A Phase 3, Randomized, Double-Blind Study of Pembrolizumab Plus Ipilimumab vs Pembrolizumab Plus Placebo in Previously Untreated, Stage IV, Metastatic Non-small Cell Lung Cancer Subjects Whose Tumors Are PD-L1 Positive (TPS ≥ 50%) (KEYNOTE-598)
Phase: PHASE3
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03302234 
Document Date: 
11-Dec-2020
A Phase 3, Randomized, Double-Blind Study of Pembrolizumab plus 
Ipilimumab vs Pembrolizumab plus Placebo in Previously Untreated, 
Stage IV, Metastatic Non-small Cell Lung Cancer Subjects Whose 
Tumors are PD-L1 Positive (TPS ≥ 50%) (KEYNOTE-598)

Product:  MK-3475 
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Protocol/Amendment No.: 598-06 
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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 3, Randomized, Double-Blind Study of Pembrolizumab plus Ipilimumab vs 
Pembrolizumab plus Placebo in Previously Untreated, Stage IV, Metastatic Non-small Cell 
Lung Cancer Subjects Whose Tumors are PD-L1 Positive (TPS ≥ 50%) (KEYNOTE-598)
IND NUMBER:  132864
EudraCT NUMBER:  2016-004364-20
NCT NUMBER:  NCT03302234
 
 
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 13
1.0
TRIAL SUMMARY.................................................................................................. 17
2.0
TRIAL DESIGN........................................................................................................ 18
Trial Design ........................................................................................................... 18
Trial Diagram........................................................................................................ 19
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 21
Primary Objective(s) & Hypothesis(es).............................................................. 21
Secondary Objective(s) & Hypothesis(es)........................................................... 21
Exploratory Objectives......................................................................................... 22
4.0
BACKGROUND & RATIONALE.......................................................................... 22
Background ........................................................................................................... 22
Pharmaceutical and Therapeutic Background .................................................... 23
Summary of Pembrolizumab Clinical Activities ................................................ 24
4.1.2.1
Completed Clinical Trials............................................................................ 24
4.1.2.2
Ongoing Clinical Trials with Pembrolizumab............................................. 26
Rationale................................................................................................................ 26
Rationale for the Trial and Selected Subject Population .................................... 26
Rationale for Dose Selection/Regimen/Modification......................................... 30
4.2.2.1
Justification for Treatment Regimen ........................................................... 30
4.2.2.1.1
Rationale for Fixed Dose Pembrolizumab............................................ 30
4.2.2.1.2
Rationale for Dose and Regimen of Ipilimumab/Placebo in 
Combination With Pembrolizumab ...................................................... 31
Rationale for Endpoints ...................................................................................... 34
4.2.3.1
Efficacy Endpoints....................................................................................... 34
4.2.3.1.1
Primary Endpoints ................................................................................ 34
4.2.3.1.2
Secondary Endpoints ............................................................................ 34
4.2.3.1.3
Exploratory Endpoints .......................................................................... 34
4.2.3.2
Patient-reported Outcomes........................................................................... 35
 
 
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4.2.3.3
Safety Endpoints.......................................................................................... 36
4.2.3.4
Planned Exploratory Biomarker Research................................................... 36
4.2.3.5
Future Biomedical Research........................................................................ 38
Benefit/Risk ........................................................................................................... 38
5.0
METHODOLOGY ................................................................................................... 39
Entry Criteria........................................................................................................ 39
Diagnosis/Condition for Entry into the Trial...................................................... 39
Subject Inclusion Criteria.................................................................................... 39
Subject Exclusion Criteria .................................................................................. 41
Trial Treatment(s) ................................................................................................ 44
Dose Selection/Modification .............................................................................. 44
5.2.1.1
Dose Selection (Preparation) ....................................................................... 44
5.2.1.2
Dose 
Modification 
(Escalation/Titration/Other) 
and 
Toxicity 
Management................................................................................................. 45
Timing of Dose Administration.......................................................................... 50
Trial Blinding...................................................................................................... 51
Randomization or Treatment Allocation............................................................ 51
Stratification.......................................................................................................... 51
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 52
Acceptable Concomitant Medications ................................................................ 52
Prohibited Concomitant Medications and/or Treatments ................................... 52
Rescue Medications & Supportive Care............................................................. 53
Supportive Care Guidelines ................................................................................ 53
Diet/Activity/Other Considerations..................................................................... 54
Diet...................................................................................................................... 54
Contraception...................................................................................................... 54
Pregnancy............................................................................................................ 54
Use in Nursing Women....................................................................................... 54
Subject Withdrawal/Discontinuation Criteria................................................... 55
Discontinuation of Treatment ............................................................................. 55
Pembrolizumab End of Treatment Follow-up .................................................... 56
Withdrawal from the Trial .................................................................................. 57
Subject Replacement Strategy............................................................................. 57
 
 
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Beginning and End of the Trial ........................................................................... 57
Clinical Criteria for Early Trial Termination ................................................... 57
6.0
TRIAL FLOW CHART ........................................................................................... 58
Treatment and Follow-up Phase ......................................................................... 58
Second Course Treatment.................................................................................... 62
7.0
TRIAL PROCEDURES ........................................................................................... 64
Trial Procedures ................................................................................................... 64
Administrative Procedures.................................................................................. 64
7.1.1.1
Informed Consent......................................................................................... 64
7.1.1.1.1
General Informed Consent.................................................................... 64
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 65
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 65
7.1.1.3
Subject Identification Card .......................................................................... 65
7.1.1.4
Medical History ........................................................................................... 65
7.1.1.5
Prior and Concomitant Medications Review............................................... 65
7.1.1.5.1
Prior Medications.................................................................................. 65
7.1.1.5.2
Concomitant Medications..................................................................... 65
7.1.1.6
Nonsmall Cell Lung Cancer Disease Details and Treatments..................... 66
7.1.1.6.1
Disease Details...................................................................................... 66
7.1.1.6.2
Prior Treatment..................................................................................... 66
7.1.1.6.3
Subsequent Antineoplastic Therapy Status........................................... 66
7.1.1.7
Assignment of Screening Number............................................................... 66
7.1.1.8
Assignment of Treatment/Randomization Number..................................... 66
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)................................... 66
Clinical Procedures/Assessments........................................................................ 67
7.1.2.1
Adverse Event Monitoring........................................................................... 67
7.1.2.2
Physical Examination................................................................................... 67
7.1.2.2.1
Full Physical Examination.................................................................... 67
7.1.2.2.2
Directed Physical Examination............................................................. 67
7.1.2.3
Vital Signs.................................................................................................... 67
7.1.2.4
Lead Electrocardiogram............................................................................... 67
 
 
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7.1.2.5
Eastern Cooperative Oncology Group Performance Status Scale............... 68
7.1.2.6
Tumor Imaging and Assessments of Disease .............................................. 68
7.1.2.6.1
Initial Tumor Imaging........................................................................... 68
7.1.2.6.2
Tumor Imaging During the Study......................................................... 69
7.1.2.6.3
End of Treatment and Follow-up Tumor Imaging................................ 70
7.1.2.6.4
Second Course (Retreatment) Tumor Imaging..................................... 70
7.1.2.6.5
RECIST 1.1 Assessment of Disease..................................................... 71
7.1.2.6.6
iRECIST Assessment of Disease.......................................................... 71
7.1.2.7
Tumor Tissue Collection.............................................................................. 74
7.1.2.8
Patient-reported Outcomes........................................................................... 75
Laboratory Procedures/Assessments .................................................................. 75
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 75
7.1.3.2
Pregnancy Test............................................................................................. 76
7.1.3.3
Pharmacokinetic/Pharmacodynamic/Immunogenicity Evaluations ............ 76
7.1.3.4
Molecular Testing ........................................................................................ 76
7.1.3.5
Planned Genetic Analysis Sample Collection.............................................. 77
7.1.3.6
Future Biomedical Research Samples ......................................................... 77
7.1.3.7
Medical Resource Utilization and Health Economics ................................. 77
Other Procedures................................................................................................. 77
7.1.4.1
Withdrawal/Discontinuation........................................................................ 77
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 78
7.1.4.2
Subject Blinding/Unblinding ....................................................................... 78
7.1.4.3
Calibration of Equipment............................................................................. 79
Visit Requirements.............................................................................................. 79
7.1.5.1
Screening...................................................................................................... 79
7.1.5.2
Treatment Period Visit................................................................................. 80
7.1.5.3
End of Treatment Visits............................................................................... 80
7.1.5.3.1
Discontinuation Visit............................................................................ 80
7.1.5.3.2
Safety Follow-up Visit.......................................................................... 80
7.1.5.4
Follow-up Phase........................................................................................... 81
7.1.5.4.1
Follow-up Visits ................................................................................... 81
7.1.5.4.2
Survival Follow-up ............................................................................... 81
7.1.5.5
Survival Status ............................................................................................. 82
 
 
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7.1.5.6
Second Course Phase................................................................................... 82
7.1.5.7
Discontinued Subjects Continuing to be Monitored in the Trial................. 83
Assessing and Recording Adverse Events .......................................................... 83
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 84
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 85
Immediate Reporting of Adverse Events to the Sponsor.................................... 85
7.2.3.1
Serious Adverse Events ............................................................................... 85
7.2.3.2
Events of Clinical Interest............................................................................ 86
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 87
Evaluating Adverse Events................................................................................. 87
Sponsor Responsibility for Reporting Adverse Events ...................................... 90
Executive Oversight Committee......................................................................... 90
Data Monitoring Committee............................................................................... 90
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 90
Statistical Analysis Plan Summary ..................................................................... 91
Responsibility for Analyses/In-House Blinding ................................................. 92
Hypotheses/Estimation......................................................................................... 93
Analysis Endpoints ............................................................................................... 93
Efficacy Endpoints.............................................................................................. 93
Safety Endpoints ................................................................................................. 94
Analysis Populations............................................................................................. 94
Efficacy Analysis Populations ............................................................................ 94
Safety Analysis Populations ............................................................................... 94
Patient-reported Outcomes Analysis Populations............................................... 94
Statistical Methods................................................................................................ 95
Statistical Methods for Efficacy Analyses.......................................................... 95
8.6.1.1
Overall Survival........................................................................................... 95
8.6.1.2
Progression-free Survival............................................................................. 95
8.6.1.3
Objective Response Rate ............................................................................. 97
8.6.1.4
Duration of Response................................................................................... 97
8.6.1.5
Change from Baseline in Global Health Status/Quality of Life .................. 98
 
 
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8.6.1.6
Time to True Deterioration in Cough, Pain in Chest, and Shortness of 
Breath........................................................................................................... 98
8.6.1.7
Analysis Strategies for Key Efficacy Endpoints.......................................... 98
Statistical Methods for Safety Analyses ........................................................... 100
Summaries of Demographic and Baseline Characteristics ............................... 101
Interim Analyses ................................................................................................. 102
Interim Safety Analyses.................................................................................... 102
Interim Efficacy Analyses................................................................................. 102
Multiplicity .......................................................................................................... 102
Objective Response Rate .................................................................................. 103
Progression-free Survival.................................................................................. 103
Overall Survival................................................................................................ 104
Safety Analyses................................................................................................. 106
Sample Size and Power Calculations ................................................................ 106
Subgroup Analyses ............................................................................................. 107
Compliance (Medication Adherence)................................................................ 107
Extent of Exposure.............................................................................................. 107
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 107
Investigational Product ...................................................................................... 107
Packaging and Labeling Information ............................................................... 108
Clinical Supplies Disclosure............................................................................... 108
Storage and Handling Requirements................................................................ 108
Discard/Destruction/Returns and Reconciliation ............................................ 108
Standard Policies................................................................................................. 109
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 109
Confidentiality..................................................................................................... 109
Confidentiality of Data ..................................................................................... 109
Confidentiality of Subject Records................................................................... 109
Confidentiality of Investigator Information...................................................... 109
Confidentiality of IRB/IEC Information........................................................... 110
Compliance with Financial Disclosure Requirements..................................... 110
Compliance with Law, Audit and Debarment ................................................. 110
 
 
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Compliance with Trial Registration and Results Posting Requirements...... 112
Quality Management System............................................................................. 113
Data Management............................................................................................... 113
Publications ......................................................................................................... 113
11.0
LIST OF REFERENCES....................................................................................... 114
12.0
APPENDICES......................................................................................................... 119
Merck Code of Conduct for Clinical Trials...................................................... 119
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 121
Eastern Cooperative Oncology Group Performance Status........................... 125
Description of the iRECIST Process for Assessment of Disease 
Progression .......................................................................................................... 126
Contraceptive Guidance and Pregnancy Testing ............................................ 130
List of Abbreviations .......................................................................................... 133
13.0
SIGNATURES......................................................................................................... 136
Sponsor's Representative ................................................................................... 136
Investigator.......................................................................................................... 136
 
 
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LIST OF TABLES
Table 1
Objective Response Rate and Duration of Response for Patients Who 
Received Nivolumab 3 mg/kg Q2W and Ipilimumab 1 mg/kg by 
Investigator Review per RECIST 1.1.................................................................. 28
Table 2
Potential Immune-Mediated Adverse Events Among Patients Treated With 
Nivolumab 3 mg/kg Q2W Plus Ipilimumab 1 mg/kg ......................................... 29
Table 3
Objective Response Rate and Duration of Response for Subjects Who 
Received Pembrolizumab 2 mg/kg Q3W and Ipilimumab 1 mg/kg by 
Independent, Central Review per RECIST 1.1 ................................................... 32
Table 4
Adequate Organ Function Laboratory Values..................................................... 40
Table 5
Trial Treatment.................................................................................................... 44
Table 6
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with Pembrolizumab or Previously-Administrated 
Ipilimumab .......................................................................................................... 46
Table 7
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines............................................................................................................ 49
Table 8
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease................................................................................................................. 73
Table 9
Laboratory Tests.................................................................................................. 75
Table 10
Evaluating Adverse Events ................................................................................. 88
Table 11
Censoring Rules for Primary and Sensitivity Analyses of PFS .......................... 96
Table 12
Censoring Rules for Duration of Response......................................................... 97
Table 13
Analysis Strategy for Key Efficacy Endpoints.................................................... 99
Table 14
Analysis Strategy for Safety Parameters........................................................... 101
Table 15
Efficacy Boundaries and Properties for Progression-free Survival Analyses... 104
Table 16
Efficacy Boundaries and Properties for Overall Survival Analyses ................. 105
Table 17
Product Descriptions ......................................................................................... 108
Table 18
Highly Effective Contraception Methods.......................................................... 131
 
 
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LIST OF FIGURES
Figure 1
Trial Design Overview ........................................................................................ 20
Figure 2
Second Course Overview .................................................................................... 20
Figure 3
Imaging and Treatment for Clinically Stable Subjects After First Radiologic 
Evidence of PD Assessed by the Investigator..................................................... 74
Figure 4
Multiplicity Graph for Type I Error Control..................................................... 103
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
MK-3475-598-06
11-DEC-2020
Data from IA1 of KEYNOTE-598 (data cutoff: 01-SEP-2020) indicated that the 
study did not meet the prespecified success criteria for improvement in PFS or OS
for the combination of pembrolizumab plus ipilimumab compared with 
pembrolizumab plus placebo. Furthermore, a nonbinding futility analysis was 
performed at IA1 at the request of the eDMC. This analysis showed the study met 
the criteria for declaring futility and the benefit-risk assessment was not 
considered positive to continue the trial. Based upon these data and at the 
recommendation of the eDMC, MSD implemented this amendment to direct all 
ipilimumab and placebo administrations to stop, and to unblind the study. The 
study will remain open so ongoing subjects will have continued access to 
pembrolizumab.
MK-3475-598-05
14-JUL-2020
To update the assumptions and the timing of interim analyses (IA) in the 
Statistical Analysis Plan (SAP), and to include a Patient-reported Outcomes (PRO)
secondary objective, endpoint, and statistical method for analysis.
MK-3475-598-04
14-FEB-2020
The primary reasons for this amendment is to update assumptions in the SAP.
MK-3475-598-03
15-FEB-2018
The primary reasons for this amendment were to add a new exploratory objective 
(Objective 8) to evaluate the immunogenicity, exposure, antidrug antibodies 
(ADA), and pharmacokinetic (PK) samples; to add a new Exclusion Criterion #25 
“Has known ROS1 mutation:  if treatment and testing for ROS1 is approved and 
accessible.”; and to add required thyroid (TSH, FT3/T3, FT4/T4) and adrenal 
(ACTH) function monitoring before to each dose of ipilimumab/placebo. Other 
clarifications and minor revisions were also included.
 
 
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Document
Date of Issue
Overall Rationale
MK-3475-598-02
4-DEC-2017
The primary reason for this amendment was to update the background information 
and rational for the dose and regiment of ipilimumab based on input from 
regulatory agencies. Additional revisions and clarifications were made to align 
with the pembrolizumab program template and updated risk language.
MK-3475-598-01
10-OCT-2017
The primary reasons for this amendment was to implement revisions 
recommended by regulatory agencies, including updates to the rationales for the 
selected population, dose regimen for ipilimumab, and the use of a comparator. 
Agency requests also included adding the specific IHC assay to Inclusion 
Criterion #8, clarifying Exclusion #24, updating test describing urine pregnancy 
testing, adding pembrolizumab dose medication guidance for myocarditis, adding 
a 550 mL cap to the amount of blood drawn over an 8-week period, and clarified 
that PD-L1 testing would be performed by a central laboratory. Additional updates 
and clarifications included the removal of the PFS2 exploratory endpoint and 
associated monitoring, and changes to align with the pembrolizumab program 
template.
MK-3475-598-00
28-JUL-2017
Original protocol.
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Amendment: 06
Overall Rationale for the Amendment: Data from IA1 of KEYNOTE-598 (data cutoff: 01-SEP-2020) indicated that the study did 
not meet the prespecified success criteria for improvement in PFS or OS for the combination of pembrolizumab plus ipilimumab
compared with pembrolizumab plus placebo. Furthermore, a nonbinding futility analysis was performed at IA1 at the request of the 
eDMC. This analysis showed the study met the criteria for declaring futility and the benefit-risk assessment was not considered 
positive to continue the trial. Based upon these data and at the recommendation of the eDMC, MSD implemented this amendment to 
direct all ipilimumab and placebo administrations to stop and to unblind the study. The study will remain open so ongoing subjects
will have continued access to pembrolizumab.
Section Numbers
Section Titles
Description of Changes
Rationale
1
Trial Summary
Revised text, tables, and figures to 
remove ipilimumab and placebo 
references, as well as
assessments/procedures specific to 
these treatments. Added clarifying 
notes to subsections.
In accordance with the overall 
rationale for the Amendment, 
ipilimumab and matching placebo 
have been removed from the study.
2
Trial Design
5.2
Trial Treatments
5.8
Subject Withdrawal/Discontinuation 
Criteria
7.1.3.1
Laboratory Safety Evaluations
9
Labeling, Packaging, Storage and 
Return of Clinical Supplies
 
 
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Section Numbers
Section Titles
Description of Changes
Rationale
4.2.2.1.2
Rationale for Dose and Regimen of 
Ipilimumab/Placebo in Combination 
With Pembrolizumab
Added note to clarify that no 
further subjects will be 
randomized in the study and these
sections are no longer applicable.
Ipilimumab and matching placebo 
have been removed from the study.
5.3
Randomization or Treatment 
Allocation
4.2.3.2
Patient-reported Outcomes
Added note to clarify that PROs 
will no longer be collected.
In accordance with the overall 
rationale for the amendment, 
PROs, pharmacokinetic, 
pharmacodynamic, and 
immunogenicity are no longer 
required.
7.1.2.8
Patient-reported Outcomes
Deleted section content and added 
a note to clarify.
7.1.3.3
Pharmacokinetic/
Pharmacodynamic/
Immunogenicity Evaluations
4.3
Benefit/Risk
Added note to clarify that the 
benefit-risk assessment of 
ipilimumab is no longer applicable 
and related text has been removed.
In accordance with the overall 
rationale for the amendment, the 
benefit/risk assessment of 
ipilimumab is no longer 
applicable.
5.2.3
Trial Blinding
Added note to clarify that blinding
and emergency unblinding are no 
longer applicable. All subjects will 
receive open-label pembrolizumab
monotherapy.
Ipilimumab and matching placebo 
have been removed from the study
and the study has been unblinded.
7.1.4.2
Subject Blinding/Unblinding
 
 
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Section Numbers
Section Titles
Description of Changes
Rationale
5.10
Beginning and End of the Trial
Added language to state that upon 
study completion, subjects are 
discontinued and may be enrolled 
in a pembrolizumab extension 
study, if available.
Subjects may be enrolled in a 
pembrolizumab extension study 
upon study completion.
6
Trial Flow Chart
Revised tables to remove
assessments/procedures specific to 
ipilimumab and placebo 
treatments. Added a clarifying 
note.
In accordance with the overall 
rationale for the amendment, all 
references to ipilimumab and 
placebo, as well as
assessments/procedures specific to 
these treatments, are removed from 
the protocol.
7.1.5.6
Second Course Phase
Revised text to remove
ipilimumab and placebo 
references, as well as
assessments/procedures specific to 
these treatments. Added a
clarifying note.
Ipilimumab and matching placebo 
have been removed from the study.
7.2.1
Definition of an Overdose for This 
Protocol and Reporting of Overdose 
to the Sponsor
8
Statistical Analysis Plan
Added notes to clarify that a 
nonbinding futility analysis 
planned for IA2 was performed at 
IA1 at the request of the eDMC, 
the study has been unblinded, and
no further prespecified analysis of 
primary and secondary endpoints 
will be performed.
In accordance with the overall 
rationale for the amendment.
 
 
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Section Numbers
Section Titles
Description of Changes
Rationale
7.2.7
Data Monitoring Committee
Added a statement that no 
additional eDMC reviews will 
take place.
In accordance with the overall 
rationale for the amendment.
8.7.1
Interim Safety Analyses
8.8.4
Safety Analyses
5.1.2
Subject Inclusion Criteria
Added note to clarify that
contraception is no longer required 
for male participants and sperm 
donation is acceptable.
Since ipilimumab have been 
removed from the study, male 
contraception is no longer 
required.
12.5
Contraceptive Guidance and 
Pregnancy Testing
Throughout
Throughout
All references to ipilimumab and 
placebo were removed. Where 
deletion of text could cause 
confusion due to the original 
design of the study, the text has 
been left unchanged and a note
was added.
In accordance with the overall 
rationale for the amendment.
Made typographical corrections 
and minor administrative edits.
To correct typographical errors and 
clarify intended meaning.
No additional changes.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase 3 1L Study of Pembrolizumab ± Ipilimumab in NSCLC
Sponsor 
Product 
Identifiers
MK-3475
Pembrolizumab
Trial Phase
3
Clinical Indication
First-line treatment of Stage IV metastatic programmed cell death-ligand 1 (PD-L1)
positive (TPS ≥50%) NSCLC
Trial Type
Interventional
Type of control
Active control with placebo
NOTE: As of Amendment 06, active control with placebo has been removed.
Route 
of 
administration
Intravenous (IV)
Trial Blinding
Double-blind
NOTE: As of Amendment 06, the study is unblinded.
Treatment Groups
Pembrolizumab (MK-3475) 200 mg IV every 3 weeks (Q3W) + ipilimumab 1
mg/kg IV every 6 weeks (Q6W)
OR
Pembrolizumab (MK-3475) Q3W 200 mg IV + Placebo IV Q6W
NOTE: As of Amendment 06, ipilimumab and matching placebo have been
removed from the treatment groups. Subjects remaining on treatment will 
receive open-label pembrolizumab monotherapy as per protocol.
Number of trial 
subjects
Approximately 568 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
NOTE: As of Amendment 06, this section has been updated.
Each subject will participate in the trial for approximately 3 years from the time the 
subject signs the informed consent form through the final contact.
After a screening phase of 30 days, each subject will be assigned to receive trial 
treatment until disease progression is radiographically documented and verified by 
blinded independent central review (BICR), when clinically appropriate, confirmed 
by the site per modified Response Evaluation Criteria in Solid Tumors 1.1 for 
immune-based therapeutics (iRECIST), unacceptable AEs, intercurrent illness that 
prevents further administration of treatment, investigator’s decision to discontinue
the subject, noncompliance with trial treatment or procedures requirements,
administrative reasons requiring cessation of treatment, withdrawal of consent, or 
until the subject has received 35 administrations of pembrolizumab (approximately 
2 years). Subjects who stop trial treatment after receiving 35 administrations of 
pembrolizumab for reasons other than disease progression or intolerability, or 
subjects who attain a complete response and stop trial treatment may be eligible for 
up to 17 additional administrations of pembrolizumab (approximately 1 year) upon 
experiencing disease progression, (Section 7.1.5.6 – Second Course Phase).
 
