A subject’s corrected calcium will be compared with the upper limit of normal of institution serum calcium. 
Sites will be provided with a worksheet that utilizes these criteria for calculating the IMDC 
risk group. The group will be entered into the IVRS as a stratification factor at the time of 
randomization.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
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 subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
5.5.1

All treatments that the investigator considers necessary for a subject’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 CRF 
including all prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids.  If changes occur during the trial period, documentation of 
drug dosage, frequency, route, and date may also be included on the CRF.

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
All medications received within 30 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2. 

Concurrent anti-cancer therapy with agents other than those assigned for each 
treatment arm (i.e., axitinib plus pembrolizumab or sunitinib) is not allowed.  
Medications intended solely for supportive care (i.e., antiemetics, analgesics, 
megestrol acetate for anorexia) are allowed. 
Caution Use of Inhibitors and Inducers of CYP Enzymes (Axitinib) 
5.5.1.1
In vitro studies with human liver microsomes and recombinant CYP enzymes indicate that 
axitinib metabolism is primarily mediated by the CYP3A4/5, and to a lesser extent by 
CYP1A2, CYP2C19, and UGT1A1.  
The concomitant use of strong CYP3A4/5 inhibitors (e.g., ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, 
nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, and voriconazole) should be avoided. Grapefruit or grapefruit juice may also 
increase axitinib plasma concentrations and should be avoided. Selection of an alternate 
concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. 
Although axitinib dose adjustment has not been studied in patients receiving strong 
CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose 
decrease of axitinib by approximately half is recommended, as this dose reduction is 
predicted to adjust the axitinib area under the plasma concentration vs. time curve (AUC) to 
the range observed without inhibitors. The subsequent doses can be modified based on 
individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, 
the axitinib dose should be returned (after 3-5 half-lives of the inhibitor) to that used prior to 
initiation of the strong CYP3A4/5 inhibitor. 
Co-administration of 
axitinib
with 
strong 
CYP3A4/5 
inducers 
(e.g., 
rifampin, 
dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and 
St. John’s wort) should be avoided. Selection of concomitant medication with no or minimal 
CYP3A4/5 induction potential is recommended.  Moderate CYP3A4/5 inducers (e.g., 
bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma 
exposure of axitinib and should be avoided if possible.
Caution Use of Inhibitors and Inducers of CYP Enzymes (Sunitinib)
5.5.1.2
In vitro studies indicated that sunitinib does not induce or inhibit major CYP enzymes. The in 
vitro studies in human liver microsomes and hepatocytes of the activity of CYP isoforms 
CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, 
CYP3A4/5, and CYP4A9/11 indicated that sunitinib and its primary active metabolite are 
unlikely to have any clinically relevant drug-drug interactions with drugs that may be 
metabolized by these enzymes.
Strong CYP3A4 inhibitors such as ketoconazole may increase sunitinib plasma 
concentrations. Selection of an alternate concomitant medication with no or minimal enzyme 
inhibition potential is recommended. Concurrent administration of SUTENT with the strong 
CYP3A4 inhibitor, ketoconazole, resulted in 49% and 51% increases in the combined 

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(sunitinib + primary active metabolite) Cmax and AUC0-∞ values, respectively, after a single 
dose of SUTENT in healthy volunteers. 
Co-administration of SUTENT with strong 
inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, 
atazanavir, 
indinavir, 
nefazodone, 
nelfinavir, 
ritonavir, 
saquinavir, 
telithromycin, 
voriconazole) may increase sunitinib concentrations. Grapefruit may also increase plasma 
concentrations of sunitinib. A dose reduction for SUTENT should be considered when it 
must be co-administered with strong CYP3A4 inhibitors. 
CYP3A4 inducers such as rifampin may decrease sunitinib plasma concentrations. Selection 
of an alternate concomitant medication with no or minimal enzyme induction potential is 
recommended. Concurrent administration of SUTENT with the strong CYP3A4 inducer, 
rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + primary active 
metabolite) maximum concentration (Cmax) and AUC0-∞values, respectively, after a single 
dose of SUTENT in healthy volunteers. Co-administration of SUTENT with inducers of the 
CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentin, phenobarbital, St. John’s wort) may decrease sunitinib concentrations. St. John’s 
wort may decrease sunitinib plasma concentrations unpredictably. 
Patients receiving 
SUTENT should not take St. John’s wort concomitantly. A dose increase for SUTENT 
should be considered when it must be co-administered with CYP3A4 inducers.
The investigator should refer to the approved prescribing information for sunitinib (Sutent) 
for guidance on permitted medications and non-drug therapies [Sutent Package Insert, 2011].
Hematopoietic Growth Factors
5.5.1.3
Primary prophylactic use of granulocyte-colony stimulating factors may be used to treat 
treatment emergent neutropenia as indicated by the current American Society of Clinical 
Oncology guidelines [55]. The use of hematopoietic growth factors is at the discretion of the 
treating physician in line with local guidelines.  Subjects who enter the study on stable doses 
of erythropoietin or darbepoietin may continue this treatment, and subjects may start either 
drug during the study at the discretion of the treating physician.
Concomitant Surgery
5.5.2
Subjects can receive surgical procedures during the study treatment period for indications 
other than treating RCC. 
Axitinib
5.5.2.1
No formal studies of the effect of axitinib on wound healing have been conducted; however,
caution is advised based on the mechanism of action.  If a major surgery or an interventional 
procedure (e.g., endoscopy) is required, treatment with axitinib must be interrupted at least 
24 hours before the procedure and subject’s BP should be monitored closely for hypotension.  
Subject may resume axitinib 7 days after minor surgery and 2 to 3 weeks after major surgery, 
provided that the wound has completely healed and there are no wound healing 
complications (e.g., delayed healing, wound infection or fistula).

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Pembrolizumab
5.5.2.2
Dosing interruptions are permitted in the case of surgical events such as elective surgery. 
Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor.  The reason for the interruption 
should be documented.
Sunitinib
5.5.2.3
Cases of impaired wound healing have been reported during sunitinib therapy. Temporary 
interruption of sunitinib therapy is recommended for precautionary reasons in patients 
undergoing major surgical procedures.
There is limited clinical experience regarding the 
timing of re-initiation of therapy following major surgical intervention. 
Therefore, the 
decision to resume sunitinib therapy following a major surgical intervention should be based 
upon clinical judgment of recovery from surgery [refer to the Sutent Label for details].
Prohibited Concomitant Medications
5.5.3
Subjects are prohibited from receiving the following therapies during the study treatment 
period (including re-treatment for post-complete response relapse) of this trial:

Any anti-cancer therapy not assigned per protocol (e.g., systemic treatment, surgery, 
radiation).
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
considered an exception on a case-by-case basis after consultation with Sponsor.  The 
radiation treatment field may not include a target or measurable lesion by RECIST 
1.1. 

Investigational agents other than those specified in this protocol (i.e., pembrolizumab, 
axitinib or sunitinib based on what is assigned) 

Live vaccines within 30 days prior to the first dose of pembrolizumab and through 
30 days following the last dose of pembrolizumab.  Examples of live vaccines 
include, but are not limited to, the following: measles, mumps, rubella, chickenpox, 
yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and oral typhoid vaccine.  
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines, and are not allowed.
Note: If precluded by local regulations, live vaccines should not be given for 
120 days after the last dose of pembrolizumab is administered.

Drugs with proarrhythmic potential: Concomitant treatment with a drug having 
known proarrhythmic risks (terfenadine, quinidine, procainamide, disopyramide, 
sotalol, probucol, bepridil, haloperidol, risperidone, indapamide and flecainide) is not 
permitted during treatment with sunitinib. 

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The following applies exclusively to subjects being treated with pembrolizumab plus 
axitinib:

Prolonged therapy with systemic glucocorticoids for any purpose other than to 
modulate symptoms from an AE, SAE, or ECI or for use as a pre-medication for 
chemotherapy or in participants with a known history of an IV contrast allergy 
administered as part of computed tomography (CT) radiography.  Brief, limited use of 
systemic corticosteroids (≤7 days) is permitted where such use is considered standard 
of care (e.g., for COPD exacerbation).
Replacement doses of steroids (for example, prednisone 5 to 7.5 mg daily) are 
permitted while on study, as is the use of local steroids.
Subjects who, in the assessment by the investigator, require additional anti-cancer treatments 
will be discontinued from study treatment and continue on survival follow-up. Subjects who, 
in the assessment by the investigator, require any other prohibited medications for the 
assigned study treatment for long-term clinical management should be discontinued from 
trial treatment but continue on disease assessments and survival follow-up. Subjects may 
receive other medications that the investigator deems to be medically necessary.
Rescue Medications & Supportive Care
5.6
Management of Treatment-emergent Hypertension
5.6.1
Subjects are encouraged to have home BP monitoring and to measure their BP prior to taking 
each axitinib or sunitinib dose.  All BP measurements will be recorded in a diary and brought 
to the nurse or study coordinator at each clinic visit.  Subjects should contact the site for 
guidance if their SBP rises above 150 mm Hg, DBP rises above 100 mm Hg, or if they 
develop symptoms perceived to be related to an elevated BP (e.g., headache, visual 
disturbance).
Standard anti-hypertensive medications can be used to manage treatment-emergent BP 
elevation (e.g. thiazide or thiazide-like diuretics, angiotensin II receptor blockers, angiotensin 
converting-enzyme inhibitors, and dihydropyridine calcium channel blockers).  See 
Section 5.5 for concomitant medications that are prohibited or should be used with caution. 
General Supportive Care Guidelines 
5.6.2
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below: 

Diarrhea: All patients who experience diarrhea 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. 

Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration 
should be given in subsequent cycles to the administration of prophylactic antiemetic 
therapy according to standard institutional practice.  Patients should be strongly 
encouraged to maintain liberal oral fluid intake. 

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
Anti-infectives: Patients with a documented infectious complication should receive oral 
or IV antibiotics or other anti-infective agents as considered appropriate by the treating 
investigator for a given infectious condition, according to standard institutional practice. 

Anti-inflammatory or narcotic analgesics may be offered as needed.  Acetaminophen/ 
paracetamol to a MAXIMUM total daily dose of 2 g is permitted.  Daily intake over 2 g 
is prohibited.

Patients who need to be on anticoagulant therapy during treatment should be treated with 
low molecular weight heparin.  If low dose heparin cannot be administered, the 
administration of coumadin or other coumarin derivatives or other anti-coagulants may 
be allowed; however appropriate monitoring of prothrombin time/International 
normalized ratio (PT/INR) should be performed.
Diet/Activity/Other Considerations
5.7
Diet 
5.7.1
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
Contraception
5.7.2
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 subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).
Female subjects will be considered of non-reproductive potential if they are either:
1. Postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);
OR 
2. Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;
OR 
3. Have a congenital or acquired condition that prevents childbearing.

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Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:
1) 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 subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and 
ERCs/IRBs.  Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, 
post-ovulation methods, etc.) and withdrawal are not acceptable methods of 
contraception.
OR 
2) Use (or have their partner use) acceptable contraception during heterosexual activity.
Acceptable methods of contraception are‡:
Single method (1 of the following is acceptable):

Intrauterine device (IUD)

Vasectomy of a female subject’s male partner

Contraceptive rod implanted into the skin
Combination method (requires use of 2 of the following):

Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)

Cervical cap with spermicide (nulliparous women only)

Contraceptive sponge (nulliparous women only)

Male condom or female condom (cannot be used together)

Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection.
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 
120 days after the last dose of trial therapy.  If there is any question that a subject of 
childbearing potential will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study.
Monthly pregnancy testing is recommended per local standards if applicable.

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Use in Pregnancy 
5.7.3
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, 
axitinib, or sunitinib, the subject will immediately be removed from the study treatment.  The 
site will contact the subject at least monthly and document the subject’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 (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn).  The study 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 subject impregnates his female partner, the study 
personnel at the site must be informed immediately and the pregnancy reported to the 
Sponsor and followed as described above and in Section 7.2.2.
Use in Nursing Women
5.7.4
It is unknown whether pembrolizumab, axitinib, or sunitinib are 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, subjects who are breast-feeding are not eligible for
enrollment.
Subject Withdrawal/Discontinuation Criteria
5.8
Discontinuation of Treatment
5.8.1
Discontinuation of study treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond study treatment discontinuation are important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued study treatment.  Therefore, all subjects who discontinue trial 
treatment prior to completion of the study will still continue to participate in the trial as 
specified 
in 
Section 
6.0 
-
Trial 
Flow 
Chart 
and 
Section 
7.1.4.1
–
Withdrawal/Discontinuation.
Subjects may discontinue study treatment at any time for any reason or be dropped from 
study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a subject 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 7.1.4 – Other Procedures.
A subject must be discontinued from study treatment but continue to be monitored in the trial 
for any of the following reasons:
○
The subject or subject’s legally acceptable representative requests to discontinue study 
treatment.

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Subjects with AEs meeting discontinuation criteria as described in Section 5.2.1.
o
The subject has a medical condition or is non-compliance to study treatments or 
procedures which, in the opinion of the investigator and/or Sponsor, places the subject at 
unnecessary risk from continued administration of study drug.
o
Female subject with confirmed positive serum pregnancy test.
When a subject is first identified with radiologic PD by the investigator, all scans must be 
submitted to the central imaging vendor for verification of PD by BICR. Clinically stable 
subjects may remain on study treatment while waiting for BICR verification and/or have 
further scans to confirm PD by the site. Details pertaining to BICR verification of PD, 
confirmation of PD by the site and timing for discontinuation of study treatment due to PD 
are described in Section 7.1.2. 
Subjects in the combination arm must discontinue pembrolizumab after receiving 35 doses of 
but may continue receiving axitinib until disease progression.
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
all visits and procedures, as outlined in the Trial Flow Chart (Section 6.0), should be 
completed. 
Subjects who discontinue treatment for reasons other than BICR verified PD should continue 
with imaging assessments per the protocol defined schedule until: 1) PD is BICR verified or 
further confirmed by investigator, 2) initiation of a new anti-cancer treatment, 3) death, 
4) withdrawal of consent from trial or 5) study conclusion or early termination, whichever 
occurs first.
For information about the Safety Follow-up Visit, please refer to Section 7.1.5.3.2.
For information about the Second Course Phase (Retreatment Period), please refer to 
Section 7.1.5.2.1.
Withdrawal from the Trial
5.8.2
Subjects may withdraw from the trial at any time for any reason.  If a subject withdraws from 
the trial, they will no longer receive treatment or be followed at scheduled protocol visits.
A subject will be withdrawn from the trial if:
○
The subject or subject’s legally acceptable representative withdraws consent from the 
trial.
○
The subject is lost to follow-up.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including specific details regarding withdrawal from Future Biomedical Research are 
outlined in Section 7.1.4 – Other Procedures.
Lost to Follow-up
5.8.2.1
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 

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The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered lost to 
follow-up. 
Second Course Phase (Retreatment)
5.8.3
Subjects enrolled in the pembrolizumab plus axitinib arm who stop pembrolizumab with SD 
or better may be eligible for up to 17 additional infusions of pembrolizumab therapy if they 
progress after stopping. This re-treatment is termed the Second Course Phase of this study 
and is only available if the study remains open and the subject meets the following 
conditions:
Stops initial treatment with pembrolizumab after a confirmed CR according to 
RECIST 1.1 per investigator assessment and has received
at least 8 doses of 
pembrolizumab 
OR

Has completed 35 doses (approximately 2 years) of pembrolizumab 
treatment 
without PD
AND

Experiences
an investigator-confirmed radiographic disease progression after 
stopping their initial treatment with pembrolizumab 

Does not receive any anti-cancer treatment since the last dose of pembrolizumab 

Has a KPS of ≥ 70% 

Demonstrate adequate organ function as detailed in Table 4

Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration 
of the trial or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator.
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.

