A Phase II Single-arm, Open-label Monotherapy Clinical Trial of Pembrolizumab (MK-3475) in Locally Advanced/Metastatic Renal Cell Carcinoma (mRCC) (KEYNOTE-427)
Phase: PHASE2
Conditions: Renal Cell Carcinoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
A Phase II Single-arm, Open-label Monotherapy Clinical 
Trial of Pembrolizumab (MK-3475) in Locally Advanced/
Metastatic Renal Cell Carcinoma (mRCC) 
(KEYNOTE-427)
25-May-2021
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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. 
(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 II Single-arm, Open-label Monotherapy Clinical Trial of Pembrolizumab (MK-3475) 
in Locally Advanced/Metastatic Renal Cell Carcinoma (mRCC) (KEYNOTE-427)
IND NUMBER:  122,753 
EudraCT NUMBER:  2016-000589-47
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 10
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 12
2.0
TRIAL DESIGN........................................................................................................ 14
2.1
Trial Design ........................................................................................................... 14
2.2
Trial Diagram........................................................................................................ 16
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 17
3.1
Primary Objective(s) & Hypothesis(es).............................................................. 17
3.2
Secondary Objective(s) & Hypothesis(es)........................................................... 17
3.3
Exploratory Objectives......................................................................................... 17
4.0
BACKGROUND & RATIONALE.......................................................................... 17
4.1
Background ........................................................................................................... 17
4.1.1
Pharmaceutical and Therapeutic Background .................................................... 22
4.1.1.1
Targeting PD-1 Immune Checkpoints for Cancer Treatments .................... 22
4.1.1.2
Anti-PD-1 Antibody Pembrolizumab .......................................................... 22
4.1.1.3
Summary of Pembrolizumab Clinical Efficacy and Safety......................... 23
4.2
Rationale................................................................................................................ 27
4.2.1
Rationale for the Trial and Selected Subject Population .................................... 27
4.2.2
Rationale for Dose Selection/Regimen/Modification......................................... 27
4.2.3
Rationale for Endpoints ...................................................................................... 28
4.2.3.1
Efficacy Endpoints....................................................................................... 28
4.2.3.1.1
Immune-related RECIST ...................................................................... 28
4.2.3.2
Safety Endpoints.......................................................................................... 29
4.2.3.3
Planned Exploratory Biomarker Research................................................... 29
4.2.3.4
Future Biomedical Research........................................................................ 31
4.3
Benefit/Risk ........................................................................................................... 31
5.0
METHODOLOGY ................................................................................................... 31
5.1
Entry Criteria........................................................................................................ 31
5.1.1
Diagnosis/Condition for Entry into the Trial...................................................... 31
5.1.2
Subject Inclusion Criteria.................................................................................... 32
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5.1.3
Subject Exclusion Criteria .................................................................................. 34
5.2
Trial Treatment..................................................................................................... 35
5.2.1
Dose Selection .................................................................................................... 36
5.2.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)........................................................................................................ 36
5.2.3
Timing of Dose Administration.......................................................................... 41
5.2.4
Trial Blinding...................................................................................................... 42
5.3
Randomization or Treatment Allocation............................................................ 42
5.4
Stratification.......................................................................................................... 42
5.5
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 42
5.5.1
Acceptable Concomitant Medications ................................................................ 42
5.5.2
Concomitant Surgery .......................................................................................... 43
5.5.3
Prohibited Concomitant Medications.................................................................. 43
5.6
Rescue Medications & Supportive Care............................................................. 44
5.6.1
Supportive Care Guidelines ................................................................................ 44
5.7
Diet/Activity/Other Considerations..................................................................... 44
5.7.1
Diet...................................................................................................................... 44
5.7.2
Contraception...................................................................................................... 44
5.7.3
Use in Pregnancy ................................................................................................ 46
5.7.4
Use in Nursing Women....................................................................................... 46
5.8
Subject Withdrawal/Discontinuation Criteria................................................... 46
5.8.1
Discontinuation of Treatment ............................................................................. 46
5.8.2
Withdrawal of Consent ....................................................................................... 47
5.8.2.1
Lost to Follow-up......................................................................................... 48
5.9
Subject Replacement Strategy............................................................................. 48
5.10
Beginning and End of the Trial ........................................................................... 48
5.11
Clinical Criteria for Early Trial Termination ................................................... 48
6.0
TRIAL FLOW CHART ........................................................................................... 49
6.1
Second Course Phase Retreatment – (Maximum 17 Cycles)............................ 54
7.0
TRIAL PROCEDURES ........................................................................................... 56
7.1
Trial Procedures ................................................................................................... 56
7.1.1
Administrative Procedures.................................................................................. 56
7.1.1.1
Informed Consent......................................................................................... 56
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7.1.1.1.1
General Informed Consent.................................................................... 56
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 56
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 57
7.1.1.3
Subject Identification Card .......................................................................... 57
7.1.1.4
Medical History ........................................................................................... 57
7.1.1.4.1
History of Renal Cell Carcinoma.......................................................... 57
7.1.1.5
Prior and Concomitant Medications Review............................................... 57
7.1.1.5.1
Prior Medications.................................................................................. 57
7.1.1.5.2
Prior Treatment Details for Renal Cell Carcinoma .............................. 57
7.1.1.5.3
Concomitant Medications..................................................................... 58
7.1.1.6
Subsequent Anti-Cancer Therapy Status ..................................................... 58
7.1.1.7
Assignment of Screening Number............................................................... 58
7.1.1.8
Assignment of Treatment/Randomization Number..................................... 58
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)................................... 58
7.1.2
Clinical Procedures/Assessments........................................................................ 59
7.1.2.1
Adverse Event Monitoring........................................................................... 59
7.1.2.2
Full Physical Examination........................................................................... 59
7.1.2.3
Directed Physical Exam............................................................................... 59
7.1.2.4
Vital Signs.................................................................................................... 60
7.1.2.5
12-Lead Electrocardiogram ......................................................................... 60
7.1.2.6
Karnofsky Performance Status .................................................................... 60
7.1.2.7
Tumor Imaging and Assessment of Disease................................................ 60
7.1.2.7.1
Tumor Imaging at Screening ................................................................ 61
7.1.2.7.2
Tumor Imaging During the Trial .......................................................... 61
7.1.2.7.3
End of Treatment and Follow-up Tumor Imaging................................ 62
7.1.2.7.4
Second Course (Retreatment) Tumor Imaging..................................... 63
7.1.2.7.5
RECIST 1.1 Assessment of Disease..................................................... 63
7.1.2.7.6
irRECIST Assessment of Disease......................................................... 63
7.1.3
Laboratory Procedures/Assessments .................................................................. 69
7.1.3.1
Urine Pregnancy Test................................................................................... 69
7.1.3.2
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 69
7.1.3.2.1
Pharmacokinetic Evaluations/ Anti -pembrolizumab Antibodies ........ 70
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7.1.3.3
Tumor Tissue Collection.............................................................................. 71
7.1.3.3.1
Cohort B Substudy of PD-L1 Expression in Area of Highest 
Furhman Grade ..................................................................................... 72
7.1.3.4
Blood Collections for ctDNA, TCR, RNA, Plasma, and Serum ................. 72
7.1.3.5
Planned Genetic Analysis Sample Collection.............................................. 72
7.1.3.6
Future Biomedical Research Sample Collection ......................................... 72
7.1.4
Other Procedures................................................................................................. 72
7.1.4.1
Withdrawal/Discontinuation........................................................................ 72
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 73
7.1.4.2
Blinding/Unblinding .................................................................................... 73
7.1.4.3
Calibration of Critical Equipment................................................................ 73
7.1.5
Visit Requirements.............................................................................................. 74
7.1.5.1
Screening...................................................................................................... 74
7.1.5.2
Treatment Period.......................................................................................... 74
7.1.5.2.1
Second Course Phase (Retreatment Period) ......................................... 75
7.1.5.3
Post-Treatment Visits................................................................................... 75
7.1.5.3.1
End of Treatment Visit ......................................................................... 75
7.1.5.3.2
Safety Follow-up Visit.......................................................................... 76
7.1.5.3.3
Efficacy Follow-up Visits..................................................................... 76
7.1.5.3.4
Survival Follow-up Contacts ................................................................ 76
7.1.5.4
Survival Status ............................................................................................. 77
7.2
Assessing and Recording Adverse Events .......................................................... 77
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor ............................................................................................................... 78
7.2.2
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 78
7.2.3
Immediate Reporting of Adverse Events to the Sponsor.................................... 79
7.2.3.1
Serious Adverse Events ............................................................................... 79
7.2.3.2
Events of Clinical Interest............................................................................ 80
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 80
7.2.4
Evaluating Adverse Events................................................................................. 81
7.2.5
Sponsor Responsibility for Reporting Adverse Events ...................................... 84
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 84
8.1
Statistical Analysis Plan Summary ..................................................................... 84
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8.2
Responsibility for Analyses/In-House Blinding ................................................. 85
8.3
Hypotheses/Estimation......................................................................................... 85
8.4
Analysis Endpoints ............................................................................................... 85
8.4.1
Efficacy Endpoints.............................................................................................. 85
8.4.1.1
Primary......................................................................................................... 85
8.4.1.2
Secondary..................................................................................................... 85
8.4.2
Safety Endpoints ................................................................................................. 86
8.5
Analysis Population .............................................................................................. 86
8.5.1
Efficacy Analysis Population.............................................................................. 86
8.5.2
Safety Analysis Population................................................................................. 86
8.6
Statistical Methods................................................................................................ 86
8.6.1
Statistical Methods for Efficacy Analyses.......................................................... 86
8.6.2
Statistical Methods for Safety Analyses ............................................................. 88
8.6.3
Summaries of Demographic and Baseline Characteristics ................................. 88
8.7
Interim Analyses ................................................................................................... 88
8.8
Multiplicity ............................................................................................................ 88
8.9
Sample Size and Power Calculations .................................................................. 88
8.10
Subgroup Analyses and Effect of Baseline Factors............................................ 89
8.11
Compliance............................................................................................................ 89
8.12
Extent of Exposure................................................................................................ 89
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 90
9.1
Investigational Product ........................................................................................ 90
9.2
Packaging and Labeling Information ................................................................. 90
9.3
Clinical Supplies Disclosure................................................................................. 90
9.4
Storage and Handling Requirements.................................................................. 90
9.5
Discard/Destruction/Returns and Reconciliation .............................................. 90
9.6
Standard Policies................................................................................................... 91
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 91
10.1
Confidentiality....................................................................................................... 91
10.1.1 Confidentiality of Data ....................................................................................... 91
10.1.2 Confidentiality of Subject Records..................................................................... 91
10.1.3 Confidentiality of Investigator Information........................................................ 91
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10.1.4 Confidentiality of IRB/IEC Information............................................................. 92
10.2
Compliance with Financial Disclosure Requirements....................................... 92
10.3
Compliance with Law, Audit and Debarment ................................................... 92
10.4
Compliance with Trial Registration and Results Posting Requirements........ 94
10.5
Quality Management System............................................................................... 94
10.6
Data Management................................................................................................. 94
10.7
Publications ........................................................................................................... 95
11.0
LIST OF REFERENCES......................................................................................... 96
12.0
APPENDICES......................................................................................................... 101
12.1
Merck Code of Conduct for Clinical Trials...................................................... 101
12.2
Collection and Management of Specimens for Future Biomedical Research
.............................................................................................................................. 103
12.3
Understanding the Intent, Scope and Public Health Benefits of Exploratory 
Biomarker Research: A Guide for IRBs/IECs and Investigational Site Staff
.............................................................................................................................. 107
12.4
Karnofsky Performance Status Scale Definitions Rating (%) Criteria......... 118
12.5
IMDC Risk Evaluation....................................................................................... 119
12.6
National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) .................................................................................. 120
12.7
Abbreviations ...................................................................................................... 121
13.0
SIGNATURES......................................................................................................... 123
13.1
Sponsor's Representative ................................................................................... 123
13.2
Investigator.......................................................................................................... 123
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LIST OF TABLES
    