 
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After the end of treatment, each subject will be followed for the occurrence of AEs
and spontaneously reported pregnancy as described under Section 7.2 – Assessing 
and Recording Adverse Events of the protocol.
At the end of treatment, each subject will be followed for a minimum of 30 days for 
AE monitoring. Serious AEs occurring within 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, will be collected, whichever is earlier. Subjects will have post-
treatment follow-up for disease status, including initiating a nonstudy cancer 
treatment and experiencing disease progression, until death, withdrawing consent, 
or becoming lost to follow-up.
Subjects who discontinue for reasons other than disease progression will have post-
treatment follow-up for disease status until disease progression radiographically per 
RECIST 1.1, verified by BICR, initiating a nonstudy cancer treatment, withdrawing 
consent, or becoming lost to follow-up. All subjects will be followed by telephone 
for OS until death, withdrawal of consent, or the end of the study.
Randomization Ratio
1:1
A list of abbreviations used in this document can be found in Section 12.6 – List of 
Abbreviations.
2.0 TRIAL DESIGN
Trial Design
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed 
from the study. Subjects who remain on treatment will receive open-label 
pembrolizumab monotherapy as per protocol. This section has been amended and 
assessments no longer required have been deleted.
The original study design was a Phase 3, randomized, double-blind study to evaluate the 
efficacy of pembrolizumab plus ipilimumab vs pembrolizumab plus placebo for first-line 
(1L) treatment of subjects with Stage IV, metastatic NSCLC whose tumors are programmed 
death-ligand 1 (PD-L1) positive (Tumor Proportion Score [TPS] ≥50%) and lack epidermal 
growth factor receptor (EGFR)-sensitizing mutations and anaplastic lymphoma kinase (ALK) 
translocations.
Approximately 568 subjects with previously untreated, Stage IV metastatic NSCLC whose 
tumors are PD-L1 positive (TPS ≥50%) and in whom EGFR- or ALK-directed therapy is not 
indicated were projected to be enrolled in this trial for examination of the efficacy and safety 
of pembrolizumab plus ipilimumab versus pembrolizumab plus placebo. Subjects were
randomized in a 1:1 ratio to receive pembrolizumab plus ipilimumab or pembrolizumab plus 
placebo.
The subjects were stratified prior to randomization by ECOG Performance Status (0 versus
1), geographic region of the enrolling site (East Asia versus non-East Asia), and predominant 
tumor histology (squamous versus nonsquamous) (see Section 5.4 – Stratification for more 
details).
 
 
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As of Amendment 06, ipilimumab and matching placebo have been removed from the study. 
All subjects remaining on treatment in the study will receive open-label pembrolizumab 
monotherapy.
Subjects will be evaluated with radiographic imaging to assess response to treatment every 
9 weeks (63 ± 7 days) from randomization through 54 weeks, then every 12 weeks (84 days 
±7 days) subsequently. All imaging obtained on study will be submitted to the imaging 
vendor for BICR, which will assess the images using RECIST 1.1 (see Section 7.1.2.6.5) for 
determination of ORR, PFS, and DOR. Initial tumor imaging showing site-assessed 
progressive disease (PD) should be submitted immediately for verification by BICR prior to 
treatment discontinuation.  Treatment-based decisions may utilize modified RECIST 1.1 for 
immune-based therapeutics (iRECIST), as described in the Merck Imaging Tip Sheet and in 
Section 7.1.2.6.6. AE monitoring will be ongoing throughout the trial and graded in severity 
according to the guidelines outlined in the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Treatment with 
pembrolizumab will continue until 35 trial treatments of pembrolizumab have been 
administered, documented disease progression, unacceptable AEs, intercurrent illness that 
prevents further administration of treatment, investigator’s decision to withdraw the subject, 
intolerable toxicity, subject withdraws consent, pregnancy of the subject, noncompliance 
with trial treatment or procedure requirements, or administrative reasons.
Subjects treated with pembrolizumab who attain a confirmed complete response (CR), or 
who complete 35 administrations of pembrolizumab without demonstrating disease 
progression or intolerability to treatment,
may be eligible for retreatment with 
pembrolizumab only after they have experienced radiographic disease progression according 
to defined criteria in Section 7.1.5.6; this retreatment will be the Second Course Phase.
Response or progression in the Second Course Phase will not count towards the ORR and 
PFS endpoints in this trial.
Subjects will have post-treatment follow-up for disease status, including initiating a nonstudy 
cancer treatment and experiencing disease progression, until death, withdrawing consent, or 
becoming lost to follow-up.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Trial Diagram
The original study design randomized subjects into 2 treatment arms: pembrolizumab plus 
ipilimumab and pembrolizumab plus matching placebo (Figure 1). The design of the Second 
Course of treatment is depicted in Figure 2. As of Amendment 06, ipilimumab and 
matching placebo have been removed from the study, as depicted in Figure 1and 
Figure 2.
 
 
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Figure 1
Trial Design Overview
Note: As of Amendment 06, ipilimumab and matching placebo were removed from the study, as indicated by 
strikethrough.
Abbreviations: 
ALK=anaplastic 
lymphoma 
kinase; 
ECOG=Eastern 
Cooperative 
Oncology 
Group; 
EGFR=epidermal growth factor receptor; NSCLC=nonsmall cell lung cancer; PD-L1=Programmed death-
ligand 1; PS=Performance scale; Q3W=every 3 weeks; Q6W=every 6 weeks.
Figure 2
Second Course Overview
Note: As of Amendment 06, ipilimumab and matching placebo were removed from the study, as indicated by 
strikethrough.
Abbreviations: DC=discontinuation; IV=intravenous; Q3W=every 3 weeks; Q6W=every 6 weeks.
a At the discretion of the principal investigator. Original treatment arm will remain blinded.
b Discontinuation criteria are listed in Section 5.8.
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
In previously untreated subjects with Stage IV, metastatic PD-L1 positive (TPS ≥50%) 
NSCLC:
Primary Objective(s) & Hypothesis(es)
1. Objective: To compare the OS in subjects treated with pembrolizumab plus ipilimumab
versus pembrolizumab plus placebo
Hypothesis: Pembrolizumab plus ipilimumab demonstrates superior OS compared to 
pembrolizumab plus placebo
2. Objective: To compare the PFS per RECIST 1.1 based on BICR in subjects treated with 
pembrolizumab plus ipilimumab versus pembrolizumab plus placebo
Hypothesis: Pembrolizumab plus ipilimumab demonstrates superior PFS per RECIST 1.1 
(based on BICR) compared to pembrolizumab plus placebo
The study is considered to have met its primary objective if pembrolizumab plus ipilimumab
is superior to pembrolizumab plus placebo in PFS or OS at an IA or FA.
Secondary Objective(s) & Hypothesis(es)
1. Objective: To compare the confirmed ORR per RECIST 1.1 based on BICR in subjects 
treated with pembrolizumab plus ipilimumab versus pembrolizumab plus placebo
Hypothesis: Pembrolizumab plus ipilimumab demonstrates superior confirmed ORR per 
RECIST 1.1 (based on BICR) compared to pembrolizumab plus placebo
2. Objective: To evaluate the DOR per RECIST 1.1 (based on BICR) in subjects treated 
with pembrolizumab plus ipilimumab and pembrolizumab plus placebo.
3. Objective: To evaluate the mean change from baseline in EORTC QLQ-C30 global 
health status/quality of life score (items 29 and 30) in subjects treated with 
pembrolizumab plus ipilimumab compared to pembrolizumab plus placebo.
4. Objective: To evaluate TTD in the composite endpoint of cough (European Organization 
for Research and Treatment of Cancer Quality of Life Questionnaire and Lung Cancer 
Module 13 [EORTC QLQ-LC13] Q1), pain in chest (EORTC QLQ LC13 Q10), and 
shortness of breath (EORTC QLQ-C30 Q8) in subjects treated with pembrolizumab plus 
ipilimumab and pembrolizumab plus placebo.
5. Objective: To evaluate the safety and tolerability profile of pembrolizumab plus 
ipilimumab in subjects treated with pembrolizumab plus ipilimumab.
 
 
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Exploratory Objectives
1. Objective: To evaluate patient-reported outcomes using the EORTC QLQ-C30, EORTC 
QLQ-LC13, and the EQ-VAS in subjects treated with pembrolizumab plus ipilimumab 
compared to pembrolizumab plus placebo.
2. Objective: To evaluate clinically meaningful thresholds for change in cough, pain in 
chest, and shortness of breath from the EORTC QLQ-LC13/QLQ-QC30 questionnaires
using Patient Global Impression of Change – Lung Symptoms Questionnaire (PGIC-L).
3. Objective: To evaluate clinically meaningful thresholds for change in lung cancer 
symptoms from the NSCLC-SAQ Questionnaire using the Patient Global Impression of 
Severity – Lung Cancer Symptoms (PGIS-LC) Questionnaire and the Patient Global 
Impression of Change – Lung Cancer Symptoms (PGIC-LC) questionnaires.
4. Objective: To characterize utilities using the EQ-5D-5L.
5. Objective: To conduct psychometric analyses on the NSCLC Symptom Assessment 
Questionnaire (SAQ).
6. Objective: To evaluate PFS and ORR using modified RECIST 1.1 for immune-based 
therapeutics (iRECIST) [1], as assessed by the investigator in subjects treated with 
pembrolizumab plus ipilimumab compared to pembrolizumab plus placebo.
7. Objective: To identify molecular (genomic, metabolic, and/or proteomic) biomarkers 
that may be indicative of clinical response/resistance, safety, pharmacodynamic activity, 
and/or the mechanism of action of pembrolizumab and other treatments.
8. Objective: To evaluate the immunogenicity and exposure of pembrolizumab and 
ipilimumab and the drug-drug effects of pembrolizumab and ipilimumab used in 
combination by analysis of ADA and pharmacokinetic (PK) samples.
4.0 BACKGROUND & RATIONALE
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with PD-L1 and programmed cell death ligand 2 (PD-L2).  Based on 
preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking 
activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an IV immunotherapy for advanced malignancies.  Keytruda®
(pembrolizumab) is indicated for the treatment of patients across a number of indications.  
For more details on specific indications, refer to the IB.
Refer to the IB/approved labeling for detailed background information on MK-3475.
 
 
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Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [2]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies [2]. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in solid malignancies such as ovarian, colorectal, and pancreatic cancer;
hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma (RCC). Tumor-
infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable objective 
tumor responses in cancers such as melanoma [3] [4].
The programmed cell death protein-1 (PD-1) receptor-ligand interaction is a major pathway 
hijacked by tumors to suppress immune control. The normal function of PD-1, expressed on 
the cell surface of activated T-cells under healthy conditions, is to down-modulate unwanted 
or excessive immune responses, including autoimmune reactions. Programmed cell death 
protein-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and 
CTLA-4 that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or programmed death-ligand 2 [PD-L2]) [5] [6]. 
The mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct 
from that of CTLA-4, as both molecules regulate an overlapping set of signaling proteins [7] 
[8]. Programmed cell death protein-1 was shown to be expressed on activated lymphocytes 
including peripheral CD4+ and CD8+ T-cells, B-cells, T regs, and natural killer cells [9] 
[10]. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be 
induced in a variety of cell types, including non-hematopoietic tissues as well as in various 
tumors [8] [11] [12] [13]. Both ligands are type I transmembrane receptors containing both 
IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions 
with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell 
activation triggered through the T-cell receptor. Programmed death-ligand 1 is expressed at 
low levels on various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments. Programmed death-ligand 2 is 
thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to 
dampen unwarranted T-cell function in peripheral tissues [11]. Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant 
levels of this T-cell inhibitor. High expression of PD-L1 on tumor cells (and to a lesser extent 
of PD-L2) has been found to correlate with poor prognosis and survival in various cancer 
types, including RCC [14], pancreatic carcinoma [15], hepatocellular carcinoma [16], and 
ovarian carcinoma [4]. Furthermore, PD-1 has been suggested to regulate tumor-specific T-
cell expansion in subjects with melanoma [3].
Antimouse PD-1 or antimouse PD-L1 antibodies have demonstrated antitumor responses as a 
monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, and 
colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted CD8+ T-cell 
infiltration into the tumor and the presence of interferon-gamma, granzyme B and perforin, 
indicating that the mechanism of action involved local infiltration and activation of effector 
T-cell function in vivo [15] [17] [18] [19] [20] [21].
 
 
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In-house experiments have confirmed the in vivo efficacy of PD-1 blockade as a 
monotherapy as well as in combination with chemotherapy in syngeneic mouse tumor 
models (see the IB).
Summary of Pembrolizumab Clinical Activities
4.1.2.1
Completed Clinical Trials
Four clinical studies have been conducted to evaluate the efficacy of pembrolizumab
monotherapy in the treatment of NSCLC:  KEYNOTE-001, KEYNOTE-010, KEYNOTE-
024, and KEYNOTE-042.
KEYNOTE-001:
An open-label Phase 1 trial (KEYNOTE-001) was conducted to evaluate the safety and 
clinical activity of single-agent pembrolizumab. The dose escalation portion of this trial 
evaluated 3 dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W), in subjects with advanced solid tumors. All 3 dose levels were well tolerated and no 
dose-limiting toxicities were observed. Based on PK data showing a half-life of 21 days, the 
protocol was amended to change the dosing frequency in the expansion cohort to every 3 
weeks (Q3W). All cohorts have completed enrollment.
In KEYNOTE-001, a total of 550 NSCLC subjects were treated in several dose expansion 
cohorts with at least 1 dose of pembrolizumab. The initial data from 495 NSCLC subjects 
were published and reported. The ORR was 19.4% (18.0% in the 394 previously treated 
subjects and 24.8% in the 101 previously untreated subjects). The response rate (RR) was 
similar regardless of dose, schedule, and histologic analysis. Current or former smokers had a 
RR of 22.5%, as compared with 10.3% among subjects who had never smoked cigarettes.
Subjects were required to submit a newly obtained tumor biopsy prior to initiating therapy 
with pembrolizumab to evaluate the tumors for expression of PD-L1. After evaluation of 
several methods for pathological assessment, in a training set, membranous PD-L1 
expression in at least 50% of tumor cells (TPS ≥50%) was selected as the cutoff point 
defining PD-L1 high. In a validation set of 313 subjects, the RR was 45.2% in the 73 subjects 
with a TPS ≥50%, including 43.9% in previously treated subjects and 50% in previously 
untreated subjects, values that numerically exceeded the RR in the training group [22].
Pembrolizumab has been generally well tolerated. The most common treatment-related AEs
were fatigue (19.4%), pruritus (10.7%), and decreased appetite (10.5%). AEs of Grade 3 or 
higher were reported in 47 of 495 patients (9.5%). The only treatment-related AEs of an 
inflammatory or immune-mediated nature that occurred in more than 2% of patients were 
infusion-related reactions (in 15 patients [3.0%]), hypothyroidism (in 34 patients [6.9%]), 
and pneumonitis (in 18 patients [3.6%]). One infusion reaction led to treatment 
discontinuation. All the patients with hypothyroidism were successfully treated with medical 
therapy [22].
 
 
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KEYNOTE-010:
KEYNOTE-010 was a randomized, adaptively designed Phase 2/3 trial of pembrolizumab at 
2 dose levels versus docetaxel in subjects with NSCLC with PD-L1 positive tumors who had 
experienced disease progression after platinum-containing systemic therapy.  Subjects were 
randomized according to their TPS (extent of PD-L1 expression) defined as follows:  a TPS 
≥50% was considered strongly positive and a TPS = 1% to 49% was considered weakly 
positive. Approximately 920 subjects were planned to be enrolled in this trial to examine the 
efficacy compared of pembrolizumab to docetaxel in an enriched population.
Overall, the results from KEYNOTE-001 and KEYNOTE-010 demonstrated that 
pembrolizumab provided substantial, clinically meaningful benefits in OS, PFS, and ORR in 
subjects with NSCLC who progressed after platinum-containing chemotherapy and whose 
tumor cells expressed PD-L1. The PD-L1 selection employed in KEYNOTE-010 identified 
patients more likely to benefit from pembrolizumab and resulted in favorable hazard ratios 
(HR) in OS compared to docetaxel.
In previously treated subjects with NSCLC with PD-L1, TPS ≥1%, and disease progression 
following platinum-containing chemotherapy, pembrolizumab provides a statistically 
significant and clinically meaningful OS benefit compared to standard docetaxel 
chemotherapy.
In KEYNOTE-010, pembrolizumab was superior to docetaxel in the strongly positive TPS
≥50% stratum with regard to OS, with an HR of 0.54 (p = 0.00024) and 0.50 (p = 0.00002) 
for pembrolizumab 2 mg/kg Q3W versus docetaxel and 10 mg/kg Q3W versus docetaxel, 
respectively [23]. Pembrolizumab was superior to docetaxel in the overall positive TPS ≥1% 
population with regard to OS, with an HR of 0.71 (p = 0.00076) and 0.61 (p<0.00001) for 
pembrolizumab 2 mg/kg Q3W and 10 mg/kg Q3W, respectively. Pembrolizumab was 
superior to docetaxel in the strongly positive TPS ≥50% stratum with regard to PFS by 
independent review committee based on RECIST 1.1, with an HR of 0.58 (p = 0.00009) and 
0.59 (p = 0.00007) for pembrolizumab 2 mg/kg Q3W and 10 mg/kg Q3W, respectively, 
compared to docetaxel. Pembrolizumab provided numerically superior benefit in PFS by 
independent review committee based on RECIST 1.1 compared to docetaxel in the overall 
positive TPS ≥1% population, with an HR of 0.88 and 0.79 for pembrolizumab 2 mg/kg 
Q3W and 10 mg/kg Q3W, respectively; however, the differences were not statistically 
significant at the 0.001 level required per protocol.
KEYNOTE-024:
KEYNOTE-024 was a multicenter, international, randomized, open-label, controlled trial of 
intravenous (IV) pembrolizumab monotherapy versus the choice of multiple standard of care 
(SOC) platinum-based chemotherapies in subjects previously untreated for their Stage IV
NSCLC and whose tumors expressed PD-L1 at ≥50%.  First-line treatment with 
pembrolizumab significantly prolonged PFS (HR 0.50; 95% confidence interval [CI]: 0.37, 
0.68; p<0.001) and OS (HR 0.60; 95% CI:  0.41, 0.89; p = 0.005) compared with SOC 
chemotherapy, inclusive of pemetrexed maintenance for subjects with nonsquamous tumors
[24]. In addition, pembrolizumab was associated with a higher ORR, including a higher CR 
rate, as well as a longer DOR as compared to SOC. Pembrolizumab was better tolerated than 
chemotherapy and AEs were easily managed. The observed safety profile of the 
 
 
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pembrolizumab arm was consistent with the safety profile for pembrolizumab established to 
date.  Based on the mechanism of action of pembrolizumab, immune-mediated AEs, 
including pneumonitis occurred at a greater frequency with pembrolizumab compared to 
chemotherapy.  Most immune-mediated events were of Grade 1 or 2 severity, and none led to 
death. These data underscore the substantial benefit of pembrolizumab as initial therapy for
subjects with previously untreated, advanced NSCLC whose tumors express high levels of 
PD-L1 (TPS ≥50%).
KEYNOTE-042:
KEYNOTE-042, a randomized, open-label, Phase 3 study, compared pembrolizumab 
monotherapy to SOC platinum-based chemotherapy in previously untreated participants with 
advanced or metastatic NSCLC whose tumors express PD-L1 TPS ≥1%. This study
confirmed the OS treatment effect of pembrolizumab monotherapy observed in participants 
with TPS ≥50% NSCLC in KEYNOTE-024, and extended these benefits to a broader 
population with TPS ≥1% NSCLC. Results from the FA of KEYNOTE-042 indicated a 
significant OS benefit for pembrolizumab over platinum-doublet therapy, with a HR of 0.82 
(95% CI, 0.71-0.93) for PD-L1 TPS ≥1%, and HR of 0.70 (95% CI, 0.58-0.86) for PD-L1 
TPS ≥50%. Median OS was 16.4 months (95% CI, 14.0-19.7 months) with pembrolizumab 
and 12.1 months (95% CI, 11.3-13.3 months) with platinum-doublet in PD-L1 TPS ≥1%. In 
the population with PD-L1 TPS ≥50%, median OS was 20.0 months (95% CI, 15.9-24.2 
months) with pembrolizumab and 12.2 months (95% CI, 10.4-14.6 months) with platinum-
doublet. There was no observed PFS benefit with pembrolizumab versus chemotherapy, with 
PFS HR of 0.83 (95% CI, 0.69-1.00), and median PFS of 6.5 months (95% CI, 5.9-8.5 
months) with pembrolizumab and 6.4 months (95% CI, 6.2-7.2 months) with platinum-
doublet in PD-L1 TPS ≥50% [25]. The ORR was 39.1% vs 32% pembrolizumab vs 
chemotherapy in PD-L1 TPS ≥50% population [26]. 
4.1.2.2
Ongoing Clinical Trials with Pembrolizumab
Several additional studies to evaluate the efficacy of pembrolizumab combination therapy in 
the treatment of NSCLC are in progress.  Refer to the current pembrolizumab IB for a 
description of ongoing studies.
Rationale
Rationale for the Trial and Selected Subject Population
The global incidence for lung cancer was 1.8 million in 2012, resulting in an estimated 
1.6 million deaths [27]. NSCLC accounts for approximately 85% of all lung cancer cases. 
Progress has been made in the clinical management of early stage NSCLC by establishing 
comprehensive, multimodality treatment regimens; however, the prognosis for advanced 
disease has not improved substantially. With an overall 5-year survival rate of 9% to 13%, 
the treatment of NSCLC remains a highly unmet medical need. Cytotoxic chemotherapy as 
single agents or in combination has served as the mainstay of treatment for decades with 
platinum-containing doublets and maintenance strategies conferring the greatest advances in 
OS gains.
 