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Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form. The overall 
trial ends when the clinical cutoff for the final OS analysis has been achieved.
Clinical Criteria for Early Trial Termination
5.11
Early trial termination will be the result of the criteria specified below:
1. The trial may be stopped early for futility or safety at the recommendation of the 
eDMC
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 subjects
5. Plans to modify or discontinue the development of the study drug
6. In the event of Sponsor decision to no longer supply study drug, ample notification 
will be provided so that appropriate adjustments to subject treatment can be made

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6.0 TRIAL FLOW CHART
Trial Flow Chart (Pembrolizumab in Combination With Axitinib)
6.1
Trial Period:
Screening
Treatment Cycles (1 cycle = 21 days)a
End of 
Treatment
Post-Treatment
Scheduled Clinic Visit:
Screening
Cycles 1-8
To be repeated 
Beyond Cycle 12
End of 
Treatment
Safety 
Follow-up
30 days 
from last 
dose 
Imaging 
Follow-up
Q6W
or
Q12Wb
Survival Follow-up
Q12Wc
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
-28 to -1
D1a
D8
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Clinic Visit Windows (Days):
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
(± 7)
(± 7) 
ADMINISTRATIVE PROCEDURES
Informed Consentd
X
Informed Consent - FBR 
X
Inclusion/Exclusion Criteria
X
Subject Identification Carde
X
X
Demographics & Medical History
X
Prior and Concomitant 
Treatment/Medication Reviewf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Post-study Anti-cancer Therapies
X
X
X
Survival Statusg
X
STUDY DRUG ADMINISTRATION/COMPLIANCE
Pembrolizumab Infusionh
X
X
X
X
X
X
X
X
X
X
X
X
Axitinib Dosingh
X (continuous BID dosing)
Dispense Axitinib and Dosing 
Diaryi
X
X
X
X
X
X
X
X
X
X
X
X
Review Axitinib Compliancei
X
X
X
X
X
X
X
X
X
X
X
X
CLINICAL PROCEDURES/ ASSESSMENTS
AE Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xj
Xj
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
X
X
X
X
X
Vital Signsk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Trial Period:
Screening
Treatment Cycles (1 cycle = 21 days)a
End of 
Treatment
Post-Treatment
Scheduled Clinic Visit:
Screening
Cycles 1-8
To be repeated 
Beyond Cycle 12
End of 
Treatment
Safety 
Follow-up
30 days 
from last 
dose 
Imaging 
Follow-up
Q6W
or
Q12Wb
Survival Follow-up
Q12Wc
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
-28 to -1
D1a
D8
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Clinic Visit Windows (Days):
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
(± 7)
(± 7) 
12-Lead ECGl
X
X
X
X
Karnofsky Performance Statusm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EFFICACY MEASUREMENTS – TUMOR IMAGING
Chest, Abdomen, Pelvis (CAP)
Xn
Xo
Xp
Bone Scan 
Xn,q
Xq
Xq
Brain Scan
Xn,r
Xr
Xr
PATIENT-REPORTED OUTCOMES
QoL (FKSI-DRS, EORTC QLQ-
C30, EQ-5D-3L)s
X
X
X
X
X
X
X
X
X
X
X
X
LABORATORY PROCEDURES/ASSESSMENTS – Local Laboratory
Pregnancy Testt
X
PT/INRu
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematologyu
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistryu
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysisu
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Thyroid Function Testingu
X
X
X
X
X
X
X
X
X
X
X
X
X
X
LABORATORY PROCEDURES/ASSESSMENTS – Central Laboratory
PKv,w
X
X
X
X
X
ADAv
X
X
X
X
X
TUMOR BIOPSY/ ARCHIVAL TISSUE COLLECTION/BLOOD FOR CORRELATIVE STUDIES
Tumor Tissue Collection
Xx
Blood for genetic analysesy
X
Blood for ctDNA analysesz
X
X
X
X
Blood for TCR repertoirez
X
X
X
X
Blood for RNA analysesz
X
X
X
X

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Trial Period:
Screening
Treatment Cycles (1 cycle = 21 days)a
End of 
Treatment
Post-Treatment
Scheduled Clinic Visit:
Screening
Cycles 1-8
To be repeated 
Beyond Cycle 12
End of 
Treatment
Safety 
Follow-up
30 days 
from last 
dose 
Imaging 
Follow-up
Q6W
or
Q12Wb
Survival Follow-up
Q12Wc
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
-28 to -1
D1a
D8
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Clinic Visit Windows (Days):
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
(± 7)
(± 7) 
Blood for plasma biomarker 
analysesz
X
X
X
Blood for serum biomarker 
y
X
X
X
a. Each treatment cycle in the pembrolizumab plus axitinib arm is 21 days ± 3 days. C1D1 denotes the first dose of study treatment, which can be on the date of 
randomization or within 3 days of randomization. 
b. Imaging follow-up visits are for subjects who have discontinued study treatment without reaching BICR verified or further investigator confirmed PD.  See 
footnotes “n” and “o” for further details. 
c. Survival follow-up may be conducted as a telephone call or a clinic visit Q12W (visit window is ± 7 days through Week 104 and ± 14 days after Week 104).  
Survival contact may be requested more frequently at the time of interim and final analysis or an eDMC safety review (see Section 7.1.5.3.4).
d. Written consent must be obtained prior to performing any protocol-specified procedures. 
e. The Subject Identification Card should be dispensed at Screening and collected at the End of Treatment visit.
f. Prior treatments/medications: record all prior treatments for RCC.  Record all other medications taken within 30 days prior to the first dose of trial treatment.  
Concomitant medications: enter new medications started during the trial and up to 30 days after last dose of trial treatment regardless of when the Safety Follow-up 
visit occurs.  All medications related to reportable SAEs and ECIs should be recorded as defined in Section 7.2. 
g. Following verification of disease progression by BICR or further confirmation by the investigator, or the start of new anticancer treatment; contacts are 
approximately every 12 weeks by telephone. Updated survival status may be requested by the Sponsor at any time during the course of the study. 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 death event previously recorded).
h. Trial treatment should begin within 3 days of randomization for both pembrolizumab and axitinib. See Section 5.2.3 for dose administration details.
i. Subjects will be given a dosing diary for axitinib when axitinib bottles are provided; the dosing diary should be returned at the next visit and be assessed for dosing 
compliance. See details in Section 7.1.1.9.
j. After the end of treatment, each subject will be followed for 30 days for AE monitoring (SAEs will be collected for 90 days after the end of treatment or 30 days 
after the end of treatment if the subject initiates new anti-cancer therapy, whichever is earlier).  See Section 7.2.3.1 for details.
k. Vital Signs will be assessed at Screening (within 10 days of randomization) and D1 of every cycle beginning at Cycle 2, the End of Treatment visit and the Safety 
Follow-up visit.  C1D8 will only collect BP and pulse rate. Height will only be collected at Screening and will be recorded in the vital signs form. See Section 
7.1.2.4 for BP assessments at baseline and during treatment.
l. An ECG is performed at Screening (within 10 days of randomization), after the completion of every 4 cycles (12 weeks) on treatment (C5D1, C9D1, C13D1,…) 
and Safety Follow-up.
m. KPS is assessed at Screening (within 10 days of randomization), on Day 1 visit of every cycle starting from C2 and Safety Follow-up.
n. Baseline imaging must be performed within 28 days prior to randomization.  Scans performed as part of routine clinical management are acceptable if they are of 

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Trial Period:
Screening
Treatment Cycles (1 cycle = 21 days)a
End of 
Treatment
Post-Treatment
Scheduled Clinic Visit:
Screening
Cycles 1-8
To be repeated 
Beyond Cycle 12
End of 
Treatment
Safety 
Follow-up
30 days 
from last 
dose 
Imaging 
Follow-up
Q6W
or
Q12Wb
Survival Follow-up
Q12Wc
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
-28 to -1
D1a
D8
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Clinic Visit Windows (Days):
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
(± 7)
(± 7) 
diagnostic quality and within the 28 day window.  See Sections 7.1.2.7.1 and 7.1.2.7.2 for additional imaging requirement at baseline and follow up if RCC 
metastatic lesions identified outside of the standard imaging assessment anatomic regions per protocol.
o. Imaging after randomization will be performed at Week 12 (84 days ±7 days), then Q6W (42 days ±7 days) through Week 54, then Q12W (84 days ±7 days) 
thereafter until PD is BICR verified. Imaging visit window may be ± 14 days after Week 104. Unscheduled imaging can be performed as clinically indicated.  The 
timing of imaging assessments should follow calendar days from randomization and should not be adjusted for dose delays or cycle starts. Imaging anatomic 
coverage should be the same as that at screening; see Section 7.1.2.7.2 for details.
p. Subjects who discontinue treatment for reasons other than BICR verified PD should continue with imaging assessments per the protocol defined schedule as 
outlined in footnote “n” until: 1) PD is BICR verified, 2) initiation of a new anti-cancer treatment, 3) death, 4) withdrawal of consent or 5) study conclusion or early 
termination, whichever occurs first.  
q. Baseline bone scan is required for all subjects.  If a subject has a positive baseline bone scan, after randomization, bone scans will be performed at Week 18 
(Day 126 ± 7 days) and should continue to be performed Q12W (84 days ±7 days) through Week 54, subsequently Q24W (168 days ±7 days) until PD is BICR 
verified or further confirmed by the investigator. The timing of imaging assessments should follow calendar days from randomization and should not be adjusted 
for dose delays or cycle starts.  Bone scans must be performed for the confirmation of Complete Response (CR) for subjects with a positive bone scan at baseline.
r. A brain scan will be performed during screening for subjects with brain metastasis to ensure subject is stable. After randomization, brain imaging should be 
performed as clinically indicated and to confirm a CR in subjects with brain metastasis at baseline.
s. At each clinic visit, Quality of Life (QoL) measurements should be performed before all other study procedures and assessments, including the dosing of study 
medication. QoL will be assessed on D1 visit of every cycle from C1-C8, D1 visit of every other cycle from C9 to C19, D1 visit of every 4 cycles from C19 
(approximately Week 54) until study treatment is discontinued.  In addition, QoL is to be assessed at the Treatment Discontinuation visit and 30-day Safety follow-
up visit.  QoL is only assessed once if these two visits are combined.  
t. Pregnancy tests – Urine or serum -hCG: See Section 5.1.2 for pregnancy tests requirements for screening. If the randomization pregnancy test is more than 
72 hours prior to the first dose of study treatment, it should be repeated.  If urine pregnancy results are positive or cannot be confirmed as negative, a serum 
pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local 
guidelines.  Monthly pregnancy testing should be conducted as per local regulations where applicable.
u. PT/INR, hematology, chemistry, urinalysis, and thyroid function testing will be performed at Screening (within 10 days of randomization), on Day 1 visit of every
cycle (starting from C2), End of Treatment visit and at the Safety Follow-up visit. Routine safety laboratory values of chemistry and hematology results should be 
available prior to each pembrolizumab dosing.  
v. Pre-dose trough PK and ADA samples for the pembrolizumab plus axitinib arm will be collected on Day 1 of Cycles 1, 3, 5, every 4 cycles thereafter (C9D1, 
C13D1, C17D1,…) and 30 days after discontinuation. Pre-dose trough samples should be drawn within 24 hours prior to pembrolizumab infusion. 
w.Additional post-dose peak PK samples will be drawn within 30 minutes after end of pembrolizumab infusion at Cycles 1 and 9. See Section 7.1.3.3 for additional 
guidance for PK sampling when dosing is interrupted/delayed.
x. Tumor tissue from an archival tissue sample or newly obtained biopsy should be submitted at Screening for biomarker analysis.

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Trial Period:
Screening
Treatment Cycles (1 cycle = 21 days)a
End of 
Treatment
Post-Treatment
Scheduled Clinic Visit:
Screening
Cycles 1-8
To be repeated 
Beyond Cycle 12
End of 
Treatment
Safety 
Follow-up
30 days 
from last 
dose 
Imaging 
Follow-up
Q6W
or
Q12Wb
Survival Follow-up
Q12Wc
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
-28 to -1
D1a
D8
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Clinic Visit Windows (Days):
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
(± 7)
(± 7) 
y. 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 if the IRB/IEC does not approve) sample collection for these purposes, then such samples will not be collected at the corresponding sites. 
Leftover DNA extracted from the planned genetic analysis samples will be stored for Future Biomedical Research only if the subject signs the FBR consent. If the 
planned genetic analysis is not approved, but FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
z. Blood for ctDNA, TCR repertoire, RNA analyses and blood for serum/plasma biomarker analyses should be collected pre-dose according to time points on the flow 
chart regardless of missing dose. If visit is skipped, sample should be collected at the next visit. Leftover samples may be kept for Future Biomedical Research if 
the subject signs the FBR consent. 

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Trial Flow Chart (Sunitinib)
6.2
Trial Period:
Screening
Treatment Cycles (1 cycle = 42 days)a
End of 
Treat-
ment
Post-Treatment
Treatment Cycle:
Screening
Cycles 1-4
To be repeated 
Beyond Cycle 6
Discon
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
C1
C2
C3
C4
C5
C6
Scheduled clinic visit:
-28 to -1
D1a
D15
D29
D1
D29
D1
D29
D1
D29
D1
D1
End of 
Treatment
30 days
from last 
dose
(± 3 days)
Q6W
or
Q12Wb
(± 7 days)
Q12Wc
(± 7 days) 
Clinic visit Windows (Days):
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
ADMINISTRATIVE PROCEDURES
Informed Consentd
X
Informed Consent - FBR 
(optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Carde
X
X
Demographics & Medical 
History
X
Prior and Concomitant 
Treatment/Medication
Reviewf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Post-study Anti-cancer
Therapy Status
X
X
X
Survival Statusg
X
STUDY DRUG ADMINISTRATION/ COMPLIANCE
Sunitinib Dosingh
X [scheduled dosing is 4 weeks on (D1-D28) and 2 weeks off (D29-D42) for 
each cycle] from C1D1
Dispense Sunitinib and Dosing 
Diaryi
X
X
X
X
X
X
Review Sunitinib Compliancei
X
X
X
X
X
X

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Trial Period:
Screening
Treatment Cycles (1 cycle = 42 days)a
End of 
Treat-
ment
Post-Treatment
Treatment Cycle:
Screening
Cycles 1-4
To be repeated 
Beyond Cycle 6
Discon
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
C1
C2
C3
C4
C5
C6
Scheduled clinic visit:
-28 to -1
D1a
D15
D29
D1
D29
D1
D29
D1
D29
D1
D1
End of 
Treatment
30 days
from last 
dose
(± 3 days)
Q6W
or
Q12Wb
(± 7 days)
Q12Wc
(± 7 days) 
Clinic visit Windows (Days):
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
CLINICAL PROCEDURES/ ASSESSMENTS
AE Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
Xj
Xj
Full Physical Examination
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
Vital Signsk
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGl
X
X
X
X
KPSm
X
X
X
X
X
X
X
X
X
X
EFFICACY MEASUREMENTS – TUMOR IMAGING
Chest, Abdomen, Pelvis
Xn
Xo
Xp
Bone Scan 
Xn,q
Xq
Xq
Brain Scan
Xn,r
Xr
Xr
PATIENT REPORTED OUTCOMES
QoL (FKSI-DRS, EORTC 
QLQ-C30, EQ-5D-3L)s
X
X
X
X
X
X
X
X
X
X
X
X
LABORATORY PROCEDURES/ ASSESSMENTS – Local Lab
Pregnancy Testt
X
PT/INRut
X
X
X
X
X
X
X
X
X
X
X
Hematologyu
X
X
X
X
X
X
X
X
X
X
X
Chemistryu
X
X
X
X
X
X
X
X
X
X
X
Urinalysisu
X
X
X
X
X
X
X
X
X
X
X
Thyroid Function Testingu
X
X
X
X
X
X
X
X
X
X
X

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Trial Period:
Screening
Treatment Cycles (1 cycle = 42 days)a
End of 
Treat-
ment
Post-Treatment
Treatment Cycle:
Screening
Cycles 1-4
To be repeated 
Beyond Cycle 6
Discon
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
C1
C2
C3
C4
C5
C6
Scheduled clinic visit:
-28 to -1
D1a
D15
D29
D1
D29
D1
D29
D1
D29
D1
D1
End of 
Treatment
30 days
from last 
dose
(± 3 days)
Q6W
or
Q12Wb
(± 7 days)
Q12Wc
(± 7 days) 
Clinic visit Windows (Days):
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
TUMOR BIOPSY/ ARCHIVAL TISSUE COLLECTION/ BLOOD FOR CORRELATIVE STUDIES
Tumor Tissue Collection
Xv
Blood for genetic analysesw
X
Blood for ctDNA analysesx
X
X
X
X
Blood for TCR repertoirex
X
X
X
X
Blood for RNA analysesx
X
X
X
X
Blood for plasma biomarker
analysesx
X
X
X
Blood for serum biomarker 
analysesx
X
X
X
a.
Each treatment cycle in the sunitinib arm is 6 weeks long (42 days ± 3 days). C1D1 denotes the first dose of study treatment, which can be on the date of 
randomization or within 3 days of randomization. See Section 5.2.3.4 for scenarios regarding dose interruptions.
b.
Imaging Follow-up visits are for subjects who have discontinued study treatment without reaching BICR verified or further investigator confirmed PD. See 
footnotes “n” and “o” for further details. 
c.
Survival Follow-up may be conducted as a telephone call or a clinic visit Q12W (visit window is ± 7 days through Week 104 and ± 14 days after Week 104).  
Survival contact may be requested more frequently at the time of interim and final analysis or an eDMC safety review (see Section 7.1.5.3.4).
d.
Written consent must be obtained prior to performing any protocol-specified procedures.
e.
The Subject Identification Card should be dispensed at Screening and collected at the End of Treatment visit.
f.
Prior treatments/medications: record all prior treatment for RCC. Record all medications taken within 30 days prior to the first dose of trial treatment.  
Concomitant medications: enter new medications started during the trial and up to 30 days after last dose of trial treatment regardless of when the safety 
follow-up visit occurs.  All medications related to reportable SAEs and ECIs should be recorded as defined in Section 7.2. 
g.
Following verification of disease progression by BICR or further confirmation by the investigator, or the start of new anticancer treatment; contacts are 
approximately every 12 weeks by telephone. Updated survival status may be requested by the Sponsor at any time during the course of the study. 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 death event previously recorded).
h.
Trial treatment should begin within 3 days of randomization for sunitinib. See Section 5.2.3 for dose administration details. 