Table 1
Summary of Clinical Efficacy from Randomized Phase III Studies in First-line 
Advanced RCC................................................................................................. 19
Table 2
Summary of Treatment-emergent AEs ≥ 20% (n, %) of All Causality............ 25
Table 3
Laboratory Results (n, %) by Maximum CTCAE Grade (N = 52).................. 26
Table 4
Adequate Organ Function ................................................................................ 33
Table 5
Trial Treatment................................................................................................. 35
Table 6
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse 
Events 
Associated 
with 
Pembrolizumab 
Monotherapy, 
Coformulations or IO Combinations................................................................ 37
Table 7
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines......................................................................................................... 40
Table 8
Imaging and Treatment after First Radiologic Evidence of PD....................... 66
Table 9
Laboratory Tests............................................................................................... 69
Table 10 Evaluating Adverse Events .............................................................................. 82
Table 11 Analysis Strategy for Key Efficacy Variables ................................................. 87
Table 12 Censoring Rules for DOR ................................................................................ 87
Table 13 Product Descriptions ........................................................................................ 90
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LIST OF FIGURES
Figure 1 Study Schema................................................................................................... 16
Figure 2 Imaging and Treatment for Clinically Stable Subjects in Cohort A after First 
Radiologic Evidence of PD Assessed by the Site ............................................ 67
Figure 3 Imaging and Treatment for Clinically Stable Subjects in Cohort B after First 
Radiologic Evidence of PD Assessed by the Site ............................................ 68
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 04
25-MAY-2021
To update the dose modification and toxicity management guidelines for irAEs.
Amendment 03
09-NOV-2020
To remove reference to “sub-trial” in the Future Biomarker Research sections 
of the protocol. Revision due to EU CTR changes that will require FBR results 
to be reported if FBR is indicated as a substudy to the clinical protocol.
Amendment 02
14-NOV-2017
To change the timing of bone scans at screening (accepting scans that have been 
performed within 42 days of screening) in order to minimize patient burden.
To update the dose modification and toxicity management guidelines for 
pembrolizumab in order to be in alignment with the most current label and safety 
information for pembrolizumab.
Amendment 01
20-MAR-2017
To clarify eligibility so that inclusion and exclusion criteria are not overly 
restrictive.
To provide a clear and concise guide to investigators on management of AEs
associated with pembrolizumab. 
To allow enrollment in Cohort B upon local laboratory confirmation of 
diagnosis, and central laboratory confirmation that the submitted tissue is 
adequate for central review (previously, central laboratory
diagnosis 
confirmation was required before allocation).
Original
16-JUN-2016
Not applicable
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SUMMARY OF CHANGES
PRIMARY REASON FOR THIS AMENDMENT:
Section Number
Section Title
Description of Change
Rationale
5.2.2
Immune-Related Events and 
Dose Modification (Withhold, 
Treat, Discontinue)
The dose modification and 
toxicity 
management 
guidelines for irAEs and table 
were updated.
The dose modification and 
toxicity 
management 
guidelines for irAEs and table 
were updated as requested by 
the U.S. FDA in an effort to 
harmonize the presentation of 
safety information across all 
FDA-approved 
PD-1/L1 
antibody 
prescribing 
information.
ADDITIONAL CHANGE FOR THIS AMENDMENT:
No additional changes.
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1.0 TRIAL SUMMARY
Abbreviated Title
Pembrolizumab in advanced renal cell carcinoma
Sponsor Product 
Identifiers
MK-3475
Pembrolizumab
Trial Phase
Phase II
Clinical Indication
Renal cell carcinoma
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
The study will include 2 cohorts
1. Clear-cell renal cell carcinoma (Cohort A)
2. Non-clear-cell renal cell carcinoma (Cohort B)
Number of trial subjects
Approximately 255 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require 
approximately 5 years 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 of 
signing the Informed Consent Form through the final 
protocol-specified contact.  
After a screening phase of 28 days, each subject will receive
pembrolizumab for approximately 2 years.  After the end of 
treatment, each subject will be followed for survival.
Written consent must be obtained prior to performing any 
protocol-specified procedures. Informed consent may be 
obtained greater than 28 days prior to treatment allocation; 
however, it MUST be obtained prior to performing any 
protocol-specified procedures. Tumor tissue collection for 
biomarker studies and histologic confirmation of non-clear 
cell RCC diagnosis should be submitted after obtaining 
written consent; however, tissue samples may be submitted 
to the central laboratory greater than 28 days prior to 
treatment allocation.  This is in order for sites to gather 
tumor tissue samples and/or other information from the 
subjects. It is recommended that the tumor samples be 
collected and submitted for central laboratory review as 
soon as the informed consent is signed.
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Study treatments will continue until progressive disease is 
determined, or further confirmed by the investigator, 
unacceptable adverse events (AEs), intercurrent illness that 
prevents further administration of treatment, Investigator’s 
decision to discontinue the subject, subject discontinuation 
from the study, subject receives 35 administrations of 
pembrolizumab (approximately 2 years), or administrative 
reasons requiring the cessation of treatment. Subjects who 
stop pembrolizumab after receiving 35 doses of 
pembrolizumab without progressive disease (PD), or after
achieving a complete response (had a minimum of 8 
administrations of pembrolizumab and at least 2 treatments 
beyond initial complete response [CR]) may be eligible for 
a second course of pembrolizumab treatment for up to 17 
additional doses of pembrolizumab (approximately one 
year) upon experiencing PD.
After the end of treatment, each subject will be followed for 
30 days after the last dose of pembrolizumab for adverse 
event monitoring (serious adverse events will be collected 
up to 90 days after the last dose of trial treatment or 30 days 
following cessation of treatment if the subject initiates new 
anticancer therapy, whichever comes first).  
Subjects who discontinue treatment for any reason other 
than confirmed disease progression should continue with 
imaging assessments per the protocol defined schedule 
until: 1) disease progression, 2) initiation of a new anti-
cancer treatment, 3) death, 4) withdrawal of consent or 5) 
study conclusion/early termination, whichever occurs first.
Following confirmation of PD, all subjects will be followed 
for survival (by phone contact or clinic visit) until death, 
withdrawal of consent from trial, loss to follow-up, or until 
the study is concluded or terminated early, whichever 
comes first.  
Once the study has ended, the participant is discontinued 
from this study and may be enrolled in an extension study 
to continue protocol-defined assessments and treatment.
A list of abbreviations used in this document can be found in Section 12.7.
Randomization Ratio
Not applicable
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2.0 TRIAL DESIGN
2.1
Trial Design
This is a Phase II, open-label, multicenter, global trial to evaluate the efficacy and safety of 
pembrolizumab as a first-line treatment for advanced/metastatic renal cell carcinoma (mRCC).
The trial will be conducted in conformance with Good Clinical Practices.
The safety and efficacy of pembrolizumab (200 mg every 3 weeks [Q3W]) will be studied in 
approximately 255 subjects with advanced RCC (105 subjects with clear cell (cc) RCC [Cohort 
A] and up to 150 subjects with non-clear cell (ncc) RCC [Cohort B]).  The primary objective 
of the study for both cohorts is to evaluate the objective response rate (ORR), using Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), as assessed by blinded 
independent central review (BICR).
See Section 3 for a complete description of study 
objectives. 
An interim analysis will be performed for the non-clear cell RCC cohort when the 30th subject 
in this cohort has had the opportunity to complete the 3rd scan. The analysis will include all 
scans up to this cut-off time point (see Section 8 for details). A futility check will be conducted 
based on the observed ORR. During the futility analysis the enrollment of subjects will 
continue (see Section 8 for details).  
Subjects in both cohorts A and B must have confirmation of measurable disease at baseline as 
assessed by BICR per RECIST 1.1 and must provide an adequate tumor tissue sample for 
biomarker analysis in order to be eligible for the study. For Cohort B, sites will submit tissues 
for histologic confirmation of the diagnosis of non-clear cell RCC by central histology review 
during the screening phase. Sites should enroll subjects in Cohort B after receiving notice that 
the submitted tissue was adequate for central review.  Confirmation of non-clear cell RCC 
histology by the central laboratory will be made available to the sites at a later date.  See 
Section 5 for a complete list of study inclusion/exclusion criteria.
After a screening phase of 28 days, eligible subjects will receive pembrolizumab until 
progressive disease is initially determined or further confirmed by the investigator,
unacceptable toxicity, intercurrent illness preventing further administration of treatment, 
investigator’s decision to withdraw the subject, withdrawal of consent, noncompliance with 
trial treatment or procedure requirements, administrative reasons requiring the cessation of 
treatment, or until the subject has received 35 doses of pembrolizumab (approximately 
2 years).
During the treatment period, subjects will have routine clinical visits for administering study 
treatment, monitoring safety and well-being, and changes in disease status.  Key study safety 
assessments include physical examinations, vital signs, electrocardiography (ECG), 
hematology and chemistry laboratories including thyroid function test and urinalysis.  At each 
visit, adverse events (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, and the dose may be withheld or discontinued upon experiencing 
severe AEs in accordance with the guidelines in Section 5.2.1.
Scheduled on-study imaging assessments include computed tomography (CT) and/or magnetic 
resonance imaging (MRI) for chest, abdomen, and pelvis.  These imaging assessments will be 
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performed at baseline, after allocation at Week 12, then every 6 weeks (Q6W) until Week 54, 
and every 12 weeks (Q12W) thereafter. Baseline bone scans will be performed for all subjects 
at screening. Bone scans are not required to be repeated at screening if performed within 
42 days prior to treatment allocation.  If a subject has a positive bone scan at screening, bone 
scans will be performed at Weeks 18, 30, 42, and 54, and then every 24 weeks (Q24W) 
thereafter.  For indeterminate bone lesions at baseline, these lesions should be followed 
according to the bone scan imaging time points until these lesions are determined non-
cancerous. In addition, a bone scan is also required for confirmation of a complete response.  
Additional imaging for baseline and follow up may be required if lesions outside the 
aforementioned regions are identified. See Section 7.1.2.7 for details.
Imaging assessments will be performed according to the aforementioned schedule regardless 
of study treatment status until PD is initially determined or further confirmed by the 
investigator, initiation of another anti-cancer therapy, death, withdrawal of consent from the 
trial or study conclusion or early termination, whichever occurs first. All disease assessment 
imaging scans must be submitted promptly to the designated central imaging vendor. 
For both cohorts when a subject is identified with PD by the site investigator/radiologist, PD 
will be confirmed by subsequent scans at the site (for subjects who are clinically stable). 
Subjects who are clinically stable may also continue on treatment at the discretion of the 
investigator until progression is confirmed with a repeat scan. Details are provided in Sections
7.1.2.7.2 and 7.1.2.7.6.
For the non-clear cell cohort (Cohort B), when a subject is identified with PD by the site 
investigator/radiologist, the site will submit scans to the central imaging vendor for PD 
verification by BICR. Subjects who are clinically stable may continue on treatment at the 
discretion of the investigator while awaiting verification of PD by BICR. Following PD 
verification by BICR, subjects who are clinically stable may continue on treatment until 
progression is confirmed by subsequent scans at the site. Details are provided in Sections
7.1.2.7.2 and 7.1.2.7.6.   
In the event that a subject has experienced a partial response (PR) or CR, confirmation of 
response should be performed at the next scheduled imaging assessment visit. Refer to Section 
7.1.2.7.2 for details pertaining to confirmation of response.
After 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. 
All AEs and events of clinical interest (ECIs) occurring within 30 days after the last dose of 
trial treatment must be recorded regardless of when the Safety Follow-up visit occurs.  After 
30 days, record all SAEs occurring up to 90 days after the last dose of trial treatment or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, whichever
comes first.  Any treatment related SAEs must be reported regardless of time they occur (see 
Sections 7.2.3.1 and 7.2.3.2 for further details regarding serious adverse events (SAEs) and 
ECIs reporting).
Subjects who discontinue for reasons other than disease progression will stay on study and will 
have post-treatment follow-up for disease status until disease progression, initiating a non-
study cancer treatment, withdrawing consent, becoming lost to follow-up, or death. All 
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subjects will be followed by telephone or clinic visit for overall survival until death, withdrawal 
of consent, loss to follow-up, or the end of the study.
In the event that a 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 and at least 2 treatments beyond initial CR). Subjects who 
discontinue after 35 doses/infusions for reasons other than disease progression or intolerability, 
or who discontinue after attaining a CR [and had at least 2 treatments beyond initial CR] may 
be eligible for up to 17 additional doses of pembrolizumab after they have experienced 
radiographic disease progression. The decision to re-treat will be at the discretion of the 
investigator only if no cancer treatment was administered since the last dose of 
pembrolizumab, the subject still meets the safety parameters listed in the Inclusion/Exclusion 
criteria, and the trial remains open (refer to Section 7.1.5.2.1 for further details). 
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.
2.2
Trial Diagram

Treatment will continue until disease progression, prohibitive toxicity, death, withdrawal of consent or until 35 
infusions/doses of pembrolizumab have been administered.

Radiographic disease assessments will be performed at Week 12, then every 6 weeks until Week 54, then every 12 weeks 
thereafter.  Unscheduled imaging can be performed as clinically indicated. 

Primary endpoint is ORR by RECIST 1.1
Subjects who discontinue treatment for reasons other than disease progression should continue with imaging assessments per 
the protocol-defined schedule until disease progression, initiation of a new anti-cancer treatment, death, withdrawal of consent 
or study conclusion or early termination, whichever occurs first.
For the non-clear cell cohort (Cohort B), 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.
Figure 1
Study Schema
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
There will be no formal hypothesis testing in this study.
3.1
Primary Objective(s) & Hypothesis(es)
(1) Objective: To estimate the ORR per RECIST 1.1 as assessed by BICR in subjects 
with clear cell RCC.
(2) Objective: To estimate the ORR per RECIST 1.1 as assessed by BICR in subjects 
with non-clear cell RCC.
3.2
Secondary Objective(s) & Hypothesis(es)
(1) Objective: To estimate the duration of response (DOR), disease control rate (DCR),
and progression-free survival (PFS) per RECIST 1.1 as assessed by BICR and overall 
survival (OS) in subjects with clear cell or non-clear cell RCC by cohort.
(2) Objective: To determine the safety and tolerability of pembrolizumab in subjects with 
clear cell or non-clear cell RCC by cohort.
(3) Objective: To describe the patient population using the International Metastatic RCC 
Database Consortium (IMDC) risk group (see Section 12.5 for IMDC criteria): 
favorable versus intermediate versus poor risk groups in subjects with clear cell or non-
clear cell RCC by cohort [1] [2] [3].
3.3
Exploratory Objectives 
(1) Objective: To estimate ORR, DOR, DCR, and PFS per RECIST 1.1 as assessed by 
BICR and OS by centrally determined tumor programmed death-ligand 1/2 (PD-L1/2)
status in subjects with clear cell or non-clear cell RCC by cohort.
(2) Objective: To estimate ORR, DOR, DCR, and PFS per RECIST 1.1 assessed by BICR
and OS for patients with any sarcomatoid differentiation identified by cohort.
(3) Objective: To evaluate pharmacokinetic (PK) parameters and the presence of anti-drug 
antibodies in subjects by cohort.
(4) Objective: To estimate ORR, DOR, DCR, and PFS per immune-related RECIST 
(irRECIST) by BICR in subjects with clear cell or non-clear cell RCC by cohort.  
(5) Objective: To identify molecular (genomic, metabolic and/or proteomic) determinants 
of response or resistance to pembrolizumab in clear cell or non-clear cell RCC so as to 