 
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KEYNOTE-024 established pembrolizumab as first-line therapy for patients with metastatic 
NSCLC whose tumors express high PD-L1 (TPS ≥50%) and with no EGFR or ALK genomic 
tumor aberrations. While the benefit observed in the trial was substantial with significant 
improvement in PFS and OS, the benefits may be improved in this patient population.
In CheckMate 026, a total of 541 patients were randomized to treatment. In patients with ≥ 
5% PD-L1 expression (n = 423), nivolumab did not improve PFS over platinum-doublet 
chemotherapy (HR, 1.15; 95% confidence interval [CI] 0.91 to 1.45; p = 0.25) [28]. Median 
PFS was 4.2 months and 5.9 months with nivolumab and investigator's choice (IC) of 
platinum-based doublet chemotherapy, respectively. Among all treated patients, any CTCAE 
Grade AEs and Grade 3 or 4 treatment-related AEs were 71% and 18% with nivolumab, as 
compared to 92% and 51% with IC platinum-based doublet chemotherapy, respectively. 
Nivolumab did not show superior PFS when compared to IC platinum-based doublet 
chemotherapy as first-line therapy in Stage IV/recurrent NSCLC patients with ≥5% PD-L1 
tumor expression. The safety profile of nivolumab was favorable to IC platinum-based 
doublet chemotherapy and consistent with that reported in previous studies.
While monotherapy pembrolizumab provides efficacy in patients with metastatic NSCLC 
whose tumors express high PD-L1 (TPS ≥50%), there is still medical need to further improve 
on the efficacy observed with PD-1 monotherapy in a biomarker selected population, reduce 
the time to response, and improve symptom control. Therefore, the combination of another 
therapy with pembrolizumab should be explored. The blocking of PD-1 receptors and 
CTLA4 receptors results in T-lymphocytes being fully disinhibited. Preclinical studies have 
demonstrated synergy between nivolumab and ipilimumab.  A clinical trial in patients with 
advanced NSCLC has shown antitumor activity when combining these 2 checkpoint 
inhibitors in CheckMate 012. Patients who had not received prior chemotherapy or 
immunotherapy with recurrent Stage IIIB or IV NSCLC were randomly assigned to 
nivolumab 1 mg/kg every 2 weeks (Q2W) plus ipilimumab 1 mg/kg every 6 weeks (Q6W), 
nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg every 12 weeks (Q12W), or nivolumab 3 
mg/kg Q2W plus ipilimumab 1 mg/kg Q6W.  Seventy-eight patients were randomized into 
the last 2 arms and the data from these patients are summarized here.  One patient assigned to 
ipilimumab Q6W did not begin treatment because of rapid clinical deterioration.  The median 
follow-up times were 12.8 months (IQR 9.3, 15.5) and 11.8 months (IQR 6.7, 15.9) for the 
ipilimumab Q12W and Q6W arms, respectively.  Table 1 shows the ORRs by investigator 
per RECIST 1.1 for the 2 nivolumab and ipilimumab cohorts.  Of the 6 patients with 50% or 
more tumor cells staining for PD-L1 in their baseline tumor sample who were treated with 
ipilimumab 1 mg/kg Q12W, all (100%) had an objective response. Of the 7 patients with 
50% or more tumor cells staining for PD-L1 in their baseline tumor sample who were treated 
with ipilimumab 1 mg/kg Q6W, 6 (83%) patients had an objective response [29]. 
As presented at American Society of Clinical Oncologists (ASCO) 2017, with longer follow 
up of 2 years, and using pooled data from arms of ipilimumab Q12W and Q6W in 
combination with nivolumab (77 total number of patients, 47 patients with PD-L1 ≥1%, 
13 patients with PD-L1 ≥50%), ORR was 43% (compared to 23% in nivolumab 
monotherapy) in all treated patients, and 57% and 92% in patients with ≥1% and ≥50% 
tumor PD-L1 expression, respectively. Both OS and PFS showed clinical benefits in all 
patients, those with ≥1%, and in those with ≥50% tumor PDL1 expression. The OS rates at 2 
 
 
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years were 49%, 58%, and 62%, respectively, in each group. The PFS rates at 2 years were 
29%, 38%, and 54% in each group, respectively. With the limitation of a very small number 
of patients whose tumors express PD-L1 ≥50% (13 patients); these data suggest that the PD-
L1 status of the tumor may predict those patients most likely to benefit from the combination
treatment [30].
Table 1
Objective Response Rate and Duration of Response for Patients Who Received 
Nivolumab 3 mg/kg Q2W and Ipilimumab 1 mg/kg by Investigator Review per RECIST 1.1
Nivolumab Plus Ipilimumab 
Q12W
Nivolumab Plus Ipilimumab 
Q6W
All Patients (N=38)
All Patients (N=39)
ORR, n (%) [95% CI]
18 (47) [31, 64]
15 (38) [23, 55]
DCR, n (%) [95% CI]
30 (79) [63, 90]
22 (56) [40, 72]
Best overall response, n (%)
CR
0 (0)
0 (0)
PR
18 (47)
15 (38)
SD
12 (32)
7 (18)
PD
5 (13)
11 (28)
Unable to Determine
3 (8)
6 (15)
DOR
median (range), months
NR (11.3, NR)
NR (8.4, NR)
Abbreviations: CR=complete response; DCR=disease control rate; NR=not reached; ORR=objective response 
rate; PD=progressive disease; PR=partial response; Q2W=every 2 weeks, RECIST=Response Evaluation 
Criteria in Solid Tumors; SD=stable disease.
The combination regimen was tolerable in this patient population.  Treatment-related AEs 
were reported as Grade 1-2 in 17 (45%), Grade 3 in 13 (34%), and Grade 4 in 1 (3%) of the 
38 patients who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q12W and as Grade 
1 to 2 in 15 (38%), Grade 3 in 11 (28%), and Grade 4 in 2 (5%) of the patients who received 
nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W.  The most frequent treatment-
related Grade 3 to 4 AEs were increased lipase 3 (8%) on the nivolumab 3 mg/kg Q2W plus 
ipilimumab 1 mg/kg Q12W arm and adrenal insufficiency 2 (5%) and colitis 2 (5%) on the 
nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W arm.  Nine patients (24%) 
discontinued treatment because of AEs in the nivolumab 3 mg/kg Q2W plus ipilimumab 
Q12W arm and 7 patients (18%) discontinued treatment because of AEs in the nivolumab 3 
mg/kg Q2W plus ipilimumab Q6W arm.  There were no treatment-related deaths.  Table 2
summarizes select potentially immune-mediated AEs, which were consistent with 
monotherapy nivolumab or ipilimumab. The toxicity was manageable.
Also with longer follow up as presented in ASCO 2017, and using pooled nivolumab plus 
ipilimumab Q12W/Q6W, any CTCAE Grade TRAE was reported in 79% compared to 73% 
in the nivolumab only cohort, TRAE Grade 3-4 was 36% compared to 19% in the nivolumab 
only cohort. Treatment-related AEs leading to discontinuation was reported in 18% of pooled 
 
 
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nivolumab plus ipilimumab Q12W/Q6W, when compared to 12% in the nivolumab 
monotherapy cohort.
Table 2
Potential Immune-Mediated Adverse Events Among Patients Treated With 
Nivolumab 3 mg/kg Q2W Plus Ipilimumab 1 mg/kg
Nivolumab Plus Ipilimumab 
Q12W, All Patients (N=38)
n (%)
Nivolumab Plus Ipilimumab 
Q6W, All Patients (N=39)
n (%)
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Endocrine
3 (8)
1 (3)
0 (0)
6 (15)
2 (5)
0 (0)
 Adrenal Insufficiency
0 (0)
1 (3)
0 (0)
3 (8)
2 (5)
0 (0)
 Hyperthyroidism
0 (0)
0 (0)
0 (0)
4 (10)
0 (0)
0 (0)
Gastrointestinal
7 (18)
2 (5)
0 (0)
7 (18)
2 (5)
0 (0)
 Diarrhea
7 (18)
1 (3)
0 (0)
8 (21)
0 (0)
0 (0)
 Colitis
0 (0)
1 (3)
0 (0)
1 (3)
2 (5)
0 (0)
Hepatic
1 (3)
0 (0)
0 (0)
0 (0)
1 (3)
1 (3)
  Increased 
Alanine 
Aminotransferase
1 (3)
0 (0)
0 (0)
0 (0)
1(3)
0 (0)
  Increased 
Aspartate 
Aminotransferase
1 (3)
0 (0)
0 (0)
0 (0)
1 (3)
0 (0)
 Increased transaminases
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (3)
Pneumonitis
2 (5)
2 (5)
0 (0)
1 (3)
1 (3)
0 (0)
Renal
1 (3)
2 (5)
0 (0)
3 (8)
0 (0)
0 (0)
 Acute Kidney Injury
1 (3)
1 (3)
0 (0)
0 (0)
0 (0)
0 (0)
  Increased 
blood 
creatinine
1 (3)
1 (3)
0 (0)
3 (8)
0 (0)
0 (0)
Skin
14 (37)
1 (3)
0 (0)
12 (31)
2 (5)
0 (0)
 Pruritus
9 (24)
0 (0)
0 (0)
5 (13)
0 (0)
0 (0)
 Maculopapular Rash
5 (13)
0 (0)
0 (0)
3 (8)
1 (3)
0 (0)
 Rash
5 (13)
1 (3)
0 (0)
3 (8)
1 (3)
0 (0)
 Generalized Rash
0 (0)
0 (0)
0 (0)
4 (10)
0 (0)
0 (0)
Considering the entire efficacy and safety data, the combination of an anti-PD-1 mAb and an 
anti-CTLA4 mAb is a reasonable regimen to evaluate in a first-line treatment setting 
compared to the established SOC of pembrolizumab monotherapy for subjects whose PD-L1 
TPS ≥50%. Details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and informed consent documents.
 
 
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Rationale for Dose Selection/Regimen/Modification
4.2.2.1
Justification for Treatment Regimen
4.2.2.1.1 Rationale for Fixed Dose Pembrolizumab
The planned dose of pembrolizumab for this study 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 for adults across all indications and regardless of tumor 
type.  As outlined below, this dose is justified by:
o
Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 
o
Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg 
Q3W across multiple indications, and
o
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 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and 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 versus 10 mg/kg 
Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort 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. Second, 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 participant 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 
 
 
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dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
4.2.2.1.2 Rationale for Dose and Regimen of Ipilimumab/Placebo in Combination With
Pembrolizumab
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed 
from the study. This section is no longer applicable.
Ipilimumab is currently approved for melanoma patients alone, and in combination with the 
anti-PD1 antibody. Ipilimumab has demonstrated efficacy with doses ranging from 1 mg/kg 
to 10 mg/kg, with lower toxicity rates at lower doses. In addition, in adjuvant melanoma IV 
ipilimumab is approved at 10 mg/kg every 12 weeks for up to 3 years or until documented 
disease recurrence or unacceptable toxicity. 
The ipilimumab dose selected for the current study KEYNOTE-598, 1 mg /kg, was formed 
on the basis of having a well-tolerated safety profile in combination with pembrolizumab, 
improved ORR (30%), and durable DCR (55%) observed in KEYNOTE 021 Cohorts D and 
H. Cohort D focused on establishing a safe dose for the combination, while Cohort H was 
designed to generate preliminary efficacy data of the combination. Key eligibility criteria for 
Cohorts D and H included age ≥18 years; advanced or metastatic NSCLC of any histology; 
≥1 prior therapy (including ≥1 line of platinum-doublet chemotherapy); ECOG Performance 
Status 0 or 1; ≥1 measurable lesion; any PD-L1 status; any EGFR or ALK status; no prior 
anti-PD-1, anti-PD-L1, or anti–CTLA-4 therapy; no autoimmune disease; and no current 
interstitial lung disease or prior interstitial lung disease requiring steroids.  Patients with 
EGFR-sensitizing mutation or ALK translocation were required to have had prior treatment 
with the appropriate targeted therapy. Initially, a 3+3 dose escalation design was pursued for 
adding 4 treatments of ipilimumab to a constant dose of pembrolizumab every 3 weeks for a 
total of 2 years in Cohort D.  Three subjects were treated at pembrolizumab 10 mg/kg Q3W 
and ipilimumab 1 mg/kg Q3W and then 3 additional subjects were treated at pembrolizumab 
10 mg/kg Q3W and ipilimumab 3 mg/kg Q3W. Although no dose-limiting toxicities were 
observed, the dose of the combination was changed to pembrolizumab 2 mg/kg Q3W and 
ipilimumab 1 mg/kg Q3W x 4 doses because of emerging concerns regarding the safety, 
including some treatment-related deaths, of subjects with NSCLC treated with labeled doses 
of ipilimumab in combination with nivolumab. Forty-five subjects were treated at this lower 
dose of both agents.
Forty-four subjects were available for the efficacy assessment because one was later 
identified as having melanoma instead of NSCLC.  The median duration of follow-up was 
11.3 months (0.3-26.9 months). The ORR was 30%, one of which was CR (2%), by 
independent central review per RECIST 1.1, as shown in Table 3.
 
 
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Table 3
Objective Response Rate and Duration of Response for Subjects Who Received 
Pembrolizumab 2 mg/kg Q3W and Ipilimumab 1 mg/kg by Independent, Central Review per
RECIST 1.1
Pembrolizumab 2 mg/kg + Ipilimumab 1 mg/kg (n=44)
Total Population 
n=44
TPS ≥50%
n=6
TPS ≥1%
n=24
TPS <1%
n=20
ORR, n (%) [95% CI]
13 (30) [17-45]
1 (17) [<1-64]
8 (33) [16-55]
5 (25) [9-49]
DCR, n (%) [95% CI]
24 (55) [39-70]
2 (33) [4-78]
13 (54) [33-74]
11 (55) [32-77]
Best overall response, n (%)
CR
1 (2)
0
0
1 (5)
PR
12 (27)
1(17)
8 (33)
4 (20)
SD
11 (25)
1 (17)
5 (21)
6 (30)
PD
13 (30)
2(33)
6 (25)
7 (35)
Not evaluable
7 (16)
2 (33)
5 (21)
2 (10)
DOR
median (range), 
months
10.5 (2.5+ to 21.0)
3.5 (3.5 to 3.5)
15.3 (3.5 to 21)
7.7 (2.5+ to 
10.7)
CR=complete response; DCR=disease control rate; ORR=objective response rate; PD=progressive disease; 
PR-partial response; SD=stable disease; TPS=tumor proportion score. 
Database Cutoff Date: 07-NOV-2016
The combination regimen was tolerable for subjects.  Adverse events were reported in 42 
(98%) of the 45 subjects who received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg; 
the most frequent AE was fatigue (44%).  Twenty-two (49%) of these subjects experienced 
Grade 3 to 5 AEs, the most frequent of which was fatigue, and syncope (7% each). The 
toxicity was manageable. Eleven (24%) subjects discontinued treatment because of AEs. 
There was one treatment-related death from pancreatitis. While the dataset for the regimen 
combining pembrolizumab and ipilimumab is small with 44 subjects, the ORR in previously 
treated subjects with the combination is greater than what would be expected from 
pembrolizumab monotherapy in a broad population of subjects with NSCLC whose tumors 
expressed PD-L1 with a TPS ≥1% (18.0% [95% CI: 14.1, 22.5] for pembrolizumab 2 mg/kg 
in KEYNOTE-010). The addition of ipilimumab to pembrolizumab did not add excessive 
toxicity in this dose and schedule. These data indicate that the combination regimen of 
pembrolizumab and ipilimumab may enhance the efficacy of pembrolizumab monotherapy in 
a first-line setting, without substantially increasing the toxicity. The Sponsor has also 
conducted a Phase 1b study of pembrolizumab at 2 mg/kg every 3 weeks in combination with 
ipilimumab at 1 mg/kg Q3W (4 doses) in participants with advanced melanoma (KEYNOTE-
029). Results of a melanoma expansion cohort (N=153) showed that the combination was 
reasonably well tolerated with 38% treatment-related Grade 3 to 4 AEs and highly 
efficacious with a 57% ORR [31].
The proposed dose and schedule of ipilimumab 1 mg /kg every 6 week to be combined with 
IV pembrolizumab 200 mg every 3 weeks for the duration of treatment in KEYNOTE-598 is 
based on open-label, Phase 1, multicohort study CheckMate-012, which evaluated nivolumab 
plus ipilimumab in previously untreated advanced NSCLC.  CheckMate-012 included 
multiple cohorts with different treatment regimen schedules including 3 cohorts of 
nivolumab (1-3 mg/kg) every 2 weeks plus ipilimumab (1-3 mg /kg) every 3 weeks for 4 
 
 
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cycles followed by nivolumab monotherapy, and 3 other cohorts with nivolumab (1-3 mg 
/kg) every 2 weeks plus ipilimumab 1 mg /kg every (6-12) weeks for the duration of 
treatment.  The toxicity observed in the first 3 cohorts, when ipilimumab dosing was every 3 
weeks for 4 cycles was high with Grade 3 to 4 TRAEs of (29-58%), and TRAEs leading to 
discontinuation (13-40%), with 3 reported treatment-related deaths from respiratory failure, 
pulmonary hemorrhage, and toxic epidermal necrolysis.
The combination of nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg at dosing 
intervals of every 6 or 12 weeks had manageable toxicity after a median follow-up of 
approximately 1 year, with Grade 3 to 4 TRAEs occurring in 13 (33%) patients taking 
nivolumab 3 mg /kg Q2W + ipilimumab 1 mg/kg Q6W and treatment-related AEs leading to 
discontinuation 5 (13%), with no treatment related death. The most commonly reported 
Grade 3 to 4 TRAEs were increased lipase (3 [8%] and no patients, respectively), 
pneumonitis (2 [5%] and 1 [3%] patients), adrenal insufficiency (1 [3%] and 2 [5%] 
patients), and colitis (1 [3%] and 2 [5%] patients) [29]. The median number of doses in (39 
patients) the cohort receiving nivolumab 3mg /kg Q2W + ipilimumab 1mg/kg Q6W was 8 
(3−18) doses for nivolumab and 2 (1−6) doses for ipilimumab, with the median duration of 
therapy 4.1 (1.9–10.1) months for nivolumab, and 3.4 (1.4–9.4) months for ipilimumab. 
Based on CheckMate-012 findings, the Phase 3 study CheckMate 227 of the combination of 
nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (until PD or 
discontinuation due to toxicity) was started and is ongoing.
The above overall experience of the ipilimumab dose in combination with PD1 inhibitors, 
and the assumption of potential additive antitumor activity of ipilimumab when combined 
with pembrolizumab for the duration of treatment, supports the dose selected for this Phase 3 
study of IV ipilimumab 1 mg /kg every 6 weeks to be combined with IV pembrolizumab 200 
mg every 3 weeks.
Based on the results of KEYNOTE-024, pembrolizumab monotherapy has become a SOC for 
treating Stage IV NSCLC in patients with PD-L1 TPS ≥50% with no EGFR or ALK genomic 
tumor aberrations. The study resulted in a significant PFS benefit for pembrolizumab over 
the SOC at the time (platinum-doublet therapy), with an HR of 0.50 (95% CI: 0.37-0.68, p 
<0.001; median PFS 10.3 months [95% CI: 6.7-not reached] with pembrolizumab and 6.0 
months [95% CI: 4.2-6.2] with platinum-doublet), as well as an OS benefit with an HR of 
0.60 (95% CI: 0.41-0.89, p=0.005; median OS was not reached in either treatment arm) [24]. 
The results from KEYNOTE-024 established pembrolizumab as first-line therapy for patients 
whose tumors have a TPS ≥50% and in whom EGFR or ALK-directed therapies are not 
indicated; the regimen has received regulatory approval for this use by the FDA and EMA. 
The use of an ipilimumab matching placebo in combination with pembrolizumab will ensure 
the objectivity of the local investigators’ treatment decision and AE causality assessments, 
while still providing subjects a SOC treatment.
 
 
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Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
4.2.3.1.1 Primary Endpoints
OS has been recognized as the gold standard for the demonstration of superiority of a new 
antineoplastic therapy in randomized clinical studies and is a standard assessment of clinical 
benefit in subjects with metastatic NSCLC.
PFS is an acceptable measure of clinical benefit for a randomized Phase 3 trial that 
demonstrates superiority of a new antineoplastic therapy, especially if the magnitude of 
effect is large and the therapy has an acceptable risk-benefit profile. Furthermore, it is an 
endorsed regulatory endpoint for 1L NSCLC trials with recent FDA approvals of 
pembrolizumab for the 1L treatment of patients with metastatic NSCLC whose tumors have 
high PD-L1 positive expression (TPS ≥50%) and no EGFR or ALK genomic tumor 
aberrations, and European Medicines Agency (EMA) approvals including the EGFR 
inhibitors, afatinib and erlotinib. PFS will be assessed per RECIST 1.1 by blinded
independent central, which will be blinded to the treatment assignment to minimize any bias 
in the response assessments.
4.2.3.1.2 Secondary Endpoints
ORR by RECIST 1.1 criteria as assessed by BICR is considered preliminary evidence of 
efficacy.
DOR based on RECIST 1.1 and assessed by BICR is a commonly accepted endpoint by both 
regulatory authorities and the oncology community.
Change from baseline in global health status/quality of life score from the EORTC QLQ-C30 
(items 29 and 30) is a common PRO endpoint in trials of immunotherapy for advanced 
NSCLC [32] [33].
TTD in cough, pain in chest, or shortness of breath, defined as the time to the first onset of a 
10-point or greater score deterioration from baseline in any one of the 3 symptoms, 
confirmed by a second adjacent 10-point or greater score deterioration from baseline has 
been used as an endpoint in advanced NSCLC immunotherapy trials [34] [35].
4.2.3.1.3 Exploratory Endpoints
NOTE: As of Amendment 06, data for exploratory endpoints are no longer being 
collected.
The EORTC QLQ-C30 and EORTC QLQ-LC13 will be used to investigate (1) quality of life 
and (2) disease- and treatment-related symptoms. They are not pure efficacy or safety 
endpoints because they are affected by both disease progression and treatment tolerability. 
The EQ-5D-5L will be used to calculate health utilities for health economic models.
The Non-small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) will 
be used to add to existing psychometric analyses of the instrument.  The NSCLC-SAQ has 
been developed in accordance with FDA guidance on patient-reported outcomes (PRO).
Results from a quantitative pilot study generated evidence of good item and scale 
 
 
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performance and provided support for the content validity, reliability, and validity of the 
instrument [36]. These data, along with initial qualitative work [37], were submitted to FDA 
to support qualification of the NSCLC-SAQ for use in NSCLC clinical trials to measure a 
patient-reported, symptom-based endpoint.
The PGIC-L PGIS-LC, and PGIC-LC questionnaires will be used to investigate clinically 
meaningful thresholds for change in the cough, pain in chest, or shortness of breath scales 
from the EORTC QLQ-LC13/QLQ-C30 and the NSCLC-SAQ total score.
PFS and ORR will be evaluated using modified RECIST 1.1 for immune-based therapeutics 
(iRECIST) [1], as assessed by the investigator in subjects treated with pembrolizumab plus 
ipilimumab compared to pembrolizumab plus placebo. RECIST 1.1 will be adapted to 
account for the unique tumor response characteristics seen following treatment with 
pembrolizumab. Immunotherapeutic agents such as pembrolizumab may produce antitumor 
effects by potentiating endogenous cancer-specific immune responses.  The response patterns 
seen with such an approach may extend beyond the typical time course of responses seen 
with cytotoxic agents, and subjects may manifest a clinical response after an initial increase 
in tumor burden or even the appearance of new lesions.  Standard RECIST 1.1 may, 
therefore, not provide an accurate response assessment of immunotherapeutic agents such as 
pembrolizumab.  Based on an analysis of subjects with melanoma enrolled in KEYNOTE-
001 (KN001), 7% of evaluable subjects experienced delayed or early tumor 
pseudoprogression.  Of note, subjects who had PD by RECIST 1.1 but not by the immune-
related response criteria [38] had longer OS than subjects with PD by both criteria [39].  
Additionally, the data suggest that RECIST 1.1 may underestimate the benefit of 
pembrolizumab in approximately 15% of subjects.  These findings support the need to apply 
a modification to RECIST 1.1 that takes into account the unique pattern of atypical responses 
in immunotherapy and enables treatment beyond initial radiographic progression, if the 
subject is clinically stable. 
Modified RECIST 1.1 for immune-based therapeutics assessment has been developed and 
published by the RECIST Working Group, with input from leading experts from industry and 
academia, along with participation from the US FDA and the EMA [1].  It is adapted to 
account for the unique tumor response seen with immunotherapeutics.  The unidimensional 
measurement of target lesions, qualitative assessment of nontarget lesions, and response 
categories are identical to RECIST 1.1, until progression is seen by RECIST 1.1.  However, 
if a subject is clinically stable, additional imaging may be performed to confirm radiographic 
progression.  iRECIST will be used by investigators to assess tumor response and 
progression, and make treatment decisions.
4.2.3.2
Patient-reported Outcomes
NOTE: As of Amendment 06, PROs will no longer be collected.
The EORTC QLQ-C30 was developed to assess the quality of life of cancer subjects. It has 
been translated and validated into 81 languages and used in more than 3,000 studies 
worldwide. It contains 5 functioning scales (i.e., physical, role, cognitive, emotional, and 
social), 3 symptom scales (i.e., fatigue, nausea, pain) and additional single symptom items. It 
is scored on a 4-point scale (1 = not at all, 2 = a little, 3 = quite a bit, 4 = very much). The 
 
 
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EORTC QLQ-C30 instrument also contains 2 global scales that use 7-point scale scoring 
with anchors (1 = very poor; 7 = excellent).
The EORTC QLQ-LC13, a supplemental lung cancer-specific module, comprises multi-item 
and single-item measures of lung cancer-associated symptoms (i.e., coughing, hemoptysis, 
dyspnea, pain) and side-effects from chemotherapy and radiation (i.e., hair loss, neuropathy, 
sore mouth, dysphagia). It is scored on a 4 point scale (1 = not at all, 2 = a little, 3 = quite a 
bit, 4 = very much) and has been translated and validated into 64 languages.
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome. The 
EQ-5D-5L will provide data for use in economic models and analyses including developing 
health utilities or quality-adjusted life years. The 5 health-state dimensions in this instrument 
include the following:  mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension is rated on a five-point scale from 1 (no problem) to 
5 (extreme problem or unable to perform).
The NSCLC-SAQ contains 7 items assessing symptoms of metastatic NSCLC (i.e., 
coughing, pain, dyspnea, fatigue, and reduced appetite).  The recall period is 7 days.  Each 
item has a 5-point verbal rating scale from either “No symptom at all” to “Very severe 
symptom” or from “Never to Always” depending on the item’s format (i.e., severity or 
frequency). A single total symptom score is computed based on item responses.
The PGIC-L and PGIC-LC will be administered to assess change since the last visit in cough, 
pain in chest, shortness of breath and total lung cancer symptoms, as measured with the 
EORTC QLQ-C30/ EORTC QLQ-LC13 and the NSCLC-SAQ, respectively. The response 
options are much better, better, a little better, no change, a little worse, worse, and much 
worse for the 4 questions in these 2 instruments.  
The PGIS-LC will be administered to assess the current severity of overall lung cancer 
symptoms. The response options for this question are not severe, mildly severe, moderately 
severe, very severe, and extremely severe.  
4.2.3.3
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs; and changes in vital signs and laboratory values. AEs
will be assessed as defined by CTCAE, Version 4.0.
4.2.3.4
Planned Exploratory Biomarker Research
Introduction:  Cancer immunotherapies represent an important and novel class of antitumor
agents.  However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding 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 
AEs
in the course of our clinical trials.  These efforts will identify novel 
predictive/pharmacodynamic biomarkers and generate information that will better guide 
single-agent and combination therapy with immuno-oncology drugs. To identify novel 
biomarkers, we will collect biospecimens (blood components, tumor material, etc.) to support 
 
 
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analyses of cellular components (e.g., protein, deoxyribonucleic (DNA), RNA, metabolites)
and other circulating molecules.  Investigations may include but are not limited to:
Germline (blood) genetic analyses (e.g., single nucleotide polymorphisms 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 AEs, the data might 
inform optimal use of 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 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 (e.g., mutations, methylation status, microsatellite instability).  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) may generate 
neo-antigen presentation in the tumor microenvironment.  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 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 
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).  Programmed 
death-ligand 1 protein level in tumor sections, assessed by IHC, has been shown to correlate 
with response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic 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., triple-negative breast cancer, 
head and neck cancer, and gastric cancer). 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.
 