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Trial Period:
Screening
Treatment Cycles (1 cycle = 42 days)a
End of 
Treat-
ment
Post-Treatment
Treatment Cycle:
Screening
Cycles 1-4
To be repeated 
Beyond Cycle 6
Discon
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
C1
C2
C3
C4
C5
C6
Scheduled clinic visit:
-28 to -1
D1a
D15
D29
D1
D29
D1
D29
D1
D29
D1
D1
End of 
Treatment
30 days
from last 
dose
(± 3 days)
Q6W
or
Q12Wb
(± 7 days)
Q12Wc
(± 7 days) 
Clinic visit Windows (Days):
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
i.
Subjects will be given a dosing diary for sunitinib when sunitinib bottles are provided; the diary should be returned at the next visit and assessed for dosing 
compliance. See details in Section 7.1.1.9. 
j.
After the end of treatment, each subject will be followed for 30 days for AE monitoring (SAEs will be collected for 90 days after the end of treatment or 
30 days after the end of treatment if the subject initiates new anti-cancer therapy, whichever is earlier).  See Section 7.2.3.1 for details.
k.
Vital Signs will be assessed at Screening (within 10 days of randomization), Day 15 and Day 29 of C1 and Day 1 and Day 29 C2 to C4, then Day 1 of all 
subsequent visits, the End of Treatment visit and the Safety Follow-up visit.  C1D15 will only collect BP and pulse rate. Height will only be collected at 
Screening and will be recorded in the vital signs form. See Section 7.1.2.4 for BP assessments at baseline and during treatment.
l.
An ECG is performed at Screening (within 10 days of randomization), after the completion of every 2 cycles (12 weeks) on treatment (C3D1, C5D1, C7D1, 
C9D1,…) and Safety Follow-up.
m. KPS is assessed at Screening (within 10 days of randomization), on Day 29 of C1, Day 1 and D29 of cycle C2-C3, Day 1 of every cycle thereafter (C4D1, 
C5D1, C6D1,…) and Safety Follow-up.
n.
Baseline imaging must be performed within 28 days prior to randomization.  Scans performed as part of routine clinical management are acceptable for use as 
the screening scan if they are of diagnostic quality and performed within the 28 day window. See Section 7.1.2.7.1 for additional imaging requirements at 
baseline and follow-up in subjects with RCC metastatic lesions identified outside of the standard imaging assessment anatomic regions per protocol.
o.
Imaging after randomization will be performed at Week 12 (84 days ± 7 days), then Q6W (42 days ±7 days) through Week 54, then Q12W (84 days ±7 days) 
thereafter until PD is BICR verified or further confirmed by the investigator. Imaging visit window can be ± 14 days after Week 104. Unscheduled imaging can 
be performed as clinically indicated.  The timing of imaging assessments should follow calendar days from randomization and should not be adjusted for dose 
delays or cycle starts. Imaging anatomic coverage should be the same as that at screening; see Section 7.1.2.7.2 for details.
p.
Subjects who discontinue treatment for reasons other than BICR verified PD should continue with imaging assessments per the protocol defined schedule as 
outlined in footnote n until: 1) PD is BICR verified or further confirmed by investigator, 2) initiation of a new anti-cancer treatment, 3) death, 4) withdrawal of 
consent or 5) study conclusion or early termination, whichever occurs first.  See footnote B for Imaging Follow-up schedule and windows.
q.
Baseline bone scan is required for all subjects.  If a subject has a positive baseline bone scan, after randomization, bone scans will be performed at Week 18 
(126 days ± 7 days)and should continue to be performed Q12W (84 days ±7 days) through Week 54.  After Week 54, subsequently Q24W (168 days ±7 days) 
through Week 54 until PD is BICR verified or further confirmed by investigator. The timing of imaging assessments should follow calendar days from 
randomization and should not be adjusted for dose delays or cycle starts.  Bone scans must be performed for the confirmation of Complete Response (CR) for 
subjects with a positive bone scan at baseline.
r.
A brain scan will be performed during screening for subjects with brain metastasis to ensure subject is stable. During the trial, brain imaging should be 
performed as clinically indicated and to confirm a CR in subjects with brain metastasis at baseline.

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Trial Period:
Screening
Treatment Cycles (1 cycle = 42 days)a
End of 
Treat-
ment
Post-Treatment
Treatment Cycle:
Screening
Cycles 1-4
To be repeated 
Beyond Cycle 6
Discon
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
C1
C2
C3
C4
C5
C6
Scheduled clinic visit:
-28 to -1
D1a
D15
D29
D1
D29
D1
D29
D1
D29
D1
D1
End of 
Treatment
30 days
from last 
dose
(± 3 days)
Q6W
or
Q12Wb
(± 7 days)
Q12Wc
(± 7 days) 
Clinic visit Windows (Days):
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
s.
At each clinic visit, Quality of Life (QoL) measurements should be performed before all other study procedures and assessments, including the dosing of study 
medication. QoL will be assessed D1 and D29 visits of C1-C4; D1 visit of C5 to C10, and D1 visit of every other cycle from C10 (D1C10, D1C12) 
(approximately Week 54) until study treatment is discontinued.  In addition, QoL is to be assessed at the Treatment Discontinuation visit and 30-day Safety 
Follow-up visit.  QoL is only assessed once if these two visits are combined. 
t.
Pregnancy tests – Urine or Serum -hCG: See Section 5.1.2 for pregnancy tests requirements for screening. If the randomization pregnancy test is more than 
72 hours prior to the first dose of trial treatment, it should be repeated. If urine pregnancy results are positive or cannot be confirmed as negative, a serum 
pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local 
guidelines.  Monthly pregnancy testing should be conducted as per local regulations where applicable.
u.
PT/INR, hematology, chemistry, urinalysis and thyroid function testing will be performed at Screening (within 10 days of randomization), C1D29, C2D1, 
C2D29, C3D1, C3D29, Day 1 of every cycle thereafter (C4D1, C5D1, C6D1,…), the End of Treatment visit and the Safety Follow-up visit. 
v.
Tumor tissue from an archival tissue sample or newly obtained biopsy should be submitted at screening for biomarker analysis.
w.
Samples should be collected for planned analysis of the association between genetic variants in germline/tumor DNA and drug response. If a documented law 
or regulation prohibits (or if the IRB/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 samples will be stored for Future Biomedical Research only if the subject signs the FBR 
consent. If the planned genetic analysis is not approved, but FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
x.
Blood for ctDNA, TCR repertoire, RNA analyses and blood for serum/plasma biomarker analyses should be collected pre-dose according to time points on the 
flow chart. Leftover samples may be kept for Future Biomedical Research if the subject signs the FBR consent.

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Trial Flow Chart Second Course Phase (Retreatment)
6.3
Second course re-treatment subjects may receive up to 17 cycles (approximately 1 year) of pembrolizumab therapy.
Trial Period:
Treatment Cycles
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
Cycles 1-8
To be repeated 
Beyond 12 
Cycles
Discon
Safety Follow-up
Imaging Follow-up 
Visits
Survival 
Follow-up
1
2
3
4
5
6
7
8
9
10
11
12
Scheduling Window (Days):
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
At time of 
Discon
30 days from last 
dose
(± 3 days)
Every 6 or 12
weeks post discon
(± 7 days)
Every 12 
weeks
(± 7 days) 
ADMINISTRATIVE PROCEDURES
Re-treatment Criteria
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab Administration
Xa
X
X
X
X
X
X
X
X
X
X
X
Post-study Anti-cancer Therapy Status
X
X
Survival Statusb
X
CLINICAL PROCEDURES/ASSESSMENTS
AE Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
Xc
Xc
Full Physical Examination
X
Directed Physical Examination
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
Karnofsky Performance Statuse
X
X
X
X
X
X
X
X
X
X
X
X
X
EFFICACY MEASUREMENTS
Tumor Imaging - chest, abdomen, pelvis (CAP) 
Xf
Xg
Tumor Imaging – bone scan 
Xf,h
Xh
Tumor Imaging – brain scan
Xi
Xi
LABORATORY PROCEDURES/ASSESSMENTS: ANALYSIS PERFORMED BY LOCAL LABORATORY
Pregnancy Test – Urine or Serum -hCGj
X
PT/INR
Xk
Hematologyl
Xk
X
X
X
X
X
X
X
X
X
X
X
X
X

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Trial Period:
Treatment Cycles
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
Cycles 1-8
To be repeated 
Beyond 12 
Cycles
Discon
Safety Follow-up
Imaging Follow-up 
Visits
Survival 
Follow-up
1
2
3
4
5
6
7
8
9
10
11
12
Scheduling Window (Days):
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
At time of 
Discon
30 days from last 
dose
(± 3 days)
Every 6 or 12
weeks post discon
(± 7 days)
Every 12 
weeks
(± 7 days) 
Chemistryl
Xk
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysism
Xk
X
X
X
X
X
X
X
X
T3, FT4, and TSHm
Xk
X
X
X
X
X
X
X
X
a.
Cycle 1 re-treatment must be given within 3 days. 
b. Following documented disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated survival status may 
be requested by the Sponsor at any time during the course of the study. 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 death event previously recorded)..
c.
After the end of treatment each subject will be followed for 30 days for AE monitoring (SAEs will be collected for 90 days after the end of treatment or 30 days after the end of 
treatment if the subject initiates new anti-cancer therapy, whichever is earlier). See Section 7.2.3.1 for details.
d.
Height will be measured prior to re-treatment. Vital signs will be performed within 10 days prior to the first re-treatment dose of pembrolizumab.
e.
Karnofsky Performance Status will be performed prior to re-treatment (within 10 days prior to the first re-treatment dose of pembrolizumab) and Day 1 visit of every cycle.
f.
The initial tumor imaging will be performed within 28 days prior to first re-treatment cycle and then every 12 weeks thereafter (84 days ±7 days). 
g.
Subjects who discontinue treatment for reasons other than BICR verified PD should continue with imaging assessments per the protocol defined schedule until 1) PD is BICR 
verified or further confirmed by the investigator, 2) initiation of a new anti-cancer treatment, 3) death or 4) withdraw of consent from trial or 5) study conclusion or early 
termination, whichever occurs first.
h.
A bone scan will be performed prior to first re-treatment cycle. If a subject has a positive bone scan, bone scans will be performed additionally every 24 weeks thereafter 
(168 days ±14 days). The timing of imaging assessments should follow calendar days from C1 of re-treatment and should not be adjusted for dose delays or cycle starts.  Bone 
scans must be performed for the confirmation of Complete Response (CR).
i.
A brain scan is as clinically indicated but is required for subjects with brain metastasis if the subject achieves a CR.
j.
For women of childbearing potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial re-treatment.  If urine pregnancy results are positive
or cannot be confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be 
repeated if required by local guidelines.  Monthly pregnancy testing should be conducted as per local regulations where applicable.
k.
Laboratory tests for determining eligibility are to be performed within 10 days prior to the first re-treatment dose of pembrolizumab.
l.
Hematology and chemistry assessments will be performed prior to re-treatment, Day 1 visit of every cycle, at treatment discontinuation, and 30 days after discontinuation.
m. Urinalysis and T3, FT4, and TSH will be performed prior to re-treatment, then every other cycle starting at Cycle 2, at treatment discontinuation, and 30 days after 
discontinuation.

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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
Informed Consent
7.1.1.1
The investigator or qualified designee must obtain documented consent from each potential 
subject prior to participating in a clinical trial or Future Biomedical Research. If there are 
changes to the subject’s status during the trial (e.g., health or age of majority requirements), 
the investigator or qualified designee must ensure the appropriate consent is in place.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’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 subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’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 subject’s dated signature or 
by the subject’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/ERC requirements, applicable laws and regulations 
and Sponsor requirements.

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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
Inclusion/Exclusion Criteria
7.1.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
7.1.1.3
All subjects will be given a Subject 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 subject with a Subject Identification Card immediately after the subject 
provides written informed consent. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
7.1.1.4
A medical history will be obtained by the investigator or qualified designee.  The medical 
history will include all active conditions and any conditions diagnosed within the prior 
10 years that are considered clinically significant by the Investigator.  Details pertaining to 
the subject’s renal cell carcinoma diagnosis will be recorded separately and not listed as 
medical history.
7.1.1.4.1 History of Renal Cell Carcinoma
The investigator or qualified designee will obtain information regarding the subject’s renal 
cell carcinoma. This information will include but is not limited to the presentation at primary 
diagnosis, date and stage at primary diagnosis, date of most recent recurrence, and location of 
metastases at screening (if applicable).
Prior and Concomitant Medications Review
7.1.1.5
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use and record prior 
medication taken by the subject within 30 days before the first dose of trial medication. Prior 
treatment for RCC will be recorded separately and not listed as prior medication.

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7.1.1.5.2 Prior Treatment Details for Renal Cell Carcinoma
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation, and surgeries and record in the trial database on forms 
specific for each topic.
7.1.1.5.3 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial and until 30 days after the last dose of trial treatment regardless of when the 
safety follow-up visit occurs.  All medications related to reportable SAEs and ECIs should be 
recorded as defined in Section 7.2.
Subsequent Anti-Cancer Therapy Status
7.1.1.6
All new anti-cancer therapy initiated after the study start must be recorded in the eCRF. If a 
subject initiates another anti-cancer therapy other than the assigned study treatment(s), the 
study treatment(s) should be discontinued and the subject will move into the survival follow-
up phase; if a subject initiates a new anti-cancer therapy within 30 days after the last dose of 
the trial treatment, the 30 day Safety Follow-up visit must occur before the first dose of the 
new therapy.
Assignment of Screening Number
7.1.1.7
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject 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 7.1.5.1.  
Assignment of Treatment/Randomization Number
7.1.1.8
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Trial Compliance (Medication)
7.1.1.9
Interruptions from the protocol specified treatment for pembrolizumab greater than 3 weeks 
for events unrelated to study therapy or 12 weeks for toxicities, interruptions for axitinib 
greater than 3 weeks for toxicities, or interruptions for sunitinib greater than 2 weeks beyond 
the scheduled off treatment portion (2 weeks) at the end of the cycle, require consultation 

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between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
Administration of pembrolizumab will be witnessed by the investigator and/or trial staff. The 
total volume of trial treatment infused will be compared to the total volume prepared to 
determine compliance to each dose administered. 
The instructions for preparing and 
administering pembrolizumab will be provided in the Pharmacy Manual.
Each subject will be dispensed a dosing diary for axitinib and sunitinib. The diary will 
record the date and time (if applicable) of daily dose, the tablets or capsules taken of each 
strength dispensed, the blood pressure (if subject is doing home blood pressure monitoring), 
whether the dose was vomited or missed and any comments regarding missed doses. 
Compliance with axitinib and sunitinib treatment will be reviewed at each visit for the dose 
prescribed and dose taken based on the diary.
Clinical Procedures/Assessments
7.1.2
Adverse Event Monitoring
7.1.2.1
The investigator or qualified designee will assess each subject to evaluate for potential new
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically
indicated. Adverse events will be graded and recorded throughout the study and during the
follow-up period according to NCI CTCAE Version 4.0 (see Section 12.5). Toxicities will
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken
with regard to trial treatment.  
All AEs must be reported through 30 days following the last dose of trial treatment and 
should be recorded regardless of when the Safety Follow-up visit occurs.  All SAEs must be 
reported through 90 days following the last dose of trial treatment or until the start of new 
anti-cancer treatment, whichever comes first.  Drug related AEs must be reported regardless 
of seriousness and whether or not they occur outside of any reporting timeframes.
Full Physical Examination
7.1.2.2
The investigator or clinical designee will perform a complete (full) PE during the screening 
period and at discontinuation of treatment, as specified in the Trial Flow Chart in Section 6.0. 
Full physical examination includes a review of the patient’s history, evaluation of the 
patient’s general appearance, and examination of the major systems, including 
cardiovascular, pulmonary, GI, musculoskeletal, lymphatic, and neurologic. 
Clinically 
significant abnormal findings at screening should be recorded as medical history. After 
randomization, new clinically significant abnormal findings should be recorded as AEs.
Directed Physical Exam
7.1.2.3
Other than the Screening and End of Treatment visit, the investigator or qualified designee 
will perform a directed physical exam as specified in the Trial Flow Charts in Section 6.0. 
Directed PE refers to a symptoms-directed PE. New clinically significant abnormal findings 
should be recorded as AEs.