define novel predictive and pharmacodynamic biomarkers and understand the 
mechanism of action of pembrolizumab. 
4.0 BACKGROUND & RATIONALE
4.1
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
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Disease Background: 
Advanced Renal Cell Carcinoma (RCC)
Epidemiology and Disease Characteristics of RCC
RCC 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, 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 64% of patients have localized disease; 17% 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 presence of distant metastasis [6].
Current Systemic Treatments for Advanced RCC
Advanced RCC has previously been treated with immunotherapies such as interferon alpha 
(IFNα) and interleukin 2 (IL-2) with limited clinical activity. A novel group of anti-cancer 
agents has been developed for the treatment of advanced RCC since 2005. These agents 
demonstrate significant improvement in clinical efficacy and have acceptable safety profiles. 
They include vascular endothelial growth factor receptor (VEGFR) TKIs (sunitinib, 
pazopanib, sorafenib, and axitinib), an anti-VEGF monoclonal antibody (bevacizumab given 
in combination with IFNα), and mammalian target of rapamycin inhibitors (temsirolimus and 
everolimus). Recently, the PD-L1 checkpoint inhibitor nivolumab received approval from the 
Food and Drug Administration (FDA) to treat patients with advanced RCC whose disease 
progressed on an anti-angiogenic therapy [7].
Clinical Trials and Recommended Treatments for Renal Cell Carcinoma 
Clinical Trials in Treatment-Naïve Advanced RCC 
Table 1 summarizes the clinical efficacy of systemic treatments in patients with treatment-
naïve advanced clear cell 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 EMA for the treatment of advanced RCC in treatment-naïve patients without
regard to histology, as each demonstrated a statistically significant improvement in PFS
compared to IFNα or placebo alone.  Pazopanib has also demonstrated non-inferiority to 
sunitinib for PFS and with similar OS in a large randomized Phase III study using a non-
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inferiority design.  Temsirolimus received regulatory approval for first-line treatment of poor-
risk patients with advanced RCC without regard to histology.
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; RCC=renal cell carcinoma.
a Results demonstrated statistically significant improvement of the testing arm versus 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. 
National Comprehensive Cancer Network and European Society for Medical Oncology
Recommended First Line Treatments for Advanced Clear Cell RCC 
Based on the data described above, the current recommendations by National Comprehensive 
Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) for first-
line treatment of advanced clear cell 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 two 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=.0006) [15]. 
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Clinical Studies in the Previously Treated Advanced Clear Cell Renal Cell Carcinoma 
Population
Sorafenib was approved by the FDA for advanced RCC without regard to histology based on 
a phase III randomized trial by demonstrating significant improvement in PFS compared to 
placebo in patients having received one prior systemic therapy. The median PFS for sorafenib
compared to placebo was 167 days versus 84 days, respectively (HR: 0.44; 95% CI: 0.35 to 
0.55) [17]. Patients receiving placebo were recommended to cross over to the sorafenib 
treatment arm. After censoring of crossover data, treatment with sorafenib was shown to 
improve survival (17.8 months versus 14.3 months for sorafenib and placebo, respectively; 
HR: 0.78; 95% CI: 0.62 to 0.97, P=.029) [17].
Everolimus was approved by the FDA and EMA for the treatment of advanced RCC without 
regard to histology after failure of treatment with sunitinib or sorafenib based on a Phase III 
randomized trial that demonstrated a statistically significant improvement in PFS. The median 
PFS was 4.9 months versus 1.9 months in the everolimus and placebo groups, respectively 
(HR: 0.33; 95% CI: 0.25 to 0.43; P<.001). The final median OS was 14.8 months for 
everolimus versus 14.4 months for placebo (HR: 0.87; 95% CI: 0.65 to 1.15; P=.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 versus sorafenib (median PFS 6.7 
versus 4.7 months; HR: 0.665; 95% CI: 0.544 to 0.812; P<.0001). The secondary endpoint of 
ORR was also significantly higher in axitinib versus sorafenib (19% versus 9%; P=.0001) [20].
However, the final OS data showed no significant difference between the two arms; median 
OS was 20.1 months for axitinib versus 19.2 months for sorafenib (HR: 0.969; 95% CI: 0.800 
to 1.174; one-sided P=.3744) [21]. Based on these data, axitinib gained approval for use in 
advanced RCC patients after failure of one prior systemic treatment (FDA) (INLYTA Label) 
or after failure of sunitinib or cytokine therapy (EMA) without regard to histology [22] [23].  
Recently, nivolumab, an immune checkpoint inhibitor targeting programmed cell death protein 
1 (PD-1), has received approval from the FDA for the treatment of patients with advanced 
RCC who have received prior anti-angiogenic therapy without regard to RCC histology [7].
The approval was based on data from a randomized Phase III open-label study in advanced 
RCC patients following prior treatment with targeted therapy. Nivolumab demonstrated 
statistically significant improvement in the primary endpoint OS versus everolimus during the 
planned interim analysis (median 25.0 versus 19.6 months; HR: 0.73; 98.5% CI: 0.57 to 0.93; 
P=.002). The objective response rate was 25% for nivolumab versus 5% for everolimus (odds 
ratio 5.98; 95% CI: 3.68 to 9.72; P<.001). Progression-free survival was not significantly 
improved (median 4.6 months for nivolumab versus 4.4 months for everolimus; HR: 0.88; 95% 
CI: 0.75 to 1.03; P=.11) [24].
NCCN and ESMO Recommended Subsequent Treatments for Advanced Clear Cell RCC 
Subsequent treatments following the failure of first-line have been divided into two categories: 
treatment choices after prior cytokine therapy and treatment choices after prior targeted 
therapy. Axitinib, sorafenib, sunitinib, and pazopanib have demonstrated improved efficacy 
(PFS) in the cytokine failure population and, hence, have been recommended by NCCN and 
ESMO for use in this population [4] [6]. However, cytokine use in the first-line has been 
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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. 
In addition, NCCN has recently recommended cabozantinib as a treatment choice after prior 
targeted therapy [6]. Cabozantinib is a multi-target tyrosine kinase inhibitor targeting VEGFR, 
MET, and AXL. In a Phase III randomized trial versus everolimus in patients who failed prior 
targeted therapy, cabozantinib demonstrated significantly improved primary endpoint PFS 
(median 7.4 versus 3.8 months; HR: 0.58; 95% CI: 0.45 to 0.75; P<.001) and secondary 
endpoint ORR (21% versus 5%; P<0.001). The interim OS (49% full information) showed a 
trend favoring cabozantinib but did not reach pre-defined statistical significance (HR: 0.67; 
95% CI: 0.51 to 0.89; P=.0050) favoring cabozantinib. The criteria for early rejection of the 
hypothesis was not met (P≤.0019) [25]. As of April 2016, cabozantinib has been approved for
the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy
[26].
Clinical Trials and Recommended Treatments for Non-Clear Cell RCC
Clinical Trials in Treatment-Naïve Advanced Non-Clear Cell RCC 
Because of the low prevalence of nccRCC, it is difficult to accrue enough patients for a large 
Phase III trial. All registration trials in advanced RCC described above, with the exception of 
the temsirolimus registration trial, were limited to clear cell or predominately clear cell 
histology. Evidence for efficacy in nccRCC therefore comes either from the retrospective 
subset analysis of the temsirolimus Phase III trial in poor risk patients or data from small Phase 
II trials.
A retrospective subgroup analysis of different tumor histologies of the Phase III trial of 
temsirolimus vs IFNα cited above [16] demonstrated a median OS of 11.6 months (95% CI:
8.9 to 14.5, N=37) in the temsirolimus arm compared to a median OS of 4.3 months (95% CI:
3.2 to 7.3, N=36) in the IFNα arm [27]. In the ASPEN trial, 108 patients with nccRCC were 
randomized to treatment with sunitinib or everolimus and the median PFS was found to be 8.3 
months and 5.6 months, respectively (HR: 1.41; 80% CI: 1.03 to 1.92; P=.16) [28]. In a non-
randomized Phase II study (SUPAP) conducted by the French Genitourinary Group, 61 
subjects with papillary RCC, 15 with type 1 and 46 with type 2, were treated with sunitinib.  
Objective response rates of 13% and 11% were reported, respectively. Median PFS was 6.6 
months (95% CI: 2.8 to 14.8) in type 1 and 5.5 months (95% CI: 3.8 to 7.1) in type 2 [29]. In 
a single-arm Phase II study, 46 subjects with advanced or metastatic papillary RCC were 
treated with erlotinib. The ORR was 11% (95% CI: 3 to 24%) with a disease control rate 
(defined as stable disease for 6 weeks or CR or PR per RECIST 1.1) of 64%. The median OS 
was 27 months (95% CI: 13 to 36 months) [30].
NCCN and ESMO Recommended First Line Treatments for Advanced Non-Clear Cell RCC  
Due to limited data in nccRCC patients, the role of various agents in the treatment of nccRCC 
is poorly defined and there is no standard of care. As such, the NCCN consensus guidelines 
state that enrollment in clinical trials is the preferred strategy for subjects with nccRCC [6].  
Because there is some evidence from the Phase III temsirolimus trial demonstrating that 
subjects with poor prognosis risk factors may benefit from treatment with temsirolimus 
compared to IFNα, NCCN recommends this agent for this clinical setting. Of note, this was 
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not a pre-specified analysis but rather a retrospective analysis of these two arms of the trial 
(temsirolimus N=37, interferon alpha N= 36) [27].  The NCCN guidelines list everolimus, 
sorafenib, bevacizumab, pazopanib, and axitinib as other agents that may be used in the first-
line treatment of nccRCC. The sorafenib North American expanded access program enrolled 
subjects with advanced disease without regard to number of prior lines of therapy. Subjects 
with papillary nccRCC (N= 107) had a response rate of 3% and clinical benefit rate (CR+PR 
+stable disease>8 weeks) of 84%. Subjects with chromophobe nccRCC had a response rate of 
5% and clinical benefit rate of 90% [31].  Bevacizumab is included as a possible agent due to 
results of a small Phase II study that closed due to poor accrual. The PFS from 5 subjects 
treated with bevacizumab are reported as 25, 15, 11, 10, and 6 months [32]. Although data are 
not yet available from ongoing clinical trials, pazopanib and axitinib are included in the 
guidelines by extrapolation of their effects in clear cell RCC.  
Based on the same dataset as above, ESMO guidelines recommend temsirolimus, sunitinib or 
sorafenib for the first-line treatment of nccRCC [4].
4.1.1
Pharmaceutical and Therapeutic Background
4.1.1.1 Targeting PD-1 Immune Checkpoints for Cancer Treatments
The adaptive immune system plays a major role in controlling and eradicating cancer in 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 (APC) [33] [34] [35].
T cell activation is tightly controlled by co-stimulatory and co-inhibitory signals which are 
triggered by the interactions between T cell receptors (TCR) 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. PD-1 is a 
member of the extended CD28/CTLA4 family of T cell regulators. Activation of the 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 ligand PD-L1 and/or 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 [33] [36] [37] [38].  PD-L1 was found expressed on the surface of many human cancer 
cells; and PD-L1 expression by tumor cells was found associated with poor progression in 
several cancers including RCC [39].
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, in particular the PD-1 inhibitors, has 
significantly changed the landscape of cancer treatment [34] [35] [36] [40] [41] [42] [43]. 
4.1.1.2
Anti-PD-1 Antibody Pembrolizumab 
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 
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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 has received accelerated 
approval for the treatment of 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 
two indications is 2 mg/kg Q3W [44].   
4.1.1.3
Summary of Pembrolizumab Clinical Efficacy and Safety
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 week (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 [45]. 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 two 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 [46]. 
Clinical efficacy of pembrolizumab in advanced melanoma was further demonstrated via two 
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 
two pembrolizumab arms compared with the chemotherapy arms. 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<.0.001 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 two pembrolizumab arms, respectively, versus 63% in 
the chemotherapy arm. There was no statistically significant difference in efficacy parameters 
between the two pembrolizumab arms [47]. 
In 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%, 
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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 [48].
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 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), the ORR was 19.4% (95% CI: 16.0 to 23.2)
and the median DOR was 12.5 months. In the validation data set, the 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); 
the 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 [49]. 
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 who 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 track cancer, and triple negative breast cancer were enrolled. 
An ORR of 31% was observed in subjects with advanced gastric cancers (N = 39) [50]; an 
ORR of 27.6% (95% CI: 12.7 to 47.2%) was observed in subjects with advanced urothelial 
tract cancer (N = 33) [51]; an ORR of 24.8% (95% CI: 17.3 to 33.6%) was observed in subjects 
with advanced head and neck cancer (N = 132) [52]. Impressive responses have also been 
reported by Nanda et al., in triple negative breast cancer at the 2014 San Antonio Breast Cancer 
Symposium [53].
In all these cohorts, durable responses were observed in those who 
responded, including some durable stable diseases. Higher PD-L1 expression seemed to be 
associated with higher response.
Preliminary clinical activity of pembrolizumab in combination with axitinib in advanced 
RCC
Pembrolizumab monotherapy has not been evaluated in advanced RCC. However, the
pembrolizumab and axitinib combination has recently been evaluated in treatment-naïve 
subjects with advanced RCC. 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 maximum tolerated doses were determined to be 5 mg twice a 
day (BID) by mouth (PO) for axitinib and 2 mg/kg Q3W intravenous (IV) for pembrolizumab.
A total of 52 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 cut off of March 2016 (data not published).  The demographic features are typical for 
advanced RCC population: median age was 61.2, 78.8% male and 86.5% white.  All had an 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 1. Of the 52 
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patients, 12 had discontinued pembrolizumab treatment: 7 (13.5%) due to AEs, 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 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 are: all grade, 100%; grade 4, 3.8%; grade 3, 53.8%; grade 2, 32.7% and grade 1, 
9.6%. There was 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 
Total
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
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Table 3
Laboratory Results (n, %) by Maximum CTCAE Grade (N = 52)
Laboratory 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
Percentage is based on the number of patients receiving at least one dose of study treatment.
Preliminary unpublished efficacy data from these 52 patients showed an ORR of 67.3% (CR = 
3.8%, PR = 63.5%); stable disease (SD) of 21.2%, PD of 3.8%, and with 4 subjects (7.7%) 
with best response indeterminate.  This study is ongoing. 
Based on the scientific rationale of targeting angiogenesis and immune-check point pathways, 
as well as the promising data from these 52 patients, a phase III study is planned to evaluate 
the pembrolizumab/axitinib combination versus sunitinib in the first line treatment of 
metastatic clear cell renal cell carcinoma.
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4.2
Rationale
4.2.1
Rationale for the Trial and Selected Subject Population
Renal cell carcinoma 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 [49] 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 the PD-1 receptor on tumor-infiltrating lymphocytes and its ligand PD-L1 on tumors is 
associated with more aggressive disease and poor prognosis [38] [54].  The evidence above 
supports targeting RCC with an immunotherapeutic approach.  Single agent anti-tumor activity 
has been demonstrated by another anti-PD-1 antibody, nivolumab, in advanced RCC [24]. 
Even though the successful clinical development of 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, most patients will progress 
within 2 years following a standard first-line treatment.  As of now, the best median overall 
survival seen with the 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. in 645 patients who received 
first-line anti-VEGF/VEGFR agents including sunitinib, sorafenib, and bevacizumab in the US 
and Canada, the median survival was 22 months [1]. Based on Surveillance, Epidemiology, 
and End Results data from 2004-2010, the 5-year survival rate of advanced RCC was only 
12% [5]. Therefore, further development of novel agents, such as pembrolizumab, with 
durable clinical benefit and potential curative effect is still highly needed for advanced RCC. 
4.2.2
Rationale for Dose Selection/Regimen/Modification
Rationale for using 200 mg Q3W dose for pembrolizumab
The planned dose of pembrolizumab for this trial is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab across all indications and regardless of tumor type. As 
outlined below, this dose is justified by: 