 
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Other blood-derived biomarkers: In addition to expression on the tumor tissue, PD-L1 and 
other tumor-derived proteins can be shed from the tumor and released into the blood.  Assays 
such as enzyme-linked immunoassay 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 
assessing tumor biomarkers.  This research would serve to develop such assays for future 
clinical use.
4.2.3.5
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting/retaining specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
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.
Benefit/Risk
NOTE: The results of IA1 of this study indicated that the study did not meet the 
prespecified success criteria for improvement in PFS or OS for the combination of 
pembrolizumab plus ipilimumab compared with pembrolizumab plus placebo. 
Furthermore, a nonbinding futility analysis was performed at IA1 at the request of the 
DMC. This analysis showed the study met the criteria for declaring futility and the 
benefit-risk assessment was not considered positive to continue the trial. Therefore, the 
benefit-risk assessment of pembrolizumab plus ipilimumab is no longer applicable and 
has been removed.
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.
Despite the substantial improvement in PFS and OS observed with pembrolizumab as 
compared to SOC platinum-doublet chemotherapy in KEYNOTE-024, the clinical outlook of 
patients with previously untreated metastatic/recurrent NSCLC whose tumors express high 
levels of PD-L1 can be improved with further gains in cure rates and long-term OS needed. 
As such, urgency remains to investigate new treatments for this patient population.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and informed consent documents.
 
 
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5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/female subjects with Stage IV metastatic NSCLC whose tumors are PD-L1 positive 
(TPS ≥50%), do not harbor EGFR-sensitizing mutations and ALK translocations that are 
amenable to treatment with respective tyrosine kinase inhibitor therapy, and who have 
received no systemic anticancer therapy for their Stage IV metastatic NSCLC will be 
enrolled in this trial.
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/assent for FBR; however, the subject may participate in the main 
trial without participating in FBR.
2. Be at least 18 years of age on the day of signing informed consent.
3. Have a histologically or cytologically confirmed diagnosis of Stage IV metastatic
NSCLC (AJCC version 8).
4. Have measurable disease per RECIST 1.1 as assessed by the local site 
investigator/radiology.  Lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesion.
5. Have a life expectancy of at least 3 months.
6. Have an ECOG Performance Status of 0 or 1.
7. Have adequate organ function as indicated by the following laboratory values in
Table 4.  Specimens must be collected within 10 days prior to the start of trial treatment.
 
 
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Table 4
Adequate Organ Function Laboratory Values
System
Laboratory Valuea
Hematological
Absolute neutrophil count
≥1,500/mcL
Platelets
≥100,000/mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/Lb
Renal
Serum creatinine OR calculated CrClc
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5 × upper limit of normal (ULN) OR
≥30 mL/min for subjects with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 × ULN OR direct bilirubin ≤ULN for subjects with 
total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN 
Coagulation
INR or PT
aPTT or (PTT)
≤1.5 × ULN unless subject is receiving anticoagulant 
therapy as long as PT/INR or aPTT/PTT is within 
therapeutic range of intended use of anticoagulants
a All screening laboratory tests (local) must be reviewed by the investigator or qualified designee and 
acceptable prior to randomization.
b Criteria must be met without erythropoietin dependency and without packed red blood cell transfusion 
within last 2 weeks.
c Creatinine clearance should be calculated per institutional standard. If no local guideline is available, 
creatinine clearance should be calculated using the Cockcroft-Gault Method:
CrCl = [(140-age) * weight (kg) * (0.85 for females only)] / (72 * serum creatinine)
Note:  This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies.
Abbreviations:  ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); aPPT = 
activated partial thromboplastin time AST (SGOT)=aspartate aminotransferase (serum glutamic 
oxaloacetic transaminase); CrCl = creatinine clearance; GFR=glomerular filtration rate; INR = international 
normalized ratio; PT = prothrombin time; PTT = partial thromboplastin time; ULN=upper limit of 
normal.
8. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy 
of a tumor lesion not previously irradiated.  Tumor demonstrates PD-L1 expression in 
≥50% of tumor cells (TPS ≥50%) as assessed by IHC as determined by an FDA-approved 
test (22C3 Pharm IHC PharmDx [Dako] assay) at a central laboratory. Formalin-fixed, 
paraffin-embedded (FFPE) tissue blocks are preferred to slides.  Newly obtained biopsies 
are preferred to archived tissue.
Note: If submitting unstained cut slides, newly cut slides should be submitted to the 
testing laboratory within 14 days from the date slides are cut (details pertaining to tumor 
tissue submission can be found in the Procedures Manual).
9. Female subjects of childbearing potential must have a negative serum pregnancy test 
within 72 hours prior to receiving the first dose of study medication. 
 
 
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10. A female subject is eligible to participate if she is not pregnant (see Section 12.5), not 
breastfeeding, and at least one of the following conditions applies: (1) is not considered 
to be a woman of childbearing potential (WOCBP) as described in Section 12.5 or (2) is a 
WOCBP who agrees to follow the contraceptive guidance in Section 12.5 during the 
treatment period and for at least 120 days (corresponding to time needed to eliminate any 
study treatment(s) (MK and or any active comparator/combination).
11. A male subject must agree to use contraception as detailed in Section 12.5 of this 
protocol during the treatment period and for at least 120 days after the last dose of study 
treatment 
and 
refrain 
from 
donating 
sperm 
during
this 
period.
Note: As of amendment 06, contraception is no longer required for male 
participants. Sperm donation is also acceptable.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has received prior systemic chemotherapy/other targeted or biological antineoplastic 
therapy treatment for their Stage IV metastatic NSCLC.
Note:  Treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant 
therapy is allowed as long as therapy was completed at least 6 months prior to the 
diagnosis of metastatic disease.
2. Tumor harbors an EGFR-sensitizing (activating) mutation or an ALK translocation.
Note:  EGFR-sensitizing mutations are those mutations that are amenable to treatment 
with tyrosine kinase inhibitors including erlotinib, gefitinib, or afatinib. Subjects with 
nonsquamous histologies will not be randomized until EGFR mutation status and/or ALK
translocation status is available in source documentation at the site.  
For subjects enrolled who are known to have a tumor of predominantly squamous 
histology, molecular testing for EGFR mutation and ALK translocation will not be 
required as this is not SOC and is not part of current diagnostic guidelines.
3. Is currently participating in or has participated in a trial of an investigational agent or has 
used an investigational device within 4 weeks prior to the first dose of trial treatment.
Note:  Subjects who have entered the Follow-up Phase of an investigational trial may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an 
agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-
40, CD137).
5. Has received prior radiotherapy within 2 weeks of start of trial treatment or received lung 
radiation therapy of >30 Gy within 6 months of the first dose of trial treatment. Subjects 
 
 
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must have recovered from all radiation-related toxicities, not require corticosteroids, and 
not have had radiation pneumonitis. A 1-week washout is permitted for palliative 
radiation (≤2 weeks of radiotherapy) to non-CNS disease.
6. The subject’s NSCLC can be treated with curative intent with surgical resection, 
localized radiotherapy, or chemoradiation.
Note:  If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting trial treatment.
7. Tumor specimen is not evaluable for PD-L1 expression.
8. Is receiving systemic steroid therapy ≤7 days prior to the first dose of trial treatment or 
receiving any other form of immunosuppressive medication.
a.
Corticosteroid use on study after Cycle 1 for management of AEs, SAEs, and events 
of clinical interest (ECIs), as a premedication for IV contrast allergies/reactions or if 
considered necessary for a subject’s welfare, is allowed.
b. Subjects who receive daily steroid replacement therapy serve as an exception to this 
rule. Daily prednisone at doses of 5 to 7.5 mg (or hydrocortisone equivalent doses) is 
an example of replacement therapy.
c.
Subjects who use inhaled steroids for the control of asthma serve as an exception to 
this rule.
9. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.  
Note:  Subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
10. Has known untreated CNS metastases and/or carcinomatous meningitis. Subjects with 
previously treated brain metastases may participate provided they are radiologically 
stable (i.e., without evidence of progression for at least 4 weeks by repeat imaging [note 
that the repeat imaging should be performed during study screening]), clinically stable,
and without requirement of steroid treatment for at least 14 days prior to first dose of trial 
treatment.
11. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed.
 
 
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12. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(i.e., doses exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of trial drug.
13. Has a history of (noninfectious) pneumonitis that required systemic steroids or current 
pneumonitis/interstitial lung disease.
14. Has had an allogeneic tissue/solid organ transplant.
15. Has received a live vaccine within 30 days prior to the first dose of trial treatment.  
Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-
Guérin (BCG), and typhoid vaccine.  Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza vaccines 
(e.g., FluMist®) are live attenuated vaccines and are not allowed.
16. Has an active infection requiring systemic therapy.
17. Has a known history of HIV infection.  No HIV testing is required unless mandated by 
local health authority.
18. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] 
reactive) or known active hepatitis C virus (defined as hepatitis C virus (HCV) RNA 
[qualitative] is detected) infection. 
Note: no testing for hepatitis B and hepatitis C is required unless mandated by local 
health authority.
19. Has a known history of active tuberculosis (TB; Bacillus Tuberculosis).
20. 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.
21. Has known psychiatric or substance abuse disorders that would interfere with cooperating 
with the requirements of the trial.
22. Is, at the time of signing informed consent, a regular user (including “recreational use”) 
of any illicit drugs or had a recent history (within the last year) of substance abuse 
(including alcohol).
23. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the Screening Visit (Visit 1) through 120 days 
after the last dose of pembrolizumab or 90 days after the last dose of ipilimumab.
24. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
and/or to ipilimumab and/or any of its excipients.
 
 
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25. Subjects with known ROS1 mutation:  if treatment and testing for ROS1 is approved and 
accessible.  
Trial Treatment(s)
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed 
from the study. This section has been updated accordingly.
The treatment(s) to be used in this trial are outlined below in Table 5.
Table 5
Trial Treatment
Trial
Treatment 
Name
Dosage 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Sourcing
Pembrolizumab
Solution for 
Infusion
25 mg / mL
200 mg Q3W
IV infusion
Central
Abbreviations:  IV=intravenous; NA=not applicable; Q3W=every 3 weeks.
Trial treatment must begin as close to treatment allocation/randomization as possible but no 
more than three days later.
All trial treatments will be administered on an outpatient basis.
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.
Dose Selection/Modification
5.2.1.1
Dose Selection (Preparation)
Details on the dose calculation, preparation, and administration are provided in the Pharmacy
Manual.
Pembrolizumab will be administered as per the approved product labels.
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
 
 
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5.2.1.2
Dose Modification (Escalation/Titration/Other) and Toxicity Management
NOTE: As of Amendment 06, text in this section relating to dose modification of 
ipilimumab/matching placebo is no longer applicable. This section has been updated 
accordingly.
Pembrolizumab:
Dose increase or decrease of pembrolizumab will not be permitted in individual subjects. If a 
dose of pembrolizumab is withheld for toxicity, then subjects may resume dosing, if 
appropriate, at their next scheduled appointment or when toxicity has improved as described 
in Table 6 below. 
AEs (both nonserious and serious) observed may occur shortly after the first dose through
several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 6 below. See Section 5.6 –
Rescue Medications & Supportive Care for supportive care guidelines, including use of 
corticosteroids.
In addition, subjects should receive appropriate supportive care measures as deemed 
necessary by the treating investigator.  Suggested supportive care measures, as described in 
Section 5.6.1 – Supportive Care Guidelines, are also included in Table 6.
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose through several 
months after the last dose of treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, or 
skin biopsy may be included as part of the evaluation. Based on the severity of irAEs, 
withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab 
are provided in Table 6.
 
 
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Table 6
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab or 
Previously-Administrated Ipilimumab
Immune-related 
AEs
Toxicity Grade 
or Conditions 
(CTCAEv4.0)
Action Taken to 
Pembrolizumab
irAE Management with Corticosteroid 
and/or Other Therapies
Monitor and Follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer 
corticosteroids 
(initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
pneumonitis

Evaluate 
subjects 
with 
suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add 
prophylactic 
antibiotics 
for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea/colitis 
Grade 2 or 3
Withhold

Administer 
corticosteroids 
(initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
enterocolitis (i.e. diarrhea, abdominal pain, 
blood or mucus in stool with or without 
fever) 
and 
of 
bowel 
perforation 
(i.e. 
peritoneal signs and ileus).

Subjects with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Subjects with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
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
 
 
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Immune-related 
AEs
Toxicity Grade 
or Conditions 
(CTCAEv4.0)
Action Taken to 
Pembrolizumab
irAE Management with Corticosteroid 
and/or Other Therapies
Monitor and Follow-up 
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
Newly 
onset 
T1DM or 
Grade 
3 
or 
4 
hyperglycemia 
associated 
with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement therapy for 
subjects with T1DM 

Administer 
antihyperglycemic 
in 
subjects with hyperglycemia

Monitor subjects for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated  

Monitor 
for 
signs 
and 
symptoms 
of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinuea
Hyperthyroidism 
Grade 2
Continue 

Treat with nonselective beta-blockers 
(e.g. propranolol) or thionamides as 
appropriate

Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4 
Withhold or 
permanently 
discontinuea
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement hormones 
(e.g. 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 or 2
Withhold

Based on severity of AE administer 
corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity Grade 
or Conditions 
(CTCAEv4.0)
Action Taken to 
Pembrolizumab
irAE Management with Corticosteroid 
and/or Other Therapies
Monitor and Follow-up 
All Other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include but not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis, 
Stevens-Johnson 
Syndrome and 
toxic epidermal 
necrolysis
Grade 
4 
or 
recurrent Grade 3 
Permanently 
discontinue
a
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
Note: For subjects with Grade 3 or 4 immune-related endocrinopathy where withholding of pembrolizumab is required, pembrolizumab may be resumed when AE resolves to 
≤Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).
General Instructions:
1.
Corticosteroid taper should be initiated upon AE improving to ≤Grade 1 and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. 
Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or 
equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be initiated if irAEs 
cannot be controlled by corticosteroids.
Abbreviations: AEs=adverse events; ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic 
oxaloacetic transaminase); CTCAE=Common Terminology Criteria for Adverse Events; DKA=diabetic ketoacidosis; GI = gastrointestinal; IV=intravenous; irAE=immune-
related adverse events; T1DM=Type 1 diabetes mellitus
 
 
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Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 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 hours
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 withheld until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued 
from 
further 
treatment
with 
pembrolizumab.
Subject may be 
premedicated 1.5 h (± 
30 minutes) prior to 
infusion of 
pembrolizumab with:
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine).
Acetaminophen 
500-1000 mg po (or 
equivalent dose of 
analgesic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged 
(i.e., 
not 
rapidly 
responsive 
to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial 
improvement; 
hospitalization indicated 
for 
other 
clinical 
sequelae 
(e.g., 
renal 
impairment, 
pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor 
or 
ventilatory 
support 
indicated
Stop Infusion.
Additional appropriate medical therapy may include 
but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from further 
treatment with pembrolizumab.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
at http://ctep.cancer.gov
Abbreviations: CTCAE=Common Terminology Criteria for Adverse Events; IV=intravenous; NCI=National Cancer 
Institute; NSAIDs=nonsteroidal anti-inflammatory drugs; PO=oral.
Other Allowed Dose Interruption for Pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record.
Timing of Dose Administration
NOTE: As of Amendment 06, ipilimumab and matching placebo are removed from the 
study. This section has been updated accordingly.
Trial treatment may be administered up to 3 days after randomization for Cycle 1, Day 1 due 
to administrative reasons.  After Cycle 1, there is a 3-day window for all trial treatment
administration.
The specific time of pembrolizumab infusion (e.g., time of the week for first administration; 
time of the day for each administration) should be taken into consideration for study visit 
procedures.
All trial treatments will be administered on an outpatient basis.
 
 
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Pembrolizumab: Pembrolizumab will be administered as a 30-minute IV infusion Q3W. 
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible; however, given the variability of infusion pumps from site to site, a window 
of 
-5 minutes 
and 
+10 
minutes 
is 
permitted 
(i.e., 
infusion 
time 
is 
30 minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for pembrolizumab dose calculation, 
preparation of the infusion fluid, and administration.
Trial Blinding 
NOTE: As of Amendment 06, blinding is no longer applicable as ipilimumab and 
matching placebo have been removed from the study. Subjects who remain on 
treatment will receive open-label pembrolizumab monotherapy as per protocol. This 
section is no longer applicable.
A double-blinding technique will be used.  Ipilimumab and placebo will be prepared and/or 
dispensed in a blinded fashion by an unblinded pharmacist or qualified trial site personnel. 
The subject and the investigator who is involved in the treatment administration or clinical 
evaluation of the subjects are unaware of the group assignments.
Imaging data for the primary analysis will be centrally reviewed by independent 
radiologist(s) without knowledge of subject treatment assignment.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization or Treatment Allocation
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed 
from the study and no further subjects will be randomized in the study. This section is 
no longer applicable.
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 2 treatment arms.  
Subjects will be assigned randomly in a 1:1 ratio to pembrolizumab plus ipilimumab or 
pembrolizumab plus placebo, respectively.
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1. ECOG Performance Status: 0 versus 1.
2. Geography: East Asia versus non-East Asia.
3. Predominant tumor histology: squamous versus nonsquamous.
East Asians have a better prognosis than other ethnic groups regarding NSCLC.  It is well 
established that the higher a subject’s ECOG Performance Status, the worse his/her
prognosis.
 
 
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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 trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
Treatment of complications or AEs, or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) the study intervention. Antiemetic or any other prophylaxis should be 
considered in accordance with institutional guidelines. The following concomitant 
medications are also allowed:

Hormone replacement therapy (HRT)

Thyroid hormone suppressive therapy

Anti-inflammatory agents

Bisphosphonates or denosumab 
All concomitant medications received within 30 days before the first dose of trial treatment 
through the Safety Follow-up Visit should be recorded. After the Safety Follow-up Visit, 
record all medications taken for SAEs and ECIs as defined in Section 7.2 – Assessing and 
Recording Adverse Events.  If a subject enters into second course therapy, all concomitant 
medications received within 30 days before the first dose of second course treatment should 
be recorded.  Following second course therapy Safety Follow-up Visit, record all medications 
taken for SAEs and ECIs as defined in Section 7.2 – Assessing and Recording Adverse 
Events.
Prohibited Concomitant Medications and/or Treatments
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed 
from the study. This section has been updated accordingly.
Subjects are prohibited from receiving the following therapies during the screening, 
treatment, and second course phases of this trial:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Oncologic surgery for tumor control
 
 
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
Radiation therapy to RECIST 1.1-defined target disease
Note:  Palliative radiotherapy is permitted for nontarget lesions if considered medically 
necessary by the treating physician. Please note, for continuation of treatment beyond 
progression per RECIST 1.1, clinical stability criteria per Section 12.4 must be met, 
including the no requirement for radiation. Trial therapy should be held during the course 
of palliative radiotherapy and should be resumed no earlier than the next scheduled 
administration of trial therapy.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, 
seasonal flu (that contain a live virus), rabies, BCG, and typhoid vaccine.

Glucocorticoids for any purpose other than to modulate symptoms from an AE, SAE, or 
for use as a premedication in subjects with a known history of an IV contrast allergy 
administered as part of computed tomography (CT) radiography. Replacement doses of 
steroids (for example, prednisone 5 to 7.5 mg daily) are permitted while on study, as is 
the use of local steroids and the use of inhaled steroids for the control of asthma.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from treatment but 
continue in the trial for assessment of disease status and survival.
Subjects may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria describe other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Rescue Medications & Supportive Care
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 5.2.1.2 – Dose Modification (Escalation/Titration/Other), (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 or previously-administered ipilimumab.
Note:  If after the evaluation of the event, it is determined not to be related to pembrolizumab
or previously-administered ipilimumab, the investigator does not need to follow the treatment 
 
 
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guidance. 
 
Refer 
to 
Table 
6
in 
Section
5.2.1.2 
–
Dose 
Modification 
(Escalation/Titration/Other) 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.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Refer to Section 12.5 for 
approved methods of contraception.
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 
(Section 12.5) 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 study medication.  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. 
Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will be immediately discontinued from 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 (eg, 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 in Section 7.2.2 – Reporting of Pregnancy and Lactation to the 
Sponsor.
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breastfeeding are not eligible for enrollment.
 
 
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Subject Withdrawal/Discontinuation Criteria
Discontinuation of Treatment
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed 
from the study. This section has been updated accordingly.
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be/are important to 
the study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment period will still continue to participate in the trial as 
specified in Section 6.0 – Trial Flow Chart and Section 7.1.5.6 – Discontinued Subjects 
Continuing to be Monitored in the Trial.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at 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:
o
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
BICR-verified radiographic disease progression as outlined in Section 7.1.2.6.5 
(exception if the Sponsor approves treatment continuation or investigator is awaiting 
radiographic disease progression confirmation by – iRECIST Assessment of Disease 
as outlined in Section 7.1.2.6.6)
o
Unacceptable adverse experiences as described in Section 7.2 – Assessing and 
Recording 
Adverse 
Events
and 
Section 
5.2.1.2 
–
Dose 
Modification 
(Escalation/Titration/Other)
o
Any progression or recurrence of any malignancy, or occurrence of another 
malignancy that requires active treatment
o
Intercurrent illness other than another malignancy as noted above that prevents 
further administration of treatment
o
Recurrent Grade 2 pneumonitis
o
A confirmed positive serum pregnancy test
o
Noncompliance with trial treatment or procedure requirements
o
Investigator’s decision to withdraw the subject
o
Completion of 35 treatments (approximately 2 years) with pembrolizumab. Note: The 
number of treatments is calculated starting with the first dose. Subjects who stop after 
receiving 35 doses of pembrolizumab may be eligible for retreatment if they progress 
 
 
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after stopping trial treatment provided they meet the requirements detailed in Section 
7.1.5.6 – Second Course Phase.
o
The subject is lost to follow-up
o
Administrative reasons
If a subject attains an investigator-assessed confirmed CR by RECIST 1.1, has been treated 
for at least 8 cycles with pembrolizumab, and received at least 2 treatments with 
pembrolizumab beyond the date when the initial CR was declared, the subject and 
investigator may consider stopping therapy with pembrolizumab. Subjects who discontinue 
therapy after attaining a confirmed CR (or have experienced a CR, PR or stable disease (SD)
after 35 administrations of therapy) and then experience radiographic disease progression 
according to RECIST 1.1 will be eligible for retreatment with pembrolizumab in the Second 
Course Phase at the discretion of the investigator as described in Section 7.1.5.6 – Second 
Course Phase. Subjects who discontinue therapy due to a PR and/or SD after 35 trial 
treatments should follow procedures as scheduled in the End of Treatment Phase of the study 
and then move to the Follow-up Phase of the study and have assessments performed as 
indicated in Section 6.0 – Trial Flow Chart.
After the end of treatment, each subject will be followed for a minimum of 30 days for AE 
monitoring. Serious AEs will be collected for up to 90 days following cessation of treatment 
or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, as described in Section 7.2.3.1 – Serious Adverse Events. Subjects will 
have post-treatment follow-up for disease status every 9 weeks until disease progression and 
every 2 months after disease progression.
Pembrolizumab End of Treatment Follow-up
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed 
from the study. This section has been updated accordingly.
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR and have been treated for at least 8 cycles (at least 24 weeks), and receive at least 2 
doses of pembrolizumab beyond the date when the initial CR was declared. 
Subjects who have completed 35 cycles of initial treatment with SD, PR, or CR or who stop 
pembrolizumab early due to CR may be eligible for up to 1 year (17 cycles) of 
pembrolizumab if they experience disease progression after stopping pembrolizumab 
treatment.  This retreatment is termed the Second Course Phase (Retreatment) and is 
described in detail in Section 7.1.5.6 – Second Course Phase.
A subject may discontinue treatment for any of the reasons outlined in Section 5.8.1 –
Discontinuation of Treatment; however, they will remain in the trial for post-treatment 
observation for disease status until disease progression, initiating a nonstudy cancer 
treatment, withdrawing consent, becoming lost to follow-up or entering the Second Course 
Phase. After documented disease progression and/or cessation of treatment with 
pembrolizumab, each subject will be followed for OS until death.
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
see Section 6.0 – Trial Flow Chart, and Section 7.1.5.7 – Discontinued Subjects Continuing 
to be Monitored in the Trial for those procedures to be completed at each specified visit.
 
 
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Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she shall 
not be allowed to restart treatment except as described in Section 7.1.5.6 – Second Course 
Phase.
Withdrawal from the Trial
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.4 
– Other Procedures.
Subject Replacement Strategy
A subject who discontinues from trial treatment or withdraws from the trial will not be 
replaced.
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 
from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the 
investigator).
Upon study completion, subjects are discontinued and may be enrolled in a pembrolizumab
extension study, if available.
Clinical Criteria for Early Trial Termination
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP) and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
 
 
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6.0 TRIAL FLOW CHART
Treatment and Follow-up Phase
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed from the study. Subjects who remain on
treatment will receive open-label pembrolizumab monotherapy as per protocol. Study procedures have been simplified. The 
Trial Flow Chart has been amended and assessments no longer required have been deleted.
Activity
Screen-
ing
(Visit 1)
Treatment Perioda
End of Treatment 
Phase
Follow-up Phase
Survival 
Follow-up
1
2 
Every 3 
Months 
after Visit 
2
Every 12 
weeks
or as directed 
by the 
Sponsorb
Treatment Cycle/ Scheduled 
Time
-30 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13 and 
beyond
Discon-
tinuation 
Visit
Safety
Follow-
up Visit
Follow-
up 
Visit 1
Follow-
up 
Visit 2
Follow- up 
Visit 3 and 
beyond
Survival 
Follow-up 
Visit 1 and 
beyond
Scheduling Window (Days):
±3
±3
±3
±3
±3
±3 ±3 ±3 ±3 ±3
±3
±3
±3
At study 
drug 
discontin-
uation
±3
30 Days 
from 
last 
dose
±3
±7 
Days
±7 Days
±7 Days
±14 Days
Administrative Procedures
Informed Consent
X
Informed Consent for FBR
(optional)c
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical 
History
X
Review Prior and 
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NSCLC Disease Details and 
Prior Treatment
X
Subsequent Antineoplastic 
Therapy Status
X
X
X
X
X
X
Survival Statusb
<------------------------------------------------------------------------------------------------------------------------------------ >
X
 
 
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Activity
Screen-
ing
(Visit 1)
Treatment Perioda
End of Treatment 
Phase
Follow-up Phase
Survival 
Follow-up
1
2 
Every 3 
Months 
after Visit 
2
Every 12 
weeks
or as directed 
by the 
Sponsorb
Treatment Cycle/ Scheduled 
Time
-30 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13 and 
beyond
Discon-
tinuation 
Visit
Safety
Follow-
up Visit
Follow-
up 
Visit 1
Follow-
up 
Visit 2
Follow- up 
Visit 3 and 
beyond
Survival 
Follow-up 
Visit 1 and 
beyond
Scheduling Window (Days):
±3
±3
±3
±3
±3
±3 ±3 ±3 ±3 ±3
±3
±3
±3
At study 
drug 
discontin-
uation
±3
30 Days 
from 
last 
dose
±3
±7 
Days
±7 Days
±7 Days
±14 Days
Clinical Procedures/Assessments
Review AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weightd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
ECOG Performance Status
X
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Administration
Pembrolizumab
X
X
X
X
X
X
X
X
X
X
X
X
X
Local Laboratory Procedures/Assessments
Pregnancy Test
Serum β-hCGi
X
PT/INR and aPTTj
Xk
CBC with Differentiall,m
Xk
X
X
X
X
X
X
X
X
X
X
Xl
X
X
X
X
Comprehensive Chemistry 
Panell,m
Xk
X
X
X
X
X
X
X
X
X
X
Xl
X
X
X
X
Urinalysism,n
Xk
X
X
Xn
X
X
TSH, FT3/T3, FT4/T4m,o
Xk
X
X
X
X
X
Xp
X
X
ACTHm
Xk
X
X
X
X
X
Xp
X
X
ALK Translocation Testing
X
 
 
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Activity
Screen-
ing
(Visit 1)
Treatment Perioda
End of Treatment 
Phase
Follow-up Phase
Survival 
Follow-up
1
2 
Every 3 
Months 
after Visit 
2
Every 12 
weeks
or as directed 
by the 
Sponsorb
Treatment Cycle/ Scheduled 
Time
-30 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13 and 
beyond
Discon-
tinuation 
Visit
Safety
Follow-
up Visit
Follow-
up 
Visit 1
Follow-
up 
Visit 2
Follow- up 
Visit 3 and 
beyond
Survival 
Follow-up 
Visit 1 and 
beyond
Scheduling Window (Days):
±3
±3
±3
±3
±3
±3 ±3 ±3 ±3 ±3
±3
±3
±3
At study 
drug 
discontin-
uation
±3
30 Days 
from 
last 
dose
±3
±7 
Days
±7 Days
±7 Days
±14 Days
EGFR Mutation Testing
X
Efficacy Measurements
Tumor Imagingq
X
X
X
X
X
X
X
X
X
X
Tumor Biopsies/Archival Tissue Collection
Tumor Tissue Collection for 
PD-L1 Expression
X
a In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of trial treatment for each cycle unless otherwise specified. Treatment cycles are 
3 weeks (21 days). If treatment cycles are adjusted, all procedures except imaging will be completed according to the cycle number and not based on weeks on treatment; 
imaging will be performed every 9 weeks (63 days ± 7 days) from the date of randomization through 54 weeks, then every 12 weeks (84 days ±7 days) subsequently regardless 
of any treatment delays.
b After verification of disease progression by BICR or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated survival status may
be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects 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 subjects that have a death event previously recorded).
c This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at that site if there is 
either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If the sample is collected, leftover 
extracted DNA will be stored for FBR if the participant signs the FBR consent. If the planned genetic analyses are not approved, but FBR is approved and consent is given, this 
sample will be collected for the purpose of FBR.
d Vital signs to include temperature, pulse, respiratory rate, weight, and blood pressure. Height will be measured at screening only.
e ECOG assessment for eligibility needs to be performed within 7 days of the first dose of trial treatment but before randomization.
i
For women of reproductive potential, a serum pregnancy test will be performed within 72 hours prior to the first dose. Serum pregnancy test should be repeated if required by 
local guidelines.
j
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
k Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment.
l
CBC with differentials and chemistry will be performed every cycle up to Cycle 11, then thereafter at Cycle 13, Cycle 15 etc.
m After Cycle 1, laboratory samples can be collected up to 7 days prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing, except 
 
 
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Activity
Screen-
ing
(Visit 1)
Treatment Perioda
End of Treatment 
Phase
Follow-up Phase
Survival 
Follow-up
1
2 
Every 3 
Months 
after Visit 
2
Every 12 
weeks
or as directed 
by the 
Sponsorb
Treatment Cycle/ Scheduled 
Time
-30 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13 and 
beyond
Discon-
tinuation 
Visit
Safety
Follow-
up Visit
Follow-
up 
Visit 1
Follow-
up 
Visit 2
Follow- up 
Visit 3 and 
beyond
Survival 
Follow-up 
Visit 1 and 
beyond
Scheduling Window (Days):
±3
±3
±3
±3
±3
±3 ±3 ±3 ±3 ±3
±3
±3
±3
At study 
drug 
discontin-
uation
±3
30 Days 
from 
last 
dose
±3
±7 
Days
±7 Days
±7 Days
±14 Days
endocrine testing which must be reviewed prior to the next dose of treatment.
n Perform every 4 cycles.
o FT3/T3 and FT4/T4 are only required if TSH is out of the normal range.
p Perform TSH, FT3/T3, and FT4/T4 testing every other cycle from 13 onward (13, 15, 17, etc.), and ACTH as clinically indicated.
q Details are provided in the Site Imaging Manual and Section 7.1.2.6.
Abbreviations: ACTH=adrenocorticotropic hormone; AE=adverse event; ALK=anaplastic lymphoma kinase; aPTT/PTT=Activated Prothrombin Time/Partial thromboplastin time;
BICR=blinded independent central review; β-hCG=beta-human chorionic gonadotropin; CBC=complete blood count; ECG=electrocardiogram; ECOG=Eastern Cooperative 
Oncology Group; EGFR=epidermal growth factor receptor; 5-level Questionnaire; FBR=Future Biomedical Research; FT3=Free triiodothyronine; FT4=Free thyroxine; 
NSCLC=nonsmall cell lung cancer; PD-L1=programmed cell death protein-1; PT/INR=Prothrombin Time/International Normalized Ratio; TSH=thyroid stimulating hormone.
 
 
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Confidential
Second Course Treatment 
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed from the study. Subjects who enter 
Second Course treatment will receive open-label pembrolizumab monotherapy as per protocol. The Trial Flow Chart has been 
revised accordingly.
Activity
Second Course Treatment Cyclesa
End of Second Course 
Treatment
Follow-up
Survival 
Follow-up
1
2
Every 3 
Months 
after 
Visit 2
Every 12 
weeks
or as directed 
by the 
Sponsorb
Treatment Cycle/ Scheduled 
Time
1
2
3
4
5
6
7
8
9
10
11
12
13 and 
beyond
Discontinuation 
Visit
Safety 
Follow-
up Visit
Follow-
up Visit 
1
Follow-
up Visit 
2
Follow-
up Visit 
3 and 
Beyond
Survival 
Follow-up 
Visit 1 and 
Beyond
Scheduling Window (Days):
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At study drug 
discontinuation
±3
30 days 
from last 
dose
±3
±7 days
±7 days
±7 days
±14 days
Administrative Procedures
Eligibility Criteria
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subsequent Antineoplastic 
Therapy Status
X
X
X
X
X
X
Survival Statusb
<------------------------------------------------------------------------------------------------------------------------------------ >
X
Study Drug Administration
Pembrolizumab
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Review AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
Directed Physical Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weightd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: Analysis Performed by Local Laboratory
Pregnancy Test - Serum 
β-hCGf
X
PT/INR and aPTTg
Xh
CBC with Differentiali,j
Xh
X
X
X
X
X
X
X
X
X
X
Xi
X
X
X
X
Comprehensive Chemistry 
Xh
X
X
X
X
X
X
X
X
X
X
Xi
X
X
X
X
 
 
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Activity
Second Course Treatment Cyclesa
End of Second Course 
Treatment
Follow-up
Survival 
Follow-up
1
2
Every 3 
Months 
after 
Visit 2
Every 12 
weeks
or as directed 
by the 
Sponsorb
Treatment Cycle/ Scheduled 
Time
1
2
3
4
5
6
7
8
9
10
11
12
13 and 
beyond
Discontinuation 
Visit
Safety 
Follow-
up Visit
Follow-
up Visit 
1
Follow-
up Visit 
2
Follow-
up Visit 
3 and 
Beyond
Survival 
Follow-up 
Visit 1 and 
Beyond
Scheduling Window (Days):
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At study drug 
discontinuation
±3
30 days 
from last 
dose
±3
±7 days
±7 days
±7 days
±14 days
Paneli,j
Urinalysisj,k
Xh
X
X
Xk
X
X
TSH, FT3/T3, FT4/T4j,l
Xh
X
X
X
X
X
Xm
X
X
ACTHj
Xh
Xm
Efficacy Measurements
Tumor Imaging
X
X
X
X
X
X
X
X
X
X
a
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of trial treatment for each cycle unless otherwise specified. Treatment cycles are 3 weeks (21 days). If 
treatment cycles are adjusted, all procedures except imaging will be completed according to the cycle number and not weeks on treatment; imaging will be performed every 12 weeks (84 ± 7 days) 
from the date of first dose of second course. 
b
After documented local site-assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated survival status may be requested 
by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects 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 subjects that have a death event previously recorded).
d
Vital signs to include temperature, pulse, respiratory rate, blood pressure, and weight.
e
ECOG assessment for eligibility needs to be performed no more than 7 days prior first dose.  If ECOG can’t be performed within that time frame, second course Cycle 1, Day 1 ECOG may be 
utilized.
f
For women of reproductive potential, a serum pregnancy test will be performed within 72 hours prior to the first second course dose. Serum pregnancy test should be repeated if required by local 
guidelines.
g
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
h
Laboratory tests for determining eligibility for Second Course Phase are to be performed within 10 days prior to the first dose of pembrolizumab. See Section 7.1.3 – Laboratory 
Procedures/Assessments for details regarding laboratory tests.
i
CBC with differentials and chemistry will be performed every cycle up to Cycle 11, then thereafter at Cycle 13, Cycle 15 etc.
j
After the first dose, laboratory samples can be collected up to 7 days prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing, except endocrine testing 
which must be reviewed prior to the next dose of treatment. See Section 7.1.3 – Laboratory Procedures/Assessments for details regarding laboratory tests.
k
Perform every 4 cycles.
l
FT3/T3 and FT4/T4 are only required if TSH is out of the normal range. 
m Perform TSH, FT3/T3, and FT4/T4 testing every other cycle from 13 onward (13, 15, 17, etc.), and ACTH as clinically indicated.
 Abbreviations: ACTH=adrenocorticotropic hormone; AE=adverse event; aPTT/PTT=activated prothrombin time/partial thromboplastin time; β-hCG=beta-human chorionic gonadotropin; 
CBC=complete blood count; ECOG=Eastern Cooperative Oncology Group; EGFR=epidermal growth factor receptor; FT3=Free triiodothyronine; FT4=Free thyroxine; PT/INR=prothrombin 
time/International Normalized Ratio; TSH=thyroid stimulating hormone.
 
 
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Confidential
7.0 TRIAL PROCEDURES
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.
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/IEC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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Confidential
7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to 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 condition diagnosed within the prior 
10 years that are considered to be clinically significant by the investigator. In addition, record 
any prior cancer other than NSCLC even if diagnosed greater than 10 years prior to Visit 1. 
NSCLC history will be recorded separately and not listed as medical history. The medical 
history will also include an assessment of smoking history.
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, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this trial will be recorded separately and not listed as a prior medication.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial through the Safety Follow-up Visit.  In addition, new medications started 
during the Second Course Phase through the Second Course Safety Follow-up Visit should 
be recorded.
 
 
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All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7.2 – Assessing and Recording Adverse Events.
7.1.1.6
Nonsmall Cell Lung Cancer Disease Details and Treatments
7.1.1.6.1 Disease Details
The investigator or qualified designee will obtain prior and current NSCLC disease details.
7.1.1.6.2 Prior Treatment
The investigator or qualified designee will review all prior treatments for NSCLC including 
systemic treatments, radiation, and surgeries.
7.1.1.6.3 Subsequent Antineoplastic Therapy Status
The investigator or qualified designee will review all new antineoplastic therapy initiated 
after the last dose of trial treatment. If a subject initiates a new antineoplastic therapy within 
30 days after the last dose of trial treatment, the “30-day Safety Follow-up Visit” must occur 
before the first dose of the new therapy. Once new antineoplastic therapy has been initiated
the subject will move into Survival Follow-up.
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 – Screening.
7.1.1.8
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after randomization.  Once a treatment/randomization number is assigned to a 
subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks due to 
pembrolizumab toxicity require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on subject management.
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the Pharmacy Manual. The total volume of trial medication infused 
 
 
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Confidential
will be compared with the total volume prepared to determine compliance with each dose 
administered.
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 Section 6.0 – Trial Flow Chart and more frequently if 
clinically indicated. AEs will be graded and recorded throughout the study and during the 
Follow-up Period according to NCI CTCAE Version 4.0. Toxicities will be characterized in 
terms including seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.
Please refer to Section 7.2 – Assessing and Recording Adverse Events for detailed 
information regarding the assessment and recording of AEs.
7.1.2.2
Physical Examination
7.1.2.2.1 Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical examination are described in Section 6.0 – Trial 
Flow Chart. After the first dose of trial treatment, new clinically significant abnormal 
findings should be recorded as AEs.
7.1.2.2.2 Directed Physical Examination
For cycles that do not require a full physical examination per the Section 6.0 – Trial Flow 
Chart, the investigator or qualified designee will perform a directed physical examination as 
clinically indicated prior to trial treatment administration. New clinically significant 
abnormal findings should be recorded as AEs.
7.1.2.3
Vital Signs
Vital signs include temperature, pulse, respiratory rate, weight, and blood pressure. The 
investigator or qualified designee will take vital signs at screening, prior to the administration 
of each dose of trial treatment and during the Follow-up period as specified in Section 6 –
Trial Flow Chart. Height will be measured at Visit 1 only.
7.1.2.4
Lead Electrocardiogram
A standard 12-lead ECG will be performed using local standard procedures once at 
screening. Clinically significant abnormal findings should be recorded as medical history. 
Further monitoring by ECG should be performed as clinically indicated.
 
 
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7.1.2.5
Eastern Cooperative Oncology Group Performance Status Scale
The investigator or qualified designee will assess ECOG Performance Status (see 
Section 12.3 – ECOG Performance Status) at screening, prior to the administration of each 
dose of study treatment and during the Follow-up Period as specified in Section 6 – Trial 
Flow Chart.
7.1.2.6
Tumor Imaging and Assessments of Disease
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual (SIM).  All scheduled tumor imaging, including screening, 
must include complete imaging of the chest, abdomen, and pelvis.  Tumor imaging is 
strongly preferred to be acquired by CT with iodinated contrast.  For the abdomen and pelvis, 
magnetic resonance imaging (MRI) may be used when CT with iodinated contrast is 
contraindicated, or when local practice mandates it.  Chest imaging must be done by CT, but 
may be done without contrast when iodinated contrast is contraindicated.  Brain imaging 
should be provided when clinically indicated and at screening, as described below, for 
subjects with previously treated brain metastases.  MRI is the strongly preferred modality for 
imaging the brain.  The same imaging technique regarding modality, ideally the same 
scanner, and the use of contrast should be used in a subject throughout the study to optimize 
the reproducibility of the assessment of existing and new tumor burden and improve the 
accuracy of the assessment of response or progression based on imaging.
Subject eligibility will be determined using local assessment (investigator assessment) based 
on RECIST 1.1.  All scheduled images for all study subjects from the sites will be submitted 
to the central imaging vendor.  In addition, images (including via other modalities) that are 
obtained at an unscheduled time point to determine disease progression, as well as imaging 
obtained for other reasons, which show radiologic progression, should also be submitted to 
the central imaging vendor.
When the investigator identifies radiographic progression per RECIST 1.1, the central 
imaging vendor will perform expedited verification of radiologic PD and communicate the 
results to the trial site and Sponsor. If the investigator elects to implement iRECIST 
following initial investigator determination of PD, the investigator will assess for 
confirmation of progression by iRECIST at subsequent time points.  Images should continue 
to be submitted to the central imaging vendor. 
7.1.2.6.1 Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 30 days prior to the date of 
randomization.  The site study team must review screening images to confirm the subject has 
measurable disease per RECIST 1.1. 
The screening images must be submitted to the central imaging vendor for retrospective 
review.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if they are of diagnostic quality and performed within 30 days prior 
to the date of randomization and can be assessed by the central imaging vendor. 
 
 
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Subjects with previously treated brain metastases may participate provided they are:
a) Radiologically stable, i.e., without evidence of progression (confirmed by MRI if 
MRI was used at prior imaging, or confirmed by CT imaging if CT was used at prior 
imaging) for at least 4 weeks by repeat imaging (note that the repeat imaging should 
be performed during study screening).
b) Clinically stable and without requirement of steroid treatment for at least 14 days 
prior to first dose of trial treatment.   This exception does not include carcinomatous 
meningitis, as subjects with carcinomatous meningitis are excluded regardless of 
clinical stability.  
Imaging used to confirm no evidence of progression of brain metastases must be submitted to 
the central imaging vendor for retrospective review as part of the screening assessment.
7.1.2.6.2 Tumor Imaging During the Study
The first on-study imaging assessment should be performed at 9 weeks (63 days ±7 days) 
from the date of randomization.  Subsequent tumor imaging should be performed every
9 weeks (63 days ±7 days) or more frequently if clinically indicated.  After 54 weeks 
(378 days ±7 days), subjects who remain on treatment will have imaging performed every 12
weeks (84 days ±7 days).  Imaging timing should follow calendar days and should not be 
adjusted for delays in cycle starts.  Imaging should continue to be performed until disease 
progression is identified by the investigator and verified by the central imaging vendor
(unless the investigator elects to continue treatment and follow iRECIST), the start of new 
anticancer treatment, withdrawal of consent, or death, whichever occurs first.  All 
supplemental imaging must be submitted to the central imaging vendor.
PR and CR should be confirmed by a repeat imaging assessment.  The imaging may be 
performed, at the earliest, 4 weeks after the first indication of a response, or at the next 
scheduled scan (i.e., 9 or 12 weeks later), whichever is clinically indicated.  Subjects will 
then return to regular scheduled imaging every 9 or 12 weeks as described above, starting 
with the next scheduled imaging time point.  Subjects who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 4 
weeks later; tumor imaging may resume at the subsequent scheduled imaging time point.  
Per iRECIST (Section 7.1.2.6.6), disease progression should be confirmed by the site 4 to 
8 weeks after central verification of site-assessed first radiologic evidence of PD in clinically 
stable subjects.  Subjects who have unconfirmed disease progression may continue on 
treatment at the discretion of the investigator until progression is confirmed by the site 
provided they have met the conditions detailed in Section 7.1.2.6.6.  Subjects who receive 
confirmatory imaging do not need to undergo the next scheduled tumor imaging if it is less 
than 4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time 
point, if clinically stable.  Subjects who have confirmed disease progression by iRECIST, as 
assessed by the site, will discontinue study treatment.  Exceptions are detailed in 
Section 7.1.2.6.6.
 
 
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7.1.2.6.3 End of Treatment and Follow-up Tumor Imaging
In subjects who discontinue study treatment, tumor imaging should be performed at the time 
of treatment discontinuation (±4 week window).  If previous imaging was obtained within 
4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation is not 
mandatory.  In subjects who discontinue study treatment due to documented disease 
progression, and the investigator elects not to implement iRECIST, this is the final required 
tumor imaging.
In subjects who discontinue study treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by tumor imaging using the 
same imaging schedule used while on treatment (every 9 weeks in Year 1 or every 12 weeks 
after Year 1) to monitor disease status until the start of a new anticancer treatment, disease 
progression, death, withdrawal of consent, or the end of the study, whichever occurs first.
7.1.2.6.4 Second Course (Retreatment) Tumor Imaging
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed 
from the study. This section has been updated accordingly.
Tumor imaging must be performed within 30 days prior to restarting treatment with 
pembrolizumab monotherapy. Before a subject may enter Second Course Phase, BICR 
verification of PD must have occurred. The PD imaging may also be used as the second 
course baseline imaging if it is within 30 days prior to restarting treatment and otherwise 
meets the baseline standards outlined in the SIM.
The first second course on study imaging assessment should be performed at 12 weeks 
(84 days ±7 days) after the restart of treatment. Subsequent tumor imaging should be 
performed every 12 weeks (84 days ±7 days) or more frequently if clinically indicated. 
Imaging for the Second Course Phase is not required to be transmitted to the central imaging 
vendor.
If during the second course tumor imaging shows initial PD per local RECIST 1.1, the 
investigator may elect to implement iRECIST and repeat the imaging 4 to 8 weeks later in 
order to confirm PD with the option of continuing treatment on second course while awaiting 
radiologic confirmation of progression.  Subjects who obtain confirmatory imaging do not 
need to undergo scheduled tumor imaging if it is less than 4 weeks later and may wait until 
the next scheduled imaging time point, if clinically stable.
Imaging should continue to be performed until disease progression, the start of a new 
anticancer treatment, withdrawal of consent, death, or notification by the Sponsor, whichever 
occurs first.  
In subjects who discontinue second course study treatment, tumor imaging should be 
performed at the time of treatment discontinuation. If previous imaging was obtained within 
4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation is not 
mandatory. In subjects who discontinue study treatment due to documented PD, this is the 
final required tumor imaging.
In subjects who discontinue second course study treatment without documented PD, every 
effort should be made to continue monitoring their disease status by radiologic imaging every 
 
 
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12 weeks (84 days ± 7 days) until the start of new anticancer treatment, disease progression, 
death, or the end of the study, whichever occurs first. For these subjects, the next imaging 
would occur at the Discontinuation Visit, and then 12 weeks later. If a previous scan was 
obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment 
discontinuation is not mandatory. The timing of second course follow-up visits (Section 6.2) 
may be scheduled to coincide with the subject’s follow-up imaging. Once imaging is 
complete (e.g., PD, new antineoplastic therapy), the subject enters into Survival Follow-up.
7.1.2.6.5 RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by BICR 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 treatment).  Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, the Sponsor allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
7.1.2.6.6 iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and make treatment decisions. When clinically stable, subjects 
should not be discontinued until progression is confirmed by the investigator, working with 
local radiology, according to the rules outlined in Section 12.4. 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. This data will be captured in the clinical 
database.
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of 
disease

No decline in ECOG Performance Status 

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any subject deemed clinically unstable should be discontinued from study treatment at site-
assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging for 
confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the subject may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per investigator assessment.  Images should continue to be sent in to the central 
imaging vendor for potential retrospective BICR. 
 
 
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If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
subject continues to be clinically stable, study treatment may continue and follow the regular 
imaging schedule.  If PD is confirmed, subjects will be discontinued from study treatment.
If a subject has confirmed radiographic progression (iCPD) as defined in Section 12.4, study 
treatment should be discontinued; however, if the subject is achieving a clinically meaningful 
benefit, an exception to continue study treatment may be considered following consultation 
with the Sponsor.  In this case, if study treatment is continued, tumor imaging should 
continue to be performed following the intervals as outlined in the Trial Flow Chart in 
Section 6 and submitted to the central imaging vendor. 
A description of the adaptations and iRECIST process is provided in Section 12.4, with 
additional details in the iRECIST publication [1]. A summary of imaging and treatment 
requirements after first radiologic evidence of progression is provided in Table 8 and 
illustrated as a flowchart in Figure 3.
 
 
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Table 8
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 per 
investigator 
assessment.
Submit the imaging to 
BICR for verification.
Repeat imaging at 4 
to 8 weeks to confirm 
PD per iRECIST.
May continue study 
treatment at the discretion 
of the investigator.
Submit the imaging to 
BICR for verification.
Discontinue study 
treatment
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per 
investigator assessment
No additional imaging 
required.
Discontinue study 
treatment (exception is 
possible upon consultation 
with Sponsor).
No additional imaging 
required.
Not applicable
Repeat tumor imaging 
shows iUPD by 
iRECIST per 
investigator assessment
Repeat imaging at 4 
to 8 weeks to confirm 
PD.  
Continue study treatment 
at the investigator’s 
discretion.
No additional imaging 
required.
Discontinue study 
treatment
Repeat tumor imaging 
shows iSD, iPR, or 
iCR by iRECIST per 
investigator 
assessment.
Continue regularly 
scheduled imaging 
assessments.
Continue study treatment 
at the investigator’s 
discretion.
No additional imaging 
required.
Discontinue study 
treatment
Abbreviations: BICR=blinded independent central review; iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iRECIST=modified Response 
Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iPR=iRECIST partial response; iSD=iRECIST stable disease; iUPD=iRECIST unconfirmed 
progressive disease; PD=progressive disease; RECIST 1.1=Response Evaluation Criteria in Solid Tumors 1.1.
Note:  If progression has been centrally verified, further management is by the site, based on iRECIST.  Any further imaging should still be submitted to the central imaging 
vendor, but no rapid review will occur. If RECIST 1.1 PD has not been centrally verified, ideally the site should continue treatment. Whether or not treatment continues, 
imaging should be collected and submitted to the central imaging vendor with verification of progression (VOP) request until RECIST 1.1 PD is verified by BICR.
 
 
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Figure 3
Imaging and Treatment for Clinically Stable Subjects After First Radiologic 
Evidence of PD Assessed by the Investigator
7.1.2.7
Tumor Tissue Collection
Programmed death-ligand 1 expression will be tested by a central laboratory as part of 
screening. Only subjects whose tumors demonstrate PD-L1 expression (TPS ≥50%) are 
eligible for enrollment.
Archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion 
not previously irradiated must be provided to the central laboratory for testing.  
Formalin-fixed, paraffin-embedded tissue blocks are preferred to slides.  Newly obtained 
biopsies are preferred to archived tissue.
If the subject signs the FBR consent, any leftover tissue biopsies that would ordinarily be 
discarded at the end of the main study will be retained for FBR, again providing the subject 
has signed the FBR consent.
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual. Older biopsy material or surgical specimens may be used to assess 
EGFR mutation.
 
 
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7.1.2.8
Patient-reported Outcomes
NOTE: As of Amendment 06, PROs will no longer be collected. This section is no longer 
applicable and has been deleted.
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 Trial Procedures 
Manual. Refer to Section 6 −Trial Flow Chart for the timing of laboratory assessments.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed 
from the study. This section has been updated accordingly.
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 9.  These 
tests are required at visits as noted in the Trial Flow Charts (Section 6) or as clinically 
indicated.
Table 9
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
FSH
Hemoglobin
Alkaline phosphatase
Glucose
Serum β-hCG
Platelet count
ALT
Protein
Triiodothyronine (FT3 
or T3)
WBC 
(total 
and/or 
differential) RBC
AST
Specific gravity 
Thyroxine (FT4 or T4)
Carbon dioxide (CO2 or
bicarbonate)a
Microscopic 
examination, 
if 
abnormal results are 
noted
TSH
Calcium
ACTH levelc
Chloride
PT (INR)
Creatinine
aPTT/PTT
Glucose
Magnesium
Phosphorus
Blood 
for 
FBR 
(optional)
Potassium
Blood for genetics
Sodium
Blood for correlative 
studies
Total bilirubin  
Blood for biomarkers
Direct 
bilirubin, 
if 
total 
bilirubin is elevated above the 
ULN
 
 
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Hematology
Chemistry
Urinalysis
Other
Total protein
BUNb
Ureab
Uric acid
a If these tests are not done as part of standard of care in your region, then these tests do not need to be performed.
b BUN or urea should be collected per institutional standard. It is not required to perform both of these laboratory 
tests. 
c Perform ACTH testing as clinically indicated.
Abbreviations: ACTH = adrenocorticotropic hormone; ALT = Alanine aminotransferase; AST = aspartate 
aminotransferase; BUN=Blood urea nitrogen; β-hCG=beta-human chorionic gonadotropin; CBC=complete blood 
count; CO2=Carbon dioxide; FBR = future biomedical research; FSH=Follicle stimulating hormone;
PPT/INR=Prothrombin time/international normalized ratio; aPTT/PTT=Activated
prothrombin time/partial 
thromboplastin time; TSH = thyroid stimulating hormone; WBC=white blood cell.
Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of trial treatment. After Cycle 1, predose laboratory 
procedures can be conducted up to 7 days prior to dosing.
All protocol-required screening and safety laboratory results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment. 
Note: For endocrine testing (TSH, FT3/T3, FT4/T4, and ACTH as listed above), where 
results are not available prior to the dose of trial treatment, testing must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to the following dose of 
trial treatment (eg, within 3 weeks of the laboratory procedure date).
7.1.3.2
Pregnancy Test
For all women who are being considered for participation in the trial, and who are of 
reproductive potential, a serum pregnancy test after screening should be repeated if required 
by local guidelines. Subjects must be excluded/discontinued from the trial in the event of a 
positive or borderline-positive test result. 
7.1.3.3
Pharmacokinetic/Pharmacodynamic/Immunogenicity Evaluations
NOTE: 
As 
of 
Amendment 
06, 
pharmacokinetic, 
pharmacodynamic, 
and 
immunogenicity evaluations will not be pursued and blood samples for these endpoints 
will not be collected. This section is no longer applicable and has been deleted.
7.1.3.4
Molecular Testing
Site must be able to provide documentation of subject’s tumor EGFR mutation and/or ALK
translocation status. Investigators must be able to produce the source documentation of the 
EGFR mutation and ALK translocation in all subjects with nonsquamous histologies AND for 
subjects in whom testing is clinically recommended. If either an EGFR-sensitizing mutation 
or ALK translocation is detected, additional information regarding the mutation status of the 
other molecule is not required. If documentation is unavailable or the site is unable to test for 
these molecular changes, formalin-fixed paraffin-embedded tumor tissue of any age should 
be submitted to a local laboratory designated by the Sponsor for such testing. If the site is 
unable to provide this source documentation, then the Sponsor will offer this molecular 
 
 
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testing of the tumor. Tissue PD-L1 testing is assessed by IHC as determined by an FDA-
approved test (22C3 Pharm IHC PharmDx [Dako]) assay) at a central laboratory. Local 
testing of PD-L1 is NOT allowed per protocol. Detailed instructions for tissue collection, 
processing, and shipment are provided in the Procedures Manual.
If treatment with ROS1-targeted therapy and testing for ROS1 are approved and accessible, 
then local testing for ROS1 is required.  Testing for ROS1 is not required in subjects whose 
tumor is known to have predominantly squamous histology, and in subjects where ROS1-
targeted therapy is not accessible.
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 Procedure Manual.  Samples should be collected for planned analysis 
of associations between genetic variants in germline/tumor DNA and drug response.  If a 
documented law or regulation prohibits (or local IRB/Independent Ethics Committee [IEC] 
does not approve) sample collection for these purposes, then such samples should not be 
collected at the corresponding sites.  Leftover DNA extracted from planned genetic analysis 
samples will be stored for future biomedical research only if subject signs the Future 
Biomedical Research consent.
7.1.3.6
Future Biomedical Research Samples
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research

Leftover main study tumor tissue

Leftover RNA from RNA analyses

Leftover plasma from plasma biomarker analyses

Leftover serum from serum biomarker analyses
7.1.3.7
Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency room visits must be reported in the eCRF, from the 
time of treatment allocation/randomization through 90 days following cessation of study 
treatment, or 30 days following cessation of study treatment if the participant initiates new 
anticancer therapy (whichever is earlier).
Other Procedures
7.1.4.1
Withdrawal/Discontinuation
When a subject withdraws from participation in the trial, all applicable activities scheduled 
for the final trial visit should be performed at the time of withdrawal.  Any adverse events 
which are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 7.2 - Assessing and Recording Adverse Events.
 
 
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7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research.  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).  Subsequently, 
the subject's consent for Future Biomedical Research will be withdrawn.  A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the subject of completion of withdrawal.  Any analyses in progress at 
the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research trial data and results.  
No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (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 withdrawal cannot be processed.
7.1.4.2
Subject Blinding/Unblinding
NOTE: As of Amendment 06, blinding is no longer applicable as ipilimumab and 
matching placebo have been removed from the study. Subjects who remain on 
treatment will receive open-label pembrolizumab monotherapy as per protocol. Text 
related to ipilimumab/matching placebo and emergency unblinding in this section is no 
longer applicable.
STUDY TREATMENT IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND THE PARTICIPANT UNLESS
NECESSARY.
For emergency situations where the investigator or delegate needs to identify the drug used 
by a subject and the dosage administered in case of emergency e.g., the occurrence of serious 
adverse events, he/she will contact the emergency unblinding call center by telephone and 
make a request for emergency unblinding.  As requested by the investigator or delegate the 
emergency unblinding call center will provide the information to him/her promptly and 
report unblinding to the Sponsor.  Prior to contacting the emergency unblinding call center to 
request unblinding of a subject’s treatment assignment, the investigator or delegate must 
enter the toxicity grade of the adverse events observed, the relation to study drug, the reason 
thereof, etc., in the medical chart etc.
For studies that require non-emergency unblinding as part of the study design (eg, disease 
progression) to support treatment decisions, instructions in this section below should be 
followed. The emergency unblinding center should not be used for this purpose.
Subjects whose treatment assignment has been unblinded by the investigator/delegate and/or 
non-study treating physician must be discontinued from study drug, but should continue to be 
monitored in the trial.
 
 
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For studies that require unblinding as part of the study design (e.g., disease recurrence, 
progression, or completion of study treatment) to support treatment decisions, the site must
first contact the Sponsor for approval of nonemergent unblinding at the time of central
laboratory confirmation of disease recurrence, disease progression, or completion of study
treatment. Once authorization is granted by the Sponsor for nonemergent unblinding, the site 
will contact IVRS/IVXS to receive the participant’s unblinded treatment arm. The emergency 
unblinding center should not be used for nonemergency unblinding.
Treatment/Vaccine identification information is to be unmasked ONLY if necessary for the 
welfare of the subject.  Every effort should be made not to unblind the subject unless 
necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. Only the principal investigator or 
delegate and the respective subject’s code should be unblinded. Other trial site personnel and 
Sponsor personnel directly associated with the conduct of the trial should not be unblinded.
7.1.4.3
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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
Within 30 days prior to treatment randomization, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1.
Visit 
requirements are outlined in the Trial Flow Chart (Section 6). Screening procedures may be 
repeated.
Written consent must be obtained prior to performing any protocol-specific procedure. 
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. Screening procedures are to be completed within 30 days prior to the first dose of 
trial treatment except for the following:
Laboratory tests are to be performed within 10 days prior to the first dose of trial treatment.

ECOG performance must be assessed within 7 days of the first dose of trial treatment but 
before randomization.

For women of reproductive potential, a serum pregnancy test will be performed within 
72 hours prior to first dose of trial treatment.
 
 
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
Tumor imaging must be performed within 30 days prior to the date of randomization.
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments performed during the initial screening period are acceptable in lieu 
of repeating a screening test if performed within the specified time frame and the results meet 
the inclusion/exclusion criteria.
7.1.5.2
Treatment Period Visit
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures.
7.1.5.3
End of Treatment Visits
7.1.5.3.1 Discontinuation Visit
The Discontinuation Visit should occur at the time study drug is discontinued for any reason. 
If the Discontinuation Visit occurs 30 days from the last dose of study treatment, at the time 
of the mandatory Safety Follow-up Visit, procedures do not need to be repeated. Procedures 
at the time of discontinuation are detailed in Section 6.0 - Trial Flow Chart.
All subjects who discontinue trial treatment for a reason other than disease progression 
should continue to receive all assessments until PD by RECIST 1.1 or initiation of a new 
antineoplastic therapy.
Imaging assessments should continue as per the interval stated in the protocol; every 9 weeks 
for the first 54 weeks and then every 12 weeks thereafter. Additional imaging at the 
Discontinuation Visit is not required provided that a scan was obtained within 4 weeks prior 
to the date of discontinuation.  In subjects who discontinue trial treatment due to documented 
disease progression, the scan documenting disease progression is the final required tumor 
imaging.
7.1.5.3.2 Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new antineoplastic treatment, 
whichever comes first. Subjects with an AE of Grade >1 will be further followed until the 
resolution of the AE to Grade 0 or 1 or until beginning of a new antineoplastic therapy, 
whichever occurs first.
Subjects who are eligible for retreatment during the Second Course Phase may have up to 2
Safety Follow-up Visits, the first after the Treatment Phase and the second after the Second 
Course Phase per the requirements in Section 7.1.5.5 – Second Course Phase.
Imaging assessments should continue as per the interval stated in the protocol; every 9 weeks 
for the first 54 weeks and then every 12 weeks thereafter. Additional imaging at the Safety 
Follow-up Visit is not required provided that imaging assessments have been performed per 
schedule.
 
 
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7.1.5.4
Follow-up Phase
All subjects will have post-treatment follow-up for disease status, including initiating a 
non-study cancer treatment and experiencing disease progression, until death, withdrawing 
consent, or becoming lost to follow-up.
7.1.5.4.1 Follow-up Visits
All subjects who discontinue initial trial treatment or Second Course Phase trial treatment for 
a reason other than disease progression should continue to receive all assessments until PD 
by RECIST 1.1 or initiation of a new antineoplastic therapy.
Subjects who have received the maximum administrations of pembrolizumab indicated above
for either initial treatment or Second Course Phase trial treatment, should be followed as 
indicated in the Follow-up Phase of the study outlined in Section 6.0 - Trial Flow Chart.
Follow-up Visit 1 should be scheduled to coincide with the next scheduled imaging visit to 
occur at least 9 weeks after the last dose of trial treatment. Assessment for drug-related AEs, 
including those consistent with immune phenomena, should occur at Follow-up Visit 1. 
Follow-up Visit 2 should be scheduled to coincide with the next scheduled imaging visit to 
occur at least 18 weeks after the last dose of trial treatment. After Follow-up Visit 2, subjects 
only need to be assessed every 9 weeks (63 ± 7 days) or 12 weeks (84 ± 7 days) as defined in 
Section 7.1.2.6 – Tumor Imaging and Assessments of Disease, by radiologic imaging to 
monitor disease status, development of drug-related SAEs and ECIs, and initiation of new 
antineoplastic therapy. Unless otherwise noted in Section 6.0 - Trial Flow Chart, every effort 
should be made to collect subject information on the start of new antineoplastic therapy, 
disease progression, and/or death.
Subjects who are eligible to receive retreatment according to the criteria in Section 7.1.5.6 –
Second Course Phase will move to the Second Course Phase when they experience disease 
progression.
7.1.5.4.2 Survival Follow-up
Once the subject stops the imaging assessments for this protocol (e.g., for PD or starting a 
new antineoplastic therapy), the subject moves into the Survival Follow-up Phase and should 
be contacted by telephone every 12 weeks (84 ± 14 days) to assess for survival status. 
Survival assessments and its respective entry into the database may be required more 
frequently around the projected interim or final analyses. Post-study treatments and the 
subject’s response to them will also be collected at the same time.
Survival status data may be requested more frequently than every 12 weeks (84 ± 14 days) at 
specific time points during the study.  For example, survival status may be requested prior to 
an external DMC safety review, efficacy IA, and FA. All subjects who are in the Survival 
Follow-up Phase, and not known to have died prior to the request for this additional survival 
status time points, will be contacted at that time.
Subjects may withdraw their consent at any time from any or all portions of the study. 
Subjects who withdraw consent for treatment and/or imaging are encouraged to remain on 
the noninvasive Survival Follow-up portion of the study. The only procedures associated 
with this phase are telephone contacts to assess survival status and the current state of the 
 
 
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subject’s NSCLC. The noninvasive nature and societal benefit of Survival Follow-up should 
be explained to the subject by the site staff, particularly when discontinuing treatment and 
imaging.
7.1.5.5
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, IA and/or FA. Upon Sponsor notification, all 
subjects 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 subjects that have a 
previously recorded death event in the appropriate eCRF).
7.1.5.6
Second Course Phase
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed 
from the study. This section has been updated accordingly.
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures. Subjects may be eligible to 
receive up to 17 additional trial treatments of pembrolizumab in the Second Course Phase.
After the Second Course Phase, subjects should be followed for progression and survival as 
indicated, with no option for further retreatment on study.
Subjects will be eligible to receive pembrolizumab at the discretion of the investigator in the 
Second Course Phase of this study if the subject meets the following conditions:
Either

Stopped their initial treatment with pembrolizumab after attaining a confirmed CR 
according to RECIST 1.1, and
o
Was treated for at least 8 cycles with pembrolizumab 
o
Received at least 2 treatments with pembrolizumab beyond the date when the initial 
CR was declared
OR

Had SD, PR, or CR and stopped study treatment after completion of 35 cycles 
(approximately 2 years) of study treatment for reasons other than disease progression or 
intolerability
And

Experienced radiographic disease progression verified by BICR based on RECIST 1.1 
after stopping initial treatment, and:

Did not receive any anticancer treatment since the last dose of pembrolizumab

Not more than 2 years have elapsed since discontinuing their initial treatment with 
pembrolizumab 
 
 
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
The subject meets all of the safety parameters listed in the inclusion criteria and none of 
the safety parameters listed in the exclusion criteria, and

The study is ongoing
Subjects will be retreated at the same dose they last received pembrolizumab.
Imaging will be performed every 12 weeks (84 ± 7 days) after the first dose of Second 
Course Phase trial treatment until disease progression, or start of new antineoplastic therapy. 
The timing of imaging should follow calendar days and should not be adjusted for delays in 
cycle starts or extension of cycle frequencies. The same imaging technique should be used in 
a subject throughout the trial. Continued imaging is not needed for subjects who start another 
anticancer treatment regimen. An objective response or disease progression that occurs 
during the Second Course Phase for a subject will not be counted as an event for the primary 
analysis of either endpoint in this trial.
7.1.5.7
Discontinued Subjects Continuing to be Monitored in the Trial
Subjects who discontinue treatment will be followed up for efficacy and OS until consent 
withdrawal from trial, becoming lost to follow-up, death, or end of the study, whichever 
comes first.
Date of disease recurrence or metastatic progression, start and stop dates of subsequent 
anticancer treatments, and reasons for treatments should be recorded in the appropriate 
eCRF. For subjects who die during the follow up period, the date and cause of death should 
be recorded in the appropriate eCRF.
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.
 
 
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Progression of the cancer under study is not considered an adverse event. 
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
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.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed 
from the study. Subjects who remain on treatment will receive open-label 
pembrolizumab monotherapy as per protocol. Text related to ipilimumab/matching 
placebo in this section is no longer applicable and has been removed.
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab as any dose of 1000 mg or exceeding 5 times the protocol-
prescribed dose. 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, 
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 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).
 
 
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Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 
30 days following cessation of trial treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies  must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
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 10 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 
 
 
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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 trial treatment, or 30 days following cessation of trial treatment if the 
subject initiates new anticancer therapy, whichever is earlier, any serious adverse event, or 
follow up to a serious adverse event, including death due to any cause other than progression 
of the cancer under study (reference Section 7.2.3.3 for additional details), whether or not 
related to the Sponsor's product, must be reported within 24 hours to the Sponsor either by 
electronic media or paper. Electronic reporting procedures can be found in the EDC data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
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.*
 
 
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*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 monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to Global Safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse event to the single agent.
 
 
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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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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.
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
DMC regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.7 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
The DMC has responsibility for assessment of the overall risk:benefit. Periodic safety 
monitoring will be specified in the DMC Charter with input from the DMC members. When 
prompted by safety concerns, the DMC can request corresponding efficacy data. Any DMC 
recommendation will be communicated to the Sponsor as agreed to in the DMC Charter. As 
of Amendment 06, no additional DMC reviews will take place.
8.0 STATISTICAL ANALYSIS PLAN
NOTE: Data from the IA1 of KEYNOTE-598 (data cutoff: 01-SEP-2020) indicated that 
the study did not meet the prespecified success criteria for improvement in PFS or OS 
for the combination of pembrolizumab plus ipilimumab compared with pembrolizumab 
plus placebo. Furthermore, a nonbinding futility analysis was performed at IA1 at the 
request of the eDMC. This analysis showed the study met the criteria for declaring 
futility and the benefit-risk was not considered positive to continue the trial. Based 
upon these data and at the recommendation of the eDMC, no further prespecified 
analysis of primary and secondary endpoints will be performed. Exploratory objectives 
may not be pursued. Updates to the safety analyses are provided in Sec. 8.1 and Sec. 
8.6.2.
 
 
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This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary and/or key secondary hypotheses or the 
statistical methods related to those hypotheses, but prior to any unblinding/final database 
lock, then the protocol will be amended (consistent with ICH Guideline E9). Changes to 
exploratory or other nonconfirmatory analyses made after the protocol has been finalized, but 
prior to unblinding/final database lock, will be documented in a supplemental SAP (sSAP) 
and referenced in the Clinical Study Report (CSR) for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR. Separate analysis plans (i.e., separate 
documents from the sSAP) will be developed to detail PK analysis as well as biomarker 
analysis. The PRO analysis plan will be included in the sSAP.
Statistical Analysis Plan Summary
Key elements of the SAP are summarized in this section.  The comprehensive plan is 
provided in Section 8.2 – Responsibility for Analyses/In-House Blinding through Section 
8.12 – Extent of Exposure.
Study Design
Overview
Phase 3 study of Pembrolizumab + Ipilimumab versus Pembrolizumab + placebo in 
1L, Stage IV, metastatic NSCLC subjects whose tumors express PD-L1 (TPS ≥ 
50%).
Treatment
Assignment
Subjects will be randomized in a 1:1 ratio between 2 treatment arms: 
(1) pembrolizumab plus ipilimumab and (2) pembrolizumab plus placebo.
Stratification factors are as follows:
1) ECOG Performance Status (0 versus 1)
2) Geographic region (East Asia versus Non-East Asia)
3) Predominant tumor histology (squamous versus nonsquamous)
Analysis
Populations
Efficacy: Intent-to-Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary
Endpoints/
Hypotheses

OS

PFS per RECIST 1.1 based on BICR
Secondary 
Endpoints

ORR per RECIST 1.1 based on BICR

DOR

Safety and tolerability

Change from baseline in global health status/quality of life score from the 
EORTC QLQ-C30 (items 29 and 30)

TTD in PRO composite endpoint
Statistical Methods
for Key Efficacy
Analyses
The primary hypotheses will be evaluated by comparing pembrolizumab plus 
ipilimumab to pembrolizumab plus placebo in PFS and OS using a stratified
log-rank test. The hazard ratio will be estimated using a stratified Cox regression 
model. Event rates over time will be estimated within each treatment group using the 
Kaplan-Meier method. The ORR will be evaluated using a stratified Miettinen and 
Nurminen method with strata weighting by sample size [40].
Statistical Methods
for Key Safety
Analyses
As of Amendment 06, the safety analysis will include only the proportion of 
participants with certain AEs summarized by counts and percentages by treatment 
group.
 
 
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Interim Analyses
As of Amendment 06, IA1 is complete. The other prespecified analyses listed 
below will not be performed.
Two efficacy IAs and one FA are planned in this study. Results will be reviewed by
an external DMC. Details are provided in Section 8.7 – Interim Analyses.
Interim analysis 1 (IA1):  Approximately 255 deaths have been observed and 
~ 12 months after the last subject randomized. The ORR p-value from IA1 may
be evaluated for statistical significance if the PFS and/or OS null hypotheses
are rejected at IA1 or a later time.
o Purpose:  Interim PFS (~ 92% of target PFS events) and OS analyses (~ 71% 
of target OS events).
Interim analysis 2 (IA2):  Approximately 307 deaths have been observed and 
~ 19 months after the last subject randomized.
o Purpose: Final PFS analysis and interim OS analysis (~ 85% of target OS 
events).
Final analysis (FA): Approximately 361 deaths have been observed and ~ 27
months after the last subject randomized.
o Purpose: Final OS analysis.
Multiplicity
The overall Type I error rate over the multiple endpoints will be strongly controlled at 
2.5% (one-sided). A 0.6% (one-sided) Type I error rate will be allocated to test PFS 
and 1.9% (one-sided) allocated to test OS. The graphical method of Maurer and Bretz 
[41] will be applied to reallocate alpha between the hypotheses of ORR, PFS and OS. 
Group sequential methods will be used to allocate alpha between the interim and final 
analyses for the PFS and OS endpoints.
Sample Size and
Power
The planned sample size is approximately 568 subjects. With 389 PFS events, the 
study has ~ 87% power for detecting a hazard ratio of 0.69 at 0.6% (one-sided) 
significance level. With 361 deaths, the study has ~ 90% power for detecting a hazard 
ratio of 0.7 at 1.90 % (one-sided) significance level. 
Responsibility for Analyses/In-House Blinding
Note: As of Amendment 06, the study will be unblinded to the Sponsor, the 
investigational sites, and the participants. 
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blinded study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in an IVRS/IWRS.
Planned interim analyses are described in Section 8.7 – Interim Analyses. Blinding to 
treatment assignment will be maintained at all investigational sites. Treatment-level results of
the planned interim analyses will be provided by the external unblinded statistician to the 
DMC. Limited additional Sponsor personnel may be unblinded to the treatment level results 
of the interim analyses, if required, in order to act on the recommendations of the DMC (e.g., 
interaction with regulatory agencies). The extent to which individuals are unblinded with 
respect to results of interim analyses will be documented by the unblinded statistician.
 
 
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The DMC will serve as the primary reviewer of the results of the interim analyses and will 
make recommendations for discontinuation of the study or modification to an EOC of the 
Sponsor. Depending on the recommendation of the DMC, the Sponsor may prepare a 
regulatory submission. If the DMC recommends modifications to the design of the protocol 
or discontinuation of the study, this EOC and limited additional Sponsor personnel may be 
unblinded to results at the treatment level in order to act on these recommendations. The 
DMC responsibilities, review schedules, and additional logistical details will be provided in 
the DMC Charter.
Prior to final study unblinding, the external unblinded statistician will not be involved in any 
discussions regarding modifications to the protocol, statistical methods, identification of 
protocol deviations, or data validation efforts after the interim analyses.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3 – Objective(s) & 
Hypothesis(es).
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below. Exploratory endpoints will be described in the sSAP.
Efficacy Endpoints
Primary Endpoints
Overall Survival
OS is defined as the time from randomization to death due to any cause.  Subjects without 
documented death at the time of analysis will be censored at the date of last known contact.
Progression-free Survival
PFS is defined as the time from randomization to the first documented disease progression 
per RECIST 1.1 based on BICR or death due to any cause, whichever occurs first. See 
Section 8.6.1.2 – Progression-free Survival for the definition of censoring.
Secondary Endpoints
Objective Response Rate
ORR is defined as the proportion of subjects who have a CR or a PR. Responses are based on 
confirmed assessments by BICR per RECIST 1.1.
Duration of Response
For subjects who demonstrate CR or PR, DOR is defined as the time from first documented 
evidence of CR or PR until disease progression per RECIST 1.1 as assessed by BICR or 
death due to any cause, whichever occurs first. 
Change from baseline in global health status/quality of life
This is defined as a change from baseline in the global health status/quality of life score from 
the EORTC QLQ-C30 (items 29 and 30).
 
 
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Time to true deterioration in cough, pain in chest, and shortness of breath
TTD is defined as the time to the first onset of a 10-point or greater score deterioration from 
baseline in any one of the 3 symptoms, confirmed by a second adjacent 10-point or greater 
score deterioration from baseline. Cough is based on EORTC QLQ-LC13 question 1, pain in 
chest is based on EORTC QLQ-LC13 question 10, and shortness of breath is based on 
EORTC QLQ-C30 question 8.
Safety Endpoints
Safety measurements are described in Section 4.2.3.3 – Safety Endpoints and Section 7 –
Trial Procedures. Safety and tolerability will be assessed by clinical review of all relevant 
parameters including AEs, SAEs, fatal AEs, laboratory tests, and vital signs. Safety parameters 
to be analyzed include, but are not limited to, AEs, SAEs, fatal AEs, and laboratory changes. 
Analysis Populations
Efficacy Analysis Populations
The ITT population will serve as the population for primary efficacy analysis. All 
randomized subjects will be included in this population. Subjects will be included in the 
treatment group to which they are randomized.
Details on the approach to handling missing data are provided in Section 8.6 – Statistical 
Methods.
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized subjects who received at least 
1 dose of study treatment. Subjects will be included in the treatment group corresponding to 
the study treatment they actually received for the analysis of safety data using the ASaT 
population.  For most subjects, this will be the treatment group to which they are randomized.  
Subjects who take incorrect study treatment for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received. Any subject who 
receives the incorrect study medication for 1 cycle, but receives the correct treatment for all 
other cycles, will be analyzed according to the correct treatment group and a narrative will be 
provided for any events that occur during the cycle for which the subject is incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained after at least 1 dose of study 
treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required. Details on the approach to 
handling missing data for safety analyses are provided in Section 8.6 – Statistical Methods.
Patient-reported Outcomes Analysis Populations
The PRO analyses are based on the PRO full analysis set (FAS) population, defined as 
subjects who have at least 1 PRO assessment available and have received at least 1 dose of 
study medication.
 
 
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Statistical Methods
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.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 8.8 – Multiplicity. Nominal p-values 
will be computed for other efficacy analyses, but should be interpreted with caution due to 
potential issues of multiplicity.
The stratification factors used for randomization (see Section 5.4 – Stratification) will be 
applied to all stratified analyses, in particular, the stratified log-rank test, stratified Cox 
model, and stratified Miettinen and Nurminen method [42]. In the event that there are small 
strata, for the purpose of analysis, strata will be combined to ensure sufficient number of 
participants, responses and events in each stratum. Details regarding the pooling strategy will 
be prespecified in the sSAP prior to the database lock for the first analysis when each 
applicable endpoint will be analyzed, and decisions regarding the pooling will be based on a 
blinded review of response and event counts by stratum.
8.6.1.1
Overall Survival
The nonparametric Kaplan-Meier method will be used to estimate the survival curve in each 
treatment group. The treatment difference in survival will be assessed by the stratified log-
rank test. A stratified Cox proportional hazard model with Efron's method of tie handling will 
be used to assess the magnitude of the treatment difference (i.e., the hazard ratio). The hazard 
ratio and its 95% CI from the stratified Cox model with Efron's method of tie handling and
with a single covariate for treatment will be reported. The stratification factors used for 
randomization (see Section 5.4– Stratification) will be applied to both the stratified log-rank 
test and the stratified Cox model.
In case the proportional hazards assumption does not hold, Restricted Mean Survival Time 
(RMST) method may be conducted for OS to account for the possible nonproportional 
hazards effect as a sensitivity analysis.
8.6.1.2
Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron's method of tie handling will be 
used to assess the magnitude of the treatment difference (i.e., hazard ratio) between the 
treatment groups. The hazard ratio and its 95% CI from the stratified Cox model with Efron's 
method of tie handling and with a single covariate for treatment will be reported. The 
stratification factors used for randomization (see Section 5.4 – Stratification) will be applied 
to both the stratified log-rank test and the stratified Cox model. 
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. For the primary analysis, for the subjects who have PD, the true date of disease 
 
 
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progression will be approximated by the date of the first assessment at which PD is 
objectively documented per RECIST 1.1 by BICR, regardless of discontinuation of study 
drug. Death is considered as a confirmed PD event. 
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, 
2sensitivity analyses with a different set of censoring rules will be performed. The first 
sensitivity analysis is the same as the primary analysis except that the data for any subject 
who misses more than 1 disease assessment (with or without a subsequent death or 
progression) are censored at the last disease assessment prior to missing visits. The second 
sensitivity analysis is the same as the primary analysis except that it considers 
discontinuation of treatment or initiation of an anticancer treatment subsequent to 
discontinuation of study-specified treatments, whichever occurs later, to be a PD event for 
subjects without documented PD or death.  If a subject meets multiple criteria for censoring, 
the censoring criterion that occurs earliest will be applied.  The censoring rules for primary 
and sensitivity analyses are summarized in Table 11. In case there is an imbalance between 
the treatment groups on disease assessment schedules or censoring patterns, we will perform 
an additional PFS sensitivity analysis using time from randomization to scheduled tumor 
assessment time as opposed to actual tumor assessment.
In case the proportional hazards assumption is not valid, RMST method may be conducted 
for PFS to account for the possible nonproportional hazards effect as a sensitivity analysis.
Table 11
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death documented 
after ≤1 missed disease 
assessment, and before 
new anticancer therapy, 
if any
Progressed at date 
of documented PD 
or death
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or 
death.
Death or progression 
immediately after ≥2 
consecutive missed 
disease assessments, or 
after new anticancer
therapy
Censored at last 
disease assessment 
prior to the earlier 
date of ≥2 
consecutive missed 
disease assessment 
and new anticancer
therapy, if any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or 
death.
No PD and no death; and 
new anticancer treatment 
is not initiated
Censored at last 
disease assessment 
Censored at last 
disease assessment 
Progressed at treatment 
discontinuation due to 
reasons other than CR; 
otherwise censored at 
last disease assessment 
if still on study treatment 
or completed study 
treatment.
 
 
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Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and no death; 
new anticancer treatment 
is initiated
Censored at last 
disease assessment 
before new 
anticancer 
treatment 
Censored at last 
disease assessment
Progressed at date of 
new anticancer 
treatment.
Abbreviations: PFS=progression-free survival; PD=progressive disease.
8.6.1.3
Objective Response Rate
The stratified Miettinen and Nurminen method will be used for comparison of the ORR 
between the 2 treatment groups. The difference in ORR and its 95% CI from the stratified 
Miettinen and Nurminen method with strata weighting by sample size will be reported. The 
stratification factors used for randomization (see Section 5.4– Stratification) will be applied 
to the analysis. Subjects without assessments are considered nonresponders. 
8.6.1.4
Duration of Response
For subjects who demonstrate CR or PR, DOR is defined as the time from first documented 
evidence of CR or PR until disease progression or death due to any cause, whichever occurs 
first. Censoring rules for DOR are summarized in Table 12.
For DOR analysis, a summary of the reasons responding subjects are censored will also be 
provided. Responding subjects who are alive, have not progressed, have not initiated new 
anticancer treatment, have not been determined to be lost to follow-up, and have had a 
disease assessment within ~ 5 months of the data cutoff date are considered ongoing 
responders at the time of analysis.
If a subject meets multiple criteria for censoring, the 
censoring criterion that occurs earliest will be applied.
Table 12
Censoring Rules for Duration of Response
Situation
Date of Progression or Censoring
Outcome
No 
progression 
nor 
death, 
no 
new 
anticancer therapy initiated
Last adequate disease assessment
Censor
(nonevent)
No progression nor death, new anticancer
therapy initiated
Last adequate disease assessment 
before 
new 
anticancer
therapy 
initiated
Censor
(nonevent)
Death or progression immediately after ≥2 
consecutive missed disease assessments or 
after new anticancer therapy, if any
Earlier date of last adequate disease 
assessment prior to ≥2 missed 
adequate disease assessments and 
new anticancer therapy, if any
Censor
(nonevent)
Death or progression after ≤1 missed 
disease 
assessments 
and 
before 
new 
anticancer therapy, if any
PD or death
End of response
(Event)
Abbreviations:  PD = progressive disease
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.  
 
 
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If sample size permits, DOR will be summarized descriptively using the Kaplan-Meier 
method.  Only the subset of subjects who show a CR or PR will be included in this analysis.
8.6.1.5
Change from Baseline in Global Health Status/Quality of Life
The time point for the mean change from baseline will be determined based on blinded data 
review prior to the database lock for any PRO analysis and documented in the sSAP.
To assess the treatment effects on the PRO score change from baseline in the global health 
status/quality of life, a constrained longitudinal data analysis (cLDA) model proposed by 
Liang and Zeger [43] will be applied, with the PRO score as the response variable, and 
treatment, time, the treatment by time interaction, and stratification factors used for 
randomization (see Section 5.4 – Stratification) as covariates. The treatment difference in 
terms of least square (LS) mean change from baseline will be estimated from this model 
together with 95% CI. Model-based LS mean with 95% CI will be provided by treatment 
group for PRO scores at baseline and post-baseline time point.
8.6.1.6
Time to True Deterioration in Cough, Pain in Chest, and Shortness of Breath
TTD is defined as the time to first onset of 10 or more deterioration from baseline with 
confirmation under right-censoring rule. Subjects with no confirmed deterioration from 
baseline will be censored at the date of their last observation. The nonparametric Kaplan-
Meier method will be used to estimate the deterioration curve in each treatment group. The 
treatment difference in time to deterioration will be assessed by the stratified log-rank test. A 
stratified Cox proportional hazard model with Efron’s method of tie handling will be used to 
assess the magnitude of the treatment difference (hazard ratio) between the treatment groups. 
The traditional time to deterioration, defined as the time to first onset of 10 or more 
deterioration from baseline without confirmation under right-censoring rule, may also be 
summarized.
8.6.1.7
Analysis Strategies for Key Efficacy Endpoints
Table 13 summarizes the primary analysis approach for primary and secondary efficacy 
endpoints. Sensitivity analysis methods are described above for each endpoint as applicable.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, and 
interim analyses is described in Section 8.7 – Interim Analyses and in Section 8.8 –
Multiplicity.
 
 
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Table 13
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
Statistical Methoda
Analysis 
Population
Missing Data Approach
Primary:
OS
Test: Stratified log-rank test 
to assess the treatment 
difference
Estimation: Stratified Cox 
model with Efron’s tie 
handling method to assess the 
magnitude of treatment 
difference
ITT

Censored at last known 
alive date.
PFS per RECIST 1.1 by 
BICR
Test: Stratified log-rank test 
to assess the treatment 
difference
Estimation: Stratified Cox 
model with Efron’s tie 
handling method to assess the 
magnitude of treatment 
difference
ITT

Primary censoring rule

Sensitivity analysis 1

Sensitivity analysis 2
(More details are in Table 11).
Secondary :
ORR per RECIST 1.1 by 
BICR
Stratified Miettinen and 
Nurminen method with 
sample size weights
ITT
Subjects without assessments 
are considered nonresponders.
DOR per RECIST 1.1 by 
BICR
Summary statistics using 
Kaplan-Meier method
All 
responders 
in ITT
Censoring rules in Table 12.
Change from baseline in 
global health 
status/quality of life
(items 29 and 30)
cLDA model
PRO FAS
Missing at random
TTD
Test:  Stratified log-rank test 
to assess the treatment 
difference
Estimation:  Stratified Cox 
model with Efron’s tie 
handling method to assess the 
magnitude of treatment 
difference
PRO FAS
Censoring at the last available 
assessment.
a
Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for 
randomization (Section 5.4 – Stratification) will be applied to the analysis.
Abbreviations: cLDA=constrained longitudinal data analysis; DOR=duration of response; PRO FAS=patient reported 
outcome full analysis set; ITT=intent-to-treat; ORR=objective response rate; OS=overall survival; RECIST=Response 
Evaluation Criteria in Solid Tumors Version 1.1; TTD=time to true deterioration.
 
 
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Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements.
As of Amendment 06, the following safety analyses will be performed: individual events 
and the broad AE categories including the proportion of participants with any AE, a drug-
related AE, a serious AE, an AE which is both drug-related and serious, a Grade 3-5 AE, a 
drug-related Grade 3-5 AE, a fatal AE, dose interruption due to an AE, and discontinuation 
due to an AE will be summarized by counts and percentages by treatment group. 
As of Amendment 06, all other safety analyses listed in this section below will not be 
performed.
The analysis of safety results will follow a tiered approach (Table 14). The tiers differ with 
respect to the analyses that will be performed. Adverse experiences (specific terms as well as 
system organ class terms) and events that meet predefined limits of change in laboratory and 
vital signs, and ECG parameters are either prespecified as Tier-1 endpoints or will be 
classified as belonging to “Tier 2” or “Tier 3,” based on observed proportions of participants 
with an event.  
Tier 1 Events
Safety parameters or AEOSI that are identified a priori constitute “Tier 1” safety endpoints 
that will be participant to inferential testing for statistical significance with p-values and 95% 
CIs provided for between-group comparisons. AEOSI that are immune-mediated or 
potentially immune-mediated are well documented and will be evaluated separately; 
however, these events have been characterized consistently throughout the pembrolizumab 
clinical development program and determination of statistical significance is not expected to 
add value to the safety evaluation. Based on toxicity data across the pembrolizumab program, 
the combination of pembrolizumab with ipilimumab is not anticipated to produce toxicity 
beyond what is expected for these therapies alone. Thus, there are no AEs that warrant 
elevation to Tier 1 in this study.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method, an 
unconditional, asymptotic method [40].
Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the event. The threshold of at least 10% of participants was chosen for Tier 2 event because 
the population enrolled in this study are in critical condition and usually experience various 
AEs of similar types regardless of treatment; events reported less frequent than 10% of 
participants would obscure the assessment of overall safety profile and add little to the 
interpretation of potentially meaningful treatment differences. In addition, Grade 3 to 5 AE 
(≥5% of participants in 1 of the treatment groups) and SAE (≥2% of participants in 1 of the 
treatment groups) will be considered Tier 2 endpoints. Because many 95% CIs may be 
 
 
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provided without adjustment for multiplicity, the CIs should be regarded as a helpful 
descriptive measure to be used in safety review, not a formal method for assessing the 
statistical significance of the between-group differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters (Table 14).
Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters, summary statistics for baseline, on treatment, and change from baseline values 
will be provided by treatment group in table format.  
Table 14
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Specific AEs (incidence ≥10% of participants in one 
of the treatment groups)
X
X
Specific Grade 3-5 AEs (incidence ≥5% of 
participants in one of the treatment groups)
X
X
Specific serious AEs (≥2% of participants in one of 
the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <10% of 
participants in all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, Vital 
Signs)
‡
Includes only those endpoints not prespecified as Tier 1 or not already prespecified as Tier-2 endpoints.
Note: SOC=System Organ Class; PDLC=Predefined Limit of Change; X = results will be provided.
Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of subjects randomized, and the primary reasons 
for discontinuation will be displayed.  Demographic variables (e.g., age, gender) and baseline 
characteristics will be summarized by treatment either by descriptive statistics or categorical 
tables.
 
 
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Interim Analyses
Interim Safety Analyses
The DMC will conduct regular safety monitoring. The timing of the safety monitoring will 
be specified in the DMC Charter. As of Amendment 06, no additional eDMC reviews will 
take place.
Interim Efficacy Analyses
Note: As of Amendment 06, based on the eDMC’s recommendation after reviewing IA1 
efficacy and safety data, the originally planned IA2 and FA described below will not be 
performed. The nonbinding futility analysis prespecified at IA2 was performed at IA1 
at the recommendation of the eDMC. 
There are 2 planned interim efficacy analyses in addition to the final efficacy analysis for this 
study.
Interim Analysis 1
The interim analysis 1 (IA1) is an interim analysis for OS. It will be performed when ~ 255
deaths have been observed and ~ 12 months after the last subject randomized, whichever 
occurs later. An interim analysis of PFS will also be performed at this time. It is estimated 
that ~ 357 PFS events will have been observed, but there is no requirement for the number of 
PFS events to proceed with the analysis. IA1 will also be the only analysis for ORR.
Interim Analysis 2
The interim analysis 2 (IA2) is an interim analysis for OS. It will be performed when ~ 307 
deaths have been observed and ~ 19 months after the last subject randomized, whichever 
occurs later. The final analysis of PFS will also be performed at this time. It is estimated that 
~ 389 PFS events will have been observed, but there is no PFS event count requirement to 
proceed with the analysis. A nonbinding futility analysis based on OS may be conducted at 
IA2. Further details of any futility evaluation will be specified in the sSAP.
Final Analysis
The FA will evaluate OS only. The analysis is planned when ~ 361 deaths have been 
observed and ~ 27 months after the last subject randomized, whichever occurs later.
The Type I error control for efficacy analyses as well as efficacy bounds are described in 
Section 8.8 – Multiplicity.
Multiplicity
The overall Type I error rate is strongly controlled at 0.025 (one-sided) α level. The trial uses 
the graphical method of Maurer and Bretz [41] to provide strong multiplicity control for 
multiple hypotheses as well as interim analyses.
Figure 4 shows the initial one-sided 
α-allocation for each hypothesis in the ellipse representing the hypothesis. The initial weights 
for reallocation from each hypothesis to the others are represented in the boxes on the lines 
connecting hypotheses.
 
 
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Figure 4
Multiplicity Graph for Type I Error Control
Abbreviations:  PFS=progression-free survival; ORR=objective response rate; OS=overall survival.
Objective Response Rate
No initial alpha is allocated to test ORR. However, the ORR p-value from IA1 (ie, no new 
data is added after IA1) can be compared to an α-level of eg, 0.025 if the null hypotheses for 
both PFS and OS are rejected at IA1 or a later time. The power at the updated α-level of 
0.025 is 99.8%, with an approximate treatment difference (ΔORR) required for reaching the 
efficacy bound being 8.1%, assuming underlying 39% and 59% ORR in the control and 
experimental groups, respectively. 
Progression-free Survival
The trial initially allocates α=0.006, one-sided, to test PFS. If the null hypothesis for OS is 
rejected, its α=0.019 is essentially fully reallocated to PFS hypothesis testing. Thus, the PFS 
null hypothesis may be tested at α=0.006 or eg. α=0.025 (if both ORR and OS null 
hypotheses are rejected). Table 15 below shows the boundary properties for each of these α-
levels for the IAs and FA, which were derived using a Lan-DeMets O'Brien-Fleming 
spending function. Note that the final row indicates the total power to reject the null 
hypothesis for PFS at each α-level. Also note that if the OS null hypothesis is rejected at an 
IA or FA, each PFS IA and FA test may be compared to its updated bounds considering the α 
reallocation from the OS hypothesis.
 
 
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Table 15
Efficacy Boundaries and Properties for Progression-free Survival Analyses
Analysis
Value
=0.006
=0.025
IA1: 92% a
N: 568
Events: 357
Month: ~ 32 f
Z
2.6394 
2.0667 
p (1-sided)b
0.0042 
0.0194 
HR at boundc
0.7562 
0.8034 
P(Cross) if HR=1d
0.0042 
0.0194 
P(Cross) if HR=0.69e
0.8085 
0.9251 
IA2: Final 
PFS Analysis
N: 568
Events: 389
Month: ~ 39 f
Z
2.5869 
2.0575 
p (1-sided)b
0.0048 
0.0198 
HR at boundc
0.7690 
0.8115 
P(Cross) if HR=1d
0.0060 
0.0250 
P(Cross) if HR=0.69e
0.8692
0.9517
a
Percentage of total planned events at each interim analysis.
b
The nominal α for testing.
c
The approximate HR required to reach an efficacy bound
d
The probability of crossing a bound under the null hypothesis
e
The probability of crossing a bound under the alternative hypothesis
f
The approximate number of months since first subject randomized
Overall Survival
The OS hypothesis may be tested at α=0.019 or eg. α=0.025 (if both ORR and PFS null 
hypothese are rejected). Table 16, analogous to the PFS table explained above, demonstrates 
the boundary properties for each of these α-levels for the IAs and FA, which were derived 
using a Lan-DeMets O'Brien-Fleming spending function. Note that if the PFS null hypothesis 
is rejected at an IA, each OS interim and final analysis test may be compared to its updated 
bounds considering the α reallocation from the PFS hypothesis.
 
 
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Table 16
Efficacy Boundaries and Properties for Overall Survival Analyses
Analysis
Value
=0.019
=0.025
IA1: 71%a
N: 568
Events: 255
Month: ~ 32 f
Z 
2.5592 
2.4257 
p (1-sided)b
0.0052 
0.0076 
HR at bound c
0.7256 
0.7378 
P(Cross) if HR=1d
0.0052 
0.0076 
P(Cross) if HR=0.7 e
0.6135 
0.6631 
IA2: 85%a
N: 568
Events: 307
Month: ~ 39 f
Z 
2.3490 
2.2316 
p (1-sided) b
0.0094 
0.0128 
HR at bound c
0.7646 
0.7750 
P(Cross) if HR=1d
0.0110 
0.0151 
P(Cross) if HR=0.7e  
0.7900 
0.8228 
FA g:
N: 568
Events: 361
Month: ~ 47 f
Z 
2.1577 
2.0504 
p (1-sided) b
0.0155 
0.0202 
HR at bound c
0.7967 
0.8058 
P(Cross) if HR=1d
0.0190 
0.0250 
P(Cross) if HR=0.7e
0.8985
0.9167
a
Percentage of total planned events at each interim analysis.
b
The nominal α for testing.
c
The approximate HR required to reach an efficacy bound
d
The probability of crossing a bound under the null hypothesis
e
The probability of crossing a bound under the alternative hypothesis
f
The approximate number of months since first subject randomized
g
FA will be conducted at 34 months after the enrollment of the last participant at the latest, if the event 
accumulation is slower than expected.
The bounds provided in Table 15 and Table 16 are based on the assumption that the expected 
number of PFS events at IA1 and IA2 (FA for PFS) are 357 and 389, respectively, the 
number of OS events at IA1, IA2, and FA (FA for OS) are 255, 307, and 361, respectively. 
At the time of an analysis, the observed number of events may differ substantially from the 
expected. To avoid overspending at an interim analysis and leave reasonable alpha for the 
final analysis, the minimum alpha spending strategy will be adopted. At an IA, the 
information fraction used in Lan-DeMets spending function to determine the alpha spending 
at the IA will be based on the minimum of the expected information fraction and the actual 
information fraction at each analysis. Specifically,  

In the scenario that the events accrue slower than expected and the observed number of 
events is less than the expected number of events at a given analysis, the information 
fraction will be calculated as the observed number of events at the interim analysis over 
the target number of events at FA. 

In the scenario that the events accrue faster than expected and the observed number of 
events exceeds the expected number of events at a given analysis, then the information 
 
 
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fraction will be calculated as the expected number of events at the interim analysis over 
the target number of events at FA.
The final analysis will use the remaining Type I error that has not been spent at the earlier 
analyses. The event counts for all analyses will be used to compute correlations.
Of note, while the information fraction used for alpha spending calculation will be the 
minimum of the actual information fraction and the expected information fraction, the 
correlations required for deriving the bounds will still be computed using the actual 
information fraction based on the observed number of events at each analysis over the target 
number of events at FA.
The minimum spending approach assumes timing is not based on any observed Z-value and 
thus the Z test statistics used for testing conditioned on timing are multivariate normal. Given 
the probabilities derived with the proposed spending method, the correlations based on actual 
event counts are used to compute bounds that control the Type I error at the specified alpha 
level for a given hypothesis conditioned on the interim analysis timing. Since this is true 
regardless of what is conditioned on, the overall Type I error for a given hypothesis 
unconditionally is controlled at the specified level. By using more conservative spending 
early in the study, power can be retained to detect situations where the treatment effect may 
be delayed.
Safety Analyses
The eDMC has responsibility for assessment of overall risk: benefit. When prompted by 
safety concerns, the eDMC can request corresponding efficacy data. As of Amendment 06, 
no additional eDMC reviews will take place.
Sample Size and Power Calculations
The study plans to randomize approximately 568 subjects with 1:1 ratio into the 
pembrolizumab plus ipilimumab arm and the pembrolizumab plus placebo arm. 
With 389 PFS events, the study has ~ 87% power for detecting a hazard ratio of 0.69 at 
0.60% (one-sided) significance level. With 361 deaths, the study has ~ 90% power for 
detecting a hazard ratio of 0.7 at 1.90% (one-sided) significance level. 
The above sample size and power calculations for PFS and OS assume the following, with 
control arm assumption estimated from the pembrolizumab arm from KEYNOTE-042 in the 
PD-L1 TPS ≥50% population:

PFS follows a piecewise exponential distribution with a median of 6.5 months before 
6.5 months and a median of 14.5 months after 6.5 months in the control group.

OS follows an exponential distribution with a median of 20 months for the control 
group.

The HR for PFS and OS between the experimental and control groups is 0.69 and 0.7, 
respectively. 

Enrollment period of 20 months.

A yearly dropout rate of 13% and 1% for PFS and OS, respectively.
 
 
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The sample size and power calculations were performed in the software EAST and 
R (package “gsDesign”).
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoints will be estimated and plotted within each category of the following classification 
variables:

ECOG Performance Status (0 versus 1)

Geographic region (East Asia versus Non-East Asia)

Histology (squamous versus nonsquamous)

Age (<65 versus ≥65 years)

Sex (female versus male)

Race (white versus non-white)

Smoking status (never versus former/ current)

Baseline brain metastasis status (yes versus no)
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above.
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
Extent of exposure for a subject is defined as number of cycles in which the subject receives
the study medication infusion. Summary statistics will be provided on extent of exposure for 
ASaT population.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
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.
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed 
from the study. This section has been updated accordingly.
 
 
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Table 17
Product Descriptions
Product Name & 
Potency
Dosage Form
Source/Additional Information
MK-3475 25 mg/mL
Solution for Infusion
Provided centrally by the Sponsor.
All supplies indicated in Table 17 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 17 will be provided by the trial 
site, subsidiary or designee. Every attempt should be made to source these supplies from a 
single lot/batch number. The trial site is responsible for recording the lot number, 
manufacturer, and expiry date for any locally purchased product as per local guidelines 
unless otherwise instructed by the Sponsor.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed 
from the study. This section has been updated accordingly.
The open-label pembrolizumab will be provided in 2 vial kits.
Clinical Supplies Disclosure
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed 
from the study. This section is no longer applicable.
The trial is blinded but supplies are provided open label; therefore, an unblinded pharmacist 
or qualified trial site personnel will be used to blind supplies. Treatment identity (name, 
strength or potency) is included in the label text; random code/disclosure envelopes or lists 
are not provided.
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.
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 
 
 
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discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
NOTE: As of Amendment 06, ipilimumab and matching placebo have been removed 
from the study. This section is no longer applicable.
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
Confidentiality
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.
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.
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;
 
 
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2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
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.
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.
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 
 
 
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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/IEC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
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.  
 
 
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ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must 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 Protocol/CSR 
CI during the anticipated review process, thorough understanding of clinical trial methods, 
appropriate enrollment of subject cohort, timely achievement of trial milestones).  The 
Protocol CI must be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
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.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow 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.
 
 
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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.
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.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
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.
 
 
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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 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.
11.0 LIST OF REFERENCES
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Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. 
iRECIST: 
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criteria 
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immunotherapeutics. Lancet Oncol. 2017 Mar;18(3):e143-52.
[2]
Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8.
[3]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48.
[4]
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 
2001;98(24):13866-71.
[5]
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: 
Jekyll or Hyde. Cancer Metastasis Rev 2007;26(3-4):373-400.
[6]
Usubütün A, Ayhan A, Uygur MC, Özen H, Toklu C, Ruacan S. Prognostic 
factors in renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.
 
 
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[7]
Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive 
lymphocyte and dendritic cell infiltration after interleukin-2 immunotherapy. 
Report of a case. Tumori 2008;94(3):426-30.
[8]
Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema 
H, et al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary 
and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol 
Immunother 2009;58(3):449-59.
[9]
Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification 
of positive selection in the thymus of PD-1-deficient mice. J Exp Med. 2000 Mar 
6;191(5):891-8.
[10]
Pölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. 
Foxp3(+) cell infiltration and granzyme B(+)/Foxp3(+) cell ratio are associated 
with outcome in neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer 
Immunol Immunother 2010;59(6):909-19.
[11]
Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, et al. 
Intratumoral CD8+ T/FOXP3+ cell ratio is a predictive marker for survival in 
patients with colorectal cancer. Cancer Immunol Immunother 2010;59:653-61.
[12]
Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, et al. Inflammatory tumor 
microenvironment is associated with superior survival in hepatocellular carcinoma 
patients. J Hepatol 2010;52:370-9.
[13]
Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes 
correlates with poor prognosis in renal cell carcinoma. BJU Int 2011;107(9):1500-
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[14]
Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic 
value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 
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[15]
Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J 
Clin Oncol 2005;23(10):2346-57.
[16]
Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. 
Treatment of metastatic melanoma with autologous CD4+ T cells against NY-
ESO-1. N Engl J Med 2008;358(25):2698-703.
 
 
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[17]
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.
[18]
Peters S, Adjei AA, Gridelli C, Reck M, Kerr K, Felip E, et al. Metastatic non-
small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for 
diagnosis, treatment and follow-up. Annals Oncol 2012;23(Supplement 7):vii56-
vii64.
[19]
Sandler AB, Nemunaitis J, Denham C, von Pawel J, Cormier Y, Gatzemeier U, et 
al. Phase III Trial of Gemcitabine Plus Cisplatin Versus Cisplatin Alone in 
Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer. J 
Clin Oncol 2000;18(1):122-30.
[20]
Zatloukal P, Petruzelka L, Zemanova M, Kolek V, Skrickova J, Pesek M, et al. 
Gemcitabine plus cisplatin vs. gemcitabine plus carboplatin in stage IIIb and IV 
non-small cell lung cancer: a phase III randomized trial. Lung Cancer 
2003;41(3):321-31.
[21]
Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et 
al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus 
pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell 
lung cancer. J Clin Oncol 2008;26(21):3543-51.
[22]
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 May 21;372(21):2018-28.
[23]
Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. 
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced 
non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. 
Lancet. 2016 Apr 9;387(10027):1540-50.
[24]
Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. 
Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung 
Cancer. N Engl J Med. 2016 Oct 8. [Epub ahead of print].
[25]
Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, et al. Final 
analysis of the phase III KEYNOTE-042 study: pembrolizumab (pembro) versus 
platinum-based chemotherapy (chemo) as first-line therapy for patients (pts) with 
PD-L1-positive locally advanced/metastatic NSCLC [abstract]. Presented at: 
European Lung Cancer Congress (ELCC); 2019 Apr 10-13; Geneva (Switzerland). 
Ann Oncol. 2019;30(suppl 2):ii38-68. Abstract no. 1020.
 
 
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[26]
Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, et al. Final 
analysis of the phase 3 KEYNOTE-042 study: pembrolizumab vs platinum-based 
chemotherapy as first-line therapy for patients with PD-L1-positive locally 
advanced/metastatic NSCLC. Slides presented at: European Lung Cancer 
Congress (ELCC); 2019 Apr 10-13; Geneva (Switzerland). Abstract no. 1020.
[27]
Globocan 2012: Lung Cancer Estimated Incidence, Mortality and Prevalence 
Worldwide in 2012 [Internet]. Lyon (FR): World Health Organization, 
International Agency for Research on Cancer (IARC). c2014 – [updated 2014 Oct 
3]. Available from: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx
[28]
Socinski M, Creelan B, Horn L, Reck M, Paz-Ares L, Steins M, et al. A phase 3 
trial of nivolumab vs investigator s choice (IC) of platinum-based doublet 
chemotherapy (PT-DC) as first-line therapy for stage iv/recurrent programmed 
death ligand 1 (PD-L1)−positive NSCLC [abstract]. Abstracts of the 2016 ESMO 
Congress; 2016 Oct 7-11; Copenhagen; ESMO Congress; 2016. p. 1-3.
[29]
Hellmann MD, Rizvi NA, Goldman JW, Gettinger SN, Borghaei H, Brahmer JR, 
et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-
cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort 
study. Lancet Oncol. 2016 Dec 2. [Epub ahead of print].
[30]
Goldman JW, Antonia SJ, Gettinger SN, Borghaei H, Brahmer JR, Ready NE, et 
al. Nivolumab (N) plus ipilimumab (I) as first-line (1L) treatment for advanced 
(adv) NSCLC: 2-yr OS and long-term outcomes from CheckMate 012. Poster 
session presented at American Society of Clinical Oncology (ASCO), 2017 June 
2-6; Chicago, IL.
[31]
Long GV, Atkinson V, Cebon JS, Jameson MB, Fitzharris BM, McNeil CM, et al. 
Pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma: Results 
of the KEYNOTE-029 expansion cohort. Poster session presented at American 
Society of Clinical Oncology, 2016 June 3-7; Chicago, IL.
[32]
Garassino MC, Gadgeel S, Esteban E, Felip E, Speranza G, Domine M, et al. 
Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed 
and platinum in patients with previously untreated, metastatic, non-squamous non-
small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, 
placebo-controlled, phase 3 trial. Lancet Oncol. 2020 Mar;21:387-97.
[33]
Mazieres J, Kowalski D, Luft A, Vicente D, Tafreshi A, Gumus M, et al. Health-
related quality of life with carboplatin-paclitaxel or nab-paclitaxel with or without 
pembrolizumab in patients with metastatic squamous non-small-cell lung cancer. J 
Clin Oncol. 2019;38(3):271-80.
 
 
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[34]
Barlesi F, Garon EB, Kim D-W, Felip E, Han J-Y, Kim J-H, et al. Assessment of 
Health-Related Quality of Life in KEYNOTE-010: A Phase 2/3 Study of 
Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced 
NSCLC. Poster session Presented at: European Society for Medical Oncology 
(ESMO) 2016 Congress; 2016 Oct 7-11; Copenhagen, DK.
[35]
Brahmer JR, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. 
Health-related quality of life for pembrolizumab vs chemotherapy in advanced 
NSCLC with PD-L1 TPS ≥50%: data from KEYNOTE-024. Poster session 
Presented at: IASLC 17th World Conference on Lung Cancer; 2016 Dec  4-7; 
Vienna, AT.
[36]
Liepa AM, Bushnell DM, Atkinson TM, DeBusk K, McCarrier KP, Martin ML, et 
al. Evaluating the Non-Small Cell Lung Cancer Symptom Assessment 
Questionnaire (NSCLC-SAQ): results from the quantitative pilot study. Poster 
session presented at: IASLC 2016. 17th World Conference on Lung Cancer; 2016 
Dec 4-7; Vienna, AT.
[37]
McCarrier KP, Atkinson TM, DeBusk KP, Liepa AM, Scanlon M, Coons SJ; 
Patient-Reported Outcome Consortium, Non–Small Cell Lung Cancer Working 
Group. Qualitative development and content validity of the Non-small Cell Lung 
Cancer Symptom Assessment Questionnaire (NSCLC-SAQ), a patient-reported 
outcome instrument. Clin Ther. 2016 Apr;38(4):794-810.
[38]
Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, LebbéC, et al. Guidelines for 
the evaluation of immune therapy activity in solid tumors: immune-related 
response criteria. Clin Cancer Res 2009;15(23):7412-20.
[39]
Hodi FS, Ribas A, Daud A, Hamid O, Robert C, Kefford R, et al. Patterns of 
response in patients with advanced melanoma treated with Pembrolizumab (MK-
3475) and evaluation of immune-related response criteria (irRC). J Immunother 
Cancer. 2014;2(Suppl 3):P103.
[40]
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 
1985;4:213-26.
[41]
Maurer W, Bretz F. Multiple testing in group sequential trials using graphical 
approaches. Stat Biopharm Res 2013;5(4):311-20.
[42]
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 
1985;4:213-26.
[43]
Liang K-Y, Zeger SL. Longitudinal data analysis of continuous and discrete 
reponses for pre-post designs*. Sankhya: the indian journal of statistics 
2000;62:134-48.
 
 
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12.0 APPENDICES
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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Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this trial as outlined in Section 7.1.3.5 –
Future Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in Future 
Biomedical Research.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all 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 the visit designated in the 
trial flow chart.  If delayed, present consent at next possible Subject Visit.  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.
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(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the 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.  This 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 unique code will be held at the trial site.  No personal identifiers will appear on 
the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in future biomedical research 
protocol and consent. Future Biomedical Research specimens remaining with the third 
party after specific analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and ask that their 
biospecimens not be used for Future Biomedical Research.  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). 
 
 
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Subsequently, the subject's specimens will be flagged in the biorepository and restricted 
to main study use only. If specimens were collected from study participants specifically 
for Future Biomedical Research, these specimens will be removed from the biorepository 
and destroyed. Documentation will be sent to the investigator confirming withdrawal
and/or destruction, if applicable. It is the responsibility of the investigator to inform the 
subject of completion of the withdrawal and/or destruction, if applicable.  Any analyses 
in progress at the time of request for withdrawal/destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to 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 important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and subjects.  Subjects will not be identified by 
 
 
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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 FBR, risks to the subject have been minimized. No additional risks to the subject 
have been identified as no additional specimens are being collected for FBR (i.e., only 
leftover samples are being retained).
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
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
 
 
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Eastern Cooperative Oncology Group Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance 
without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden 
ET, Carbone PP: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982;5:649-655. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.
 
 
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Description of the iRECIST Process for Assessment of Disease Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For subjects who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a subject on study treatment 
until repeat imaging is obtained (using iRECIST for subject management (see Table 8 and 
Figure 3). This decision by the investigator should be based on the subject’s overall clinical 
condition.
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of 
disease

No decline in ECOG Performance Status 

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any subject deemed clinically unstable should be discontinued from study treatment at site-
assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging for 
confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the subject may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per investigator assessment. Images should continue to be sent in to the central 
imaging vendor for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
o
Note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology.

Unequivocal progression of nontarget lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
 
 
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New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.  
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline.  All other new lesions will be followed qualitatively 
as New Lesions – Nontarget.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the subject will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the initial iUPD show worsening
o
For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared to any prior iUPD time point
o
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
o
For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD 
time point 

Visible growth of new nontarget lesions 

The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule.  The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
 
 
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Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudoprogression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
subject continues to be clinically stable, study treatment may continue and follow the regular 
imaging schedule. If PD is confirmed, subjects will be discontinued from study treatment.
NOTE: If a subject has confirmed radiographic progression (iCPD) as defined above, but the 
subject is achieving a clinically meaningful benefit, an exception to continue study treatment 
may be considered following consultation with the Sponsor. In this case, if study treatment is 
continued, tumor imaging should continue to be performed following the intervals as 
outlined in the Trial Flow Chart in Section 6. and submitted to the central imaging vendor.
Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudoprogression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:

Target lesions
o
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudoprogression. 
The nadir is always the smallest sum of diameters seen during the entire trial, 
either before or after an instance of pseudoprogression.

Nontarget lesions
o
If nontarget lesions have never shown unequivocal progression, their doing so for 
the first time results in iUPD.
o
If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
nontarget lesions, taken as a whole.

New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
 
 
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o
Previously identified new target lesions show an increase of ≥5 mm in the new 
lesion sum of diameters, from the nadir value of that sum
o
Previously identified nontarget lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception:  if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [1].
 
 
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Contraceptive Guidance and Pregnancy Testing
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with 2 FSH measurements in the 
postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Requirements
Male Participants:
NOTE: As of amendment 06, contraception is no longer required for male participants. 
Sperm donation is also acceptable.
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in Section 5.1.2: 
●
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent
●
Use a male condom plus partner use of a contraceptive method with a failure rate of <1% 
per year as described in Table 18 when having penile-vaginal intercourse with a WOCBP
who is not currently pregnant.
 
 
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○
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration.
Female Participants:
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in
Table 18 during the protocol-defined time frame in Section 5.1.2. 
Table 18
Highly Effective Contraception Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing) hormonal contraception b, c
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b, c
○
Oral 
○
Injectable 
Highly 
Effective 
Methods 
That 
Have 
Low 
User 
Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implant b, c
●
Intrauterine hormone-releasing system (IUS) b
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. 
●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.) 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for participants 
of clinical studies. 
a) Typical use failure rates are higher than perfect-use failure rates (i.e. when used consistently and 
correctly). 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for at 
least 120 days, corresponding to time needed to eliminate study treatment plus 30 days for study treatments 
with genotoxic potential  after the last dose of study treatment.
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
hormonal contraceptives are limited to those which inhibit ovulation. 
 
 
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Pregnancy Testing
WOCBP should only be included after a negative highly sensitive serum pregnancy test. 
Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected; at the time points 
specified in the Schedule of Activities, and as required locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
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List of Abbreviations
Abbreviation/Term
Definition
1L
first-line
3X
3 times
ACTH
adrenocorticotropic hormone
AE
adverse event
AEOSI
adverse event of special interest
ADA
antidrug antibodies
ALT
alanine aminotransferase
ALK
anaplastic lymphoma kinase
aPTT
activated partial thromboplastin time
ASaT
All Subjects as Treated
ASCO
American Society of Clinical Oncologists
AST
aspartate aminotransferase
β-hCG
beta-human chorionic gonadotropin
BCG
Bacillus Calmette-Guérin
BICR
blinded independent central review
CBC
complete blood count
CI
confidence interval
cLDA
constrained longitudinal data analysis
Cmax
serum maximum concentration
CR
complete response
CrCl
calculated creatinine clearance
C-Path
Critical Path Institute
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DOR
duration of response
ECIs
events of clinical interest
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EOI
end of infusion
EORTC
European Organization for Research and Treatment of Cancer
EQ-5D-5L
EuroQol 5-dimension, 5-level Questionnaire
ERC
Ethics Review Committee
FA
final analysis
FBR
Future Biomedical Research
FDA
Food and Drug Administration
 
 
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Abbreviation/Term
Definition
FFPE
formalin-fixed, paraffin-embedded
FSH
follicle-stimulating hormone
FT3/T3
Free triiodothyronine
FT4/T4
Free thyroxine
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HCV
hepatitis c virus
HIV
human immunodeficiency virus
HR
hazard ratio
IA1
interim analysis 1
IA2
interim analysis 2
IB
Investigator’s brochure
ICH
International Conference on Harmonisation
IHC
immunohistochemistry
INR
international normalized ratio
IC
investigator's choice
IRB
Institutional Review Board
iCPD
iRECIST confirmed progressive disease
iCR
iRECIST complete response
iCRO
imaging clinical research organization
iPR
iRECIST partial response
irAE
immune-related AE
iRECIST
modified Response Evaluation Criteria in Solid Tumors 1.1 for 
immune-based therapeutics
iSD
iRECIST stable disease
iUPD 
iRECIST unconfirmed progressive disease;
ITT
intent-to-treat
IV
intravenous
IVRS
interactive voice response system
IWRS
integrated web response system
MRI
magnetic resonance imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
NCI
National Cancer Institute
NSCLC
nonsmall cell lung cancer
NSCLC-SAQ
The Non-small Cell Lung Cancer Symptom Assessment 
Questionnaire
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PD
progressive disease
PD-1
programmed cell death protein-1
PD-L1
programmed death-ligand 1
PD-L2
programmed death-ligand 2
PFS
progression-free survival
 
 
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Abbreviation/Term
Definition
PBPK
physiologically-based pharmacokinetic
PGIC-LC
Patient Global Impression of Change – Lung Cancer Symptoms 
questionnaires
PGIS-LC
Patient Global Impression of Severity – Lung Cancer Symptoms 
Questionnaire 
PGIC-L
Patient Global Impression of Change – Lung Symptoms 
Questionnaire 
PK
pharmacokinetic
PO
oral
PRO
patient-reported outcome
PR
partial response
PS
performance scale
PT
prothrombin time
QLQ-LC13
Quality of Life Questionnaire and Lung Cancer Module 13
QLQ-C30
Quality of Life Questionnaire Core 30
QoL
quality of life
Q2W
every 2 weeks
Q3W
every 3 weeks
Q6W
every 6 weeks
Q12W
every 12 weeks
RCC
renal cell carcinoma
RNA
ribonucleic acid
RECIST
Response Evaluation Criteria in Solid Tumors Version 1.1
RMST
restricted mean survival time
RR
response rate
SAE
serious adverse events
SAP
Statistical Analysis Plan
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SIM
Site Imaging Manual
SOC
standard of care
sSAP
supplemental statistical analysis plan
TMDD
target-mediated drug disposition 
TTD
time to true deterioration
TPS
tumor proportion score
TRAEs
treatment-related adverse events
TSH
thyroid stimulating hormone
ULN
upper limit of normal
US
United States
USPI
United States Package Insert
VOP
verification of progression
WOCBP
women of childbearing potential
 
 
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
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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