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Vital Signs
7.1.2.4
The investigator or qualified designee will assess vital signs (including weight, temperature, 
pulse rate, respiratory rate, and blood pressure) prior to administration of study treatment at 
each visit as specified in the Trial Flow Charts for each treatment arm in Section 6.0. Blood 
pressure should be taken after the subject has been at rest for 10 minutes. At baseline 
assessments, BP measurements should be performed in triplicate, at least 2 minutes apart.  
Eligibility should be based on the mean systolic and/or diastolic BP values (see Section 5.1.3,
Exclusion Criterion 19). At visits following randomization, triplicate BP measurement is 
required only if initial BP assessment has SBP ≥ 150 mmHg and/or DBP ≥ 90 mmHg. In 
that situation, dose modification should be based on the mean systolic and/or diastolic BP 
values if associated with study treatment and all 3 measurements are to be entered into the 
eCRF.
12-Lead Electrocardiogram
7.1.2.5
A standard 12-lead ECG will be performed using local standard procedures. The timing of 
ECGs is specified in the Trial Flow Chart in Section 6.0.  Clinically significant abnormal 
findings at screening should be recorded in the medical history. Additional ECGs may be 
performed as clinically necessary. 
Karnofsky Performance Status
7.1.2.6
The KPS is a standard way of measuring the ability of cancer patients to perform ordinary 
tasks, with scores ranging from 0% to 100%. A higher score means the patient is better able 
to carry out daily activities. See Section 12.4 for a description of the full scale. The KPS 
will be assessed as specified in the Trial Flow Charts in Section 6.0.
A KPS ≥70% is 
required for study eligibility.
Tumor Imaging and Assessment of Disease
7.1.2.7
The process for image collection and transmission to the blinded central imaging vendor
(CIV) can be found in the Site Imaging Manual (SIM).  Acceptable imaging modalities for 
each anatomic region are described as follows: 

For chest, abdomen and pelvis, 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 subjects with renal impairment, the following 
choices may be selected at the discretion of the investigator:  1) CT without IV 
contrast for all three anatomic regions or 2) a combination of MRI with or without IV 
contrast for abdomen and pelvis plus a chest CT without IV contrast. 

For brain metastasis, MRI is preferred but CT is also acceptable. 

For bone metastasis, bone scintillation or local standard of care modality should be 
used. X-ray may also be taken for symptomatic sites even if bone scan is negative and 
there is clinical suspicion for metastatic disease.

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The same imaging technique regarding modality and use of contrast should be used in a 
subject for each anatomic region throughout the trial to optimize the visualization of existing 
and new tumor burden.
All scheduled images for all subjects must be submitted to the designated CIV for BICR 
review. Imaging (including other modalities) obtained to determine disease progression at 
unscheduled time points must also be submitted to CIV. In addition, imaging obtained for 
other reasons but capturing radiologic progression, should also be submitted to CIV for BICR
review.
BICR will verify PD following the first radiologic evidence of PD identified by the 
investigator.  BICR PD verification will be expedited and will be communicated to the study 
site and sponsor (See Section 7.1.2.7.6).
7.1.2.7.1 Tumor Imaging at Screening
Tumor imaging at screening must be performed within 28 days prior to the date of 
randomization.  For this study, imaging of the chest, abdomen, and pelvis (CAP) are required 
for all subjects at Screening. A subject must have measurable disease per RECIST 1.1 as 
determined by the investigator at baseline in order to be eligible. Although RECIST 1.1 
references a maximum of 5 target lesions in total and 2 per organ, the sponsor allows 
maximum of 10 target lesions in total and maximum of 5 per organ to be selected at baseline, 
if clinically relevant, to enable a broader sampling of tumor burden.  
Bone scans will be acquired for all subjects at baseline. Additionally, an X-ray may also be 
taken for symptomatic sites even if bone scan is negative and there is clinical suspicion for 
metastatic disease.
Subjects with stable brain metastases may participate if they are stable without evidence of 
progression for at least 4 weeks by repeat imaging. Please note that the repeat imaging 
should be performed during study screening (see Section 5.1.3 Exclusion 9 for detailed 
requirement).
Imaging scans performed as part of routine clinical management are acceptable as screening
tumor imaging if they are of diagnostic quality, complete and performed within 28 days prior 
to the date of randomization and can be assessed by BICR. 
If a subject has RCC metastatic lesions identified outside of the aforementioned regions, 
additional imaging of the corresponding anatomic region should also be acquired. For 
example, if metastases occurred in the head and/or neck area, a soft tissue head and/or neck 
CT or MRI should be acquired. These lesions can be selected as target or non-target lesions 
per RECIST 1.1.  See Section 7.1.2.7.2 on follow up of these lesions. 
7.1.2.7.2 Tumor Imaging During the Trial 
Details regarding imaging collection timepoints are provided in the Trial Flow Charts
(Section 6.0).
The first post-randomization imaging assessment of CAP will be performed at Week 12 
(84 days ± 7 days from the date of randomization). Subsequent tumor imaging of CAP 
should be performed Q6W (42 days ±7 days) through Week 54 and Q12W (84 days ±7 days) 

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thereafter until PD is verified by BICR or further confirmed by the investigator. The imaging 
visit window can be ± 14 days after Week 104. Unscheduled imaging can be performed as 
clinically indicated.  For RCC metastatic lesions identified outside of the protocol-defined 
regions (i.e., CAP, bone, brain), the lesions should be followed in accordance with the same 
imaging assessment schedule as CAP and same modality should be used before and after  
randomization.  
If a subject has a positive bone scan at baseline (Screening), post randomization bone scans 
should be performed at Week 18 (126 days ± 7 days) and then Q12W (84 days ±7 days) 
through Week 54.  After Week 54, bone scans will be performed every 24 weeks (168 days 
±7 days). A bone scan may also be obtained if there are new symptoms of bone pain in 
subjects with negative bone scans at baseline. Additionally, an X-ray may also be taken for 
symptomatic sites even if the bone scan is negative and there is clinical suspicion for 
metastatic disease.
For subjects with equivocal bone lesions at baseline, the bone scan 
should be performed in accordance with the aforementioned schedule until the lesions are 
determined to be non-cancerous.
The timing of imaging assessments should follow calendar dates and should not be adjusted
for dose delays or cycle starts.
Imaging should continue until PD is verified by BICR or further confirmed by investigator
(i.e., following PD verification by BICR), initiation of a new anti-cancer treatment, death, 
withdrawal of consent or study conclusion/ early termination, whichever occurs first.
All supplemental imaging must be submitted to the central imaging vendor for BICR.
When PD is first identified by the investigator/local radiologist for a subject, based on 
imaging assessment, the site should submit all the scans for the subject for an expedited 
verification of radiologic PD by BICR. The outcome of PD verification by BICR will be 
communicated to the study site and sponsor and the investigator should decide the next steps 
as outlined in Section 7.1.2.7.6.
Per irRECIST (Section 7.1.2.7.6), disease progression should be confirmed by the site in 
clinically stable subjects ≥4 weeks after BICR verification of site-assessed first radiologic 
evidence of PD. Subjects who have unconfirmed PD may continue on treatment at the 
discretion of the investigator until progression is confirmed by the site and provided that 
subjects have met the conditions detailed in Section 7.1.2.7.6.
Subjects who obtain a 
confirmation scan do not need to undergo the next scheduled imaging if it is scheduled
< 4 weeks after the confirmation scan. Subjects will return to their regular imaging schedule
starting with the next timepoint.
Subjects who have confirmed disease progression (as 
assessed by the site) will discontinue treatment. Exceptions are detailed in Section 7.1.2.7.6.
In the event that a subject has experienced a PR or CR, confirmation of response should be 
performed at the next scheduled imaging assessment visit. For subjects who are enrolled 
with baseline brain metastases, brain imaging should be performed at confirmation of a CR.
Bone scans must also be performed for the confirmation of a CR for those subjects who have 
a positive bone scan at baseline.

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7.1.2.7.3 End of Treatment and Follow-up Tumor Imaging
Subjects who discontinue treatment for reasons other than BICR verified PD should continue 
with imaging assessments per the protocol-defined schedule until PD is BICR verified or 
further confirmed by investigator (i.e., following PD verification by BICR), initiation of a 
new anti-cancer treatment, death, withdrawal of consent or study conclusion/early 
termination, whichever occurs first. See Section 7.1.5.3.3 for more details.
7.1.2.7.4 Second Course (Retreatment) Tumor Imaging
A subject who is eligible for the second course must have baseline imaging (CAP and bone 
scan) performed within 28 days prior to restarting treatment with pembrolizumab.  A local 
reading (investigator assessment with site radiology reading) will be used to determine 
eligibility.  All second course imaging will be submitted to BICR for retrospective review.
The first on study imaging assessment (CAP) should be performed at Week 12 (84 days 
±7 days) after the restart of treatment.  Subsequent tumor imaging should be performed 
Q12W (84 days ±7 days) or more frequently if clinically indicated.
A bone scan will be performed prior to first re-treatment cycle and then Q24W thereafter 
(168 ± 14 days) for subjects with positive bone scan at the start of re-treatment. Brain scan is 
as clinically indicated. For subject with known brain metastasis, a brain scan is required to 
confirm a CR. 
Imaging should continue until disease progression, initiation of a new anti-cancer treatment, 
death, withdrawal of consent or study conclusion/ early termination, whichever occurs first.  
Per irRECIST (Section 7.1.2.7.6), if tumor imaging shows initial PD, the tumor assessment 
should be repeated ≥ 4 weeks later in order to confirm PD with the option of continuing 
treatment while awaiting radiologic confirmation of progression. Subjects who obtain a 
confirmation scan do not need to undergo scheduled tumor imaging if it is < 4 weeks later 
and may wait until the next scheduled imaging time point if clinically stable.
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by radiologic imaging every 
12 weeks (84 days ± 7 days) until: 1) the start of new anti-cancer treatment, 2) disease 
progression, 3) death or 4) the end of the study, whichever occurs first.
7.1.2.7.5 RECIST 1.1 Assessment of Disease
RECIST 1.1 will be applied by the BICR and the investigator as the primary method for 
assessment of tumor response, date of disease progression, and as a basis for all protocol 
guidelines related to disease status (e.g., discontinuation of study therapy). 
Initial tumor imaging showing site-assessed PD should be submitted for BICR immediately. 
The site will be notified if BICR verifies PD using RECIST 1.1.
The upper portion of
Figure 4 illustrates the imaging flow involving verification of PD for clinically stable 
subjects.

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7.1.2.7.6 irRECIST Assessment of Disease
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic drugs and therefore is only required for subjects in 
the combination arm.
For subjects in the sunitinib treatment arm, irRECIST is optional.
irRECIST will be used by site investigator/local radiology review to assess tumor response 
and progression, and make treatment decisions. This data will be collected in the clinical 
database. Treatment efficacy based on irRECIST as assessed by BICR review will be 
evaluated retrospectively.
After PD has been verified by BICR, subjects should continue study treatment, if feasible,
until progression is further confirmed by the local site investigator/radiology assessment.  
This allowance to continue treatment despite initial radiologic PD takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after 
the start of immunotherapy, and then experience subsequent disease response.  Subjects that 
are deemed clinically unstable are not required to have repeat tumor imaging for 
confirmation of PD. Tumor flare includes any of the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing non-target lesion(s)

Development of new lesion(s)
In subjects who have shown initial evidence of radiological PD by RECIST 1.1 as verified by 
BICR, it is at the discretion of the Principal Investigator whether to continue a subject on 
study treatment until repeat imaging is obtained (using irRECIST for subject management, 
see Table 13 and Figure 4).  This clinical decision by the site investigator should be based on 
the subject’s overall clinical condition, including performance status, clinical symptoms, and 
laboratory data. Subjects who are clinically stable may continue receiving study treatment 
until PD is confirmed by repeat imaging assessment. Tumor assessment should be repeated 
≥4 weeks later in order to confirm PD by irRECIST per site assessment.  Clinical stability is 
defined as the following: 
1) Absence of symptoms and signs indicating clinically significant progression of
disease, including worsening of laboratory values
2) No decline in KPS
3) Absence of rapid progression of disease 
4) Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention  
Any subject deemed clinically unstable should be discontinued from trial treatment after 
BICR verification of site-assessed first radiologic evidence of PD and is not required to have 
repeat imaging for PD confirmation.
In determining whether or not the tumor burden has increased or decreased per irRECIST,
the local site investigator should consider all target and non-target lesions as well as any 
incremental new lesion(s).

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Scenarios where PD is not confirmed at repeat imaging if ALL of the following occur by 
irRECIST:

Target lesion sum of diameters is < 20 % or < 5 mm absolute increase compared to 
nadir

Non-target disease resulting in initial PD is stable or qualitatively improved

New lesion resulting in initial PD is stable or qualitatively improved 

No incremental new lesion(s) since last evaluation

No incremental new non-target lesion progression since last evaluation
If repeat imaging does not confirm PD per irRECIST as assessed by the local site 
investigator and the subject continues to be clinically stable, treatment may continue and 
follow the regular imaging schedule. 
Scenarios where PD is confirmed at repeat imaging if ANY of the following occur by 
irRECIST:

Target lesion sum of diameters remains ≥ 20% and at least 5 mm absolute increase 
compared to nadir

Non-target disease resulting in initial PD is qualitatively worse

New lesion resulting in initial PD is qualitatively worse

Additional new lesion(s) since last evaluation

Additional new non-target lesion progression since last evaluation
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
discontinued from study therapy.
NOTE: If a subject has confirmed radiographic progression (i.e., 2 scans at least 4 weeks 
apart demonstrating PD) per irRECIST, but the subject is achieving a clinically meaningful 
benefit, and there is no further increase in the tumor burden at the confirmatory tumor 
imaging, an exception to continue pembrolizumab treatment for subjects in the combination 
arm may be considered following consultation with the Sponsor. In this case, if treatment is 
continued, tumor imaging should continue to be performed following the intervals as 
outlined in Section 6.0 - Trial Flow Chart and be submitted to BICR.
Additional details about irRECIST are referenced in the Merck TIP Sheet for RECIST 1.1 
and irRECIST. 

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Table 13
Imaging and Treatment After First Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st 
radiologic 
evidence of PD 
by RECIST 1.1 
which has been 
verified by BICR
Repeat imaging at 
> 4 weeks at site to 
confirm PD
May continue study 
treatment at the local 
site 
investigator’s 
discretion 
while 
awaiting confirmatory 
tumor imaging by site 
by irRECIST.
Repeat imaging 
at > 4 weeks to 
confirm PD per 
physician 
discretion only
Discontinue treatment
Repeat 
tumor 
imaging 
confirms PD by 
irRECIST at the 
local site
No 
additional 
imaging required
Discontinue treatment 
Exception: 
treatment 
with 
pembrolizumab 
may 
continue 
following consultation 
with the Sponsor if 
there is no further 
increase in the tumor 
burden 
at 
the 
confirmatory 
tumor 
imaging,  
No 
additional 
imaging 
required
N/A
Repeat 
tumor 
imaging 
shows 
SD, PR or CR by 
irRECIST at the 
local site
Continue regularly 
scheduled imaging 
assessments 
Continue 
study 
treatment at the local 
site 
Investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments 
May 
restart 
study 
treatment if condition 
has improved and/or 
clinically stable per 
Investigator’s 
discretion. Next tumor 
image should occur 
according 
to 
the 
regular 
imaging 
schedule outlined in 
the protocol
Abbreviations: BICR=blinded independent central imaging review; CR=complete response; PD=progressive disease;
PR=partial response; SD=stable disease

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Figure 4
Imaging and Treatment for Clinically Stable Subjects after First Radiologic 
Evidence of PD Assessed by the Site
Patient-reported Outcomes 
7.1.2.8
The FKSI-DRS, EORTC-QLQ-C30 and EuroQol EQ-5D-3L questionnaires will be 
administered by trained site personnel and completed electronically by subjects in the 

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following order: FKSI-DRS first, EORTC-QLQ-C30, and then EuroQol EQ-5D-3L at the 
time points specified in the Trial Flow Chart. It is a best practice and strongly recommended 
that ePROs are administered to randomized subjects prior to all procedures and assessments, 
including the dosing of study treatment.  If the subject does not complete the PROs, the 
MISS_MODE form must be completed to capture the reason the assessment was not 
performed. A visit window of ±7 days will apply to PRO visit assessments. The timing of 
QoL assessments should not change on the basis of dosing delays or interruptions.
7.1.2.8.1 FKSI-DRS
The FKSI-DRS is a patient-reported instrument that measures whether the patient 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 [51]. 
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 [51]. This assessment will be completed at various time points as specified in the 
Trial Flow Chart.
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 subject at Cycle 1, Day 1, then the FKSI-DRS will not be required for this subject at any 
point of the study. The other study PRO measures must be completed as scheduled. Note: 
for some sites, the translated FKSI-DRS might become available after study startup and 
should be administered to subjects 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.
7.1.2.8.2 EORTC-QLQ-C30
The EORTC QLQ-C30 was developed to assess the quality of life of cancer subjects. It has 
been translated and validated into 81 languages and used in more than 3,000 studies 
worldwide. It contains 5 functioning scales (physical, role, cognitive, emotional, and social), 
3 symptom scales (fatigue, nausea, 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 7-point scale scoring with anchors 
(1=very poor and 7=excellent). This assessment will be completed at various time points as 
specified in the Trial Flow Chart.
7.1.2.8.3 EuroQol EQ-5D-3L
The EuroQol EQ-5D-3L is a standardized instrument for use as a measure of health outcome  
and will provide data for use in economic models and analyses including developing health 
utilities or QALYs.  The five health state dimensions in this instrument include the 
following: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression [56].  
Each dimension is rated on a three-point scale from 1 (extreme problem) to 3 (no problem).  