Clinical data from eight randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every two weeks (Q2W)

Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically based 
pharmacokinetic [PBPK] analysis) at 200 mg Q3W.
Among the eight randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 
2 mg/kg Q3W vs. 10 mg/kg Q3W (KN001 B2, KN001 D, KN002, KN010 and KN021), and 
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three studies compared 10 mg/kg Q3W vs. 10 mg/kg Q2W (KN001 B3, KN001 F2 and 
KN006). All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied representing an approximate 5 to 7.5 fold difference in exposure. The 
2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses studied. 
Subsequently, flat dose-/exposure-response relationships were also observed in other tumor 
types including head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin 
Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the tumor type. 
These findings are consistent with the mechanism of action of pembrolizumab, which acts by 
interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data 
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Secondly, 
a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression. This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other subject covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported 
by these PK characteristics, and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected 
for evaluation across all pembrolizumab protocols.
4.2.3
Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
The primary efficacy endpoint, objective response rate (ORR), as well as the secondary 
endpoints of DOR, disease control rate (DCR), progression-free survival (PFS), all as assessed 
by BICR per RECIST 1.1, and overall survival (OS) are acceptable endpoints to support 
approval of new treatments in advanced RCC. Durable response has been demonstrated with
pembrolizumab and other immune checkpoint inhibitors in a subset of patients in multiple 
tumor types and these endpoints will provide meaningful supporting evidence for clinical 
efficacy. In order to avoid PD being called prematurely by the investigator, subjects in Cohort 
B with suspected radiologic progression first identified at the site will have all the scans 
submitted to the BICR for verification of PD. The results of central PD verification will be 
communicated to the site promptly.
4.2.3.1.1 Immune-related RECIST
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 can 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 
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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 PD by RECIST 1.1 but not by immune-related Response Criteria had longer 
OS than patients with PD 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 an adjustment 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., CCR 2013 [55]. 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. Immune-related RECIST 
will be used by local site investigators to assess tumor response and progression, and make 
treatment decisions as well as by the BICR in support of the PFS, ORR, DOR, and DCR
endpoints.
4.2.3.2
Safety Endpoints
The safety objective is to characterize the safety and tolerability of pembrolizumab in subjects 
with advanced RCC as first line treatment.  The following safety parameters will be analyzed: 
adverse events and serious adverse events graded per National Cancer Institute’s (NCI) 
Common Toxicity Criteria for Adverse Events (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. (Section 12.6). Concomitant medications will be collected with time and reasons of use. 
These are routine safety parameters collected and analyzed in Phase II oncology trials. 
Furthermore, specific immune-related adverse events (irAEs) will be collected as described in 
Section 7.1.2.1.
4.2.3.3
Planned Exploratory Biomarker Research
Introduction:
Cancer immunotherapies are an important novel class of anti-tumor 
agents. However, much remains to be learned about how cancer immunotherapies work and 
how best to leverage these new drugs in treating patients.
Thus, to aid future patients, it is 
important to investigate the determinants of response or resistance to cancer immunotherapy 
as well as determinants of adverse events in the course of our clinical trials. To that end we 
seek to define novel predictive/pharmacodynamic biomarkers and the best strategies of 
combination therapy with immuno-oncology drugs. To fully leverage the clinical data 
collected in this trial, we will also collect biospecimens (blood components, tumor material, 
etc) to support biomarker analyses of cellular components (e.g., protein, deoxyribonucleic acid
[DNA], 
ribonucleic 
acid
[RNA],
metabolites) 
and 
other 
blood 
soluble 
molecules. Investigations may include but are not limited to: 
Germline (blood) Genetic Analyses (e.g., SNP analyses, whole exome sequencing, whole 
genome sequencing):  This research will evaluate whether genetic variation within a clinical 
trial population correlates with response to the treatment(s) under evaluation. If genetic 
variation is found to predict efficacy or adverse events, the data might inform optimal use of 
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therapies in the patient population. Furthermore, it is important to evaluate germline DNA 
variation across the genome in order to interpret tumor-specific DNA mutations.  Finally, 
microsatellite instability (MSI) may be evaluated as this is an important biomarker for some 
cancers (i.e., colorectal cancer).  
Genetic (DNA) analyses from tumor:  The application of new technologies, such as next 
generation sequencing, has provided scientists the opportunity to identify tumor-specific DNA 
changes (i.e., mutations, methylation status, microsatellite instability, etc).  Key molecular 
changes of interest to immune-oncology drug development include (for example) the 
mutational burden of tumors and the clonality of T-cells in the tumor microenvironment.  
Increased mutational burden (sometimes referred to as a ‘hyper-mutated’ state) is one of the 
major mechanisms of neo-antigen presentation in the context of a tumor microenvironment.  
There is a potential that in the hyper-mutated state, the presence of neo-antigen mutational 
patterns and the detection of increased T-cell clonality, both of which can be determined by 
use of next-generation sequencing methods, may correlate with response to pembrolizumab 
therapy and/or that the converse, the ”hypomutated” state (the absence of neo-antigens) may
correlate with non-response.  To conduct this type of research, it is important to identify tumor-
specific mutations that occur across all genes in the tumor genome.  Thus, genome wide 
approaches may be used for this effort. Note that in order to understand tumor-specific 
mutations; it is necessary to compare the tumor genome with the germline genome.  
Microsatellite instability (MSI) may also be evaluated as this is an important biomarker for 
some cancers (i.e., colorectal cancer).  
Tumor and blood RNA analyses: Both genome-wide and targeted messenger RNA (mRNA) 
expression profiling and sequencing in tumor tissue and in blood may be performed to define 
gene signatures that correlate to clinical response to treatment with pembrolizumab or other 
immunotherapies.  Pembrolizumab induces a response in tumors that likely reflects an 
inflamed/ immune phenotype.  Specific immune-related gene sets (such as those capturing 
interferon-gamma transcriptional pathways) may be evaluated and new signatures may be 
identified.   Individual genes related to the immune system may also be evaluated (e.g., IL-10).  
MicroRNA profiling may also be pursued.
Proteomics and Immunohistochemistry (IHC) using Blood or Tumor:  Tumor and blood 
samples from this study may undergo proteomic analyses (e.g., PD-L1 IHC).  PD-L1 protein 
level in tumor sections, assessed by IHC, has been shown to correlate with response to 
pembrolizumab in patients with NSCLC, and an IVD device has been developed for use with 
pembrolizumab in NSCLC.  Preliminary data indicate that this association may also be true in 
additional cancer types (i.e., TNBC, H&N, and gastric).  Additional tumor or blood-derived 
proteins may also correlate with response to pembrolizumab.  Therefore, tumor tissue may be 
subjected to proteomic analyses using a variety of platforms that could include but are not 
limited to immunoassays, liquid chromatography/mass spectrometry.  This approach could 
identify novel protein biomarkers that could aid in patient selection for pembrolizumab (MK-
3475) therapy.
Other blood derived biomarkers:  In addition to expression on the tumor tissue, PD-L1 and 
other tumor derived proteins can be shed from tumor and released into the blood.  Assays such 
as enzyme-linked immunosorbent assay measure such proteins in serum. Correlation of
expression with response to pembrolizumab therapy may identify new approaches for 
predictive biomarkers in blood, representing a major advance from today’s reliance on 
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assessing tumor biomarkers. This research would serve to develop such assays for future 
clinical use.
4.2.3.4
Future Biomedical Research
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 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.
4.3
Benefit/Risk
It cannot be guaranteed that subjects in clinical trials will directly benefit from treatment during 
participation, as clinical trials are designed to provide information about the safety and 
effectiveness of an investigational medicine.
Pembrolizumab has been administered to a large number of cancer subjects with a well 
characterized safety profile and has received regulatory approval for advanced melanoma and 
NSCLC.  Overall, pembrolizumab is well tolerated at doses up to 10 mg/kg Q2W.  
Pembrolizumab has also demonstrated anti-cancer clinical activity and efficacy in a broad 
range of cancer indications (see Summary in Section 4.1.2.3).  
At present, there are no curative systemic treatments for advanced or metastatic RCC and only 
approximately 30% of patients develop objective responses to the 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.    
Additional details regarding specific benefits and risks for subjects participating in this clinical 
trial may be found in the accompanying Investigators Brochure (IB) and Informed Consent 
documents.
5.0 METHODOLOGY
5.1
Entry Criteria
5.1.1
Diagnosis/Condition for Entry into the Trial
Male and female subjects with advanced renal cell carcinoma (RCC) at least 18 years of age
will be enrolled in this trial.
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5.1.2
Subject Inclusion Criteria
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. Cohort A (clear cell cohort) must have histologically confirmed diagnosis of clear cell RCC 
or RCC with clear cell component (with or without sarcomatoid features). Diagnosis of 
clear cell RCC is to be made by the site and does not require central histology review.
4. Cohort B (non-clear cell cohort) must have histologically confirmed diagnosis of non-clear 
cell RCC (with or without sarcomatoid features) by the site pathologist. For Cohort B,
sites will submit tissues for histologic confirmation of the diagnosis of non-clear cell RCC 
by central histology review during the screening phase. Sites should enroll subjects in 
Cohort B after receiving notice that the submitted tissue was adequate for central review.  
Confirmation of non-clear cell RCC histology by the central laboratory will be made 
available to the sites as a later date. (See Section 7.1.3.3 and the Procedures Manual for 
further details).  Subjects with tumors that have a component of clear cell histology are not 
eligible for inclusion in Cohort B. (Subjects with a clear cell component will be eligible for 
Cohort A assuming all other entry criteria are met.) 
5. Have locally advanced/metastatic disease, i.e., newly diagnosed Stage IV RCC per 
American Joint Committee on Cancer (AJCC) or have recurrent disease. 
6. Have measurable disease per RECIST 1.1 as assessed by BICR. Lesions situated in a 
previously irradiated area are considered measurable if progression has been demonstrated 
in such lesions.
7. Have received no prior systemic therapy for advanced RCC. 
Note:  Prior neoadjuvant/adjuvant therapy for RCC is acceptable if completed > 12 months 
prior to allocation.
8. Provide adequate tissue for biomarker analysis for cohorts A and B from an archival tissue 
sample or newly obtained core or excisional biopsy of a tumor lesion not previously 
irradiated.  Adequacy of these samples for PD-L1 biomarker analysis will be evaluated by 
a central laboratory and is required for enrollment. NOTE: If submitting unstained cut 
slides, freshly cut slides should be submitted to the testing laboratory within 14 days from 
the date the slides are cut (details pertaining to tumor tissue submission can be found in the 
Procedures Manual).
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 treatment
allocation.  
10. Have Karnofsky Performance Status (KPS) ≥70%, as assessed within 10 days prior to 
treatment allocation (see Section 7.1.2.6 for more details). 
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11. Demonstrate adequate organ function as defined in Table 4 and all screening laboratory 
tests should be performed within 10 days of treatment initiation. 
Table 4
Adequate Organ Function 
System
Laboratory Value
Hematological
Absolute 
neutrophil 
count 
(ANC)
≥1,500 /mm3 or ≥ 1.5 x 109 / L
Platelets
≥100,000 / mm3 or ≥ 100 x 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 
clearancea
(GFR can also be used in place 
of creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥40 mL/min for subjects with creatinine levels > 1.5 X institutional 
ULN
Hepatic
Serum total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 
ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN  OR
≤ 5 X ULN for subjects with active liver metastases
Coagulation
International Normalized Ratio 
(INR) or Prothrombin Time 
(PT)
Activated 
Partial 
Thromboplastin Time (aPTT) 
or PTT
≤1.5 X ULN  subject  receiving anticoagulant therapy can have INR 
exceed 1.5 x ULN as long  as PT or PTT is within therapeutic range 
of intended use of anticoagulants
≤1.5 X ULN
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit 
of normal.
a Creatinine clearance should be calculated per institutional standard.
12. Female subject of childbearing/reproductive potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required. 
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13. 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. 
14. 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.
5.1.3
Subject Exclusion Criteria
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 
using an investigational device within 4 weeks prior to allocation, has had major surgery 
within 4 weeks or radiation therapy within 2 weeks prior to allocation, or who has not 
recovered (i.e., ≤Grade 1 or at baseline) from adverse events due to prior treatment.
2. 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, GITR.
3. Has a diagnosis of immunodeficiency; OR is receiving a systemic steroid therapy 
exceeding 10 mg daily dose of prednisone or equivalent or any other form of 
immunosuppressive therapy within 7 days prior to allocation, except in the case of central 
nervous system (CNS) metastases (see Exclusion Criterion 6). 
4. 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 a documented history of clinically severe autoimmune disease.  
Note:  Subjects with vitiligo, Sjøgren’s syndrome, Type I 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 would 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.   
5. Has a known additional malignancy that has had progression or has required active 
treatment in the last 3 years.  
Note: Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma 
in situ, such as breast cancer in situ, that has undergone potentially curative therapy are 
acceptable.
6. 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 the repeat 
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imaging should be performed during study screening), clinically stable and without 
requirement of steroid treatments for at least 14 days prior to first dose of trial treatment. 
7. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
8. Has an active infection requiring systemic therapy.
9. 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 patient has Human Immunodeficiency Virus infection or is otherwise mandated 
per local guidance.
10. Has a known history of hepatitis B (e.g., Hepatitis B surface antigen (HBsAG) reactive or 
known active hepatitis C virus (e.g., 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.
11. Has received a live virus vaccine within 30 days of treatment allocation (See Section 5.5.3
– Prohibited Concomitant Medications for further details).
12. 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.
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
14. Has had a prior solid organ transplant.
15. 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.
5.2
Trial Treatment
The treatment to be used in this trial is outlined below in Table 5.  
Table 5
Trial Treatment
Treatment
Regimen
Route of 
Administration
Duration of 
treatment
Use in Study
Pembrolizumab
200 mg every 3 
weeks (Q3W)
Intravenous  
infusion
Up to 35 doses 
(approximately
24 months)a
Experimental
a Upon progression, subjects may receive a second course of pembrolizumab treatment with additional 17 doses. Details 
are described in Section 7.1.5.2.1.  
Trial Treatment should begin within 3 days of allocation.
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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.
5.2.1
Dose Selection
The rationale for selection of the doses for pembrolizumab monotherapy to be used in this trial 
is provided in Section 4.0 – Background and Rationale.  Details on the preparation and 
administration of pembrolizumab is in the Pharmacy Manual.
5.2.2
Immune-Related Events and Dose Modification (Withhold, Treat, Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
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 study 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, 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 monotherapy, coformulations, or IO combinations are provided in Table 6. 
A decrease or increase of the dosage of pembrolizumab is not permitted.  The pembrolizumab 
cycle visits/procedures will remain fixed and will not be adjusted for dosing interruptions or 
delays.  See Section 5.6 for supportive care guidelines, including use of corticosteroids.
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Table 6
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid dose 
is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after 
corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring 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
Recurrent Grade 2 
or Grade 3 or 4 
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.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST 
/ 
ALT 
Elevation 
or 
Increased 
Bilirubin
Grade 2
Withhold
Administer 
corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
Administer 
corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM 
or 
Hyperglycemia
New onset T1DM 
or 
Grade 
3 
or 
4 
hyperglycemia 
associated 
with 
evidence of β-cell 
failure
Withhold a
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 
discontinue a
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 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
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
Myocarditis
Grade 1 
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold 
or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 
1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs 
(eg, vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management Infusion Reactions Related to 
Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions. Signs and symptoms 
usually develop during or shortly after drug infusion and generally resolve completely within 
24 hours of completion of infusion. Dose modification and toxicity management guidelines on 
pembrolizumab associated infusion reaction are provided in Table 7. 
Table 7
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; 
infusion interruption 
not indicated; 
intervention not 
indicated
Increase monitoring of vital signs as 
medically indicated until the 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 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 1.5h (± 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 and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 3 weeks of the originally scheduled dose 
and within 42 days of the previously administered dose, unless otherwise discussed with the 
Sponsor.  The reason for interruption should be documented in subject's study record.
5.2.3
Timing of Dose Administration
The first dose of pembrolizumab infusion will be administered on Cycle 1 Day 1 but no later 
than Cycle 1 Day 4.  Subsequent doses of pembrolizumab will be administered on Day 1 of 
each 21-day cycle (+/- 3 days). If pembrolizumab has been withheld due to toxicity or other 
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allowed reasons and subsequently can be resumed, the day of next pembrolizumab dose should 
counted as Day 1 (± 3 days) of the next cycle. 
Pembrolizumab should be administered after all pre-dose study procedures and assessments 
have been completed as specified in the trial flow chart (Section 6.0).  
Pembrolizumab should be administered as a 30-minute IV infusion every 3 weeks.  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 of the study treatment 
infusion fluid and administration of infusion solution.
5.2.4
Trial Blinding 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
5.3
Randomization or Treatment Allocation
Subjects participating in this trial will be allocated by non-random assignment.
5.4
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
5.5
Concomitant Medications/Vaccinations (Allowed & Prohibited)
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 study intervention or vaccination 
may be required.  The investigator is to discuss prohibited medication/vaccination 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.
5.5.1
Acceptable Concomitant Medications
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 case report form (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.  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.  All concomitant medications administered during SAEs or ECIs are to be 
recorded. SAEs and ECIs are defined in Section 7.2. 
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Medications intended solely for supportive care (i.e., antiemetics, analgesics, megestrol acetate 
for anorexia) are allowed.
5.5.2
Concomitant Surgery
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.
5.5.3
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during study treatment period
(including retreatment 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 
on an exceptional case-by-case basis after consultation with Sponsor.  The radiation 
treatment field may not include a target or measurable lesion by RECIST 1.1.  

Live or live-attenuated vaccines within 30 days prior to the first dose of pembrolizumab 
and through 30 days following the last dose of pembrolizumab.  Notes: Killed virus 
vaccines are allowed.
Note: If precluded by local regulations, live or live-attenuated vaccines should not be given 
for 120 days after the last dose of pembrolizumab is administered.

Systemic glucocorticoids are permitted only for the following purposes:
o
To modulate symptoms of an AE that is suspected to have an immunologic etiology
o
As needed for the prevention of emesis
o
Premedication for IV contrast allergies
o
Short-term oral or IV use in doses >10 mg/day prednisone equivalent for COPD 
exacerbations
o
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent
o
In addition, the following glucocorticoid use is allowed:

For topical use or ocular use

Intraarticular joint use

For inhalation in the management of asthma or chronic obstructive pulmonary 
disease
Note: Use of prophylactic corticosteroids to avoid allergic reactions (e.g., IV contrast 
dye or transfusions) is permitted.
Note: The use of intermittent inhaled steroids or intranasal or local injection of 
corticosteroids is permitted. Topical corticosteroids are also permitted.
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Note: The use of physiologic doses of corticosteroids under other circumstances may 
be approved after consultation with the Sponsor.
Subjects who, in the assessment by the investigator, require additional anti-cancer treatments 
will be discontinued from study treatments and continue on survival follow up. Subjects, who 
in the assessment by investigator, require any other prohibited medications for 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.
5.6
Rescue Medications & Supportive Care
5.6.1
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.2, (Table 6). Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.
Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the Investigator determines the events to be related 
to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance. Refer to Table 6 in Section 
5.2.2 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
5.7
Diet/Activity/Other Considerations
5.7.1
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
5.7.2
Contraception
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).
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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.
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 (one 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 two 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.
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‡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.
5.7.3
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, 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 must be reported to the Sponsor and followed as described above and in 
Section 7.2.2.
5.7.4
Use in Nursing Women
It is unknown whether pembrolizumab 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.
5.8
Subject Withdrawal/Discontinuation Criteria
5.8.1
Discontinuation of Treatment
Discontinuation of study treatment does not represent withdrawal of consent.
As certain data on clinical events beyond study treatment discontinuation may be 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 be monitored in the study and 
participate in the trial visits and procedures as specified in Section 6.0 - Trial Flow Chart and 
Section 7.1.4.1 Withdraw/Discontinuation.
Subjects may discontinue study treatment at any time for any reason or be discontinued 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 
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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 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 treatment

Subjects with AEs meeting discontinuation criteria as described in Section 5.2.1

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

Female subject with confirmed positive serum pregnancy test.