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The EuroQol EQ-5D-3L also includes a graded (0 to 100) vertical visual analog scale on 
which the subject rates his or her general state of health at the time of the assessment.  
Electronic PROs, in the order of FKSI-DRS, EORTC QLQ-C30 and EuroQol EQ-5D-3L, 
will be completed by the patient prior to all other study procedures and is to be completed at 
various time points as specified in the Trial Flow Chart.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory 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 pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Study Procedures 
Manual. Refer to Section 6.0 -- Trial Flow Chart for the timing of laboratory assessments.
Urine Pregnancy Test
7.1.3.1
For women of childbearing potential, a urine pregnancy test should be performed within 
72 hours prior to first dose of trial treatment.  If urine pregnancy results are positive or cannot 
be confirmed as negative, a serum pregnancy test performed by the local study site laboratory 
will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if required by 
local guidelines.  Monthly pregnancy testing should be conducted as per local regulations 
where applicable.
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
7.1.3.2
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 14.
The 
schedule of individual laboratory tests is shown in the Trial Flow Chart (Section 6.0).

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Table 14
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum or urine pregnancy 
β-human chorionic 
gonadotropin (β-hCG) testa
Hemoglobin
Alkaline phosphatase
Glucose
PT or INR
Platelet count
ALT
Protein
WBC
AST
Specific gravity 
Absolute 
Neutrophils
Bicarbonateb
Microscopic exam, if 
abnormal results are notedc
Absolute 
Lymphocytes
Blood Urea Nitrogend
Absolute 
Monocytes
Calcium
Absolute 
Eosinophils
Corrected Calciume
Absolute Basophils Chloride
Creatininef
Glucose
Lactase Dehydrogenase
Phosphorus or Phosphate
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total 
bilirubin is elevated above 
the upper limit of normal
Total protein
Thyroid function: FT3g, 
FT4, and TSH
a.
Perform on women of childbearing potential only.
b.
If considered standard of care in your region.
c.
Institutional standards are acceptable.
d.
Urea may be used if site cannot perform Blood Urea Nitrogen
e.
Corrected calcium is only needed at screening (this is used to determine IMDC criteria). 
f.
GFR (measured or calculated) or CrCl can be used in place of creatinine if site cannot perform creatinine.
g.
Free T3 may be performed in place of Total T3 per local standards
Safety laboratory tests will be performed within 10 days prior to randomization, and post 
randomization according to the schedules outlined in Section 6.0 – Trial Flow Chart. Clinical 
chemistry and hematology results should be available prior to each dosing of pembrolizumab
to determine whether pembrolizumab should be dosed.
There may be instances when sites are unable to obtain the thyroid function testing results 
prior to scheduled dosing. After Cycle 1, review of thyroid function tests (FT3, FT4 and 
TSH) results after dosing is acceptable.

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Pharmacokinetic Evaluations/Anti-pembrolizumab Antibodies
7.1.3.3
To further evaluate pembrolizumab immunogenicity and pembrolizumab exposure, samples 
for pre-dose trough PK and anti-drug (pembrolizumab) antibodies (ADA) samples will be 
collected for subjects who are randomized to the pembrolizumab plus axitinib arm as 
specified in Trial Flow Chart (Section 6.0). 
Pre-dose trough PK and ADA samples for the pembrolizumab plus axitinib arm will be 
collected on Day 1 of Cycles 1, 3, 5, every 4 cycles thereafter (C9D1, C13D1, C17D1) and 
30 days after discontinuation of pembrolizumab. Pre-dose trough samples should be drawn 
within 24 hours prior to pembrolizumab infusion. 
Additional post-dose peak PK samples will be drawn within 30 minutes after end of 
pembrolizumab infusion at C1D1
and C9D1.
If dosing of pembrolizumab is 
interrupted/delayed due to an AE, shift the PK samples to the next day of pembrolizumab 
dosing. PK post-dose sampling should occur with pembrolizumab dosing regardless of 
axitinib dosing status. If axitinib is interrupted/delayed at C9D1, but pembrolizumab is 
dosed, the post-dose PK sample should still be drawn.
Date and times of the PK pre-administration sample, start of the administration of 
pembrolizumab, completion of the administration of pembrolizumab,
and PK post-
administration samples must be recorded and entered into the eCRF.
Every effort should be taken to collect samples at 30 days after end of pembrolizumab 
treatment for ADA.  Simultaneous PK sampling is required for interpretation of ADA 
analysis.
If ongoing ADA and/or PK results continue to be consistent with existing ADA and/or PK 
data from other pembrolizumab clinical trials, it may be decided to discontinue or reduce 
further sample collection in this study.  Pharmacokinetic data may also be analyzed using 
nonlinear mixed effects modeling. Based on PK data obtained in this study as well as PK 
data obtained from other studies, a population PK analysis may be performed to characterize 
PK parameters (clearance [CL], volume of distribution [V]) and evaluate the effect of 
extrinsic and intrinsic factors to support the proposed dosing regimen. Pharmacokinetic data 
may 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. 
The results of these analyses, if performed, will be reported separately.
Tumor Tissue Collection
7.1.3.4
Obtain tissue for biomarker analysis from an archival tissue sample or newly obtained core or 
excisional biopsy of a tumor lesion not previously irradiated. It is strongly encouraged, if 
possible, to obtain a fresh biopsy if the archived tumor tissue is greater than 3 years old.
Informed consent for the study must be taken prior to collection of a fresh biopsy.  If the 
subject signs the FBR consent, any leftover tissue that would ordinarily be discarded at the 
end of the main study will be retained for FBR (see Section 7.1.3.7 for the rationale). Details 
regarding time points for collection of tumor tissue are outlined in the Trial Flow Chart, 
Sections 6.1 and 6.2.

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Detailed instructions for tissue collection, processing and shipment are provided in the
Procedures Manual.
Blood Collections for ctDNA, TCR, RNA, Plasma and Serum Biomarker 
7.1.3.5
Analyses
The following samples must be collected prior to dosing time points in accordance with the 
Trial Flow Chart in Section 6.0: ctDNA, TCR, RNA, plasma for biomarker analyses and 
blood for serum biomarker analyses.  
Leftover samples may be kept for future biomedical research if the subject signs the FBR 
consent.
Detailed instructions for sample collection, storage and shipment instructions for serum 
samples will be provided in the study Procedures Manual. 
Planned Genetic Analysis Sample Collection
7.1.3.6
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual
Future Biomedical Research Sample Collection
7.1.3.7
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research

Leftover archival or fresh biopsy tumor tissue

Leftover RNA from blood

Leftover serum and plasma from biomarker analyses
Other Procedures
7.1.4
Withdrawal/Discontinuation
7.1.4.1
Subjects who discontinue/withdraw from treatment prior to completion of the trial should be 
encouraged to continue to be followed for all remaining study visits.
When a subject 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 7.2 - Assessing and 
Recording Adverse Events.
Subjects who attain a CR or complete 35 trial treatments 
(approximately 2 years) of treatment with pembrolizumab may discontinue treatment with 
the option of restarting treatment if they meet the criteria specified in Section 7.1.5.2.1. After 
discontinuing treatment following assessment of CR or of the 35 trial treatments, these 
subjects should return to the site for a Safety Follow-up Visit (described in Section 7.1.5.3.2) 
and then proceed to the Follow-up Period of the study (described in Section 7.1.5.3.3).

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7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects 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), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for 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 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Blinding/Unblinding
7.1.4.2
This is an open label trial; there is no blinding for this trial.
Calibration of Equipment
7.1.4.3
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical trial that provides information
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or 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.
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
7.1.5.1
Written consent for the study must be obtained prior to performing any protocol-specific 
procedure including the mandatory newly obtained (fresh) tumor biopsy that is required for 
eligibility (in the event an archival sample is not available). Potential subjects will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5.1 –
Entry Criteria. Visit requirements are outlined in Section 6.0 -Trial Flow Chart. 
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame.

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Screening procedures are to be completed within 28 days prior to randomization with these 
additional required time frames: 

Safety assessments including clinical laboratory tests, ECG, vital signs, and 
evaluation of KPS are to be performed within 10 days prior to randomization.

For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to the first dose of trial treatment. If the randomization pregnancy test 
is more than 72 hours prior to the first dose of study treatment, it should be repeated.
If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test 
will be required (performed by the local study site laboratory).
Screening procedures may be repeated after consultation with the Sponsor. Subjects may be 
rescreened after initially failing to meet the inclusion/exclusion criteria after consultation 
with the Sponsor. Assessments performed during the initial screening period are acceptable 
in lieu of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria are met.
Treatment Period
7.1.5.2
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures.
7.1.5.2.1 Second Course Phase (Retreatment Period)
Section 5.8.3 describes eligibility for second course of pembrolizumab treatment. Visit 
requirements are outlined in Section 6.0 – Trial Flow Chart.
Post-Treatment
7.1.5.3
7.1.5.3.1 End of Treatment
The End of Treatment Visit should occur at the time study treatment is discontinued for any 
reason.  If the End of Treatment Visit occurs 30 days from the last dose of study treatment, at 
the time of 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 Section 6.0- Trial Flow Chart. Additional details regarding subject withdrawal 
and discontinuation are presented in Section 5.8– Subject Withdrawal/Discontinuation
Criteria.
Subjects who discontinue trial treatment for reasons other than disease progression will still 
be considered on study and should continue with regularly scheduled assessments listed in 
the Imaging Follow-up Visit on the Trial Flow Chart (Section 6.0; also refer to Section 
7.1.5.3.3).
7.1.5.3.2 Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days 
(± 3 days) after the last dose of trial treatment or before the initiation of a new anti-cancer 
treatment if this occurs prior to 30 days after the last dose of study treatments. 

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Subjects who are eligible for re-treatment
with pembrolizumab (as described in 
Section 5.8.3) may have up to two safety follow-up visits, one after the Treatment Period and 
one after the Second Course Phase.
7.1.5.3.3 Imaging Follow-up Visits
Subjects who discontinue treatment for reasons other than BICR verified PD should continue 
with imaging assessments per the protocol defined schedule until: 1) PD is BICR verified, 
2) initiation of a new anti-cancer treatment, 3) death, 4) withdrawal of consent or 5) study 
conclusion or early termination, whichever occurs first.  
Subjects who are eligible to receive second course retreatment with pembrolizumab 
according to the criteria in Section 5.8.3 will have imaging assessments and schedules per 
those set for Second Course of treatment as described in Section 6.0 – Trial Flow Chart.
7.1.5.3.4 Survival Follow-up Visits
Subjects who experience PD that is verified by BICR or further confirmed by the investigator
or start a new anticancer therapy, will move into the Survival Follow-up Phase and should be 
contacted by telephone approximately every 12 weeks to assess for survival status until 
death, withdrawal of consent, or the end of the trial, whichever occurs first. 
Survival Status
7.1.5.4
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 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).
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.

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Sponsor's product includes any
pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose is any dose exceeding 5 times the prescribed dose of pembrolizumab 
(200 mg), defined as any dose higher than 1000 mg.  No specific information is available on 
the treatment of overdose of pembrolizumab. In the event of overdose, pembrolizumab  
should be discontinued and the subject should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated.  Overdose for 
sunitinib and axitinib is any dose exceeding the prescribed maximum dose for each drug (i.e., 
5 mg BID for axitinib unless dose escalation to 7 mg or 10 mg BID is permitted per Section 
5.2.1.2.1. or 50 mg QD for sunitinib). There is no specific treatment for sunitinib or axitinib 
overdose.  In the event of overdose, the dose should be interrupted and the subject should be 
observed closely for signs of toxicity. Appropriate supportive treatment should be provided 
if clinically indicated.  The subject may resume study treatment at the discretion of the 
investigator (refer to axitinib and sunitinib labeling for more details).
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”

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All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  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.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
Serious Adverse Events
7.2.3.1
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: 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.

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Refer to Table 15 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject 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, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor. 
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
7.2.3.2
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject 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, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 

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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).
3. The following events should also be reported as an ECI if they occur after the start of 
treatment in the axitinib/ pembrolizumab combination arm: 
a.
events with ALT and/or AST > 5xULN
b. events with ALT and/or AST > 3xULN concurrently with total bilirubin 
≥2xULN
Protocol-specific Exceptions to Serious Adverse Event Reporting
7.2.3.3
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3 - Immediate Reporting of Adverse Events to the Sponsor.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The eDMC will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial.  Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events 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.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.

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Table 15
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
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
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient 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.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
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 drug 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 (AE):
Exposure
Is there evidence that the subject 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

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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
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; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
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 REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
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?
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.
Record one of the following
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
Subject 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 subject with overdose without an 
associated AE.)

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Sponsor Responsibility for Reporting Adverse Events
7.2.5
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.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Scientific Advisory Committee
7.3.1
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
7.3.2
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
Data Monitoring Committee (DMC) regarding the trial.
Data Monitoring Committee
7.3.3
An external Data Monitoring Committee (eDMC) will be formed prior to study start to 
periodically monitor safety and evaluate the interim data from this trial.  The members of the 
committee are external to the Sponsor, are not involved with the trial in any other way (e.g., 
they cannot be trial investigators) and have no competing interests that could affect their 
roles with respect to the trial. 
The eDMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the eDMC will review interim 
trial results, consider the overall risk and benefit to trial participants (see Section 8.7 -
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 eDMC charter that is 
reviewed and approved by all the eDMC members.
8.0 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 E-9).  Changes to exploratory or other non-confirmatory 
analyses made after the protocol has been finalized, but prior to the conduct of any analysis, 
will be documented in a supplemental (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study. Separate analysis plans may be developed for PK/modeling analysis,

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biomarker analysis, and genetic data analysis. Post hoc exploratory analyses will be clearly 
identified in the CSR. The PRO analysis plan will be included in the sSAP.
Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2 through 8.12.
Study Design Overview
This is a randomized, open-label, multicenter Phase III trial to evaluate efficacy 
and safety of pembrolizumab in combination with axitinib versus sunitinib 
monotherapy as a first-line treatment for locally advanced or mRCC.
Treatment Assignment
Approximately 840 subjects will be randomized 1:1 into the following two 
treatment arms: Arm 1 will receive the combination therapy of pembrolizumab 
200 mg administered intravenously (IV) every 3 weeks (Q3W) and axitinib 5 
mg twice daily (BID) taken orally; Arm 2 will receive sunitinib monotherapy 
50 mg daily (QD) taken orally for 4 weeks then off treatment for 2 weeks. 
Stratification factors are provided in Section 5.4.  This is an open-label study. 
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoints
1. Progression-free survival (PFS), per RECIST 1.1 by BICR review
2. Overall survival (OS)
Statistical Methods for
Key Efficacy Analyses
The primary hypotheses for PFS and OS will be evaluated by comparing
pembrolizumab in combination with axitinib to sunitinib 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.  Stratified Miettinen and 
Nurminen’s method with weights proportional to the stratum size will be used 
for comparison of the objective response rates (ORR) between the treatment 
arms.  
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 provided for between-group comparisons; only point 
estimates by treatment group are provided for Tier 3 safety parameters. The
95% confidence intervals for the between-treatment differences in percentages 
will be provided using the Miettinen and Nurminen method.

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Interim
and 
Final 
Analyses
Two interim analyses are planned for the study. Results will be reviewed by
an external data monitoring committee (eDMC). 
Details are provided in
Section 8.7.

First Interim Analysis (IA1) 
o
Timing: To be performed after enrollment completion, once a 
7-month minimum follow up (ie, 7 months since last subject is 
randomized) has been achieved and a minimum of 305 PFS 
events have accrued. It is expected to be 22 months after the 
first subject randomized (study start). Approximately 48% of 
the final required OS events (or 195 deaths) are expected at that 
time. 
o
Purpose: First interim analysis for PFS and OS. 