After receiving 35 doses of pembrolizumab
When a subject is first identified with radiologic PD by the investigator, all scans for subjects 
in Cohort B 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
of PD 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 7.1.2.7.2. 
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) disease progression (refer 
to Section 7.1.2.7.2), 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.
5.8.2
Withdrawal of Consent
Subjects may withdraw consent at any time for any reason.  If a subject withdraws consent, 
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.
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5.8.2.1
Lost to Follow-up
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. 
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.
5.9
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
5.10 Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit, withdraws 
consent or is lost to follow-up (i.e., the subject is unable to be contacted by the investigator).
Upon study completion, participants are discontinued and may be enrolled in a pembrolizumab 
extension study, if available.
5.11 Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. The trial may be stopped early for safety by the Sponsor
2. Quality or quantity of data recording is inaccurate or incomplete
3. Poor adherence to protocol and regulatory requirements
4. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to 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 Period:
Screening
Treatment Cycles
End of 
Treatment
Post-Treatment Visits
Treatment Cycle/Title:
Screening 
(Visit 1)
Cycles 1 to 8
Beyond Cycle 8
Discon
Safety 
Follow-up
Efficacy
Follow-up
Survival 
Follow-up
1
2
3
4
5
6
7
8
9
10
11
12
Scheduling Window (Days):
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
End of 
Treatment
30 days
from last 
dose
(± 3 days)
Every 6 or 
12 weeks 
post discon
(± 7 days) a
Every 12 
weeks
(± 7 days)b
Administrative Procedures
Informed Consent (may be done prior to 
screening period)c
Xc
Informed 
Consent 
for 
Future 
Biomedical Research (optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Cardd
X
X
Demographics and Medical History
X
Prior 
and 
Concomitant 
Treatment/Medication Reviewe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab Administration
Xf
X
X
X
X
X
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
X
Survival Statusb
X
Clinical Procedures/Assessments
Adverse Event Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xg
Xg
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead 
Electrocardiogram 
(locally 
performed)i
X
Karnofsky Performance Statusj
X
X
X
X
X
X
X
X
X
X
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Trial Period:
Screening
Treatment Cycles
End of 
Treatment
Post-Treatment Visits
Treatment Cycle/Title:
Screening 
(Visit 1)
Cycles 1 to 8
Beyond Cycle 8
Discon
Safety 
Follow-up
Efficacy
Follow-up
Survival 
Follow-up
1
2
3
4
5
6
7
8
9
10
11
12
Scheduling Window (Days):
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
End of 
Treatment
30 days
from last 
dose
(± 3 days)
Every 6 or 
12 weeks 
post discon
(± 7 days) a
Every 12 
weeks
(± 7 days)b
Efficacy Measurements
Tumor Imaging - chest, abdomen, pelvis 
(CAP) 
Xk
Xl
Xm
Tumor Imaging – bone scann
Xn
Xn
Xn
Tumor imaging – brain scano
Xo
Xo
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Pregnancy Test – Urine or Serum -HCGp
X
PT/INR and aPTTq
X
X
X
X
X
X
X
X
X
X
X
Hematologyq
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistryq
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysisq
X
X
X
X
X
X
X
X
X
X
X
T3, FT4, and TSHq
X
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: analysis performed by CENTRAL laboratory
Anti-pembrolizumab 
Antibodies 
(ADA)r
X
X
X
X
X
Pharmacokinetics (PK)r,s
X
X
X
X
X
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood
Archival or Newly Obtained Tissue 
Collection for biomarkers studies (may 
be done prior to screening period)c,t
Xc,t
Tissue for central histologic 
confirmation of nccRCC diagnosis
(may be done prior to screening 
period)c,t, u
Xc,u
Blood for Genetic Analysesv
X
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Trial Period:
Screening
Treatment Cycles
End of 
Treatment
Post-Treatment Visits
Treatment Cycle/Title:
Screening 
(Visit 1)
Cycles 1 to 8
Beyond Cycle 8
Discon
Safety 
Follow-up
Efficacy
Follow-up
Survival 
Follow-up
1
2
3
4
5
6
7
8
9
10
11
12
Scheduling Window (Days):
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
End of 
Treatment
30 days
from last 
dose
(± 3 days)
Every 6 or 
12 weeks 
post discon
(± 7 days) a
Every 12 
weeks
(± 7 days)b
Blood for ctDNA Analysesw
X
X
X
X
Blood for TCR repertoirew
X
X
X
X
Blood for RNA Analysesw
X
X
X
X
Blood for plasma biomarker Analysesw
X
X
X
Blood for serum biomarker Analysesw
X
X
X
a.
Efficacy Follow-up visits will continue on the same schedule that the subject is on at the time of discontinuation from treatment, every 6 weeks from allocation (Q6W, 42 days ± 
7 days) through week 54 and every 12 weeks (Q12W, 84 days ± 7 days) thereafter.  After Week 104 from allocation, the window for Efficacy Follow-up is ± 14 days. See Section 
7.1.5.3.3 for details on data collected.
b.
The Survival Follow-up may be conducted as a telephone call or a clinic visit approximately Q12W (visit window is ± 7 days through Week 104 and ± 14 days after Week 104). 
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.
Written consent must be obtained prior to performing any protocol-specified procedures. Informed consent may be obtained greater than 28 days prior to treatment allocation; 
however, it MUST be obtained prior to performing any protocol-specified procedures. This is in order for sites to gather tumor tissue samples and/or other information from the 
subjects. It is recommended that the tumor samples be collected and submitted for central laboratory review as soon as the informed consent is signed.
d.
The Subject Identification Card should be dispensed at Screening and collected at the End of Treatment visit.
e.
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. 
f. 
Cycle 1 treatment must be given within 3 days of treatment allocation.
g. 
Record all AEs and ECIs occurring within 30 days after the last dose of trial treatment regardless of when the Safety Follow-up visit occurs.  After 30 days, record all SAEs 
occurring up to 90 days after the last dose of trial treatment or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever comes first. Any 
treatment related SAEs must be reported regardless of time they occur (see Sections 7.2.3.1 and 7.2.3.2 for further details regarding SAE and ECI reporting).
h.
Height will be measured at screening visit only.
i.
Electrocardiogram (ECG) will be performed at screening for all subjects and as clinically indicated thereafter.
j.
Karnofsky Performance Status will be assessed at screening (within 10 days of treatment allocation), on Day 1 of Cycles 2 – 7, every other cycle thereafter (C9D1, C11D1, 
C13D1…) and Safety Follow-up. See Appendix 12.4.
k. Baseline CAP imaging must be performed within 28 days prior to treatment allocation.  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 28 days prior to allocation. See Section 7.1.2.7.1 for additional imaging requirement in subjects with RCC 
metastatic lesions identified outside of the standard imaging assessment anatomic regions per protocol BICR assessment will be used to determine eligibility for both Cohorts.
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Trial Period:
Screening
Treatment Cycles
End of 
Treatment
Post-Treatment Visits
Treatment Cycle/Title:
Screening 
(Visit 1)
Cycles 1 to 8
Beyond Cycle 8
Discon
Safety 
Follow-up
Efficacy
Follow-up
Survival 
Follow-up
1
2
3
4
5
6
7
8
9
10
11
12
Scheduling Window (Days):
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
End of 
Treatment
30 days
from last 
dose
(± 3 days)
Every 6 or 
12 weeks 
post discon
(± 7 days) a
Every 12 
weeks
(± 7 days)b
l. Imaging after allocation will be performed at Week 12 (Day 84 ± 7 days, then every 6 weeks (42 days ±7 days) until Week 54, then every 12 weeks (84 days ±7 days) thereafter
until PD is confirmed by the investigator for Cohort A and BICR verified followed by further confirmation by the investigator for Cohort B (see Section 7.1.2.7.2 for details). The 
imaging visit window can be ± 14 days after two years on study. Imaging anatomic coverage should be the same as that at screening; see Section 7.1.2.7.2 for detail. Unscheduled 
imaging can be performed as clinically indicated.  The timing of imaging assessments should follow calendar days from allocation and should not be adjusted for dose delays or 
cycle starts
m. Subjects who discontinue from study medication without documented disease progression should continue with radiographic imaging (CT/MRI and bone scans, if applicable) until 
1) the start of new anti-cancer treatment, 2) documented disease progression per 7.1.2.7.2, 3) death or 4) withdraw of consent 5) study conclusion or early termination, whichever 
occurs first. See footnote “a” for Efficacy Follow-up schedule and windows.  
n. Baseline bone scan will be performed for all subjects at Screening.  Bone scans are not required to be repeated at screening if performed within 42 days prior to treatment allocation.  
If a subject has a positive bone scan at Screening, on-study bone scans should be performed at the end of 18 weeks from treatment allocation (126 ± 7 days). Bone scans should 
continue to be performed Q12W (84 days ±7 days) through Week 54.  After Week 54, subjects will have bone scans performed every 24 weeks (168 days ±7 days). The timing of 
imaging assessments should follow calendar days from allocation and should not be adjusted for dose delays or cycle starts.  A bone scan must also be performed for confirmation 
of Complete Response (CR).
o. 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. 
p.
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.
q. PT/INR and aPTT, urinalysis and thyroid function testing will be performed at Screening (within 10 days of allocation), on Day 1 of Cycles 2-7, every other cycle thereafter 
(C9D1, C11D1, C13D1,…), End of Treatment visit and at the Safety Follow-up visit. Hematology and chemistry will be performed at Screening (within 10 days of allocation), on 
Day 1 of every treatment cycle from Cycle 2 onwards, the End of Treatment visit, and the Safety Follow-up visit.
r. 
Pre-dose trough PK and ADA samples 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.
s.
Post-dose peak PK samples will be drawn within 30 minutes after end of pembrolizumab infusion at Cycles 1 and 9.
t.
For both Cohort A and B adequacy of tissue samples for PD-L1 biomarker analysis will be evaluated by a central laboratory during the screening period. It is a requirement for 
enrollment that the tissue be adequate for biomarker analysis. The local pathology report of the clear cell RCC diagnosis should be included with the sample sent to the central 
lab, if possible. For Cohort B, sites will submit tissues for histologic confirmation of the diagnosis of non-clear cell RCC by central histology review during the screening phase. 
Sites should enroll subjects in Cohort B after receiving notice that the submitted tissue was adequate for central review.  Confirmation of non-clear cell RCC histology by the 
central laboratory will be made available to the sites as a later date. Tumor tissue collection for biomarker studies and histologic confirmation of non-clear cell RCC diagnosis 
should be submitted after obtaining written consent; however, tissue samples may be submitted to the central laboratory greater than 28 days prior to treatment allocation.
u.
The local pathology report of the nccRCC diagnosis should be included with the sample sent to the central histology lab, if possible.
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Trial Period:
Screening
Treatment Cycles
End of 
Treatment
Post-Treatment Visits
Treatment Cycle/Title:
Screening 
(Visit 1)
Cycles 1 to 8
Beyond Cycle 8
Discon
Safety 
Follow-up
Efficacy
Follow-up
Survival 
Follow-up
1
2
3
4
5
6
7
8
9
10
11
12
Scheduling Window (Days):
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
End of 
Treatment
30 days
from last 
dose
(± 3 days)
Every 6 or 
12 weeks 
post discon
(± 7 days) a
Every 12 
weeks
(± 7 days)b
v.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the subject signs the future biomedical research (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. Blood should be collected pre-dose.
w. 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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6.1
Second Course Phase Retreatment – (Maximum 17 Cycles)
See Section 7.1.5.2.1 for retreatment criteria.
Trial Period:
Treatment Cycles
End of 
Treatment
Post-Treatment Visits
Treatment Cycle/Title:
Cycles 1-8
Beyond Cycle 8
Discon
Safety 
Follow-up
Efficacy 
Follow-up 
Survival 
Follow-upb
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
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 Anticancer Therapy Status
X
X
Survival Statusb
Xb
Clinical Procedures/Assessments
Adverse Event Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
Xc
Xc
Full Physical Examination
X
X
Directed Physical Examination
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
Efficacy Measurements
Tumor Imaging - chest, abdomen, pelvis (CAP) 
Xf
Xg
Tumor Imaging – bone scan 
Xh
Tumor Imaging – brain scan
Xi
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Pregnancy Test – Urine or Serum -HCGj
X
PT/INR and aPTT
Xk
Hematologyl
Xk
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistryl
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 Visits
Treatment Cycle/Title:
Cycles 1-8
Beyond Cycle 8
Discon
Safety 
Follow-up
Efficacy 
Follow-up 
Survival 
Follow-upb
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) 
Urinalysism
Xk
X
X
X
X
X
X
X
X
T3, FT4, and TSHm
Xk
X
X
X
X
X
X
X
X
a.
Second course Cycle 1 treatment must be given within 3 days of registering this visit in the IVRS.
b.
The Survival Follow-up may be conducted as a telephone call or a clinic visit approximately Q12W (visit window is ± 14 days after Week 104). 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.
Record all AEs and ECIs occurring within 30 days after the last dose of trial treatment regardless of when the Safety Follow-up visit occurs.  After 30 days, record all SAEs 
occurring up to 90 days after the last dose of trial treatment or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever comes first.  
Any treatment-related SAEs must be reported regardless of time they occur (see Sections 7.2.3.1 and 7.2.3.2 for further details regarding SAE and ECI reporting).
d.
Height will be measured prior to retreatment.
e.
Karnofsky Performance Status will be performed prior to retreatment (within 10 days prior to the first re-treatment dose of pembrolizumab), Cycles 1–8, and every 2 cycles
thereafter (Cycles 10, 12, 14,…). 
f.
The initial tumor imaging will be performed within 28 days prior to first retreatment cycle and then every 12 weeks thereafter (84 days ±7 days). 
g.
In subjects who discontinue trial treatment without documented disease progression, subjects should continue with imaging assessments per the protocol defined schedule 
until: 1) confirmation of PD, 2) initiation of a new anti-cancer treatment, 3) withdraw of consent from trial, 4) death or 5) study conclusion or termination, whichever occurs 
first.
h.
A bone scan will be performed within 42 days prior to first re-treatment cycle. If a subject has a positive bone scan at screening, bone scans will be performed additionally 
every 24 weeks thereafter (168 days ±14 days). The timing of imaging assessments should follow calendar days from allocation 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 required for subjects with brain metastasis in the Efficacy follow up phase only 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 re-treatment dose of pembrolizumab.  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 will be performed within 10 days prior to the first retreatment dose, on Day 1 of every retreatment cycle from Cycle 2 onwards, at treatment 
discontinuation, and at the Safety Follow-up visit.
m.
Urinalysis and T3, FT4 and TSH will be performed prior to retreatment, every 2 cycles starting at Cycle 2 (Cycles 4, 6, 8,…), at treatment discontinuation, and 30 days after 
discontinuation.
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7.0 TRIAL PROCEDURES
7.1
Trial Procedures
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.
7.1.1
Administrative Procedures
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative 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 or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the 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.
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 
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performing any procedure related to the Future Biomedical Research.  A copy of the informed 
consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
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.
7.1.1.4
Medical History
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 important 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 and stage at most recent recurrence, and 
location of metastases at screening (if applicable).
7.1.1.5
Prior and Concomitant Medications Review
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.
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.
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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.
7.1.1.6
Subsequent Anti-Cancer Therapy Status
All new anti-cancer therapy initiated after the study start must be recorded in the subsequent 
anti-cancer therapy eCRF page. If a subject initiates another anti-cancer therapy while 
receiving pembrolizumab, pembrolizumab must 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.
7.1.1.7
Assignment of Screening Number
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.  
7.1.1.8
Assignment of Treatment/Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the subject 
for all procedures occurring after treatment allocation/randomization.  IVRS will be used to 
assign a treatment/randomization number to eligible subjects. 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.
If participants are enrolled in an extension study, participants will be assigned a new allocation 
number; however, each participant will retain her/her original treatment/allocation number as 
well.
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)
If there are interruptions in the study intervention schedule, the details of and reason for any 
interruption of study intervention will be documented in the participant’s medical record.
Refer to Sec. 5.2.2 for dose modification and toxicity management for irAEs associated with 
pembrolizumab and for other allowed dose interruption of pembrolizumab.
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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.
Administration of trial medication will be monitored by the investigator and/or trial staff.
7.1.2
Clinical Procedures/Assessments
7.1.2.1
Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart in section 6.0 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 12.6). 
Toxicities will be characterized in terms regarding seriousness, causality, toxicity grading, and 
action taken with regard to trial treatment.  
All AEs and ECIs occurring within 30 days after the last dose of trial treatment must be 
recorded regardless of when the Safety Follow-up visit occurs.  After 30 days, record all SAEs 
occurring up to 90 days after the last dose of trial treatment or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever comes first.  Any treatment 
related SAEs must be reported regardless of time they occur (see Sections 7.2.3.1 and 7.2.3.2 
for further details regarding SAE and ECI reporting).
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated to 
determine if it is possibly a potentially immunologic etiology (irAEs); see Section 5.6 
regarding the identification, evaluation, and management of potential irAEs.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of
AEs.
7.1.2.2
Full Physical Examination
The investigator or clinical designee will perform a complete (full) physical exam during the 
Screening visit and at End of Treatment visit, 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 the first dose of trial treatment, new clinically significant abnormal findings at End of 
Treatment visit should be recorded as AEs.
7.1.2.3
Directed Physical Exam
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 Chart in Section 6.0. Directed 
physical exam (PE) refers to symptoms directed physical exam.  New clinically significant 
abnormal findings should be recorded as AEs.
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7.1.2.4
Vital Signs
The investigator or qualified designee will assess vital signs (including temperature, pulse,
respiratory rate, and blood pressure) and weight at Screening, prior to administration of study 
medication at each visit as specified in the Trial Flow Chart in Section 6.0.  Height will be 
measured at Screening only.
7.1.2.5
12-Lead Electrocardiogram
A standard 12-lead ECG will be performed using local standard procedures once at Screening
and as clinically indicated throughout the trial. Clinically significant abnormal findings should 
be recorded in the medical history. 
7.1.2.6
Karnofsky Performance Status
Karnofsky Performance Status 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 description of the full 
scale. The KPS will be assessed as specified in the trial Flow Chart in Section 6.0.
A 
Karnofsky Performance Status ≥70% is required for study eligibility.
7.1.2.7
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the 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.
The same imaging technique regarding modality and use of contrast should be used in a subject 
throughout the trial to optimize the visualization of existing and new tumor burden.  
For both Cohorts A and B, confirmation of measurable disease by BICR per RECIST 1.1 will 
be used to determine eligibility prior to enrollment.
Although RECIST 1.1 references a 
maximum of 5 target lesions in total and 2 per organ, Merck allows maximum of 10 target 
lesions in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor
burden.
All scheduled images for all study subjects from the sites will be submitted for BICR. Images
(including other modalities) obtained to determine disease progression at unscheduled time 
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points must be submitted to the central imaging vendor.  In addition, images obtained for other 
reasons but capturing radiologic progression, should be submitted for BICR.
The local site investigator/radiologist will determine disease progression for subjects in Cohort 
A. For subjects in Cohort B, disease progression will be verified by BICR following the first 
radiologic evidence of PD determined by the local site investigator/radiologist.  Expedited 
verification of radiologic PD by BICR will be communicated to the study site and sponsor for 
subjects in Cohort B (see Section 7.1.2.7.6).
7.1.2.7.1 Tumor Imaging at Screening
Initial tumor imaging at Screening must be performed within 28 days prior to the date of
allocation.  For this study, imaging of the chest, abdomen, and pelvis (CAP) is required for all 
subjects at Screening. A subject must have measurable disease per RECIST 1.1 as assessed 
by investigator at baseline in order to be eligible. After measurable disease per RECIST 1.1 is 
determined by the site investigator/radiologist, baseline images must be submitted to the 
central imaging vendor for BICR verification of measurable disease. Blinded independent 
central imaging review confirmation of measurable disease per RECIST 1.1 is required for 
eligibility prior to allocation.
Bone scans will be acquired for all subjects at screening.  Bone scans are not required to be 
repeated at screening if performed within 42 days prior to treatment allocation. Additionally, 
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 for use as 
screening tumor imaging if they are of diagnostic quality, complete and performed within 28
days prior to the date of allocation 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 Chart (Section 
6.0).
The first post allocation imaging assessment of CAP should be performed at Week 12 (84 days 
±7 days) from the date of allocation. Subsequent tumor imaging of CAP should be performed 
Q6W (42 days ±7 days) through Week 54 and Q12W (84 days ±7 days) thereafter.  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 
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and after the allocation. All scheduled and supplemental imaging must be submitted to the 
central imaging vendor for BICR. 
If a subject has a positive bone scan at Screening, post-allocation 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 Screening. 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. For subjects with 
equivocal bone lesions at baseline, bone scan should be performed in accordance with the 
aforementioned schedule until the lesions are determined non-cancerous.
The timing of imaging assessments should follow calendar days and should not be adjusted for 
dose delays or cycle starts.
For the clear cell cohort (Cohort A), when a subject is identified with PD by the site 
investigator/radiologist, PD will be confirmed by the site ≥ 4 weeks after the first radiologic 
evidence of PD (for clinically stable subjects). Subjects who are clinically stable may continue 
on treatment at the discretion of the investigator until progression is confirmed with a repeat 
scan per irRECIST. (Details pertaining to irRECIST are provided in Section 7.1.2.7.6.)
For the non-clear cell cohort (Cohort B), when a subject is identified with PD by the site 
investigator/radiologist, the site will submit scans to the central imaging vendor for PD 
verification by BICR. Subjects who are clinically stable may continue on treatment at the 
discretion of the investigator while awaiting verification of PD by BICR. Following PD 
verification by BICR, subjects who are clinically stable may continue on treatment at the 
discretion of the investigator until progression is confirmed at the site by a repeat scan ≥ 4 
weeks after the first radiologic evidence of PD per irRECIST. (Details pertaining to irRECIST 
are provided in Section 7.1.2.7.6.)
Subjects who obtain a confirmation scan that does not confirm PD 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.
Additionally, for both cohorts imaging must be discontinued for initiation of new anti-cancer 
treatment, withdrawal of consent or study conclusion/ early termination, whichever occurs 
first. 
7.1.2.7.3 End of Treatment and Follow-up Tumor Imaging
Subjects who discontinue trial treatment without documented disease progression, should 
continue tumor imaging assessments per protocol imaging schedule until initial determination 
of PD (or if clinically stable until further confirmation of PD), initiation of a new anti-cancer 
treatment, withdrawal of consent or study conclusion/early termination, whichever occurs first.
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7.1.2.7.4 Second Course (Retreatment) Tumor Imaging
A subject who is eligible for the second course must have baseline imaging (performed within 
28 days (CAP image) or 42 days (bone scan) prior to restarting treatment with pembrolizumab.  
Local reading (site investigator/radiologist assessment) will be used to determine eligibility.  
All second course imaging will be submitted to BICR for retrospective review.
The last imaging in initial treatment phase may also be used as the Second Course baseline 
imaging if it is within 28 days prior to restarting treatment and otherwise meets the baseline 
standards outlined in the Site Imaging Manual.
A brain scan will be performed before entering the second course for subjects with brain 
metastasis to ensure subject is stable. Brain imaging should be performed as clinically 
indicated and to confirm a CR in subjects with brain metastasis at second course baseline.
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 within 42 days prior to restarting treatment with pembrolizumab
and then every Q24W thereafter (168 ± 14 days) for subjects with positive bone scan at the 
start of re-treatment.
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.
Subjects who discontinue treatment without confirmed disease progression should continue 
with imaging assessments per the protocol defined schedule until: 1) disease progression as 
described in Section 7.1.2.7.2, 2) initiation of a new anti-cancer treatment, 3) death, 4) 
withdrawal of consent or 5) study conclusion/early termination, whichever occurs first.
7.1.2.7.5 RECIST 1.1 Assessment of Disease
RECIST 1.1 will be applied by the central imaging vendor and the investigators as the primary 
measure 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). 
Figure 2 illustrates the imaging flow for clinically stable subjects in Cohort A.  Figure 3
illustrates the imaging flow involving verification of PD for clinically stable subjects in 
Cohort B.
7.1.2.7.6 irRECIST Assessment of Disease
Immune-related RECIST (irRECIST) is RECIST 1.1 adapted as described below to account 
for the unique tumor response seen with immunotherapeutic drugs. Immune-related RECIST
will be used by site investigator/local radiology review to assess tumor response and 
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progression, and make treatment decisions. This data will be collected in the clinical database. 
Treatment efficacy based on irRECIST as assessed by BICR will be evaluated retrospectively.
When feasible, subjects should not be discontinued until progression is 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 it is at the 
discretion of the PI whether to continue a subject on study treatment until repeat imaging is 
obtained (using irRECIST for subject management; see Table 8, Figure 2 and Figure 3).  This 
clinical judgment decision by the site investigator should be based on the subject’s overall 
clinical condition, including performance status, clinical symptoms, and laboratory data.
Subjects may receive study treatment and 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 performance status 
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 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).
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
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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 treatment 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 specified in Section 6 - Trial Flow Chart and be submitted to the 
central imaging vendor.
Additional details about irRECIST are referenced in the Merck TIP Sheet for RECIST 1.1 and 
irRECIST. 
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Table 8
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 
(Cohort A) OR 
1st 
radiologic 
evidence of PD by 
RECIST 
1.1 
which has been 
verified by  BICR 
(Cohort B)
Repeat imaging 
>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
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Figure 2
Imaging and Treatment for Clinically Stable Subjects in Cohort A after First 
Radiologic Evidence of PD Assessed by the Site
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Figure 3
Imaging and Treatment for Clinically Stable Subjects in Cohort B after First 
Radiologic Evidence of PD Assessed by the Site
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7.1.3
Laboratory Procedures/Assessments
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.
7.1.3.1
Urine Pregnancy Test
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.
7.1.3.2
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 9. The 
schedule of individual laboratory tests is shown in the Trial Flow Chart in Section 6.0.
Table 9
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum or urine pregnancy β-
human chorionic 
gonadotropin (β-hCG)a
Hemoglobin
Alkaline phosphatase
Glucose
PTT (INR)
Platelet count
ALT
Protein
aPTT
White Blood Cells
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
Lactate  Dehydrogenase
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Hematology
Chemistry
Urinalysis
Other
Phosphorus or Phosphate
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total bilirubin 
is elevated above the upper limit 
of normal
Total protein
Thyroid function: free thyroxine 
(FT3, FT4), and TSHg
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 [Section 12.5]).
f. GFR (measured or calculated) or CrCl can be used in place of creatinine.
g. Free T3 may be performed in place of Total T3 per local standards
Laboratory safety tests will be performed within 10 days prior to the first dose of trial 
treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours 
prior to dosing.  Results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to each dose of trial treatment.
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 test (T3, FT4, and TSH) results 
after dosing is acceptable.
7.1.3.2.1 Pharmacokinetic Evaluations/ Anti -pembrolizumab Antibodies
To further evaluate pembrolizumab immunogenicity and pembrolizumab exposure, samples 
for PK and anti-drug (pembrolizumab) antibodies (ADA) samples will be collected as specified 
in Trial Flow Chart -Section 6.0.
Pre-dose trough PK and ADA samples will be collected on Day 1 of Cycles 1, 3, and 5; every 
4 cycles thereafter (C9D1, C13D1, C17D1); and 30 days after stopping pembrolizumab. Pre-
dose trough samples should be drawn within 24 hours prior to pembrolizumab infusion.
Additional post-dose PK samples should be drawn within 30 minutes after the end of 
pembrolizumab infusion at Cycles 1 and 9.  
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.
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 
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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.
Sample collection, storage and shipment instructions will be provided in the Procedures 
Manual.
7.1.3.3
Tumor Tissue Collection
For Cohorts A and B, 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. This tissue should come from the site of metastasis, if available.  Informed 
consent for the study must be taken prior to collection of a fresh biopsy. If the subject signs 
the Future Biomedical Research (FBR) consent, any leftover tissue that would ordinarily be 
discarded at the end of the main study will be retained for FBR (see Section 4.2.3.4 for 
rationale). Details regarding time points for collection of tumor tissue are outlined in the Trial
Flow Chart-Sections 6.0. For Cohort A, include a copy of the local pathology report with the 
tissue for biomarker analysis. For Cohort B, a copy of the local pathology report will be 
included with the sample collected for central histology as described below.
Fresh tissue/FFPE block/or unstained slides may be submitted for biomarker analysis (see 
Procedures Manual for details). Adequacy of the sample submitted for biomarker analysis
must be determined by the central laboratory as a prerequisite for enrollment in both Cohort 
A and B.
Specimen Collection for Cohort B Central Confirmation of Non-clear Cell Histology
For Cohort B, sites will submit tissues for histologic confirmation of the diagnosis of non-clear 
cell RCC by central histology review during the screening phase. Sites should enroll subjects 
in Cohort B after receiving notice that the submitted tissue was adequate for central review.  
Confirmation of non-clear cell RCC histology by the central laboratory will be made available 
to the sites as a later date.
For confirmation of non-clear cell carcinoma, the entire case of stained slides used to determine 
the diagnosis must be submitted to the central laboratory. If a site cannot submit all the stained 
slides used for the diagnosis, then a set of H and E stained slides consisting of 1 slide cut from 
each block used to make the diagnosis needs to be submitted. Sites will also be required to send 
1 tumor block or 7 unstained slides (in addition to the tissue sample sent for biomarker testing).
This tissue will be used for IHC to be performed at the central lab. Once the laboratory has 
confirmed the diagnosis, the original stained slides from the case will be returned to the site.  
Detailed instructions for tissue collection, processing and shipment are provided in the
Procedures Manual.  
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7.1.3.3.1 Cohort B Substudy of PD-L1 Expression in Area of Highest Furhman Grade 
The collecting of the entire case allows for evaluation of tumor heterogeneity (including 
sarcomatoid differentiation). It has been shown that RCC tissues display significant 
intratumoral heterogeneity in the expression of candidate biomarkers. Therefore, in order to 
avoid false negative results these areas should be specifically selected for assessment. After 
confirmation of non-clear histology, the central laboratory will determine the area of highest 
Fuhrman grade in the slides that were submitted from the entire case. The central laboratory 
will then request that the site send unstained slides or a single tumor block from this area for 
further PDL-1 testing.
Submission of these additional slides or block is strongly encouraged in order to complete this 
important sub study. It is, however, not required for allocation to Cohort B.
Detailed instructions for tissue collection, processing and shipment are provided in the
Procedures Manual.
7.1.3.4
Blood Collections for ctDNA, TCR, RNA, Plasma, and Serum
The following samples must be collected prior to dosing at the time points in accordance with 
the Trial Flow Chart in Section 6.0: circulating tumor DNA (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 Procedures Manual. 
7.1.3.5
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual.
7.1.3.6
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:
DNA for future research.