Second Interim Analysis (IA2)
o
Timing: To be performed when approximately 74% of the final 
required OS events (or 299 deaths) have accrued, expected to 
be 31 months after study start. At IA2, approximately 487 PFS 
events are expected.
o
Purpose: Final analysis for PFS and IA2 for OS.

Final analysis (event-driven trial)
o
Timing: 
When approximately 404 deaths have accrued, 
expected to be 43 months after study start.
o
Purpose:
Final analysis for OS (assuming not declared 
successful at the interim analysis) 
Multiplicity
The overall Type I error rate is strongly controlled at 2.5% (1-sided) with 0.2% 
initially allocated to PFS and 2.3% initially allocated to OS. A group sequential 
approach will be used to allocate alpha between the interim and final analyses. 
The study will be considered a success if either PFS or OS is demonstrated to 
be statistically significant under multiplicity control. Note that the study would 
continue for OS even if PFS is shown to be statistically significant at IA1 or 
IA2.
Sample Size and Power
The sample size was planned for 840 but the following power calculations are 
based on the actual final number of randomized subjects (N = 861). There are 2 
primary endpoints for this study, PFS, and OS. The expected median PFS time 
in the control group is 13 months. Based on 487 PFS events, the study has 
~99% power to detect a hazard ratio of 0.60 for PFS (pembrolizumab+axitinib 
combination vs. sunitinib) at alpha=0.2% (1-sided). The expected median OS 
time in the control group is 33 months. Based on 404 death events, the study 
has 80% power to detect a hazard ratio of 0.75 for OS at alpha=2.3% (1-sided).
Responsibility for Analyses/In-house Blinding
8.2
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 for this protocol, and the randomization will be implemented in IVRS.

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Although the trial is open label, analyses or summaries generated by randomized treatment 
assignment and/or actual treatment received will be limited and documented. Further 
documentation will be provided in the sSAP.  In addition, independent central imaging 
review will be performed without knowledge of the treatment group assignments of the 
subjects. 
The eDMC will serve as the primary reviewer of the unblinded results of the PFS and OS at 
interim analyses and may 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.
Hypotheses/Estimation
8.3
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
8.4
Efficacy Endpoints
8.4.1
Primary
8.4.1.1
Progression-free Survival (PFS) – RECIST 1.1 by Blinded Central Imaging Vendor
Review
Progression-free survival is defined as the time from randomization to the first documented 
disease progression per RECIST 1.1 based on BICR or death due to any cause, whichever 
occurs first.  See Section 8.6.1 for the censoring rules.
Overall Survival (OS)
Overall survival is defined as the time from randomization to death due to any cause. 
Subjects without documented death at the time of the final analysis will be censored at the 
date of the last follow up.
Secondary
8.4.1.2
Objective Response Rate (ORR) – RECIST 1.1 by BICR
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a CR or PR per RECIST 1.1.
Duration of Response (DOR) - RECIST 1.1 by BICR
For subjects who demonstrate CR or PR, DOR is defined as the time from first documented 
evidence of CR or PR per RECIST 1.1 until disease progression per RECIST 1.1 or death 
due to any cause, whichever occurs first. See Section 8.6.1 for the censoring rules.

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Disease Control Rate (DCR) - RECIST 1.1 by BICR
Disease control rate is defined as the percentage of subjects who have achieved CR, PR, or 
SD of ≥ 6 months based on assessments by BICR per RECIST 1.1.
Safety Endpoints
8.4.2
Safety endpoints are described in Sections 4.2.3.2.
Analysis Population
8.5
Efficacy Analysis Population
8.5.1
The Intention-to-Treat (ITT) population will serve as the population for the primary efficacy 
analyses. All randomized subjects will be included in this population. Subjects will be 
analyzed in the treatment group to which they are randomized.  Details on the approach to 
handling missing data are provided in Section 8.6.1 – Statistical Methods for Efficacy 
Analyses.
The analysis population of DOR consists of responders.
Safety Analysis Population
8.5.2
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized subjects who received at least 
1 dose of study treatment. Subjects will be analyzed in the treatment group corresponding to 
the study treatment they actually received for the analysis of safety data using the ASaT 
population.  For most subjects this will be the treatment group to which they are randomized.  
Subjects 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 subject who 
receives the incorrect study medication 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 subject is incorrectly dosed.
At least 1 laboratory or vital sign 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
8.6
Statistical Methods for Efficacy Analyses
8.6.1
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to 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 8.8, Multiplicity. Nominal p-values 
may be computed for other efficacy analyses, but should be interpreted with caution due to 
potential issues of multiplicity.

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Progression-free Survival
8.6.1.1
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group including the PFS rates at 12, 18, and 24 months (based on data 
adequacy). The treatment difference in PFS will be assessed 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 (i.e., hazard ratio) between the 
treatment arms.
The hazard ratio and its 95% confidence interval 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 5.4) will be applied
to both the stratified log-rank test and the stratified Cox model.  
Since disease progression is assessed periodically, progressive disease (PD) can occur any 
time in the time interval between the last assessment where PD was not documented and the
assessment when PD is documented.  The true date of disease progression will be
approximated by the date of the first assessment at which PD is objectively documented per
RECIST 1.1 by BICR.  Death is always considered as a confirmed PD event. Subjects who 
do not experience a PFS event will be censored at the last disease assessment.  Sensitivity 
analyses will be performed for comparison of PFS based on investigator's assessment and 
PFS with PD determined per irRECIST by BICR, as indicated in the exploratory objectives.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, one 
primary and two sensitivity analyses with a different set of censoring rules will be performed.
For the primary analysis, if PD or death events occur immediately after more than one 
missing disease assessment, the PFS data are censored at the last disease assessment prior to 
the missing visits. Also, data after new anti-cancer therapy are censored at the last disease 
assessment prior to the initiation of new anti-cancer therapy.   
The first sensitivity analysis follows the intention-to-treat principle. That is, PDs/deaths are 
counted as events regardless of missed study visits or initiation of new anti-cancer therapy. 
The second sensitivity analysis considers discontinuation of treatment due to reasons other 
than complete response or initiation of new anti-cancer treatment (whichever occurs later)
to be a PD event for subjects without documented PD or death. If a subject meets multiple 
criteria for censoring, the censoring criterion that occurs earliest will be applied. The
censoring rules for primary and sensitivity analyses are summarized in Table 16.

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Table 16
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death documented 
after ≤ 1 missed disease 
assessment, and before 
new anti-cancer therapy, if 
any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
PD or death documented 
immediately after ≥ 2 
consecutive missed disease 
assessments or after new 
anti-cancer therapy, if any
Censored at last 
disease assessment 
prior to the earlier date 
of  ≥ 2 consecutive 
missed disease 
assessment and new 
anti-cancer therapy, if 
any
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
No PD and no death; and 
new anticancer treatment is 
not initiated
Censored at last 
disease assessment 
Censored at last disease 
assessment 
Progressed at treatment 
discontinuation due to 
reasons other than complete 
response; otherwise 
censored at last disease 
assessment if still on study 
treatment or completed 
study treatment.
No PD and no death; new 
anticancer 
treatment 
is 
initiated
Censored at last 
disease assessment 
before new anticancer 
treatment 
Censored at last disease 
assessment
Progressed at date of new 
anticancer treatment
PD = progressive disease; PFS = progression-free survival.
The proportional hazards assumption on PFS will be examined using both graphical and 
analytical methods if warranted.  The log [-log] of the survival function vs. time for PFS will 
be plotted for the comparison between pembrolizumab+axitinib combination and the control 
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.  Further details of sensitivity analyses will be described in 
the SAP.  
Overall Survival
8.6.1.2
The non-parametric Kaplan-Meier method will be used to estimate the survival curves in 
each treatment group including the OS rates at 12, 18, and 24 months (based on 
data adequacy).  The treatment difference in survival will be assessed by the stratified
log-rank test.
A stratified Cox proportional hazard model with Efron's method of tie
handling will be used to assess the magnitude of the treatment difference (i.e., the hazard 
ratio).
The hazard ratio and its 95% CI from the stratified Cox model with a single
treatment covariate will be reported. The stratification factors used for randomization (See 
Section 5.4) will be applied to both the stratified log-rank test and the stratified Cox model.

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Objective Response Rate
8.6.1.3
Stratified Miettinen and Nurminen’s method with weights proportional to the stratum size 
will be used for comparison of the objective response rates between the treatment arms. A 
95% CI for the difference in response rates between the treatment arms will be provided. 
The stratification factors used for randomization will be applied to the analysis.  Sensitivity 
analyses will be performed to assess ORR based on investigator's assessment.
The ORR analysis will be conducted according to the hypothesis testing plan as described in 
Section 8.7 – Interim Analyses and Section 8.8 – Multiplicity.
Duration of Response
8.6.1.4
The non-parametric Kaplan-Meier method will be used to estimate the DOR curve in
each treatment group; estimates of the percentage of subjects still in response and 95% CIs at 
specific duration time points will be provided. 
Sensitivity analyses will be performed to assess DOR based on investigator's assessment.
For each DOR analysis, a corresponding summary of the reasons responding subjects are 
censored will also be provided.  
Censoring rules for DOR are summarized in Table 17.
Table 17
Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anti-cancer therapy initiated
Last adequate disease assessment
Censor
(Non-event)
No progression nor death, new anti-
cancer therapy initiated
Last adequate disease assessment 
before new anti-cancer therapy 
initiated
Censor
(Non-event)
Death or progression immediately 
after ≥ 2 consecutive missed disease 
assessments or after new anti-cancer 
therapy, if any
Earlier date of last adequate disease 
assessment prior to ≥ 2 missed 
adequate disease assessments and 
new anti-cancer therapy, if any
Censor
(Non-event)
Death or progression after ≤ 1 
missed disease assessments and 
before new anti-cancer therapy, if 
any
PD or death
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
Subjects are considered to have an ongoing response if censored, alive, have not progressed, have not started a 
new anti-cancer therapy and have not been determined to be lost to follow-up.
Abbreviations: DOR=duration of response; PD=progressive disease.
Disease Control Rate
8.6.1.5
Stratified Miettinen and Nurminen’s method with weights proportional to the stratum size 
will be used for comparison of the DCR between the treatment arms. A 95% CI for the 
difference in response rates between the treatment arms will be provided. The stratification 
factors used for randomization will be applied to the analysis. Sensitivity analyses will be 
performed to assess DCR based on investigator's assessment.

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Summary of Statistical Methods for Efficacy
8.6.1.6
Table 18 summarizes the primary analysis approach for primary and secondary efficacy 
endpoints. Sensitivity analysis methods are described above for each endpoint.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, 
multiple populations, and interim analyses is described in Section 8.7 Interim Analyses and 
in Section 8.8 Multiplicity.
Table 18
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical 
Method†
Analysis 
Population
Missing Data/ 
Censoring
Approach
Primary Hypothesis #1
PFS per RECIST 1.1 by 
BICR
Test: Stratified Log-
rank test Estimation: 
Stratified Cox model 
with 
Efron’s
tie 
handling method
ITT 

Primary 
censoring rule

Sensitivity analysis 
1

Sensitivity analysis 
2
Primary Hypothesis #2
OS
Test: Stratified Log-
rank test Estimation: 
Stratified Cox model 
with 
Efron’s 
tie 
handling method
ITT
Censored at the last date 
the subject was known to 
be alive 
Secondary Hypothesis
ORR per
RECIST 1.1
by 
BICR
Stratified 
M 
& 
N 
method‡
ITT
Subjects with missing 
data 
are 
considered 
non-responders
† Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for
randomization (see Section 5.4) will be applied to the analysis model.
.‡ Miettinen and Nurminen method.
Abbreviations: BICR=blinded independent central imaging review; ITT=intention-to-treat; ORR=objective response rate; OS=overall
survival; PFS=progression-free survival
Statistical Methods for Safety Analyses
8.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs.
Tiered Approach
The analysis of safety results will follow a tiered approach (Table 19).  The tiers differ with 
respect to the analyses that will be performed. For this protocol, there are no Tier 1 events. 
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.

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Adverse events (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.
The threshold of at least 10% of subjects with events was chosen for Tier 2 event 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 confidence intervals 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 and vital signs that 
are not pre-specified 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 
subjects with Grade 3-5 AE (incidence ≥5% of subjects in one of the treatment groups) and
any 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 (incidence <5% of subjects in one of the treatment groups), any 
SAE (incidence <5% of subjects in one of the treatment groups), 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, and death will be considered 
Tier 3 endpoints.
Note that 95% CIs will be provided for between- treatment differences in the percentage of 
subjects with Tier 2 events; these analyses will be performed using the Miettinen and 
Nurminen method, an unconditional, asymptotic method.

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Table 19
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any Serious AE (incidence ≥5% of subjects in 
one of the treatment groups)
X
X
Any 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 (incidence <5% of subjects in 
one of the treatment groups)
X
Any Grade 3-5 AE (incidence <5% of subjects 
in one of the treatment groups)
X
Any Serious and Drug-related AE
X
Any Grade 3-5 and Drug-related AE
X 
Dose Modification 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) or 
PDLCs
X
Change from Baseline Results (Labs, ECGs, 
Vital Signs)
X
Abbreviations: AE = adverse event; CI = confidence interval; ECG = electrocardiogram; PDLC = pre-
defined limit of change; SOC = system organ class. 
Summaries of Demographic and Baseline Characteristics
8.6.3
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 subjects screened and randomized, and 
the
primary reasons for screening failure and discontinuation will be displayed.  
Demographic variables (e.g., 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
8.7
There are 2 planned interim analyses for OS and 1 planned interim analysis for PFS in this 
trial. Results of the interim analyses will be reviewed by an eDMC. Table 20 shows analysis 
strategies for each interim and final analysis in this trial based on model assumptions.
Table 20 will be updated using the actual number of events at the interim and final analyses 
and the same spending function used to derive the design in this table.  All futility boundaries 
are non-binding in this study.

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Table 20
Summary of Interim and Final Analyses Strategies
Analysis
Expected 
Months 
after 
Study 
Start
Hypo-
thesis 
Tested 
in the 
Analysis
True 
Hazard 
Ratio
n┼
Infor-
mation 
Fraction
Type I 
Error 
(Overall 
)
Efficacy Boundary Crossing
Futility Boundary Crossing
Nominal 

Z-
value
Statistics╪
Power§
Nominal 
α
Z-
value
Hazard 
Ratio
Cumulative 
Type II Error
IA1
22 
Months
PFS
0.6
365
0.75
0.20%
0.11%
3.06
0.73
~96.5%
22.1%
-0.77
1.08
<0.01%
1.35%
0.74%
2.44
0.77
~99.2%
21.8%
-0.78
1.08
<0.01%
2.5%
1.36%
2.21
0.79
~99.6%
21.6%
-0.79
1.08
<0.01%
OS
0.75
195
0.48
2.3%
0.01%
3.72
0.59
~4.3%
4.1%
-1.74
1.28
~0.01%
2.5%
0.01%
3.70
0.59
~4.5%
4.1%
-1.74
1.28
~0.01%
ORR
-
860
1.0
0.2%
0.2%
2.88
9.4%
>99.9%
-
-
-
-
1.15%
1.15%
2.27
7.4%
>99.9%
2.5%
2.5%
1.96
6.4%
>99.9%
IA2
31 
Months
PFS
0.6
487
1.0
0.2%
0.14%
3.00
0.76
>99.9%
99.8%
3.00
0.76
~3.9%
1.35%
1.02%
2.32
0.81
>99.9%
98.7%
2.32
0.81
~0.04%
2.5%
1.95%
2.06
0.83
>99.9%
97.5%
2.06
0.83
~0.02%
OS
0.75
299
0.74
2.3%
0.78%
2.42
0.76
~52.7%
20.3%
-0.84
1.10
~0.05%
2.5%
0.92%
2.36
0.76
~55.1%
20.2%
-0.85
1.10
~0.05%
FA
43
Months
OS
0.75
404
1.0
2.3%
2.07%
2.04
0.82
~80.8%
97.7%
2.04
~0.82
~19.2%
2.5%
2.22%
2.01
0.82
~81.7%
97.5%
2.01
~0.82
~18.3%
┼n means expected events at the time of corresponding analysis for PFS and OS based on model assumption. In the rare case if PFS events accumulate slower than expected, a 
minimum of 305 events is required at 22 months to trigger IA1; n means total sample size for ORR.
╪The statistics used here are hazard ratio for PFS and OS, and ORR for ORR where ORR = ORR in (pembrolizumab+axitinib group) – ORR in sunitinib group. 
§ The power calculated for OS is cumulative power. For the power calculation, the target ORR in the pembrolizuab+axitinib group and the reference ORR assumed in the 
sunitinib groups are 55% and 31%, respectively.
For OS, a linear spending function with a fixed alpha spending of 0.0001 at IA1 and the rest alpha spending approximated by a Hwang-Shih-DeCani (HSD) alpha-spending function with gamma 
parameter (-4) is used to construct Haybittle-Peto type of group sequential boundaries to control the overall Type I error rate for this endpoint at 2.3% or 2.5% (1-sided). 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 alpha-spending function with gamma parameter (-6) is used to construct group 
sequential boundaries for futility. The Type I error rate to spend at IA2 and FA will be determined by the spending function evaluated at the exact number of deaths at each analysis.
For PFS, an HSD alpha-spending function with gamma parameter (-2), is used to construct group sequential boundaries to control the overall Type I error rate for this endpoint at 0.2%, 1.35% and 
2.5% (1-sided). 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 alpha-spending function with gamma 
parameter (-6) is used to construct group sequential boundaries for futility. The Type I error rate to spend at the interim analysis will be determined by the spending function evaluated at the exact 
number of PFS events at each analysis.
For ORR, if the testing of ORR hypothesis does not reach statistical significance at interim analysis 1 (IA1), the p-value from the IA1 analysis can be compared to an updated α-level if the null 
hypothesis for PFS or OS is rejected at a later time.