Leftover tumor tissue

Leftover RNA from blood

Leftover serum and plasma from biomarker analyses
7.1.4
Other Procedures
7.1.4.1
Withdrawal/Discontinuation
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.
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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 complete 35 infusions of pembrolizumab
(approximately 2 years) must discontinue treatment. Subjects who attain a confirmed CR or 
complete 35 infusions of pembrolizumab with SD, PR or CR may have the option of restarting 
treatment if they experience disease progression after stopping pembrolizumab and meet the 
criteria specified in Section 7.1.5.2.1. After discontinuing treatment following confirmation
of CR or 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 Efficacy Follow-up (described in 
Section 7.1.5.3.3).
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.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:
•
Laboratory equipment- as required for inclusion labs and trial assessments
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•
Imaging equipment- as required for trial objectives
•
Infusion equipment- as required for administering drug product.
7.1.5
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening
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 that 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.
Written consent must be obtained prior to performing any protocol-specified procedures. 
Informed consent may be obtained greater than 28 days prior to treatment allocation; however,
it MUST be obtained prior to performing any protocol-specified procedures (Section 6 – Trial 
Flow Chart). Tumor tissue collection for biomarker studies and histologic confirmation of non-
clear cell RCC diagnosis should be submitted after obtaining written consent; however, tissue 
samples may be submitted to the central laboratory greater than 28 days prior to treatment 
allocation.  This is in order for sites to gather tumor tissue samples and/or other information 
from the subjects. It is recommended that the tumor samples be collected and submitted for 
central laboratory review as soon as the informed consent is signed.
The remaining screening procedures are to be completed within 28 days prior to the first dose 
trial treatment, except for the following: 

Clinical laboratory tests are to be performed within 10 days prior to treatment initiation, 
and evaluation of KPS is to be performed within 10 days prior to treatment allocation.

For women of reproductive potential, a urine pregnancy test will be performed within
72 hours prior to the first dose of trial treatment. If urine pregnancy results cannot be
confirmed as negative, a serum pregnancy test will be required (performed by the local 
study site laboratory).
Subjects may be rescreened once without sponsor consultation after initially failing to meet the 
inclusion/exclusion criteria. The sponsor should be consulted for approval prior to rescreening 
if a subject requires second rescreening.  Procedures performed during the initial screening 
period are acceptable in lieu of repeat screening procedures if performed within the specified 
time frame for the individual procedures and the inclusion/exclusion criteria are met.
7.1.5.2
Treatment Period
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. Specific procedure-related
details are provided above in Section 7.1 – Trial Procedures.
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7.1.5.2.1 Second Course Phase (Retreatment Period)
Subjects who stop pembrolizumab (MK-3475) with SD or better may be eligible for up to 
17 additional doses of pembrolizumab (MK-3475) therapy if they progress after stopping MK-
3745.  This retreatment 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:

Either 
o
Stopped initial treatment with pembrolizumab (MK-3475) after attaining an 
investigator-determined confirmed CR according to RECIST 1.1

Was treated for at least 8 doses with pembrolizumab (MK-3475) before 
discontinuing therapy

Received at least two treatments with pembrolizumab (MK-3475) beyond the date 
when the initial CR was declared
OR

Subject had SD, PR or CR and stopped study treatment after completion of 35 doses
(approximately 2 years) of pembrolizumab (MK-3475) treatment for reasons other than 
disease progression or intolerability
AND

Experienced an investigator-determined confirmed radiographic disease progression after 
stopping their initial treatment with pembrolizumab (MK-3475)

Did not receive any anti-cancer treatment since the last dose of pembrolizumab (MK-3475)

Has a KPS of ≥70%

Demonstrate adequate organ function as detailed in Section 5.1.2

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.
Subjects who restart treatment will be retreated at the same dose frequency as when they last 
received pembrolizumab (MK-3475).  Treatment will be administered for up to 17 additional 
doses of pembrolizumab (approximately one year).
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 
7.1.5.3
Post-Treatment Visits
7.1.5.3.1 End of Treatment Visit
The End of Treatment visit should occur at the time study treatment is discontinued for any 
reason. If the End of Treatment visit occurs 30 days from the last dose of study treatment, at 
the same time as the mandatory Safety Follow-up visit, the End of Treatment visit procedures 
and any additional Safety Follow-up procedures should be performed. Visit requirements are 
outlined in Section 6.0- Trial Flow Chart. 
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Subjects who discontinue trial treatment for a reason other than disease progression will still 
be considered as on study and should continue with regularly scheduled assessments (also refer 
to section 7.1.5.3.3), including collecting subject information on the start of new anti-cancer 
therapy, disease progression, and death.
7.1.5.3.2 Safety Follow-up Visit
The mandatory Safety Follow-Up Visit should be conducted 30 days (± 3 days) after the last 
dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes 
first. At the safety Follow up visit all AEs that have occurred prior to the Safety Follow-Up 
Visit should be recorded.
Subjects who are eligible for retreatment with pembrolizumab (as described in 
Section 7.1.5.2.1) may have up to two safety follow-up visits, one after the Treatment Period 
and one after the Second Course Phase.
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-cancer therapy, whichever occurs first.
All AEs and ECIs occurring within 30 days after the last dose of trial treatment must be 
recorded regardless of when the Safety Follow-up visit occurs.  After 30 days, record all SAEs 
occurring up to 90 days after the last dose of trial treatment or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever comes first.  Any treatment 
related SAEs must be reported regardless of time they occur. (see Sections 7.2.3.1 and 7.2.3.2 
for further details regarding SAE and ECI reporting).
7.1.5.3.3 Efficacy Follow-up Visits
Subjects who complete the protocol-required cycles of study intervention or who discontinue 
trial treatment without documented disease progression as described in Section 7.1.2.7.2, will 
begin the Efficacy Follow-up Phase and should continue with imaging assessments per the 
protocol defined schedule until: 1) disease progression, 2) initiation of a new anti-cancer 
treatment, 3) death, 4) withdrawal of consent or 5) study conclusion or early termination, 
whichever occurs first.  Participants who completed all efficacy assessments must enter the 
Survival Follow-up Phase.  
Information regarding post-study anti-cancer treatment will be collected if new treatment is 
initiated.
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.5.2.1 will move from the Efficacy Follow-Up Phase to the Second Course Phase 
as described in Section 6.0 – Trial Flow Chart.
7.1.5.3.4 Survival Follow-up Contacts
Subject Survival Follow-up status will be assessed approximately every 12 weeks (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.  Post-study treatments and the 
subject’s response to them will also be collected.  The first Survival Follow-up contact should 
be scheduled as described below:
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
For participants who discontinue treatment intervention and who will not enter the Efficacy 
Follow-up Phase, the first Survival Follow-up contact will be scheduled 12 weeks after the 
discontinuation visit and/or Safety Follow-up Visit (whichever is last). 