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The purpose of the first interim analysis is to conduct the interim testing for efficacy on both
PFS and OS endpoints.  It will be performed after enrollment completion, which is expected 
after 15 months since start of the study. The IA1 data cutoff is to occur once a minimum of 305 
PFS events have accrued and all patients have been followed up for at least 7 month after 
randomization. A minimum of 305 PFS events will ensure at least 90% power for the PFS 
analysis at IA1. The minimum follow-up time requirement is to ensure sufficient follow up for 
the PFS endpoint to characterize the PFS curves at the tail and ensure sufficient follow up for 
the ORR endpoint for this interim analysis. Based on fulfilling these two criteria for IA1, IA1 
is projected to happen at approximately 22 months after the start of the study with 
approximately 365 PFS events based on model assumptions (see Table 20). In the unexpected 
case that there are fewer than 305 PFS events when all subjects have had the opportunity to be
followed up for at least 7 months after randomization, the interim analysis will be delayed until
305 PFS events have accrued.
The second interim analysis is to conduct the final analysis for the PFS endpoint if the 
superiority of PFS has not been demonstrated in the first interim analysis and to conduct the 
second interim testing of the OS endpoint. It will be performed when approximately 74% of 
the final required OS events (or 299 deaths) have accrued, expected after 31 months from the
start of the study. It is expected to accumulate 487 PFS events at that time.
The final analysis for the study will be conducted when the target number of OS events 
(404 deaths) is reached, projected to occur at 43 months after the start of the study, if the study 
has not been stopped early for efficacy.  
In the first interim analysis, if the study demonstrates superiority of PFS but has not 
demonstrated superiority of OS (without crossing the futility boundary for OS), the study will 
continue for OS after the interim analysis.
If superiority of pembrolizumab in combination with axitinib relative to sunitinib with respect 
to PFS or OS is demonstrated, the ORR hypothesis will be tested using the p-value from the
first interim analysis with the overall Type I error = 0.2%, 1.15%, or 2.5%, depending on the 
results of the OS and PFS hypothesis tests.  Since all subjects will have an opportunity to have 
at least 4 scheduled scans at the time of the first interim analysis if not discontinued prior to the 
first interim analysis data cut-off, they all will be included in this ORR analysis.  
The DMC has responsibility for assessment of overall risk: benefit.  The DMC will review 
safety periodically (every 4 months in the first year and frequency may be reduced after one 
year if no unexpected safety signals occur). To account for any multiplicity concerns raised by 
the DMC review of unplanned efficacy data when prompted by safety concerns, a sensitivity 
analysis for OS will be pre-specified in the sSAP. This analysis will be performed if requested 
by the DMC. However, DMC review of 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 interim analysis because these analyses are not to declare a 
positive efficacy finding. Any DMC recommendation will be communicated to the Sponsor as 
agreed to in the DMC charter.  A detailed description of the multiplicity adjustment and 
hypotheses testing plan is provided in Section 8.8 Multiplicity.

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Multiplicity
8.8
The multiplicity strategy specified in this section will be applied to the 2 primary hypotheses 
(superiority of the pembrolizumab+axitinib combination relative to sunitinib on PFS or OS)
and the secondary hypothesis of superiority of pembrolizumab+axitinib combination relative to
sunitinib in ORR. Note that the study will be a success if either PFS or OS is demonstrated to 
be statistically significant under multiplicity control.
The overall Type I error across the testing of the OS, PFS, and ORR hypotheses is strongly 
controlled at =2.5% (1-sided). The multiplicity strategy will follow the graphical approach of 
Maurer and Bretz.  Figure 5 provides the multiplicity strategy diagram of the study.
Figure 5
Multiplicity Strategy
The alpha level indicated for each null hypothesis is the alpha level initially allocated. When a 
particular null hypothesis is rejected, the arrows leading to it are removed and the alpha 
allocated to the null hypothesis will be re-distributed among all arrows going out and 
re-weighted per the number on the arrow (summing to 1).  The arrows on the diagram show 
how the Type I error allocated to a hypothesis that was successfully tested will be 
re-distributed for the testing of the other two hypotheses.
Initially, =2.3% (23/25 of the 
overall total =2.5% for testing the OS, PFS and ORR) is allocated to the OS hypothesis and 
=0.2% (2/25 of the overall total =2.5%) is allocated to the PFS hypothesis.
The testing of the OS, PFS, and ORR will proceed as follows. 
PFS Hypothesis: The study allocates =0.2%, one-sided, to test PFS hypothesis initially. If 
the null hypothesis for OS is rejected, Figure 5 shows that half of its =2.3% will be 
reallocated to PFS hypothesis testing (=1.35%). If null hypotheses for OS and ORR are both 
rejected, all will be reallocated to test PFS hypothesis (=2.5%). Thus, the PFS null 
hypothesis may be tested at α=0.2%, 1.35% or 2.5%. Table 20 shows the boundary thresholds 
corresponding to a successful group sequential testing of the PFS hypothesis at each of these 
Type I error levels.  For PFS, the information fraction at interim analysis will be based on the 
final planned number of 487 events. A Hwang-Shih-DeCani (HSD) spending function with γ = 
–2 (α-spending for efficacy) is used to set efficacy bounds.  The futility spending is done by 
controlling the probability of crossing the futility bound under the null hypothesis (total of 1-

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α=97.5%); an HSD alpha-spending function with γ=-6 is used to construct group sequential 
boundaries for futility. The boundary thresholds at the interim analysis will be determined by 
the spending function evaluated at the exact number of PFS events at each analysis. Note that 
if the α-reallocation from OS hypothesis testing occurs at the final analysis after hypothesis 
testing for PFS has been completed, the previously computed PFS test statistic for the PFS 
analysis may be re-evaluated versus the updated bounds.
OS Hypothesis: The OS hypothesis may be tested at α=2.3% (initially allocated α) or at 
α=2.5% (if both the ORR and PFS null hypotheses are rejected). The nominal Type I error 
rates for the interim analysis and final analysis that will allow tight control of the overall Type 
I error for testing the OS hypothesis will be derived using the alpha-spending function 
approach based on the overall Type I error allocated to the OS hypothesis.  The group
sequential testing of the OS hypothesis will use a linear -spending function with a fixed -
spending of 0.0001 at IA1 and the rest -spending approximated by an HSD -spending
function with γ=-4 to construct Haybittle-Peto type of group sequential boundaries to control 
the overall Type I error rate for this endpoint at 2.3% or 2.5% (1-sided). The 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 alpha-spending function with γ=-6 is used to construct group 
sequential boundaries for futility. The boundary thresholds will be updated using the actual 
number of OS events at the interim and final OS analyses and the same spending function used 
to derive the design.
ORR Hypothesis: The ORR hypothesis will be tested with all subjects, since all subjects will 
have “mature ORR information,” with an opportunity to complete 4 scheduled scans at the first 
interim analysis.  The ORR hypothesis is initially allocated a Type I error =0% and thus, 
cannot be tested unless one or both of the PFS or OS null hypotheses have been rejected.  
Depending on the results of the OS and PFS hypotheses testing, the ORR hypothesis can be 
tested at an overall Type I error levels of =0.2%, 1.15%, or 2.5%.  If the testing of ORR 
hypothesis does not reach statistical significance at interim analysis 1 (IA1), the p-value from 
the IA1 analysis can be compared to an updated α-level if the null hypothesis for PFS or OS is 
rejected at a later time. Table 20 shows the boundary thresholds of the ORR hypothesis at each 
of these Type I error levels.
Sample Size and Power Calculations
8.9
The study will randomize subjects in a 1:1 ratio into the experimental arm of 
pembrolizumab+axitinib and the control arm of sunitinib.  Both PFS and OS are primary 
endpoints for this study. The sample size was planned for 840 but the following power 
calculations are based on the actual final number of randomized subjects (N = 861).
For the PFS endpoint, based on a target number of 487 PFS events and one interim analysis at 
approximately 75% of the target number of events, the study has ~99% power to detect an HR
of 0.60 (pembrolizumab+axitinib combination versus sunitinib) at alpha=0.2% (1-sided). The 
calculation assumes an HSD -spending function with γ=-2 to control the overall Type I error 
rate for this endpoint at 0.2% (1-sided). The target numbers of PFS events for the first interim 
and final analysis are projected to occur at 22 and 31 months respectively.
For the OS endpoint, based on a target number of 404 final OS events and 2 interim analyses 
(with approximately 48% of final OS events at IA1 and 74% of the final OS events at IA2), the 

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study has approximately 80% power to detect an HR of 0.75 at an overall alpha level of 2.3% 
(1-sided). The calculation assumes that a linear -spending function with a fixed -spending 
of 0.0001 at IA1 and the rest -spending approximated by an HSD -spending function with 
γ=-4 to control the overall Type I error rate for this endpoint at 2.3% (1-sided). The target 
number of OS events is projected to occur at 43 months after the start of the study. The target 
numbers of OS events for the first and second interim analyses are projected to occur at 2 2
months and 31 months respectively.
The above calculations assume an exponential distribution with a median of 13 months for PFS
and a median of 33 months for OS for the control group respectively, a yearly dropout rate of 
10% for PFS and 1% for OS, and an enrollment of 15 months, with monthly accrual of 40 to 
60 patients in the first 3 months and monthly accrual of ~60 patients after the first 3 months.
The median PFS and median OS assumptions in the control group are based on emerging data 
of sunitinib from the CheckMate 214 study (59).
Subgroup Analyses and Effect of Baseline Factors
8.10
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 dual primary endpoints 
will be estimated and plotted within each category of the following classification variables:

IMDC risk category (favorable versus intermediate versus poor; favorable versus
intermediate plus poor)

Geographic region (North America versus Western Europe versus Rest of the World)

PD-L1 status (combined positive score [CPS] <1 versus CPS ≥ 1)

Age (< 65 versus ≥ 65)

Sex (male versus female)

Race (white versus non-white)
Country-specific populations may also be analyzed per local regulatory requirements.
For tumor tissue PD-L1 expression status, a CPS cutpoint of 1 has been established based on 
data from a separate study, Keynote 427 Cohort A, in subjects with advanced/metastatic clear 
cell RCC treated with pembrolizumab monotherapy. Details regarding establishment of the 
PD-L1 CPS cutpoint will be summarized in a separate document.   
Compliance
8.11
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
8.12
The extent of exposure will be summarized as duration of treatment in cycles. Summary 
statistics will be provided on Extent of Exposure for the ASaT population.

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9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
Investigational Product
9.1
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 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 21.  
Table 21
Product Descriptions
Product Name & Potency
Dosage 
Form
Source/Additional Information
Pembrolizumab (MK-3475) 
25 mg/mL (100 mg/4 mL)
Axitinib 1 mg
Axitinib 5 mg
Sunitinib malate 
(equivalent to sunitinib 12.5 mg)
Sunitinib malate
(equivalent to sunitinib 25mg)
Solution for 
injection
Tablet
Tablet
Capsule
Capsule
Provided centrally by the Sponsor.
Provided centrally by the Sponsor or locally 
by the trial site, subsidiary, or designee.
Provided centrally by the Sponsor or locally 
by the trial site, subsidiary, or designee.
Provided centrally by the Sponsor or locally 
by the trial site, subsidiary, or designee. 
Provided centrally by the Sponsor or locally 
by the trial site, subsidiary, or designee. 
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Pembrolizumab (MK-3475) will be supplied in open-label kits containing 2 vials each.  
Axitinib and sunitinib will be supplied in open-label bottles. 
Clinical Supplies Disclosure
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.

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Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. 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.
Standard Policies
9.6
Trial site personnel will have access to a central electronic treatment allocation/randomization 
system (IVRS/IWRS system) to allocate subjects, to assign treatment to subjects and to 
manage the distribution of clinical supplies. Each person accessing the IVRS system must be 
assigned an individual unique PIN.  They must use only their assigned PIN to access the 
system, and they must not share their assigned PIN with anyone.

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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
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/ERC) 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 Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, 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 subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory submissions, 
and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  Additionally, 
the investigator’s name and business contact information may be included when reporting 
certain serious adverse events to regulatory authorities or to other investigators.  By signing 
this protocol, the investigator expressly consents to these uses and disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating investigators 
upon request.

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Confidentiality of IRB/IEC Information
10.1.4
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.
Compliance with Financial Disclosure Requirements
10.2
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.
Compliance with Law, Audit and Debarment
10.3
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 Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access to 
all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local laws, 
rules and regulations; and, for each subject participating in the trial, provide all data, and, upon 
completion or termination of the clinical trial, submit any other reports to the Sponsor as 
required by this protocol or as otherwise required pursuant to any agreement with the Sponsor.

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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 as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the conduct 
of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, correspondence 
with regulatory authorities and IRBs/ERCs, consent forms, investigator’s curricula vitae, 
monitor visit logs, laboratory reference ranges, laboratory certification or quality control 
procedures and laboratory director curriculum vitae.  By signing this protocol, the investigator 
agrees that documentation shall be retained until at least 2 years after the last approval of a 
marketing application in an ICH region or until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  Because the clinical 
development and marketing application process is variable, it is anticipated that the retention 
period can be up to 15 years or longer after protocol database lock. The Sponsor will determine 
the minimum retention period and notify the investigator when documents may be destroyed.  
The Sponsor will determine the minimum retention period and upon request, will provide 
guidance to the investigator when documents no longer need to be retained.  The sponsor also 
recognizes that documents may need to be retained for a longer period if required by local 
regulatory requirements. All trial documents shall be made available if required by relevant 
regulatory authorities. The investigator must consult with and obtain written approval by the 
Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
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.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site is 
open in an EU country, Merck, as the Sponsor, will designate, per country, a national principal 
coordinator (Protocol CI), responsible for coordinating the work of the principal investigators 
at the different trial sites in that Member State, according to national regulations.  For a single-
center trial, the Protocol CI is the principal investigator.  In addition, the Sponsor must 

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designate a principal or coordinating investigator to review the trial report that summarizes the 
trial results and confirm that, to the best of his/her knowledge, the report accurately describes 
the conduct and results of the trial [Clinical Study Report (CSR) CI].  The Sponsor may 
consider one or more factors in the selection of the individual to serve as the Protocol CI and or 
CSR CI (e.g., availability of the CI during the anticipated review process, thorough 
understanding of clinical trial methods, appropriate enrollment of subject cohort, timely 
achievement of trial milestones).  The Protocol CI must be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
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 subject to 
the requirements for submission to http://www.clinicaltrials.gov, www.clinicaltrialregister.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 trials directive mandated trials. Information posted will allow 
subjects 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.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and functional 
area standard operating procedures (SOPs) to ensure that trials are conducted and data are 
generated, documented, and reported in compliance with the protocol, 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.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her electronic 
signature is the legally binding equivalent of a written signature.  By entering his/her electronic 
signature, the investigator confirms that all recorded data have been verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be provided 
separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 

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authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided the 
complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also include 
the protocol and statistical analysis plan to facilitate the peer and editorial review of the 
manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will allow 
the journal, if it so desires, to post on its website the key sections of the protocol that are 
relevant to evaluating the trial, specifically those sections describing the trial objectives and 
hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, the 
efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, due 
to statistical concerns.  In rare cases, publication of single trial site data prior to the main paper 
may be of value.  Limitations of single trial site observations in a multicenter trial should 
always be described in such a manuscript.