For participants who completed assessments in the Efficacy Follow-up Phase, the first 
Survival Follow-up contact will be scheduled 12 weeks after the last efficacy assessment 
follow-up visit has been performed.
7.1.5.4
Survival Status
To ensure current and complete survival data is available at the time of database locks, updated 
survival status may be requested during the course of the study by the Sponsor. For example, 
updated survival status may be requested prior to but not limited to an external 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).
7.2
Assessing and Recording Adverse Events
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.
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 
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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).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol-
specified procedure or intervention.  If the subject requires a blood draw, fresh tumor biopsy 
etc., the subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting.
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
In this trial, an overdose is any dose exceeding five 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.
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.”
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).
7.2.2
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Any pregnancy complication will be reported as an AE or SAE. 
The medical reason (example: maternal health or fetal disease) for an elective termination of a 
pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born with 
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severe abnormalities/congenital anomalies that leads to an elective termination of a pregnancy 
will be reported as an SAE for the fetus. 
Pregnancy outcomes of ectopic pregnancy, 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.
7.2.3
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
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.
Refer to Table 9 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 
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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.
7.2.3.2
Events of Clinical Interest
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. 
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).
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
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 Sponsor will ensure that unblinded aggregated efficacy 
endpoint events and safety data are monitored to ensure the safeguard 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 an SAE within 24 hours of determination that the event 
is not progression of the cancer under study.
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7.2.4
Evaluating Adverse Events
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.
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Table 10
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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7.2.5
Sponsor Responsibility for Reporting Adverse Events
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.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  Changes to 
analyses made after the protocol has been finalized, but prior to final database lock, will be 
documented in a supplemental statistical analysis plan SAP (sSAP) and referenced in the 
Clinical Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly 
identified in the CSR.
8.1
Statistical Analysis Plan Summary
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 single-arm, open-label Phase II trial to evaluate the
efficacy and safety of pembrolizumab as a first line treatment for 
advanced renal cell carcinoma (RCC).
Treatment
Assignment
All subjects will receive pembrolizumab 200 mg administered 
intravenously (IV) every 3 weeks (Q3W).  
Analysis
Populations
Efficacy: The All Subjects as Treated (ASaT) population will serve 
as the primary population for the analysis of efficacy data in this 
study. 
The analysis population for DOR consists of responders. 
Safety: All Subjects as Treated (ASaT)
Primary Endpoints
Objective response rate (ORR) per RECIST 1.1 by BCIR
Secondary Endpoints
DOR per RECIST 1.1 by BCIR; disease control rate (DCR) per 
RECIST 1.1 by BCIR; progression-free survival (PFS) per 
RECIST 1.1 by BCIR; overall survival (OS)
Statistical Methods
for
Key
Efficacy
Analyses
The estimate of ORR is the observed proportion of responses 
among the analysis population of corresponding cohort. The 95% 
CI for ORR will be calculated using an exact method based on the 
binomial distribution (Clopper-Pearson method).
Statistical Methods
for
Key
Safety
Analyses
Counts and percentages of subjects with AEs will be provided. 
Confidence intervals for the rates of types of AEs of interest will 
be estimated using an exact method based on the binomial 
distribution.
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Interim Analyses
For the cohort of subjects with non-clear cell renal cell carcinoma, 
one interim analysis will be performed in this study. The interim 
analysis is summarized below. Details are provided in Section 8.7.

IA:
o
Timing: To be performed at the time when the 30th subject 
in this cohort has the opportunity to complete the 3rd scan
o
Testing: Futility check based on ORR for subjects with 
non-clear cell renal cell carcinoma
Multiplicity
No multiplicity adjustment is planned.
Sample
Size
and
Power
The planned sample size is 255 subjects. The primary objectives 
for the study are to estimate the ORR in two cohorts of subjects 
with renal cell carcinoma (ccRCC and nccRCC). No power 
calculation is provided. The planned sample size is approximately 
105 subjects in the ccRCC cohort and up to 150 subjects in the 
nccRCC cohorts.  
8.2
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This trial is being conducted as an open-label study. There is no randomization in the study.
8.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
8.4
Analysis Endpoints
8.4.1
Efficacy Endpoints
8.4.1.1
Primary
Objective Response Rate (ORR) – RECIST 1.1 by B l i n d e d Central Imaging Review
ORR is defined as the proportion of the subjects in the analysis population who have a complete 
response (CR) or partial response (PR) where responses are determined by RECIST 1.1.
8.4.1.2
Secondary
Duration of Response - RECIST 1.1 by B l i n d e d  Central Imaging Review
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 B l i n d e d  Central Imaging Review
DCR is defined as the percentage of subjects who have achieved CR, PR, or SD for at least 6 
months based on assessments by the central imaging review per RECIST 1.1.
Progression-Free Survival (PFS) – RECIST 1.1 by Blinded Central Imaging Review
PFS is defined as the time from first day of study treatment to the first documented disease 
progression per RECIST 1.1 based on central imaging review or death due to any cause, 
whichever occurs first.  See Section 8.6.1 for the censoring rules.
Overall Survival (OS)
OS is defined as the time from the first day of study treatment to the time of 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.
8.4.2
Safety Endpoints
Safety endpoints are described in Sections 4.2.3.2.
8.5
Analysis Population
Subjects will be entered into the trial when they are assigned a treatment number by the 
interactive voice response system (IVRS).
8.5.1
Efficacy Analysis Population
The All Subjects as Treated (ASaT) population will serve as the primary population for the 
analyses of efficacy data in this study. The ASaT population consists of all allocated subjects 
who received at least one dose of study treatment.
The analysis population for DOR consists of responders. Details on the approach to handling 
missing data are provided in Section 8.6.1 Statistical Methods for Efficacy Analyses.
8.5.2
Safety Analysis Population
The All Subjects as Treated (ASaT) population will be used for the analyses of safety data in 
this study.  The ASaT population consists of all allocated subjects who received at least one 
dose of study treatment. 
At least one laboratory or vital sign measurement obtained subsequent to at least one 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.
8.6
Statistical Methods
8.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
Table 11 summarizes the key efficacy analyses.
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Table 11
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis Population
Missing Data Approach
ORR per RECIST 1.1 assessed 
by blinded central imaging 
review
Observed 
proportion 
as point estimate and 
95% 
CI 
using 
Clopper-Pearson 
method 
based 
on 
binomial distribution
ASaT
Subjects with missing data 
are 
considered 
non-
responders
DOR per RECIST 1.1 assessed 
by blinded central imaging 
review
Summary 
statistics 
using Kaplan-Meier 
method
All responders
Details are provided in a 
separate table
DCR per RECIST 1.1 assessed 
by blinded central imaging 
review
Observed 
proportion 
as point estimate and 
95% 
CI 
using 
Clopper-Pearson 
method 
based 
on 
binomial distribution
ASaT
Subjects with missing data 
are considered disease not 
under control
PFS per RECIST 1.1 assessed 
by blinded central imaging 
review
Summary 
statistics 
using Kaplan-Meier 
method
ASaT
Censored at last assessment 
date
OS
Summary 
statistics 
using Kaplan-Meier 
method
ASaT
Censored at last date the 
subject was known to be 
alive
Table 12 provides the censoring rules for DOR.
Table 12
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 after ≥ 2 
missed 
adequate 
disease 
assessments
Last adequate disease assessment 
prior to the after ≥ 2 missed 
adequate disease assessments
Censor
(Non-event)
Death or progression after ≤ 1 
missed 
adequate 
disease 
assessments
PD or death
End of response
(Event)
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 
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8.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, and vital signs. Counts and percentages of subjects 
with AEs will be provided. Confidence intervals for the rates of a list of pre-defined AEs of 
special interest (AEOSI) for the pembrolizumab development program will be estimated using
an exact method based on the binomial distribution.
8.6.3
Summaries of Demographic and Baseline Characteristics
The number and percentage of subjects screened and enrolled and the primary reasons for 
screening failure and discontinuation will be displayed.  Demographic variables, baseline 
characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be 
summarized by cohort either by descriptive statistics or categorical tables.
8.7
Interim Analyses
An interim analysis will be performed for the cohort of subjects with non-clear cell renal cell 
carcinoma at the time when 30th subject in this cohort has the opportunity to complete the 3rd
scan. Analysis will include all scans up to this cut-off time point. A futility check will be 
conducted based on an observed ORR and futility will be considered if 1 or fewer responders 
are observed. During the futility analysis the enrollment of subjects will continue.  
8.8
Multiplicity
The primary objectives for the study are to estimate the ORR in two separate cohorts of subjects 
with renal cell carcinoma. Therefore, no multiplicity will be considered.
8.9
Sample Size and Power Calculations
The primary objectives for the study are to estimate the ORR in two cohorts of subjects with 
renal cell carcinoma (ccRCC and nccRCC). The overall sample size selection is based on the 
confidence interval (CI) width that will provide the appropriate level of precision needed for 
estimation. The planned sample size is approximately 105 subjects in ccRCC cohort and up 
to 150 subjects in nccRCC cohort. With the above sample sizes, the 95% confidence intervals 
for different observed response rates are listed below with the width of the 95% confidence 
level. With a sample size of 105 subjects with clear cell renal cell carcinoma, the half-width 
of 95% confidence interval varies between 8% and 10% when the observed response rates vary 
from 20% to 60%. With a sample size of 150 subjects with non-clear cell renal cell carcinoma, 
the half-width of 95% confidence interval varies between 4% and 8% when the observed 
response rates vary from 5% to 30%. No power calculation is provided.
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Sample size
Number of Subjects 
with a response
Observed 
Response Rate
95% CI
95% CI width
21
20%
(12.8%, 28.9%)
16.1%
105
32
~30%
(21.9%, 40.2%)
18.4%
(ccRCC)
42
40%
(30.6%, 50%)
19.5%
53
~50%
(40.6%, 60.4%)
19.8%
63
60%
(50%, 69.4%)
19.5%
8
~5%
(2.3%, 10.2%)
7.9%
15
10%
(5.7%, 16%)
10.3%
150
23
~15%
(9.9%, 22.1%)
12.1%
(nccRCC)
30
20%
(13.9%, 27.3%)
13.4%
38
~25%
(18.6%, 33%)
14.5%
45
30%
(22.8%, 38%)
15.2%
8.10 Subgroup Analyses and Effect of Baseline Factors
The estimate of treatment effect (with a nominal 95% CI) for the efficacy endpoints stated in 
Section 8.4.1 will be performed within each of IMDC risk categories (See Section 12.5).
The estimate of treatment effect (with a nominal 95% confidence interval [CI]) for the primary 
endpoints will be performed within each category of the following classification variables.

Geographic region   

PD-L1 status

Age 

Sex 

Race
8.11 Compliance
Drug accountability data for trial treatment will be collected during the study.  Any deviation 
from protocol-directed administration will be reported.
8.12 Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles. Summary 
statistics will be provided on Extent of Exposure for the ASaT population.
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9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
9.1
Investigational Product
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 13. 
Table 13
Product Descriptions
Product Name & Potency
Dosage Form
Source/Additional 
Information
Pembrolizumab (MK-3475) 
25 mg/mL (100 mg/4mL)
Solution for injection
Provided centrally by the 
Sponsor.
9.2
Packaging and Labeling Information
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.
9.3
Clinical Supplies Disclosure
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.
9.4
Storage and Handling Requirements
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.
9.5
Discard/Destruction/Returns and Reconciliation
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.
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9.6
Standard Policies
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.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
10.1 Confidentiality
10.1.1 Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will be 
divulged to the institutional review board, ethics review committee (IRB/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.
10.1.2 Confidentiality of Subject Records
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.
10.1.3 Confidentiality of Investigator Information
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 
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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.
10.1.4 Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names and 
qualifications of the IRB/IEC members and to make these records available for regulatory 
agency review upon request by those agencies.
10.2 Compliance with Financial Disclosure Requirements
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.
10.3 Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and diligent 
manner and in conformance with this protocol; generally accepted standards of Good Clinical 
Practice (e.g., International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
Guideline and other generally accepted standards of good clinical practice); and all applicable 
federal, state and local laws, rules and regulations relating to the conduct of the clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in 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.
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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.
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.
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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 
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.
10.4 Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007, 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are 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.
10.5 Quality Management System
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.
10.6 Data Management
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.
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Detailed information regarding Data Management procedures for this protocol will be provided 
separately.
10.7 Publications
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 
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.
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 
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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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Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, et al. 
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Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. 
Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 
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Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S. et al. 
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[10]
Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in 
locally advanced or metastatic renal cell carcinoma: results of a randomized phase III 
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Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH. et al. A 
randomised, double-blind phase III study of pazopanib in patients with advanced and/or 
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Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al.  
Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a 
randomised, double-blind phase III trial.  Lancet 2007;370:2103-11.
[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(13):2144-50.
[14]
Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al. Pazopanib versus 
sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013 Aug 22;369(8):722-
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Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, et al. Axitinib 
versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a 
randomised open-label phase 3 trial. Lancet Oncol. 2013 Dec;14(13):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 May 
31;356(22):2271-81.
[17]
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, et al. Sorafenib 
for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III 
treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009 Jul 
10;27(20):3312-8.
[18]
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 Sep 15;116(18):4256-65.
[19]
U.S. Prescribing Information: AFINITOR (everolimus) tablets for oral administration, 
AFINITOR DISPERZ (everolimus tablets for oral suspension): 2015.
[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 Dec 3;378(9807):1931-9.
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[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 
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Available 
from: 
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_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 
Nov 5;373(19):1803-13.
[25]
Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. 
Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 
2015 Nov 5;373(19):1814-23.
[26]
U.S. Prescribing Information: COMETRIQ (cabozantinib) capsules, for oral use: 2012.
[27]
Dutcher JP, de Souza P, McDermott D, Figlin RA, Berkenblit A, Thiele A, et al. Effect 
of temsirolimus versus interferon-alpha on outcome of patients with advanced renal cell 
carcinoma of different tumor histologies. Med Oncol. 2009;26(2):202-9.
[28]
Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, et al. Everolimus 
versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma 
(ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Jan 
12. [Epub ahead of print].
[29]
Ravaud A, Oudard S, De Fromont M, Chevreau C, Gravis G, Zanetta S, et al. First-line 
treatment with sunitinib for type 1 and type 2 locally advanced or metastatic papillary 
renal cell carcinoma: a phase II study (SUPAP) by the French Genitourinary Group 
(GETUG). Ann Oncol. 2015 Jun;26(6):1123-8.
[30]
Gordon MS, Hussey M, Nagle RB, Lara PN Jr, Mack PC, Dutcher J, et al. Phase II 
study of erlotinib in patients with locally advanced or metastatic papillary histology 
renal cell cancer: SWOG S0317. J Clin Oncol. 2009 Dec 1;27(34):5788-93.
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Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH Jr, et al. 
Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded 
access program in North America. Cancer. 2010 Mar 1;116(5):1272-80.
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[32]
Irshad T, Olencki T, Zynger DL, Coston A, Mortazavi A, Monk JP. Bevacizumab in 
metastatic papillary renal cell carcinoma [abstract]. J Clin Oncol. 2011 May 20; 29(15 
Suppl). Abstract  no. e15158.
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Finn OJ. Molecular origins of cancer: cancer immunology. N Engl J Med. 2008 Jun 
19;358(25):2704-15.
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Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles 
in cancer suppression and promotion. Science. 2011 Mar 25;331(6024):1565-70.
[35]
Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive 
immunity to cancer. Annu Rev Immunol. 2011;29:235-71.
[36]
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev 
Cancer 2012;12:252-64.
[37]
Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. 
Nat Rev Immunol. 2013 Apr;13(4):227-42. Erratum in: Nat Rev Immunol. 2013 
Jul;13(7):542.
[38]
Pedoeem A, Azoulay-Alfaguter I, Strazza M, Silverman GJ, Mor A. Programmed 
death-1 pathway in cancer and autoimmunity. Clin Immunol. 2014 Jul;153(1):145-52.
[39]
Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. 
Immunology 2008;8:467-77.
[40]
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 
2011;480:480-9.
[41]
Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to 
activate anti-tumor immunity. Curr Opin Immunol 2012;24:207-12.
[42]
Postow MA, Callahan MK, Wolchok JD. Immune Checkpoint Blockade in Cancer 
Therapy. J Clin Oncol. 2015 Jan 20. [Epub ahead of print].
[43]
Dizon DS, Krilov L, Cohen E, Gangadhar 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. 2016 Feb 4. [Epub ahead of print].
[44]
U.S. Prescribing Information: KEYTRUDA (pembrolizumab) injection, for 
Intravenous Use: 2015.
[45]
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and Tumor 
Responses with Lambrolizumab (Anti-PD-1) in Melanoma. N Engl J Med 
2013;369(2):134-44.
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[46]
Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-
programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory 
advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 
2014 Sep 20;384(9948):1109-17.
[47]
Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. 
Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory 
melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 
2015 Aug;16(8):908-18.
[48]
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab 
versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Apr 19. [Epub ahead 
of print]
[49]
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.
[50]
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.
[51]
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.
[52]
Seiwert TY, Burtness B, Weiss J, Gluck I, Eder JP, Pai SI, et al. 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 6011]. 2014 ASCO Annual Meeting 
on Clinical Science Symposium, Immunobiology and Immunotherapy; 2014.
[53]
Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, et al. A phase Ib study of 
pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. San 
Antonio Breast Cancer Symposium 2014; abstract S1-09.
[54]
Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, 
et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of 
PD-1 and are functionally impaired. Blood. 2009 Aug 20;114(8):1537-44.
[55]
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. 
Developing a common language for tumor response to immunotherapy: immune-related 
response criteria using unidimensional measurements. Clin Cancer Res. 2013 Jul 
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12.0 APPENDICES
12.1 Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of 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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12.2 Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens 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.
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. 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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12.3 Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff
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12.4 Karnofsky Performance Status Scale Definitions Rating (%) Criteria
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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12.5 IMDC Risk Evaluation
Assessments
Risk Factor
Baseline Karnofsky Performance Status
< 80%
Interval between initial diagnosis of RCC to start of first-
line treatment for advanced disease 
(note for this study, date of allocation will be used as the 
start of first-line treatment)
< 1year
Baseline Hemoglobin
< Lower limit of normal
Baseline Platelet Count
> Upper limit of normal
Baseline Corrected Calcium
> 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
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12.6 National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE)
NCI 
CTCAE 
version 
4.0 
will 
be 
utilized 
for 
adverse 
events 
reporting 
(http://ctep.cancer.gov/reporting/ctc.html)
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12.7 Abbreviations
Abbreviation
Definition
ADA
anti-drug (pembrolizumab) antibodies
AE
adverse event
ALT
alanine aminotransferase
APC
antigen-presenting cells
aPTT
activated partial thromboplastic time
ASaT
all subjects as treated
AST
aspartate aminotransferase
BICR
blinded independent central imaging review/reviewer
BCG
Bacillus Calmette-Guerin
β-hCG
β human chorionic gonadotropin
BID
bis in die (twice a day)
CAP
chest, abdomen, and pelvis
cc
clear-cell
ccRCC
clear-cell renal cell carcinoma
CI
confidence interval
CIV
central imaging vendor
CL
clearance
CNS
central nervous system
CR
complete response
CrCl
calculated creatinine clearance
CT
computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
ctDNA
Circulating tumor DNA
CTL
cytotoxic T lymphocytes cells
DCR
disease control rate
DNA
deoxyribonucleic acid
DOR
duration of response
e.g.
exempli gratia (for example)
ECG
electrocardiogram
ECI
events of clinical interest
ECOG
Eastern Cooperative Oncology Group
EMA
European Medicines Agency
ESMO
European Society for Medical Oncology
ERC
Ethical Review Committee ()
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
Follicle stimulating hormone
FT3, FT4
free thyroxine
GI
gastrointestinal
GFR
glomerular filtration rate
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
i.e.
id est (that is)
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
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Abbreviation
Definition
IFNα
interferon alpha
IHC
immunohistochemistry
IMDC
International Metastatic RCC Database Consortium
INR
International normalized ratio 
irAEs
immune-related adverse events
IRB
Institutional Review Board
irRECIST
immune-related RECIST
IV
intravenous
IVRS
interactive voice response system
KPS
Karnofsky Performance Status
MRI
magnetic resonance imaging
mRNA
messenger RNA
MTD
maximum tolerated dose
mTOR
mammalian target of rapamycin
ncc
non-clear cell
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/PD-L2
programmed death-ligand 1/2
PE
physical examination
PFS
progression-free survival
PK
pharmacokinetic(s)
PO
per os (by mouth)
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
Q3W
every 3 weeks
QD
quaque die (once a day)
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
SAE
serious adverse event
SD
stable disease
SEER
Surveillance, Epidemiology, and End Results [Program]
sSAP
statistical analysis plan
T3
total triiodothyronine
T4
thyroxine
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
W
week(s)
WBC
white blood cell [count]
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13.0 SIGNATURES
13.1 Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
13.2 Investigator
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
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Supplemental SAP
18SEP2018–AMENDMENT#2
Supplemental Statistical Analysis Plan (sSAP) 
TABLE OF CONTENTS
Table of Contents...................................................................................................................... 1
Listing of Tables ....................................................................................................................... 2
1
INTRODUCTION ............................................................................................................ 3
2
SUMMARY OF CHANGES............................................................................................ 3
3
ANALYTICAL AND METHODOLOGICAL DETAILS............................................... 4
3.1
Statistical Analysis Plan Summary ............................................................................ 4
3.2
Responsibility for Analyses/In-House Blinding ........................................................ 5
3.3
Hypotheses/Estimation............................................................................................... 5
3.4
Analysis Endpoints..................................................................................................... 5
3.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints..................................... 5
3.4.1.1
Primary ........................................................................................................ 5
3.4.1.2
Secondary .................................................................................................... 6
3.4.1.3
Exploratory.................................................................................................. 6
3.4.2
Safety Endpoints................................................................................................. 6
3.5
Analysis Populations.................................................................................................. 6
3.5.1
Efficacy Analysis Populations............................................................................ 6
3.5.2
Safety Analysis Populations ............................................................................... 7
3.6
Statistical Methods..................................................................................................... 7
3.6.1
Statistical Methods for Efficacy Analyses.......................................................... 7
3.6.2
Statistical Methods for Safety Analyses ............................................................. 8
3.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses.... 9
3.7
Interim Analyses ........................................................................................................ 9
3.8
Multiplicity................................................................................................................. 9
3.9
Sample Size and Power Calculations......................................................................... 9
3.10
Subgroup Analyses and Effect of Baseline Factors.............................................. 10
3.11
Compliance (Medication Adherence)................................................................... 10
3.12
Extent of Exposure ............................................................................................... 10
Revision History ..................................................................................................................... 11
 
 
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LISTING OF TABLES
Table 1 Analysis Strategy for Key Efficacy Variables ............................................................. 7
Table 2 Censoring Rules for DOR............................................................................................ 8
Table 3 Censoring Rules for PFS.............................................................................................. 8
 
 
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1
INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of 
confirmatory analyses for this trial, this supplemental SAP provides additional statistical 
analysis details/data derivations and documents modifications or additions to the analysis 
plan that are not “principal” in nature and result from information that was not available at 
the time of protocol finalization. There will be a separate PK analysis plan as well as 
biomarker analysis plan.
2
SUMMARY OF CHANGES
Section 
Number(s)
Section Title(s)
Description of Change 
(s)
Rationale
3.3
Hypotheses/Estimation
Add “All estimation 
will be applied on the 
ccRCC (cohort A) and 
nccRCC 
(cohort 
B) 
separately. 
For 
nccRCC (cohort B), 
two sets of analyses 
will be performed due 
to additional diagnosis 
confirmation 
of 
nccRCC 
by 
blinded 
central 
histology 
review. 

Primary 
analysis will be 
on the subjects 
in cohort B who 
had 
confirmation of 
nccRCC 
diagnosis by 
blinded central 
histology 
review

Sensitivity 
analysis will be 
on all subjects 
in cohort B by 
consultative 
review.”
To clarify the cohort B 
nccRCC population 
definition
3.6.1
Statistical Methods for 
Efficacy Analyses

Updated the 
table for 

To align with the 
updated oncology 
 
 
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Section 
Number(s)
Section Title(s)
Description of Change 
(s)
Rationale
censoring rules 
for DOR 

Added a table 
to provide the 
censoring rules 
for PFS
standard censoring 
rules for DOR.

To align with the 
oncology standard 
primary censoring 
rules for PFS.
3.6.2
Statistical Methods for 
Safety Analyses
Removed analysis of 
AEOSIs by confidence 
intervals. Only count 
and percentage will be 
provided.
To align with standard 
analysis of AEOSIs. No 
need to provide confidence 
intervals.
3.10
Subgroup Analyses 
and Effect of Baseline 
Factors
Addition of subgroup 
analysis 
by 
IMDC 
category 2 of favorable 
vs intermediate/poor.
IMCD favorable vs. 
intermediate/poor is a 
clinically meaning 
breakdown that has been 
commonly presented in the 
literature.
3
ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 3.2-3.12.  
Study Design Overview
This is a single-arm, open-label Phase II trial to evaluate the efficacy and
safety of pembrolizumab as a first line treatment for advanced renal cell
carcinoma (RCC).
Treatment 
Assignment
All subjects will receive pembrolizumab 200 mg administered intravenously
(IV) every 3 weeks (Q3W).
AnalysisPopulations
Efficacy: The All Subjects as Treated (ASaT) population will serve as
the primary population for the analysis of efficacy data in this study.
The analysis population for DOR consists of responders.
Safety: All Subjects as Treated (ASaT)
Primary Endpoints
Objective response rate (ORR) per RECIST 1.1 by BCIR
Secondary Endpoints
Duration of response (DOR) per RECIST 1.1 by BCIR; disease control
rate (DCR) per RECIST 1.1 by BCIR; progression-free survival (PFS) per
RECIST
Statistical Methods for Key
Efficacy Analyses
The estimate of ORR is the observed proportion of responses among the
analysis population of corresponding cohort. The 95% CI for ORR will
be calculated using an exact method based on the binomial distribution
(Clopper- Pearson method).
Statistical Methods for Key
Safety Analyses
Counts
and
percentages
of
subjects
with
AEs
will
be
provided.
Confidence intervals for the rates of types of AEs of interest will be
estimated using an exact method based on the binomial distribution.
 
 
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Study Design Overview
This is a single-arm, open-label Phase II trial to evaluate the efficacy and
safety of pembrolizumab as a first line treatment for advanced renal cell
carcinoma (RCC).
InterimAnalyses
For the cohort of subjects with non-clear cell renal cell carcinoma, one
interim analysis will be performed in this study. The interim analysis is
summarized below. Details are provided in Section 3.7.

IA:
o
Timing: To be performed at the time when 30th subject in this
cohort has the opportunity to complete the 3rd scan
o
Analysis: Futility check based on ORR for subjects with non-clear
cell renal cell carcinoma
Multiplicity
No multiplicity adjustment is planned.
Sample
Size
and Power
The planned sample size is 255 subjects. The primary objectives for the
study are to estimate the ORR in two cohorts of subjects with renal cell
carcinoma (ccRCC and nccRCC). No power calculation is provided. The
planned sample size is approximately 105 subjects in the ccRCC cohort and
up to 150 subjects in the nccRCC cohorts.
3.2
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This trial is being conducted as an open-label study. There is no randomization in the study.
3.3
Hypotheses/Estimation
There will be no formal hypothesis testing in this study. Objectives of the study are stated in 
the Protocol Section 3.0.
All estimation will be applied on the ccRCC (cohort A) and nccRCC (cohort B) separately. 
For nccRCC (cohort B), two sets of analyses will be performed due to additional diagnosis 
confirmation of nccRCC by blinded central histology review in addition to the consultative 
review. 

Primary analysis will be on the subjects in cohort B who had confirmation of nccRCC 
diagnosis by blinded central histology review

Sensitivity analysis will be on all subjects in cohort B by consultative review.
3.4
Analysis Endpoints
3.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
3.4.1.1
Primary
Objective Response Rate (ORR) – RECIST 1.1 by Blinded Independent Central Review
(BICR)
ORR is defined as the proportion of the subjects in the analysis population who have a 
complete response (CR) or partial response (PR) where responses are determined by RECIST 
1.1.
 
 
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3.4.1.2
Secondary
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 3.6.1 for the censoring rules.
Disease Control Rate (DCR) - RECIST 1.1 by BICR 
DCR is defined as the percentage of subjects who have achieved CR, PR, or stable disease 
(SD) for at least 6 months based on assessments by the central imaging review per RECIST 
1.1.
Progression-Free Survival (PFS) – RECIST 1.1 by BICR
PFS is defined as the time from first day of study treatment to the first documented disease 
progression per RECIST 1.1 based on central imaging review or death due to any cause, 
whichever occurs first. See Section 3.6.1 for the censoring rules.
Overall Survival (OS)
OS is defined as the time from the first day of study treatment to the time of 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.
3.4.1.3
Exploratory
Exploratory endpoints of this study include ORR, DOR, DCR and PFS per irRECIST by 
BICR and PK parameter.
3.4.2
Safety Endpoints
The safety objective is to characterize the safety and tolerability of pembrolizumab in 
subjects with advanced RCC as first line treatment. The following safety parameters will be 
analyzed: adverse events and serious adverse events graded per National Cancer Institute’s 
(NCI) Common Toxicity Criteria for Adverse Events (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 of use. These are 
routine safety parameters collected and analyzed in Phase II oncology trials. Furthermore, 
specific immune-related adverse events (irAEs) will be collected.
3.5
Analysis Populations
Subjects will be entered into the trial when they are assigned a treatment allocation number 
by the IVRS.
3.5.1
Efficacy Analysis Populations
The All Subjects as Treated (ASaT) population will serve as the primary population for the 
analyses of efficacy data in this study. The ASaT population consists of all allocated subjects 
who received at least one dose of study treatment.
 
 
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The analysis population for DOR consists of responders. Details on the approach to handling 
missing data are provided in Section 3.6.1 Statistical Methods for Efficacy Analyses.
3.5.2
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analyses of safety data in 
this study. The ASaT population consists of all allocated subjects who received at least one 
dose of study treatment.
At least one laboratory or vital sign measurement obtained subsequent to at least one 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.
3.6
Statistical Methods
3.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. These methods will also be applied to the exploratory endpoints of ORR, DOR, 
DCR, PFS per irRECIST by BICR. .
Table 1 summarizes the key efficacy analyses.
Table 1 Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis
Population
Missing Data
Approach
ORR per RECIST 1.1 assessed
by blinded central imaging
review
Observed proportion as point 
estimate and 95% CI using 
Clopper-Pearson method 
based on binomial 
distribution
ASaT
Subjects with missing 
data are considered 
non- responders
DOR per RECIST 1.1 assessed by 
blinded central imaging review
Summary statistics using 
Kaplan-Meier method
All responders
Details are provided 
in a separate table
DCR per RECIST 1.1 assessed by 
blinded central imaging review
Observed proportion as point
estimate and 95% CI using 
Clopper-Pearson method 
based on binomial 
distribution
ASaT
Subjects with missing 
data are considered 
disease not under 
control
PFS per RECIST 1.1 assessed by 
blinded central imaging review
Summary statistics using 
Kaplan-Meier method
ASaT
Details are provided 
in a separate table
OS
Summary statistics using 
Kaplan-Meier method
ASaT
Censored at last date 
the subject was known
to be alive
 
 
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Table 2 provides the censoring rules for DOR. Table 3 provides the censoring rules for PFS.
Table 2 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
i m m e d i a t e l y  after ≥2
consecutively 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 adequate  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.
Table 3 Censoring Rules for PFS
Situation
Outcome
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
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
No PD and no death; and new anticancer treatment is not 
initiated
Censored at last disease assessment 
No PD and no death; new anticancer treatment is initiated
Censored at last disease assessment before 
new anticancer treatment 
PD = progressive disease; PFS = progression-free survival.
3.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, and vital signs. Counts and percentages of 
subjects with AEs and AEs of special interest (AEOSI) will be provided.
 
 
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3.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The number and percentage of subjects screened and enrolled and the primary reasons for 
screening failure and discontinuation will be displayed. Demographic variables, baseline 
characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be 
summarized by cohort either by descriptive statistics or categorical tables.
The following analyses will be performed by cohort: DOR, DCR and PFS per RECIST 1.1 
by BICR and OS (with a nominal 95% confidence interval [CI]) will be estimated by 
centrally determined PD-L1 status as well as for patients with any sarcomatoid differentiation 
identified. 
3.7
Interim Analyses
An interim analysis will be performed for the cohort of subjects with non-clear cell renal cell 
carcinoma at the time when 30th subject in this cohort has the opportunity to complete the 3rd
scan. Analysis will include all scans up to this cut-off time point. A futility check will be 
conducted based on an observed ORR and futility will be considered if 1 or fewer responders 
are observed. During the futility analysis the enrollment of subjects will continue.
3.8
Multiplicity
The primary objectives for the study are to estimate the ORR in two separate cohorts of 
subjects with renal cell carcinoma. Therefore, no multiplicity will be considered.
3.9
Sample Size and Power Calculations
The primary objectives for the study are to estimate the ORR in two cohorts of subjects with 
renal cell carcinoma (ccRCC and nccRCC). The overall sample size selection is based on the 
confidence interval (CI) width that will provide the appropriate level of precision needed for 
estimation The planned sample size is approximately 105 subjects in ccRCC cohort and up to 
150 subjects in nccRCC cohort. With the above sample sizes, the 95% confidence intervals 
for different observed response rates are listed below with the width of the 95% confidence 
level. With a sample size of 105 subjects with clear cell renal cell carcinoma, the half-width 
of 95% confidence interval varies between 8% and 10% when the observed response rates 
vary from 20% to 60%. With a sample size of 150 subjects with non-clear cell renal cell 
carcinoma, the half-width of 95% confidence interval varies between 4% and 8% when the 
observed response rates vary from 5% to 30%. No power calculation is provided.
 
 
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Sample size
Number of Subjects 
with a response
Observed Response
Rate
95% CI
95% CI width
105
(ccRCC)
21
20%
(12.8%, 28.9%)
16.1%
32
~30%
(21.9%, 40.2%)
18.4%
42
40%
(30.6%, 50%)
19.5%
53
~50%
(40.6%, 60.4%)
19.8%
63
60%
(50%, 69.4%)
19.5%
150
(nccRCC)
8
~5%
(2.3%, 10.2%)
7.9%
15
10%
(5.7%, 16%)
10.3%
23
~15%
(9.9%, 22.1%)
12.1%
30
20%
(13.9%, 27.3%)
13.4%
38
~25%
(18.6%, 33%)
14.5%
45
30%
(22.8%, 38%)
15.2%
3.10 Subgroup Analyses and Effect of Baseline Factors
The estimate of treatment effect (with a nominal 95% CI) for the efficacy endpoints stated in 
Section 3.4.1 will be performed within each of IMDC risk categories (favorable, 
intermediate, and poor) as well as within IMDC risk categories of favorable and a combined 
intermediate and poor category (See Protocol Appendix 12.5).
The estimate of treatment effect (with a nominal 95% confidence interval [CI]) for the 
primary endpoints will be performed within each category of the following classification 
variables.

Geographic region

PD-L1 status

Age

Sex

Race
3.11 Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
3.12 Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles. Summary 
statistics will be provided on Extent of Exposure for the ASaT population.
 
 
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REVISION HISTORY
Date
Summary of Change
11AUG2016
Original Document
27JUL2017
Clarification of Cohort B population
29AUG2018
Updated DOR censoring rules, added PFS censoring rules, removed CIs 
for AEs and AEOSI, and added IMDC category 2
 
 
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