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Authorship credit should be based on 1) substantial contributions to conception and design, or 
acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it 
critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that contributions 
have also been made to all three of the preceding authorship criteria.  Although publication 
planning may begin before conducting the trial, final decisions on authorship and the order of 
authors’ names will be made based on participation and actual contributions to the trial and 
writing, as discussed above. The first author is responsible for defending the integrity of the 
data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. Any 
information identified by the Sponsor as confidential must be deleted prior to submission; this 
confidentiality does not include efficacy and safety results. Sponsor review can be expedited to 
meet publication timelines.

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11.0 LIST OF REFERENCES
1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, R. Ford, et al.  New 
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45:228-247.
2. Heng D, Xie W, Regan M, Warren M, Golshayan A, Sahi C, et al. Prognostic Factors for 
overall survival in patients with metastatic renal cell carcinoma treated with vascular 
endothelial growth factor–targeted agents: results from a large, multicenter study. Clin 
Oncol. 2009;27:5794-5799.
3. Heng D, Xie W, Regan M, Harshman L, Bjarnason G, Vaishampayan U.  External 
validation and comparison with other models of the international metastatic renal-cell 
carcinoma database consortium prognostic model: a population-based study. Lancet. 
2013;14:143-8.
4. Escudier B, Porta C, Schmidinger M, Algaba F, Patard J, Khoo V, et al. Renal cell 
carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 
Ann Oncol. 2014;25: vii65–vii71.
5. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7-30.
6. Motzer RJ, Jonasch E, Agarwal N, Beard C, Bhayani S, Chang S, et al. NCCN clinical 
practice guidelines in oncology (NCCN Guidelines®. Kidney Cancer. Version 2.2016.
7. U.S. Prescribing Information: PROLEUKIN® (aldesleukin) for injection, for intravenous 
infusion: 2012.
8. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O. Sunitinib 
versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-24.
9. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al. 
Overall survival and updated results for sunitinib compared with interferon alfa in patients 
with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584-90.
10. Sternberg C, Davis I, Mardiak J, Szczylik C, Lee E, Wagstaff J. Pazopanib in Locally 
Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial. J 
Clin Oncol. 2010;28:1061-8.
11. Sternberg C, Hawkins R, Wagstaff J, Salman P, Mardiak J, Barrios C, 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;49:1287-96.
12. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, et al. Bevacizumab plus 
interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-
blind phase III trial. Lancet. 2007;370:2103-2111.
13. Escudier B, Bellmunt J, Negrier S, Bajetta E, Melichar B, Bracarda S, et al. Phase III trial 
of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma 
(avoren): final analysis of overall survival. J Clin Oncol. 2010;28:2144-50.
14. Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J. Pazopanib versus sunitinib 
in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722-31.

Product:  MK-3475 
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15. Hutson TE, Lesovoy V, Al-Shukri S, Stus V, Lipatov ON, Bair AH, et al. Axitinib versus 
sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a 
randomized open-label phase 3 trial. Lancet. 2013;14:1287-94.
16. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, 
interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356:2271-
2281.
17. U.S. Prescribing Information: NEXAVAR (sorafenib) tablets, oral: 2005
18. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell 
carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 
2008;372: 449-456.
19. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of 
everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic 
factors. Cancer. 2010;116:4256-65.
20. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al. Comparative 
effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a 
randomised phase 3 trial. Lancet. 2011;378:1931-9.
21. Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, et al. 
Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: 
overall survival analysis and updated results from a randomised phase 3 trial. Lancet 
Oncol. 2013 May;14(6):552-62.
22. U.S. Prescribing Information: INLYTA (axitinib) tablets for oral administration: 2012.
23 European Medicines Agency. Committee for medicinal products for human use (CHMP): 
CHMP assessment report: Inlyta (EMA/CHMP/453325/2012) [internet]. London: 
European 
medicines 
agency; 
2012. 
available 
from: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_public_assessment_report/human/002406/WC500132190.pdf.
24. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. 
Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 
2015;373:1803-13.
25. U.S. Prescribing Information: COMETRIQ™ (cabozantinib) capsules, for oral use: 2016.
26. Choueiri T, Escudier B, Powles T, Mainwaring P, Rini B, Donskov F, et al. Cabozantinib 
versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1814-23.
27. Finn, OJ. Molecular origins of cancer: cancer immunology. N Engl J Med. 
2008;358:2704-15.
28. Schreiber RD, Old LJ, and Smyth MJ. Cancer immunoediting: integrating immunity's 
roles in cancer suppression and promotion. Science. 2011;331:1565-70.
29. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive 
immunity to cancer. Annu Rev Immunol. 2011;29:235-71.
30. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev 
Cancer. 2012;12:252-264.

Product:  MK-3475 
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31. Chen L, Flies DB. Molecular mechanisms of T-cell co-stimulation and co-inhibition. Nat 
Rev Immunol. 2013;13:227-42. Erratum in: Nat Rev Immunol. 2013;13:542.
32. Pedoeem, A., Azoulay-Alfaguter I, et al. Programmed death-1 pathway in cancer and 
autoimmunity. Clin Immunol. 2014;153:145-52.
33. Zou W, Chen l. Inhibitory B7-family molecules in the tumour microenvironment. Nat. 
Rev. Immunol. 2008;8:467Rev. Ihttp://dx.doi.org/10.1038/nri2326
34. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 
2011;480:480-489.
35. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to 
activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207-212.
36. Postow, MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. 
J Clin Oncol. 2015;33:1-9.
37. Dion DS, Krilov L, Cohen E, Gangadha T, Ganz PA, Hensing TA, et al.  Clinical Cancer 
advances 2016: annual report on progress against cancer from the American society of 
clinical oncology. J Clin Oncol. http://dx.doi.org/10.1200/JCO.2015.65.8427
38. U.S. Prescribing Information: KEYTRUDA (pembrolizumab) for injection, for 
intravenous use: 2015.
39. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor 
responses with pembrolizumab (Anti-PD-1) in melanoma. N Engl J Med 2013;369:134-
44.
40. Robert C, Ribas A, Walchak JD, et al. Anti-programmed-death-receptor-1 treatment with 
pembrolizumab in ipilimumab-refractory advanced melanoma: a randomized dose-
comparison cohort of a phase 1 trial. Lancet, 2014. 384: 1109-17.
41. Ribas A, Puzanov I, Dummer R, Schadendorf F, et al. Pembrolizumab versus investigator-
choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a 
randomised, controlled, phase 2 trial. Lancet Oncol. 2015:16:908-18.
42. Robert C, Schacter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced 
melanoma. N Engl J Med. 2015 Apr 19: [Epub ahead of print]. 
43. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab 
for the Treatment of Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Apr 19. [Epub 
ahead of print].
44. Muro K, Bang Y, Shankaran V, Geva R, Catenacci DVT, Gupta S, et al. A phase 1b Study 
of pembrolizumab (pembro; MK-3475) in patients (pts) with advanced gastric cancer 
[abstract]. Ann Oncol. 2014;25 (Suppl 5):v1-v41. Abstract no. LBA15V.
45. Plimack ER, Bellmunt J, Gupta S, Berger R, Montgomery RB, Heath K, et al. 
Pembrolizumab (MK-3475) for advanced urothelial cancer: updated results and biomarker 
analysis from KEYNOTE-012 [abstract]. Abstracts of the 2015 ASCO Annual Meeting; 
2015 May 29 to June 2; Chicago, IL. American Society of Clinical Oncology 
(ASCO);2015.

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46. Seiwert TY, Burtness B, Weiss J, Gluck I, Eder JP, Pai SI, et al. Safety A phase Ib study 
of MK-3475 in patients with human papillomavirus (HPV)-associated and non-HPV–
associated head and neck (H/N) cancer. [abstract]. J Clin Oncol. 2014;32 Suppl 20:6011.
47. Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, et al. A phase 1b study of 
pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. San 
Antonio Breast Cancer Symposium 2014; Abstract S1-09.
48. Wierecky J, Muller MR, Wirths S et al. Immunologic and clinical responses after 
vaccinations with peptide-pulsed dendritic cells in metastatic renal cancer patients. Cancer 
Res 2006; 66: 5910–5918.
49. Ahmadzadeh M., Johnson LA, Heemskerk B, Wunderlich JR, Dudley LA, White DE, 
Rosenberg SA. Tumor antigen-specific CD8 T-cells infiltrating the tumor express high 
levels of PD-1 and are functionally impaired. Blood. 2009;114:1537.
50 Topalian SL, Hodi S, Brahmer J, Gettinger S, Smith D, McDermott D, et al. Safety, 
activity, and immune correlates of anti–pd-1 antibody in cancer. N Engl J Med. 2012; 
366:2443-54.
51. Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, and Hodi FS. 
Developing a common language for tumor response to immunotherapy: immune related
response criteria using unidimensional measurements. Clin Cancer Res. 2013;19:3936-43.
52. Cella D, Yount S, Brucker PS, et al. Development and validation of a scale to measure 
disease-related symptoms of kidney cancer. Value Health. 2007;10:285-293.
53. Cella D, Li JZ, Cappelleri JC, et al. Quality of life in patients with metastatic renal cell 
carcinoma treated with sunitinib or interferon alfa: results from a phase III randomized 
trial. J Clin Oncol. 2008;26):3763-3769.
54 Danan G, Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol 
Sci. 2015;17:1-33.
55. Smith T, Khatcheressian J, Lyman G, Ozer H, Armitage J, Balducci L, et al. 2006 Update 
of recommendations for the use of white blood cell growth factors: an evidence-based 
clinical practice guideline. J Clin Oncol. 2006;24:3187-3205.
56. Finkelstein DM. A proportional hazards model for interval-censored failure time data. 
Biometrics 1986;42:845-54.
57. 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.
58. Odell PM, Anderson KM, Kannel WB. New models for predicting cardiovascular events. 
J Clin Epidemiol. 1994 Jun;47(6):583-92.
59. R.J. Motzer, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et 
al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N 
Engl J Med. 2018 Mar 21: [Epub ahead of print].

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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
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 subject 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 (e.g., 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 subject 
preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose of 
the trial.  Research subjects 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 subjects, 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. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC approval. 
For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects 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.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects 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 subject 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 subject 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 
subjects 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 subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
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/ERC 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 (e.g., 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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Collection and Management of Specimens for Future Biomedical Research
12.2
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 collected in this trial as outlined in Section 7.1.3.7 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects 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.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the Future 
Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all subjects or legal guardians, at a trial visit by 
the investigator or his or her designate.  Informed consent for Future Biomedical 
Research should be presented to the subjects on Visit 1.  If delayed, present consent at 
next possible Subject Visit. Informed consent must be obtained prior to collection of all 
Future Biomedical Research specimens.  Consent forms signed by the subject will be 
kept at the clinical trial site under secure storage for regulatory reasons.  

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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject 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 Collections
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 subject 
is having blood drawn for other trial purposes.
4. Confidential Subject 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 subject' 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 subject 
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 for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first 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 Merck Biorepository 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 this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed will 
be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects 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 

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(clinical.specimen.management@merck.com) and a form will be provided to obtain 
appropriate information to complete specimen withdrawal. Subsequently, the subject's 
specimens will be removed from the biorepository and be destroyed. Documentation will 
be sent to the investigator confirming the destruction. It is the responsibility of the 
investigator to inform the subject of completion of destruction.  Any analyses in progress at 
the time of request for 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 subject’s personal information and their specimens. In this situation, the request for 
specimen destruction can not 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 (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available through 
appropriate mechanisms (e.g., scientific publications and/or presentations). Subjects will 

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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 subjects 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 subject have been minimized. [insert: ‘No 
additional risks to the subject have been identified as no additional specimens are being 
collected for Future Biomedical Research (i.e., only leftover samples are being retained).’ 
OR ‘Risks include those associated with venipuncture to obtain the whole blood specimen.  
This specimen will be obtained at the time of routine blood specimens drawn in the main 
trial.’ OR ‘Buccal swab specimens will be collected inside the cheek with no associated 
venipuncture to obtain the specimen. Therefore, there will not be an additional risk for the 
subject.’ OR ‘Saliva specimens will be collected with no associated venipuncture to obtain 
the specimen. Therefore, there will not be an additional risk for the subject.’]
The Sponsor has developed strict security, policies and procedures to address subject 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

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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff

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Karnofsky Performance Status Scale Definitions Rating (%) Criteria
12.4
Able to carry on normal 
activity and to work; no 
special care needed.
100 
Normal no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms 
of disease. 
Unable to work; able to live 
at home and care for most 
personal 
needs; 
varying 
amount 
of 
assistance 
needed.
70 
Cares for self; unable to carry on normal activity or 
do active work. 
60 
Requires occasional assistance, but is able to care for 
most of his personal needs. 
50 
Requires 
considerable 
assistance 
and 
frequent 
medical care. 
Unable to care for self; 
requires 
equivalent 
of 
institutional 
or 
hospital 
care; 
disease 
may 
be 
progressing rapidly.
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated 
although death not imminent. 
20 
Very sick; hospital admission necessary; active 
supportive treatment necessary. 
10 
Moribund: fatal processes progressing rapidly 
0 
Dead 
Reference: http://www.hospicepatients.org/karnofsky.html

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National Cancer Institute Common Terminology Criteria for Adverse Events
12.5
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE)
version 
4.0 
will 
be 
utilized 
for 
adverse 
events 
reporting
(http://ctep.cancer.gov/reporting/ctc.html).

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Abbreviations
12.6
Abbreviation
Definition
ADA
anti-drug (pembrolizumab) antibodies
AE
adverse event
ALT
alanine aminotransferase
APC
antigen-presenting cells
ASaT
all subjects as treated
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the plasma concentration vs. time curve
β-hCG
β human chorionic gonadotropin
BCG
Bacillus Calmette-Guerin
BICR
blinded independent central imaging review/reviewer
BID
bis in die (twice a day)
BP
blood pressure
CAP
chest, abdomen, and pelvis
CI
confidence interval
CIV
Central Imaging Vendor
Cmax
maximum concentration
CNS
central nervous system
CR
complete response
CrCl
calculated creatinine clearance
CRF
case report form
CSR
clinical study report
CT
computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTL
cytotoxic T lymphocytes cells
CYP
cytochrome P450
DBP
diastolic blood pressure
DCR
disease control rate
DKA
diabetic ketoacidosis
DLT
dose-limiting toxicity
DMC
Data monitoring committee
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiography
ECI
events of clinical interest
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
eDMC
external Data Monitoring Committee
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EORTC
European 
Organization 
for 
the 
Research 
and 
Treatment of Cancer

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Abbreviation
Definition
EuroQol
European Quality of Life 
ESMO
European Society for Medical Oncology
FACT
Functional Assessment of Cancer Therapy
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed, paraffin embedded
FKSI-DRS
Functional Assessment of Cancer Therapy Kidney 
Symptom Index—Disease-related Symptoms
FSH
follicle stimulating hormone
FT3, FT4
free thyroxine
GCP
Good Clinical Practices 
GI
gastrointestinal
GFR
glomerular filtration rate
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HSD
Hwang-Shih-DeCani 
i.e.
id est (that is)
IA1
first interim analysis
IA2
second interim analysis
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IFNα
interferon alpha
IMDC
International Metastatic RCC Database Consortium
IHC
immunohistochemistry
IL-2
interleukin-2
INR
International normalized ratio 
irAEs
immune-related adverse events
IRB
Institutional Review Board
irRECIST
immune-related RECIST
ITT
Intention to treat
IUD
intrauterine device
IV
intravenous
IVRS
interactive voice response system
KPS
Karnofsky performance status
LFT  
liver function tests
mAb
monoclonal antibody
mRCC
metastatic renal cell carcinoma
MRI
magnetic resonance imaging
mRNA
messenger RNA

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Abbreviation
Definition
MSI
microsatellite instability
mTOR
mammalian target of rapamycin
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
OTC
over the counter
PD
progressive disease or disease progression
PD-1
programmed cell death protein 1
PD-L1
programmed death-ligand 1
PD-L2
programmed death-ligand 2 
PE
physical exam
PFS
progression-free survival
PIN
personal identification number
PK
pharmacokinetic(s)
PR
partial response
PRO
patient-reported outcome
PT
prothrombin time
Q
every
Q21D
every 21-day
Q2W
every 2 weeks
Q3W
every 3 weeks
Q6W
every 6 weeks
Q12W
every 12 weeks
Q24W
every 24 weeks
QALY
quality-adjusted life year
QD
quaque die (once a day)
QTc
QT interval corrected
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RR
response rate
SAC
Scientific Advisory Committee
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
stable disease
SEER
Surveillance, 
Epidemiology, 
and 
End 
Results 
[Program]
SNP
single-nucleotide polymorphism 
SOP
standard operating procedure
sSAP
supplemental Statistical Analysis Plan
T1DM
type 1 diabetes mellitus

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Abbreviation
Definition
TCR
T-cell receptors
TKI
tyrosine kinase inhibitors
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
US
United States
V
volume of distribution
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
WBC
white blood cell [count]

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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
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 (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED