A Randomized Open-Label Phase III Trial of Pembrolizumab Versus Platinum Based Chemotherapy in 1L Subjects With PD-L1 Strong Metastatic Non-Small Cell Lung Cancer
Phase: PHASE3
Conditions: Non-Small Cell Lung Carcinoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
A Randomized Open-Label Phase III Trial of Pembrolizumab 
versus Platinum based Chemotherapy in 1L Subjects with PD-L1 
Strong Metastatic Non-Small Cell Lung Cancer
20-Dec-2017
NCT02142738

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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.
This protocol amendment is applicable only to Japan.
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, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Randomized Open-Label Phase III Trial of Pembrolizumab versus Platinum based
Chemotherapy in 1L Subjects with PD-L1 Strong Metastatic Non-Small Cell Lung Cancer
IND NUMBER:  116833
EudraCT NUMBER:  2014-000323-25
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 11
1.0 
TRIAL SUMMARY.................................................................................................. 17
2.0 
TRIAL DESIGN........................................................................................................ 18
Trial Design ........................................................................................................... 18
2.1 
Trial Diagram........................................................................................................ 21
2.2 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 22
Primary Objective(s) & Hypothesis(es) .............................................................. 22
3.1 
Secondary Objective(s) & Hypothesis(es)........................................................... 22
3.2 
Exploratory Objectives......................................................................................... 22
3.3 
4.0 
BACKGROUND & RATIONALE.......................................................................... 23
Background ........................................................................................................... 23
4.1 
Pharmaceutical and Therapeutic Background .................................................... 23
4.1.1 
Ongoing Clinical Trials....................................................................................... 25
4.1.2 
Information on Other Trial –Related Therapy.................................................... 26
4.1.3 
Rationale................................................................................................................ 29
4.2 
Rationale for the Trial and Selected Subject Population .................................... 29
4.2.1 
4.2.1.1 Benefit Risk ................................................................................................. 31
Rationale for Dose Selection/Regimen/Modification......................................... 32
4.2.2 
Rationale for Endpoints ...................................................................................... 33
4.2.3 
4.2.3.1 Efficacy Endpoints....................................................................................... 33
4.2.3.2 Patient Reported Outcomes Instruments...................................................... 33
4.2.3.3 Planned Exploratory Biomarker Research................................................... 34
4.2.3.4 Future Biomedical Research........................................................................ 34
5.0 
METHODOLOGY ................................................................................................... 35
Entry Criteria........................................................................................................ 35
5.1 
Diagnosis/Condition for Entry into the Trial...................................................... 35
5.1.1 
Subject Inclusion Criteria.................................................................................... 35
5.1.2 
Subject Exclusion Criteria .................................................................................. 38
5.1.3 
Trial Treatment(s) ................................................................................................ 40
5.2 
Dose Selection/Modification .............................................................................. 41
5.2.1 
 
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5.2.1.1 Dose Selection (Preparation) ....................................................................... 41
5.2.1.2 Dose Modification (Escalation/Titration/Other).......................................... 42
Timing of Dose Administration.......................................................................... 46
5.2.2 
Trial Blinding/Masking....................................................................................... 47
5.2.3 
Randomization or Treatment Allocation............................................................ 47
5.3 
Stratification.......................................................................................................... 48
5.4 
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 48
5.5 
Acceptable Concomitant Medications ................................................................ 48
5.5.1 
Prohibited Concomitant Medications and/or Treatments ................................... 48
5.5.2 
Rescue Medications & Supportive Care............................................................. 49
5.6 
Supportive Care Guidelines ................................................................................ 49
5.6.1 
5.6.1.1  Supportive Care Guidelines for Events of Clinical Interest and Immune-
related Adverse Events ................................................................................ 51
Overview of Guidelines for Managing Suspected Pneumonitis from
5.6.2 
Pembrolizumab ................................................................................................... 51
Guidelines for Infusion Reactions....................................................................... 51
5.6.3 
Diet/Activity/Other Considerations..................................................................... 53
5.7 
Diet...................................................................................................................... 53
5.7.1 
Contraception...................................................................................................... 53
5.7.2 
Use in Pregnancy ................................................................................................ 53
5.7.3 
Use in Nursing Women....................................................................................... 54
5.7.4 
Subject Withdrawal/Discontinuation Criteria................................................... 54
5.8 
Subject Replacement Strategy............................................................................. 56
5.9 
Beginning and End of the Trial ........................................................................... 56
5.10 
Clinical Criteria for Early Trial Termination ................................................... 56
5.11 
6.0 
TRIAL FLOW CHART ........................................................................................... 57
Pembrolizumab Arm: Treatment and Follow-up Phase ................................... 57
6.1 
SOC Arm: Treatment and Follow-up Phase...................................................... 64
6.2 
Second Course Treatment and Follow-up Phase............................................... 69
6.3 
Cross Over Phase.................................................................................................. 72
6.4 
Amendment 08, Pembrolizumab Arm: Treatment and Follow-up Phase........ 76
6.5 
Amendment 08, SOC Arm: Treatment and Follow-up Phase........................... 79
6.6 
 
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Amendment 08, Second Course Treatment and Follow-up Phase................... 81
6.7 
Amendment 08, Cross Over Phase...................................................................... 84
6.8 
7.0 
TRIAL PROCEDURES ........................................................................................... 87
Trial Procedures ................................................................................................... 87
7.1 
Administrative Procedures.................................................................................. 87
7.1.1 
7.1.1.1 Informed Consent......................................................................................... 87
General Informed Consent.................................................................... 87
7.1.1.1.1 
Consent and Collection of Specimens for Future Biomedical
7.1.1.1.2 
Research................................................................................................ 88
7.1.1.2 Inclusion/Exclusion Criteria ........................................................................ 88
7.1.1.3 Subject Identification Card.......................................................................... 88
7.1.1.4  Medical History ........................................................................................... 88
7.1.1.5 Prior and Concomitant Medications Review............................................... 88
Prior Medications.................................................................................. 88
7.1.1.5.1 
Concomitant Medications..................................................................... 88
7.1.1.5.2 
7.1.1.6 Non-small cell lung cancer Disease Details and Treatments....................... 89
Disease Details...................................................................................... 89
7.1.1.6.1 
Prior Treatment..................................................................................... 89
7.1.1.6.2 
Subsequent Antineoplastic Therapy Status........................................... 89
7.1.1.6.3 
7.1.1.7 Assignment of Screening Number............................................................... 89
7.1.1.8  Assignment of Randomization Number....................................................... 89
7.1.1.9 Trial Compliance (Medication/Diet/Activity/Other) ................................... 89
Clinical Procedures/Assessments........................................................................ 90
7.1.2 
7.1.2.1 Adverse Event Monitoring........................................................................... 90
7.1.2.2 Physical Exam.............................................................................................. 90
Full Physical Exam............................................................................... 90
7.1.2.2.1 
Directed Physical Exam........................................................................ 90
7.1.2.2.2 
7.1.2.3 Vital Signs.................................................................................................... 91
7.1.2.4 Lead Electrocardiogram (ECG)................................................................... 91
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 91
7.1.2.6 Tumor Imaging ............................................................................................ 91
7.1.2.7 Brain Imaging .............................................................................................. 94
 
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7.1.2.8 Patient Reported Outcomes (PROs)............................................................. 94
7.1.2.9 Tumor Tissue Collection.............................................................................. 95
Laboratory Procedures/Assessments .................................................................. 95
7.1.3 
7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 95
7.1.3.2 Pharmacokinetic Evaluations....................................................................... 97
Blood Collection for Serum Pembrolizumab........................................ 97
7.1.3.2.1 
7.1.3.3 Anti-Pembrolizumab Antibodies ................................................................. 97
7.1.3.4 Molecular Testing........................................................................................ 97
7.1.3.5 Future Biomedical Research........................................................................ 98
Other Procedures................................................................................................. 98
7.1.4 
7.1.4.1 Withdrawal/Discontinuation........................................................................ 98
Withdrawal From Future Biomedical Research ................................... 98
7.1.4.1.1 
7.1.4.2 Blinding/Unblinding .................................................................................... 98
7.1.4.3 Calibration of Critical Equipment................................................................ 99
Visit Requirements.............................................................................................. 99
7.1.5 
7.1.5.1 Screening...................................................................................................... 99
7.1.5.2 Treatment Phase......................................................................................... 100
7.1.5.3 End of Treatment Visits............................................................................. 100
Discontinuation Visit.......................................................................... 100
7.1.5.3.1 
Mandatory Safety Follow up Visit...................................................... 100
7.1.5.3.2 
Observation Visit................................................................................ 101
7.1.5.3.3 
7.1.5.4 Follow up Phase......................................................................................... 101
Follow-up Visits ................................................................................. 101
7.1.5.4.1 
Survival Follow-up ............................................................................. 102
7.1.5.4.2 
7.1.5.5 Second Course Phase................................................................................. 102
7.1.5.6 Crossover for Subjects in the Chemotherapy Arm .................................... 103
7.1.5.7 Survival Status ........................................................................................... 104
Assessing and Recording Adverse Events ........................................................ 104
7.2 
Definition of an Overdose for This Protocol and Reporting of Overdose to
7.2.1 
the Sponsor........................................................................................................ 105
Reporting of Pregnancy and Lactation to the Sponsor ..................................... 105
7.2.2 
Immediate Reporting of Adverse Events to the Sponsor.................................. 106
7.2.3 
 
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7.2.3.1 Serious Adverse Events ............................................................................. 106
7.2.3.2 Events of Clinical Interest.......................................................................... 106
7.2.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting.......... 108
Evaluating Adverse Events............................................................................... 108
7.2.4 
Sponsor Responsibility for Reporting Adverse Events .................................... 111
7.2.5 
TRIAL GOVERNANCE AND OVERSIGHT ................................................. 111
7.3 
Scientific Advisory Committee......................................................................... 111
7.3.1 
Executive Oversight Committee....................................................................... 111
7.3.2 
Data Monitoring Committee............................................................................. 111
7.3.3 
7.3.3.1 Post Final Analysis Activities.................................................................... 112
8.0 
STATISTICAL ANALYSIS PLAN ...................................................................... 112
Statistical Analysis Plan Summary ................................................................... 112
8.1 
Efficacy Analyses ............................................................................................. 112
8.1.1 
Safety Analyses................................................................................................. 113
8.1.2 
Multiplicity ....................................................................................................... 113
8.1.3 
Power and Sample Size..................................................................................... 114
8.1.4 
ORR, PFS and OS Analyses ............................................................................. 114
8.1.5 
Statistical Analysis Plan ..................................................................................... 115
8.2 
Responsibility for Analyses/In-House Blinding............................................... 115
8.2.1 
Hypotheses/Estimation ..................................................................................... 116
8.2.2 
Analysis Endpoints ........................................................................................... 116
8.2.3 
8.2.3.1 Efficacy Endpoints..................................................................................... 116
8.2.3.2 Safety Endpoints........................................................................................ 117
Analysis Population .......................................................................................... 117
8.2.4 
8.2.4.1 Efficacy Analysis Population..................................................................... 117
8.2.4.2 Safety Analysis Populations ...................................................................... 117
Statistical Methods............................................................................................ 118
8.2.5 
8.2.5.1 Statistical Methods for Efficacy Analyses................................................. 118
Progression-Free Survival................................................................... 118
8.2.5.1.1 
Overall Survival.................................................................................. 119
8.2.5.1.2 
Objective response rate....................................................................... 120
8.2.5.1.3 
Exploratory analyses........................................................................... 120
8.2.5.1.4 
 
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8.2.5.2 Statistical Methods for Safety Analyses .................................................... 121
8.2.5.3 Summaries of Baseline Characteristics, Demographics, and Other
Analyses..................................................................................................... 122
Multiplicity ....................................................................................................... 122
8.2.6 
Sample Size and Power Calculation ................................................................. 123
8.2.7 
Subgroup Analyses and Effect of Baseline Factors .......................................... 124
8.2.8 
ORR, PFS and OS analyses .............................................................................. 125
8.2.9 
8.2.9.1 ORR, PFS analysis and interim OS analysis ............................................. 125
8.2.9.2 Final OS Analysis ...................................................................................... 126
Compliance (Medication Adherence)............................................................... 126
8.2.10 
Extent of Exposure............................................................................................ 126
8.2.11 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL
SUPPLIES ............................................................................................................... 127
Investigational Product ...................................................................................... 127
9.1 
Packaging and Labeling Information ............................................................... 127
9.2 
Clinical Supplies Disclosure............................................................................... 128
9.3 
Storage and Handling Requirements................................................................ 128
9.4 
Returns and Reconciliation................................................................................ 128
9.5 
Standard Policies................................................................................................. 128
9.6 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS..................................... 128
Confidentiality..................................................................................................... 128
10.1 
Confidentiality of Data ..................................................................................... 128
10.1.1 
Confidentiality of Subject Records................................................................... 129
10.1.2 
Confidentiality of Investigator Information...................................................... 129
10.1.3 
Confidentiality of IRB/IEC Information........................................................... 129
10.1.4  
Compliance with Financial Disclosure Requirements..................................... 130
10.2 
Compliance with Law, Audit and Debarment ................................................. 130
10.3 
Compliance with Trial Registration and Results Posting Requirements ...... 132
10.4 
Quality Management System............................................................................. 132
10.5 
Data Management............................................................................................... 132
10.6 
Publications ......................................................................................................... 133
10.7 
11.0 LIST OF REFERENCES....................................................................................... 134
 
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12.0 APPENDICES......................................................................................................... 141
Merck Code of Conduct for Clinical Trials...................................................... 141
12.1 
Collection and Management of Specimens for Future Biomedical
12.2 
Research............................................................................................................... 143
Understanding the Intent, Scope and Public Health Benefits of
12.3 
Exploratory Biomarker Research: A Guide for IRBs/IECs and
Investigational Site Staff.................................................................................... 149
List of Abbreviations .......................................................................................... 160
12.4 
ECOG Performance Status................................................................................ 162
12.5 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 163
12.6 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for
12.7 
Evaluating Response in Solid Tumors .............................................................. 164
Immune Related Response Criteria .................................................................. 165
12.8 
13.0 SIGNATURES......................................................................................................... 167
Sponsor's Representative ................................................................................... 167
13.1 
Investigator.......................................................................................................... 167
13.2 
 
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LIST OF TABLES
Table 1 Adequate Organ Function Lab Values..................................................................... 36
Table 2 Trial Treatment........................................................................................................ 41
Table 3 Dose Modification and Toxicity Management Guidelines for Immune-related
AEs Associated With Pembrolizumab..................................................................... 43
Table 4 Pembrolizumab Infusion Reaction Treatment Guidelines....................................... 52
Table 5 Imaging and Treatment Determinations After First Radiological Evidence of
PD ............................................................................................................................ 93
Table 6 Laboratory Tests ...................................................................................................... 96
Table 7 Evaluating Adverse Events.................................................................................... 109
Table 8 Analysis Strategy for Key Efficacy Endpoints...................................................... 112
Table 9 Summary of PFS and OS Analysis Strategies ....................................................... 115
Table 10 Censoring Rules for Primary and Sensitivity Analyses of PFS............................. 119
Table 11 Analysis Strategy for Safety Parameters................................................................ 122
Table 12 Product Descriptions.............................................................................................. 127
 
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LIST OF FIGURES
Figure 1 
Trial Design ........................................................................................................ 21
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section
Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.2.1.2
Dose 
Modification
(Escalation/Titration/Other)
The guidelines in Table 3 are expanded
to cover supportive care, monitoring,
and follow-up.  Myocarditis is added.
To provide current, comprehensive
guidelines 
for 
management 
of
immune-related adverse events.
6.1
Pembrolizumab Arm: Treatment
and Follow-up Phase
Survival status activities are shown
taking place throughout the trial.
The frequency of telephone contacts
during the Survival Follow-up Phase is
changed from every 2 months to
approximately every 2 months.
To allow flexibility of survival status
activities and ensure that current,
complete survival data are available
at the time of database locks
To allow flexibility ofsurvival status
activities
6.2
SOC 
Arm: 
Treatment 
and
Follow-up Phase
6.3
Second Course Treatment and
Follow-up Phase
6.4
Cross Over Phase
 
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Section
Number (s)
Section Title(s)
Description of Change (s)
Rationale
6.5
Amendment 08, Pembrolizumab
Arm: Treatment and Follow-up
Phase
Survival status activities are shown
taking place throughout the trial.
The frequency of telephone contacts
during the Survival Follow-up Phase is
changed from every 2 months to
approximately every 2 months,
To allow flexibility of survival status
activities and ensure that current,
complete survival data are available
at the time of database locks
To allow flexibility of survival status
activities
6.6
Amendment 08, SOC Arm:
Treatment and Follow-up Phase
6.7
Amendment 08, Second Course
Treatment and Follow-up Phase
6.8
Amendment 08, Cross Over
Phase
7.1.5.4.2 
Survival Follow-up 
The frequency of telephone contacts
during the Survival Follow-up Phase is
changed from every 2 months to
approximately every 2 months.
To allow flexibility of survival status
activities
7.1.5.7 
Survival Status 
This section is added to state that the
Sponsor may request updated survival
data during the course of the trial.
To allow flexibility of survival status
activities and ensure that current,
complete survival data are available
at the time of database locks
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section
Number (s)
Section Title (s)
Description of Change (s)
Rationale
1.0
Trial Summary
Once subjects have achieved the trial objective
or the trial has ended, subjects are discontinued
from this trial and will be enrolled in an
extension trial to continue protocol-defined
assessments and treatment.
This trial has been identified to roll
over into an extension trial.
2.2 
Trial Diagram
The pembrolizumab extension trial after
survival follow-up is added.  Changes from
Amendment 08 are added.
5.10
Beginning and End of the
Trial
Upon 
trial 
completion, 
subjects 
are
discontinued and enrolled in a pembrolizumab
extension trial.
2.1
Trial Design
Serious adverse events (SAEs) and Events of 
Clinical Interest (ECI) 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.
Correction of typographic error
2.1
Trial Design
Reference to the Events of Clinical Interest 
(ECI) guidance document is removed.
This document has been retired.
4.2.2
Rationale for Dose
Selection/Regimen/Modi
fication
The rationale for the pembrolizumab dose of
200 mg every 3 weeks was updated.
Updated clinical and pharmacology
data are available.
 
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Section
Number (s)
Section Title (s) 
Description of Change (s) 
Rationale
7.1.5.5
Second Course Phase 
Subjects randomized to pembrolizumab may be
eligible to receive pembrolizumab for 17 cycles
in the Second Course Phase of the trial if they
experienced progressive disease (PD) during
treatment, 
yet 
continued 
to 
receive
pembrolizumab 
beyond 
progression 
and
attained subsequent benefit, completing 24
months without further disease progression or
intolerability. in the
To allow subjects to enter the
Second Course Phase if they
experienced PD during treatment but
continued receiving pembrolizumab
beyond 
progression 
and 
had
subsequent benefit, completing 24
months without further progression
or intolerability.
2.1
Trial Design
Amendment 06 is changed to Amendment 08. 
The 
previous 
amendment 
was
Amendment 08.
2.2
Trial Diagram
6.5
Amendment 08,
Pembrolizumab Arm:
Treatment and Follow-up
Phase
6.6
Amendment 08, SOC
Arm: Treatment and
Follow-up Phase
6.7
Amendment 08, Second
Course Treatment and
Follow-up Phase
 
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Section
Number (s)
Section Title (s)
Description of Change (s) 
Rationale
6.8
Amendment 08, Cross
Over Phase
Amendment 06 is changed to Amendment 08. 
The 
previous 
amendment 
was
Amendment 08.
7.1.2.6
Tumor Imaging
7.1.2.8
Patient Reported
Outcomes (PROs)
7.1.3.2
Pharmacokinetic
Evaluations
7.1.3.2.1 
Blood Collection for
Serum Pembrolizumab
7.1.3.3
Anti-Pembrolizumab
Antibodies
7.1.5.3.3
Observation Visit
7.1.5.6
Crossover for Subjects in
the Chemotherapy Arm
8.1.3
Multiplicity
8.1.5
ORR, PFS and OS
Analyses
8.2.6
Multiplicity
 
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Section
Number (s)
Section Title (s)
Description of Change (s) 
Rationale
8.2.7
Sample Size and Power
Calculation
8.2.9
ORR, PFS and OS
Analyses
8.2.9.2
Final OS Analysis 
Amendment 06 is changed to Amendment 08. 
The 
previous 
amendment 
was
Amendment 08.
6.5
6.7
6.8
Amendment 08,
Pembrolizumab Arm:
Treatment and Follow-up
Phase
Amendment 08, Second
Course Treatment and
Follow-up Phase
Amendment 08, Cross
Over Phase
Footnote 26 corrected to 14, and footnote
added.
Footnote 16 corrected to 14, and footnote
added.
Footnote 18 corrected to 16, and footnote
added.
Correction.
12.4 
List of Abbreviations 
The following are added:
PD-L1 (Programmed Cell Death Ligand 1)
PD-L2 (Programmed Cell Death Ligand 2)
Not previously added
 
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1.0 TRIAL SUMMARY
Abbreviated Title 
Pembrolizumab versus SOC  in 1L Subjects with  PD-L1 Strong
Metastatic NSCLC
TrialPhase 
Phase III
Clinical Indication  
Non-Small Cell Lung Cancer
Trial Type 
Interventional
Type of control 
Active Control without Placebo
Route of administration  
Intravenous
Trial Blinding 
Unblinded Open-label
Treatment Groups 
Pembrolizumab (MK-3475) 200 mg intravenous (IV) every 3 weeks 
OR
SOC: 
investigator’s 
choice 
of 
one 
of 
the 
following: 
Gemcitabine 1250 mg/m2 & Cisplatin 75 mg/m  
2 Q3W for 4-6 cycles
Gemcitabine 1250 mg/m2 & Carboplatin  AUC 5-6 Q3W for 4-6 cycles
Pemetrexed 500 mg/m2 & Carboplatin AUC 5-6 Q3W for 4-6 cycles
followed by optional pemetrexed 500 mg/m2 Q3W (this arm is
permitted 
for 
nonsquamous 
histologies 
only)
Pemetrexed 500 mg/m2 & Cisplatin 75 mg/m2 Q3W for 4-6 cycles
followed by optional pemetrexed 500 mg/m2 Q3W (this arm is
permitted 
for 
nonsquamous 
histologies 
only)
Paclitaxel 200 mg/m2 & Carboplatin AUC 5-6 Q3W for 4-6 cycles
followed 
by 
optional 
pemetrexed 
maintenance 
(pemetrexed
maintenance is permitted for nonsquamous histologies only)
Number of trial subjects 
Approximately 300 subjects will be enrolled.
Estimated duration of trial 
The sponsor estimates that the trial will require approximately 3 years
from the time the first subject signs the informed consent until the last
subject’s last visit.
Duration of Participation  
Each subject will participate in the trial for up to 2.5 years from the
time the subject signs the Informed Consent Form (ICF) through the
final contact.  After a screening phase of up to 42 days, eligible
subjects can be randomized to either to pembrolizumab or SOC.
Subjects will receive assigned treatments during a 3-week (Q3W)
dosing cycle (for both the control and pembrolizumab arms). 
Treatment on study will continue until disease progression,
unacceptable adverse event(s), intercurrent illness that prevents further
administration of treatment, investigator’s decision to withdraw the
subject, 
noncompliance 
with 
trial 
treatment 
or procedures
requirements, the subject receives 35 treatments of study medication
(pembrolizumab arm only), or administrative reasons. Subjects on the
pembrolizumab arm who attain a complete response may consider
stopping trial treatment if they meet criteria for holding therapy.
Subjects receiving pembrolizumab who stop drug administration after
receiving 35 trial treatments for reasons other than disease progression
or intolerability, or subjects who attain a complete response and stop
trial treatment may be eligible for retreatment with pembrolizumab
upon experiencing disease progression. The decision to retreat will be
at the discretion of the investigator only if they meet the criteria for
retreatment and the trial is ongoing. Retreatment is limited to 17
cycles. After the end of treatment each subject will be followed for a
minimum  of 30 days for adverse event (AE) monitoring. Serious
adverse events (SAE) and Events of Clinical Interest (ECI) will be
collected for up to 90 days following cessation of treatment or 30 days
 
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following cessation of treatment if the subject initiates new anticancer
therapy, whichever is earlier. Subjects randomized to the control arm
will have the option of receiving treatment with pembrolizumab.
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.  Once subjects have achieved the trial objective or the
trial has ended, subjects are discontinued from this trial and will be
enrolled in an extension trial to continue protocol-defined assessments
and treatment.
After marketing approval of pembrolizumab, “clinical trial” will be
replaced with “post-marketing clinical trial” and this study will be
continued.
Randomization Ratio
1:1
2.0 TRIAL DESIGN
Trial Design
2.1 
This is 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 4,
Programmed Cell Death Ligand 1 (PD-L1) strong, non-small cell lung cancer (NSCLC).
Approximately 300 subjects whose tumors are classified as PD-L1 strong, who lack an
epidermal growth factor receptor (EGFR) sensitizing mutation and are anaplastic lymphoma
kinase (ALK) translocation negative NSCLC will be enrolled in this trial for examination of
the efficacy  and safety  of pembrolizumab vs SOC chemotherapies. Subjects will be
randomized in a 1:1 ratio to receive pembrolizumab or the investigator’s choice ofone of the
platinum doublets listed below: 
1) Pemetrexed 500 mg/m2 every 3 weeks (Q3W) and carboplatin Area Under Curve (AUC)
5-6 day 1 Q3W for 4-6 cycles followed by optional pemetrexed 500 mg/m2 Q3W (this
arm is permitted for nonsquamous histologies only)
2) Pemetrexed 500 mg/m2 Q3W and cisplatin 75 mg/m2 day 1 Q3W for 4-6 cycles followed
by optional pemetrexed 500 mg/m2 Q3W  (this arm is permitted for nonsquamous
histologies only)
3) Gemcitabine 1250 mg/m2 days 1 and 8 and cisplatin 75 mg/m2 day 1 Q3W for 4-6 cycles
4) Gemcitabine 1250 mg/m2 days 1 and 8 and carboplatin AUC 5-6 day 1 Q3W for 4-6
cycles
5) Paclitaxel 200 mg/m  
2 Q3W and carboplatin AUC 5-6 day 1 Q 3W for 4-6 cycles
followed by optional pemetrexed maintenance (pemetrexed maintenance is permitted for
nonsquamous histologies only) (Figure 1)
 
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The specific platinum doublet (including whether pemetrexed maintenance will be offered
for those subjects with non-squamous histologies) as well as the dose (for example, AUC 5
OR 6 for carboplatin) to be administered must be identified prior to randomization. Note:
while pemetrexed maintenance is optional, it is STRONGLY recommended in subjects with
non-squamous histologies and should be administered unless toxicity or decline in
performance status precludes its administration, and radiographic imaging does not
demonstrate PD after completion of at least 4 cycles of platinum doublet.
Subjects who have received one of the platinum doublets above in the neoadjuvant or
adjuvant setting are not permitted to receive the same platinum doublet in this trial if
randomized to the control arm, unless a known contraindication prohibits treatment with
another platinum doublet. Furthermore, pemetrexed will not be permitted as chemotherapy
for subjects with squamous histology. Subjects will be stratified by Eastern Cooperative
Oncology Group (ECOG) Performance Scale (0 vs 1), histology  (squamous vs non-
squamous), and geographic region of the enrolling site (East Asia vs non-East Asia), prior to
randomization. The investigator will decide before randomization which chemotherapy
regimen a subject would receive in case the subject is assigned to the chemotherapy arm. The
subject will then have equal chance to be randomized in the pembrolizumab arm and the
chemotherapy arm within the stratification group to which the subject belongs. 
Subjects will be evaluated every 9 weeks (63 +/- 7 days) with radiographic imaging to assess
response to treatment. All imaging obtained on study will be submitted for a central
radiologists’ review, which  will assess the images using Response Evaluation Criteria in
Solid Tumors (RECIST) 1.1 for determination of objective response rate (ORR) and
progression-free survival (PFS).
Following amendment 08, imaging will no longer be required as a study procedure and sites
will no longer be required to submit imaging for central review.
Subjects should continue with the assigned study treatment until RECIST  1.1-defined
progression of disease as assessed by the investigator, unacceptable toxicity, intercurrent
illness that prevents further administration of treatment, investigator’s decision to withdraw
the subject, subject withdraws consent, pregnancy of the subject, noncompliance with trial
treatment or procedure requirements, administrative reasons, or the subject has received 35
trial treatments of pembrolizumab. Treatment may continue despite RECIST 1.1 defined
progression if the subject is clinically stable and is considered to be deriving clinical benefit
by the investigator.  Adverse events (AEs) will be monitored throughout the trial and graded
in severity according to the guidelines outlined in the NCI Common Terminology Criteria for
Adverse Events (CTCAE) version 4.0.
Following amendment 08, subjects assigned to the control arm that meet all crossover criteria
outlined in Section 7.1.5.6 will have the opportunity to crossover to pembrolizumab. 
Section 7.1.5.6 provides crossover criteria and guidance. Treatment is limited to 35
administrations of pembrolizumab during the initial treatment phase; a cross over subject
may be treated in a second course phase if they meet criteria outlined in Section 7.1.5.5.
 
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Pembrolizumab treated subjects who attain a confirmed CR  may consider stopping trial
treatment. These subjects, as well as those subjects assigned to the pembrolizumab arm who
stop trial therapy after 35 trial treatments for reasons other than disease progression or
intolerability, may  be eligible for re-treatment with pembrolizumab in the Second Course
Phase after they have experienced radiographic disease progression at the discretion of the
investigator according to the criteria in Section 7.1.5.4.  Response or progression in the
Second Course Phase will not count towards the ORR and PFS of the primary endpoint in
this trial.
After the end of treatment, each subject (including subjects randomized to the control arm
who opt to receive pembrolizumab) will be followed for a minimum of 30 days for AE
monitoring. Serious adverse events (SAEs) and Events of Clinical Interest (ECI) 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. 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. The primary objective of the trial is PFS per RECIST 1.1 by
blinded independent central radiologists’ review. Secondary objectives include overall
survival (OS), ORR per RECIST 1.1 by blinded independent centralradiologists’ review, and
safety as assessed by a variety of parameters of AEs, including ECI with a potential
immunologic etiology. . Exploratory analyses include PFS2 (defined as the time from
randomization to disease progression on the next line of therapy, or death from any cause,
whichever first), ORR per irRC, response duration per RECIST 1.1 by blinded independent
central radiologists’ review, response duration per irRC, PFS per immune-related response
criteria (irRC), and health-related quality-of-life assessments (QoL).
Participation in this trial will be dependent upon supplying tumor tissue from locations that
have not been radiated. Formalin-fixed specimens obtained either at the time of or after the
subject has been diagnosed with metastatic disease will be required for determination of PD-
L1 status. Biopsies obtained PRIOR to receipt of neoadjuvant/adjuvant chemotherapy is
NOT permitted. The specimen will be evaluated at a central laboratory facility for expression
status of PD-L1 in a prospective manner. Only subjects whose tumors express PD-L1 at a
predefined cut point as determined by the central laboratory facility will be eligible for
randomization.
Subjects who received neoadjuvant/adjuvant therapy are permitted onto the trial as long as
therapy was completed at least 6 months prior to the diagnosis of metastatic disease.
One PFS analysis will be conducted during the course of the trial. The analysis is expected to
occur after approximately 175 PFS events per RECIST 1.1 by blinded independent central
radiologists’ review have occurred in both arms. The purpose of this analysis is to
demonstrate superiority of pembrolizumab in PFS  and to demonstrate no evidence of a
detriment in OS. One hundred and ten OS events are expected to occur at the time of the PFS
analysis. OS analyses will also be performed at the final PFS analysis. In addition, the trial
may be stopped early at the recommendation of the Data Monitoring Committee (DMC) if
 
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the risk/benefit ratio to the trial population as a whole is unacceptable. Details are described
in Section 8.0– Statistical Analysis Plan.
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.
After marketing approval of pembrolizumab, “clinical trial” will be replaced with “post-
marketing clinical trial” and this study will be continued.
Trial Diagram
2.2 
The trial design is depicted in Figure 1 below.
1L= first line; ALK= anaplastic lymphoma kinase; ECOG PS=Eastern Cooperative Oncology Group Performance Status;
EGFR=epidermal growth factor receptor; IV=intravenous; NSCLC=non-small cell lung cancer; PD-L1=Programmed Cell
Death Ligand 1; pem=pembrolizumab; Q3W=every 3 weeks; TPS=tumor proportion score.
Figure 1 
Trial Design
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1 
1) Objective:  To compare the PFS per RECIST 1.1 as assessed by blinded independent
central radiologists’ review  in  subjects with PD-L1 strong, 1L  metastatic NSCLC
treated with pembrolizumab compared to SOC chemotherapies.
Hypothesis: Pembrolizumab prolongs PFS by RECIST 1.1 (blinded independent
centralradiologists’ review) in subjects with PD-L1 strong NSCLC compared to SOC
chemotherapies.
Secondary Objective(s) & Hypothesis(es)
3.2 
1) Objective: Evaluate the safety and tolerability profile of pembrolizumab in subjects
with 1L metastatic PD-L1 strong NSCLC.
2) Objective:  Evaluate the OS in subjects with 1L metastatic PD-L1 strong NSCLC
treated with pembrolizumab compared to SOC chemotherapies.
3) Objective: Evaluate the ORR as assessed by RECIST 1.1 by blinded independent
central radiology review in subjects with 1L metastatic PD-L1 strong NSCLC treated
with pembrolizumab compared to SOC chemotherapies.
Hypothesis: Pembrolizumab improves the ORR by RECIST 1.1 (blinded
independent central radiologists’ review) in subjects with PD-L1 strong NSCLC
compared to SOC chemotherapies.
Exploratory Objectives
3.3 
1) Objective: To evaluate PFS per immune-related response criteria (irRC) in subjects
with 1L metastatic PD-L1 strong NSCLC treated with  pembrolizumab compared to
SOC chemotherapies.
2) Objective: Evaluate the PFS as assessed by RECIST 1.1 by investigator review in the
next line of therapy (PFS2) in subjects treated with pembrolizumab compared to SOC
chemotherapies.
3) Objective: To evaluate ORR per irRC in subjects with 1L metastatic PD-L1 strong
NSCLC treated with pembrolizumab compared to SOC chemotherapies.
4) Objective: To evaluate response duration per RECIST 1.1 by blinded independent
central radiologists’ review in subjects with 1L metastatic PD-L1 strong NSCLC
treated with pembrolizumab compared to SOC chemotherapies.
5) Objective: To evaluate response duration per irRC in subjects with 1L metastatic PD-
L1 strong NSCLC treated with pembrolizumab compared to SOC chemotherapies.
 
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6) Objective: To evaluate patient-reported treatment effects at pre-specified time points
while on treatment and post-discontinuation as measured by changes from baseline in
all domains and single items of the QLQ-C30 and LC13, with particular emphasis on
QLQ-C30 QoL domain, chest pain (LC13 question 10), cough (LC13 question 1) and
dyspnea domain (LC13 questions 3-5) in previously untreated advanced NSCLC
subjects receiving either pembrolizumab or comparator.
7) Objective: To summarize and compare by treatment arm, the number and proportion
of subjects who improved, worsened or remained stable for all domains and single
items of the QLQ-C30 and LC13. 
8) Objective: To describe by treatment arm, the proportion of subjects reporting “no”,
“some”, or “extreme” EQ-5D health state profiles at pre-specified time points.
9) Objective: To evaluate within each treatment arm, quality-adjusted survival using the
Quality-adjusted Time without Symptoms or Toxicity (Q-TWiST) approach.
10)Objective: To evaluate within each treatment arm, the difference in patient reported
outcome (PRO) score for progressed subjects compared to subjects with no
radiographic evidence of tumor progression.
11)Objective: To evaluate genomic signatures that predict for response in subjects
treated with pembrolizumab.
4.0 BACKGROUND & RATIONALE
Background
4.1 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background
information on pembrolizumab.
Pharmaceutical and Therapeutic Background
4.1.1 
The importance of intact immune surveillance in controlling outgrowth of neoplastic
transformation has been known for decades [1]. Accumulating evidence shows a correlation
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in
various malignancies [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]
[19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37]
[37]. 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 (MEL) and renal cell carcinoma (RCC). TILs
can be expanded ex vivo and re-infused, inducing durable objective tumor responses in
cancers such as MEL [38] [39].
 
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The Programmed Cell Death 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. PD-1 (encoded by the gene
Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 which has been shown to
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or
Programmed Cell Death Ligand 2 [PD-L2]) [40] [41]. 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 [42] [34]. PD-1 was shown to be expressed
on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and
Natural Killer cells [43] [44]. 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 [42] [45] [46] [47]. 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.  PD-L1 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. PD-L2 is thought to control immune
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell
function in peripheral tissues [45]. 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 [17],
pancreatic carcinoma [48], hepatocellular carcinoma [49], and ovarian carcinoma [50].
Furthermore, PD-1 has been suggested to regulate tumor-specific T-cell expansion in
subjects with MEL [51].
PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be
considered as an attractive target for therapeutic intervention. The prognostic implications of
PD-L1 expression in NSCLC are currently being investigated in ongoing epidemiologic
studies as well as PN 010, the Phase 2/3 trial of pembrolizumab vs docetaxel in previously
treated subjects with advanced or metastatic NSCLC. 
Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor responses
as a mono-therapy in models of squamous cell carcinoma, pancreatic carcinoma, MEL and
colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted CD8+ T-cell
infiltration into the tumor and the presence of IFN-, granzyme B and perforin, indicating
that the mechanism of action involved local infiltration and activation of effector T-cell
function in vivo [48] [52] [53] [54] [55] [56]. In addition, the combination of gemcitabine
and anti-PD-L1 mAb demonstrated synergy in the rejection of pancreatic mouse tumors [48].
In-house experiments have confirmed the in vivo efficacy of PD-1 blockade as a mono-
therapy as well as in combination with chemotherapy in syngeneic mouse tumor models (see
the Investigator Brochure (IB).
 
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Recent clinical data of pembrolizumab suggest high sustained rates of tumor regression in
subjects with advanced melanoma. Pembrolizumab was dosed intravenously at a dose of 10
mg per kilogram of body weight every 2 or 3 weeks or 2 mg per kilogram Q3W in subjects
with advanced melanoma, including a cohort of subjects who had received prior treatment
with the immune checkpoint inhibitor ipilimumab and those who had not. Tumor responses
were assessed every 12 weeks. A total of 135 subjects with advanced melanoma were treated.
Common AEs attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the
AEs were low grade. The confirmed response rate across all dose cohorts, evaluated by
central radiologic review according to the RECIST 1.1, was 38% (95% confidence interval
[CI], 25 to 44), with the highest confirmed response rate observed in the cohort that received
10 mg per kilogram every 2 weeks (52%; 95% CI, 38 to 66). The response rate did not differ
significantly between subjects who had received prior ipilimumab treatment and those who
had not (confirmed response rate, 38% (95% CI, 23 to 55) and 37% (95% CI, 26 to 49),
respectively). Responses were durable in the majority of subjects (median follow-up, 11
months among subjects who had a response); 81% of the subjects who had a response (42 of
52) were still receiving treatment at the time of analysis in March 2013. The overall median
PFS among the 135 subjects was longer than 7 months. These data indicate that high rates of
durable responses are achieved with pembrolizumab in subjects with advanced melanoma
irrespective of any prior treatment with an immune checkpoint inhibitor. Furthermore, the
toxicity profile was manageable with the majority grade of the toxicities grade 1 or 2. [57]
Ongoing Clinical Trials
4.1.2 
An open-label Phase 1 trial (Protocol 001) is being conducted to evaluate the safety and
clinical activity of single agent pembrolizumab. The dose escalation portion of this trial
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks
(Q2W), in subjects with advanced solid tumors. All three 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 Q3W.
All cohorts have completed enrollment. 
Protocol 001 (PN001) Part C enrolled 38 subjects with NSCLC  (adenocarcinoma, squamous
cell carcinoma, and large cell carcinoma) who experienced progression of cancer after
initiation of their second line of systemic therapy to receive monotherapy pembrolizumab.
By investigator-assessed irRC, the ORR; (confirmed and unconfirmed) was 24%. Similar
results were obtained using RECIST 1.1, yielding an ORR (confirmed and unconfirmed) of
21%. Most responses by irRC were observed by the time of first planned assessment at Week
9. The median duration of response by irRC has not been reached with a median duration of
follow-up of 62 weeks. The median OS for all 38 subjects treated with pembrolizumab was
51 weeks.
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, the presumptive
predictive biomarker of pembrolizumab, using a preliminary immunohistochemistry assay. A
modified H-score scoring system of PD-L1 expression was established for NSCLC by
 
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analyzing tumor specimens from resected NSCLC specimens. This scoring system was then
applied to the samples from PN001 Part C.
A total of 35 subjects from PN001 had tumor samples evaluable and a clinical response
assessed. All but 3 subjects were from Part C; 3 subjects from Part A had NSCLC, submitted
tumor tissue, and had a clinical response assessment. Seven of the 35 subjects had a clinical
response (20%) by investigator assessed irRC. Six responders (26%) were observed amongst
the twenty-three subjects whose tumors expressed PD-L1. Of note, these six responders
clustered at the higher end of the modified H-score. Six of nine (67%) subjects whose tumors
expressed PD-L1 to an extent above the preliminary cut point had a clinical response. No
responses were noted amongst the subjects whose tumors did not express PD-L1.
A training set comprised of approximately 140 tumor samples and their associated clinical
outcome data were used to assess an optimal cutpoint for PD-L1 positivity.  An optimal PD-
L1 cutpoint was identified by receiver operator characteristic curve analyses and by
considering clinical implications of false positive and false negative results. Cutpoint was
identified based upon a proportions score (PS) method of IHC analysis with the tumors
expressing at or greater than the highest cutpoint (PS >50%) referred to as PD-L1 strong
tumors, and tumors expressing >1% but less than 50% referred to as the PD-L1 weak tumors.
Outcomes based in immune related Response Criteria (irRC) were used as the primary
outcome for the analysis.  Based on the training set, the Positive Predictive Value for subjects
in the strong category was 42% while maintaining a negative predictive value of 92% for
subjects in the weak or null category.  Given the limited activity in PD-L1 weak and negative
subjects observed to date, these subjects will be excluded from this trial in 1 st line NSCLC
subjects. 
KEYNOTE 001 Part F enrolled PD-L1 positive, previously untreated subjects with advanced
NSCLC (Part F1) or previously treated subjected with advanced NSCLC (Part F2). For the
subjects enrolled onto Part F2, the median PFS by investigator assessed irRC was 26.4 weeks
in the highest PD-L1 positive cohort (PD-L1 “strong”); the median OS in the same cohort
was 13.7 months. Preliminary data from 45 subjects enrolled in KEYNOTE 001, Part F1
(previously untreated, PD-L1 positive NSCLC) indicate an ORR by investigator assessed
irRC of 36%. Median OS at 12 months has not been reached with an OS rate at 12 months of
79.7%. Analyses have not been performed to date in the PD-L1 strong cohort enrolled in
KEYNOTE 001 Part F1. 
Information on Other Trial –Related Therapy
4.1.3 
Platinum doublets are the SOC  for the treatment of patients with good performance status
(ECOG 0 or 1), advanced or metastatic, previously untreated NSCLC patients who lack an
EGFR sensitizing (activating) mutation  and ALK translocation.  These platinum doublets
include a platinum compound in combination with gemcitabine, pemetrexed, docetaxel, or
bevacizumab. [58] These combinations have demonstrated OS gain, improved quality of life,
and control of disease related symptoms compared to single agent regimens, with several
combinations demonstrating similar efficacy. As such, the phase 3 trial proposed will offer
 
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multiple platinum combinations as control arm options and will be selected by the
investigator prior to randomization.
Approval for gemcitabine in combination with cisplatin was granted based upon data
observed in Phase 3 randomized controlled trial of gemcitabine in combination with cisplatin
which demonstrated a significant improvement in response rate (30.4% compared with
11.1%, respectively; p<0.0001), median time to progressive disease (5.6 months compared
with 3.7 months, respectively; p=0.0013), and OS  (9.1 months compared with 7.6 months,
respectively, p=0.004), compared to single agent cisplatin. Toxicity was predominantly
hematologic (neutropenia and thrombocytopenia), and was more pronounced in the
combination arm, with grade 4 neutropenia occurring in 35.3% of subjects compared with
1.2% of subjects on the cisplatin monotherapy arm. [59]
A randomized Phase 3 study of gemcitabine + cisplatin vs gemcitabine + carboplatin (1200
mg/m(2) on Days 1 and 8, followed on Day 1 by cisplatin  80 mg/m(2) or carboplatin
AUC=5, each for a maximum of 6 cycles or until disease progression or unacceptable
toxicity), in previously untreated Stage 3B and 4 NSCLC subjects demonstrated ORRs,
median time to disease progression, response duration and survival of 41/29%, 5.87/4.75
months, 7.48/5.15 months, and 8.75/7.97 months for the gemcitabine/cisplatin and
gemcitabine/carboplatin arms, respectively. Toxicity profiles were similar across the two
combinations with the only significantly different grade 3/4 toxicities including nausea and
vomiting in the gemcitabine + cisplatin combination and thrombocytopenia in the
gemcitabine + carboplatin combination [60]. The comparable efficacy and toxicity of these
two combinations indicate that either platinum in combination with gemcitabine is acceptable
for the treatment of advanced or metastatic, previously untreated NSCLC.
In addition, the Phase 3 trial proposed will offer the choice of pemetrexed in combination
with  either carboplatin or cisplatin for a maximum of 6 cycles followed by optional
pemetrexed maintenance as well as carboplatin in combination with paclitaxel followed by
optional pemetrexed maintenance. Pemetrexed will only be permitted in subjects with non-
squamous histologies.
The approval of pemetrexed is limited to subjects with NSCLC with non-squamous histology
by both the FDA and EMA. The approval was based upon the Phase 3, noninferiority trial in
first line, advanced NSCLC subjects that compared the OS  of pemetrexed plus cisplatin to
gemcitabine plus cisplatin. Overall survival for the cisplatin/pemetrexed was noninferior to
the cisplatin/gemcitabine combination with median survivals of 10.3 months in both
treatment arms (adjusted hazard ratio [HR] 0.94 [95 percent CI: 0.84, 1.05]). The median
PFS was 4.8 and 5.1 months for the pemetrexed + cisplatin and gemcitabine + cisplatin arms,
respectively (adjusted HR 1.04 [95 percent CI: 0.94, 1.15]). The overall response rates were
27.1 percent and 24.7 percent for the pemetrexed + cisplatin and gemcitabine + cisplatin
arms, respectively. In a pre-specified analysis, OS  was statistically superior for the
cisplatin/pemetrexed arm in subjects with adenocarcinoma (12.6 vs 10.9 months). In contrast,
subjects with squamous cell histology had a significant improvement in OS  with the
cisplatin/gemcitabine combination (10.8 vs 9.4 months) [61], indicating differential efficacy
in histological subtypes of NSCLC.
 
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Further gains in OS have been achieved with the administration of pemetrexed maintenance.
A phase 3, double-blind study of maintenance pemetrexed plus best supportive care (BSC)
versus placebo plus BSC was conducted in subjects with NSCLC  whose disease had not
progressed following 4 cycles of cisplatin + pemetrexed induction. Subjects were randomized
2:1 to pemetrexed + BSC or placebo + BSC, which were continued until disease progression
or toxicity.  The median OS for subjects in the intent-to-treat (ITT) group was 13.4 months
for subjects receiving pemetrexed and 10.6 months for those receiving placebo (HR of 0.79
[95 percent CI: 0.65, 0.95, p=0.012]). Median OS was 15.5 months versus 10.3 months for
subjects with non-squamous NSCLC receiving pemetrexed or placebo, respectively (HR of
0.70 [95 percent CI: 0.56, 0.88]). The median OS in subjects with squamous cell NSCLC
receiving pemetrexed was 9.9 months versus 10.8 months for those receiving placebo (HR of
1.07 [95 percent CI: 0.77,1.50])[62]. These findings have established pemetrexed
maintenance following completion of 4 cycles of a platinum doublet induction as a safe and
efficacious regimen in patients with advanced or metastatic non-squamous NSCLC.
While the reciprocal use of carboplatin and cisplatin was demonstrated by Sandler and
colleagues when combined with gemcitabine [59], a meta-analysis of randomized controlled
clinical trials compared chemotherapy regimens containing either cisplatin or carboplatin in
combination with third generation antineoplastic agents including docetaxel, paclitaxel, and
gemcitabine. Cisplatin containing regimens were associated with a median survival of 9.1
months and a 1-year survival probability of 37%, while carboplatin containing regimens were
associated with a median survival of 8.4 months and a 1-year survival probability of 34%.
The risk of death was higher with carboplatin compared with cisplatin, although the
difference was not statistically significant (HR = 1.07, 95 percent CI: 0.99 t, 1.15, p=0.100).
In addition, the random-effects survival model gave an estimated value of the HR  of
mortality equal to 1.08 (95 percent CI: 1.00, 1.16, p=0.063). Toxicity data indicated that
carboplatin based doublets caused more thrombocytopenia, while cisplatin-based
chemotherapy caused more nausea, vomiting and renal toxicity. The incidence of
neurotoxicity was not different in the two treatments groups. These data indicate that while a
trend for improved efficacy is observed with cisplatin based chemotherapies, the results are
not statistically significant and are associated with an increased incidence of SAEs. [63]
These data support the interchangeable use of carboplatin or cisplatin in combination with
SOC antineoplastic agents and should be offered as options for the treatment of advanced or
metastatic NSCLC patients that have not previously received systemic cytotoxic therapies for
their metastatic disease. 
The platinum containing regimen of carboplatin in combination with paclitaxel will also be
included as a control chemotherapy option. Multiple Phase 3 studies have demonstrated
similar efficacy for carboplatin plus paclitaxel compared to other platinum doublets,
including ECOG 1594 [64]. This is especially significant given that treatment options are
limited for squamous histologies. As such, KEYNOTE 024, as planned, will additionally
allow paclitaxel 200 mg/m2 in combination with carboplatin AUC 5 or 6, both IV, dosed
every three weeks for a maximum of 6 cycles as a control, chemotherapy option, followed by
pemetrexed maintenance if the investigator chooses, in subjects with non-squamous
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Bevacizumab containing regimens will not be included among the SOC treatment options in
the Phase 3 trial proposed for multiple reasons, including a significant adverse toxicity
profile as well as multiple exclusion criteria limiting the number of subjects eligible for
treatment. 
AVAiL, a pivotal Phase 3, demonstrated improved PFS  of both a low and high dose of
bevacizumab in combination with gemcitabine and cisplatin. Overall survival was not
statistically significant. E4599, a pivotal Phase 3, demonstrated improved OS  of
bevacizumab in combination with carboplatin and paclitaxel. In both studies, subjects with
squamous cell histology were excluded from the trial. Furthermore, the incidence of serious
AEs was higher in the bevacizumab combinations and included pulmonary hemorrhage,
sometimes fatal, as well as other clinically significant manifestations of bleeding. To our
knowledge, no randomized controlled trials have been conducted which compare the
combinations of carboplatin, paclitaxel, and bevacizumab followed by bevacizumab
maintenance to cisplatin and pemetrexed followed by pemetrexed maintenance. Although OS
gains may be similar between the two regimens, the risk-benefit profile favors the platinum
in combination with pemetrexed followed by pemetrexed maintenance as a treatment option
for non-squamous, NSCLC subjects. 
The above data support multiple platinum containing chemotherapy comparators as control
options and include paclitaxel, gemcitabine, and pemetrexed containing platinum regimens.
These control options all have proven clinical benefit in a population with significant unmet
need. The further allowance of either cisplatin or carboplatin in combination with
pemetrexed and gemcitabine will allow the investigator to choose an appropriate regimen
based upon the subject’s underlying histology and co-morbidities prior to randomization.
Rationale
4.2 
Rationale for the Trial and Selected Subject Population
4.2.1 
Lung cancer had the highest incidence of malignancies globally in 2008 with more than 1.6
million cases. Mortality from lung cancer in 2008 was similar with over 1.4 million deaths
from lung cancer globally [65]. 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, multi-modality 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 have served as the mainstay of treatment for decades with
platinum containing doublets and maintenance strategies conferring the greatest advances in
OS gains.
Platinum-based combination chemotherapy prolongs survival, improves quality-of-life, and
controls disease related symptoms. Platinum chemotherapy, thus, is the backbone treatment
for initial (first line) treatment of patients not candidates for treatment with tyrosine kinase
 
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inhibitors (TKIs) and who have an ECOG PS of 0 or 1. Single agent cytotoxic agents such as
gemcitabine or docetaxel are considered SOC for patients with an ECOG PS of 2. Approved
therapies for previously untreated, advanced/metastatic NSCLC patients who lack an EGFR
sensitizing mutation  and are ALK  translocation  negative include paclitaxel, gemcitabine,
docetaxel, pemetrexed and bevacizumab, all in combination with platinum based
chemotherapy. While ECOG 1594 demonstrated that the four platinum-doublets tested
(cisplatin combined with either paclitaxel, gemcitabine, or docetaxel, and carboplatin and
paclitaxel) have equivalent activity in the first-line setting [64], neither pemetrexed nor
bevacizumab is appropriate for patients with squamous histology [61] [66] [67] 
Recently, targeted therapies for specific tumor genetic alterations have resulted in higher
response rates in specific subpopulations of NSCLC patients. Examples include inhibitors
against the EGFR family and the ALK. Because of the highly significant demonstration of
clinical benefit in these molecularly defined sub-populations, ESMO and NCCN guidelines
indicate that first-line treatment with an approved TKI, should be prescribed to patients with
tumors bearing an activating (sensitizing) EGFR mutation because of significantly higher
response rate (RR), longer PFS, and better quality of life (QoL) (ESMO) when compared
with first-line chemotherapy. [58] Recently, a third EGFR inhibitor, afatinib, was approved
for the treatment of EGFR inhibitor (TKI) naïve patients with advanced or metastatic
NSCLC who bear EGFR activating mutations on the basis of a significantly improved PFS
and acceptable safety, as compared to a SOC  platinum doublet of cisplatin + pemetrexed.
The composite of data demonstrated a favorable benefit-risk ratio and thus contributes to the
arsenal of options for NSCLC patients who harbor EGFR activating mutations. 
Furthermore, recent retrospective analyses indicate that continuation of TKI treatment
beyond RECIST defined progression is associated with a significantly improved OS as
compared to subjects who were switched to cytotoxic chemotherapies at the time of RECIST
defined PD [68]. The ongoing single arm, Phase 2 ASPIRATION trial (NCT01310036) aims
to prospectively determine if continuation of erlotinib beyond RECIST defined progression
in Asian subjects with EGFR mutations confers clinical benefit. To our knowledge, no
randomized studies comparing treatment beyond progression to the traditional paradigm in
which cytotoxic chemotherapy is initiated at the time of progression have been performed. 
Despite these definitive data, the NCCN guidelines recommend that EGFR inhibitors be
continued despite PD in  asymptomatic patients who harbor EGFR sensitizing mutations,
further underscoring the potential to slow the rate progression and ultimately provide clinical
benefit in a patient population with limited therapeutic options in the 2L and beyond.
Patients with NSCLC harboring an ALK translocation  should be considered for crizotinib
(Xalkori) for the treatment of ALK translocated, previously treated NSCLC.
Despite the development of these targeted therapies, most patients relapse and die from their
lung cancer; therefore, advanced and metastatic NSCLC remain a major unmet medical need.
Patients who harbor EGFR sensitizing mutations and/or ALK translocations will be excluded
from this study. Significant preclinical and clinical data indicate that activation of these
respective pathways fundamentally alter the natural history of tumors that bear these
 
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mutations as compared to tumors that do not, which ultimately affect sensitivity to SOC
chemotherapies including pemetrexed in the case of ALK translocations [69]. In addition,
EGFR sensitizing mutations confer significant prognostic implications as illustrated by the
improved PFS to the SOC platinum doublet, carboplatin and paclitaxel, and OS in the EGFR
sensitizing mutation  population  [70].  These mutations also potentially alter PD-L1
expression, likely due to yet undefined interactions between the PD-1/PD-L1/2, EGFR, and
EML4/ALK pathways [71].  These observations indicate that tumors that bear EGFR
sensitizing mutations or ALK translocations may be fundamentally different from tumors
that do not bear these mutations and may have a different safety and efficacy profile with
pembrolizumab as compared to tumors that do not bear these mutations. Given that little data
exist regarding the safety and/or efficacy implications of pembrolizumab on these tumors,
tumors that bear these mutations will be excluded from this study. 
Details regarding specific benefits and risks for subjects participating in this clinical trial may
be found in the accompanying IB and Informed Consent documents.
Subjects in clinical trials generally cannot expect to receive direct benefit from
treatment/vaccination during participation, as clinical trials are designed to provide
information about the safety and effectiveness of an investigational medicine.
4.2.1.1 Benefit Risk
The clinical outlook of patients with metastatic, previously untreated NSCLC is bleak with
median OSs of approximately 1 year. Survival estimates are especially bleak for patients who
do not harbor EGFR sensitizing mutations and ALK translocations, for whom targeted
therapies do not exist. Patients that do not have an EGFR sensitizing mutation and/or do not
harbor an ALK translocation are treated with SOC  platinum doublets. The majority of
patients treated with SOC platinum doublets experience early disease progression, significant
grade 3 or 4 toxicity, and succumbs to their disease because of the lack of curative therapies
in this setting. Thus, there is an urgency to develop new agents for this patient population.
Results from KEYNOTE -001, a large Phase 1 study with multiple Phase 1B like NSCLC
cohorts indicate that sustained responses are achieved in patients with metastatic or recurrent
NSCLC who express PD-L1 by immunohistochemistry.  Preliminary data in 159 pretreated,
advanced/metastatic NSCLC patients indicate that pembrolizumab is associated with a 23%
ORR by centrally assessed RECIST in PD-L1 positive patients as compared to only a 9%
ORR by centrally assessed RECIST in PD-L1 negative patients. Furthermore, the DCR
(disease control rate) was 42% in the PD-L1 positive cohort with a median response duration
of 7.4 months.
Preliminary safety data indicate that pembrolizumab has an acceptable AE profile. The most
common drug related AEs observed in the previously treated cohort described above
included fatigue, arthralgia, decreased appetite, pruritus, diarrhea, nausea, pyrexia, rash and
hypothyroidism, with the majority being grade 1-2 in severity.  Rates of any grade 3-5 drug
related AEs were ~ 10%. Immune related AE, including serious AEs, can occur.   Based on
these preliminary data, the on-going studies (KEYNOTE-001, KEYNOTE-010 and
 
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KEYNOTE-024) and planned study (KEYNOTE-042) are expected to provide confirmatory
data demonstrating clinical benefits with pembrolizumab.
In conclusion, pembrolizumab demonstrates a very promising anti-cancer activity in NSCLC
patients with an acceptable safety profile compared to those of existing therapeutic options.
On-going and planned studies will allow for a more comprehensive analysis of benefit/risk
balance of pembrolizumab.
Rationale for Dose Selection/Regimen/Modification
4.2.2 
The planned dose of pembrolizumab for this trial is 200 mg Q3W. Based on the totality of
data generated in the pembrolizumab development program, 200 mg Q3W is the appropriate
pembrolizumab dose across all indications, and regardless of tumor type. As outlined below,
this dose is justified by:
 Clinical data from 8 randomized trials demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg Q2W
 Clinical data showing a meaningful improvement in the benefit-risk relationship,
including OS, at 200 mg Q3W across multiple indications
 Pharmacology data showing full target saturation in both systemic circulation
(inferred from PK data) and tumor (inferred from physiologically based
pharmacokinetic [PBPK] analysis) at 200 mg Q3W.
In the 8 randomized dose comparison trials, a total of 2262 subjects 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 trials (KN001 B2, KN001 D, KN002, KN010, and
KN021) compared 2 mg/kg Q3W vs 10 mg/kg Q3W, and 3 trials (KN001 B3, KN001 F2,
and KN006) compared 10 mg/kg Q3W vs 10 mg/kg Q2W . All these trials demonstrated flat
dose- and exposure-response relationships across the doses studied, representing an
approximate 5- to 7.5-fold difference in exposure.  Responses to the dose of 2 mg/kg (or 200
mg fixed dose) Q3W  responses were similar to responses to the highest doses studied.
Subsequently, flat dose/exposure-response relationships were 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
interacts with immune cells and does not act via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK
data from KN001, evaluating target-mediated drug disposition, 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.
 
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Finally, population PK analysis for pembrolizumab, which characterized the influence of
body weight and other subject covariates on exposure, has shown that fixed dosing provides
control of PK variability similar to that with weight-based dosing, with considerable overlap
in the distribution of exposures from the 200 mg Q3W fixed dose and the 2 mg/kg Q3W
dose. Supported by these PK characteristics, and given that a fixed dose has advantages of
less dosing complexity and reduced potential for dosing errors, the 200 mg Q3W fixed dose
was selected for evaluation across all pembrolizumab protocols.
Rationale for Endpoints
4.2.3 
4.2.3.1 Efficacy Endpoints
Primary: Progression free survival 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 and EMA approvals including the EGFR inhibitors afatinib and erlotinib. PFS will be
assessed by RECIST 1.1 by an independent central radiologists’ review which  will be
blinded to treatment assignment so as to minimize any bias in the response assessments.
Secondary: Overall survival will be included as it is a standard assessment of clinical benefit
in subjects with advanced or metastatic NSCLC. Achieving superiority in OS, however, is
likely to be limited by dilution of benefit with multiple post-progression therapies as well as
optional, planned crossover to pembrolizumab available to subjects randomized to the SOC
arm. ORR  by RECIST 1.1 criteria as assessed by blinded independent central radiology
review and the duration of response by RECIST 1.1 as assessed by  blinded independent
centralradiologists’ review willserve as additionalmeasures of efficacy.
Patient Reported Outcomes: EORTC QLQ-C30 version 3.0 and EORTC QLQ-LC13 will
be used to investigate (i) quality of life and (ii) disease related symptoms. They are not pure
efficacy or safety endpoints because they are affected by both disease progression and
treatment tolerability. EQ-5D-3L will be used to calculate health utilities for incorporation
into QTWiST and health economic models.
4.2.3.2 Patient Reported Outcomes Instruments
EORTC QLQ-C30 was developed to assess the quality of life of cancer subjects. It has been
translated and validated into 81 languages and used in more than 3,000 studies worldwide.  It
contains 5 functioning scales (physical, role, cognitive, emotional, and social), 3 symptom
scales (fatigue, nausea, pain) and additional single symptom items. It is scored on a 4 point
scale (1=not at all, 2=a little, 3= quite a bit, 4=very much). The EORTC QLQ-C30
instrument also contains 2 global scales that use 7 point scale scoring with anchors (1=very
poor and 7=excellent).
 
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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 eEuroQol-5D (eEQ-5D) is a standardized instrument for use as a measure of health
outcome. The eEQ-5D-3L will provide data for use in economic models and analyses
including developing health utilities or QALYs. The five health state dimensions in this
instrument include the following: mobility, self-care, usual activities, pain/discomfort, and
anxiety/depression (5). Each dimension is rated on a three point scale from 1 (extreme
problem) to 3 (no problem). The eEQ-5D will always be completed by subjects first before
completing the eEORTC QLQC30 and eEORTC QLQ-LC13.
4.2.3.3 Planned Exploratory Biomarker Research
Additional biomarker research to identify factors important for pembrolizumab therapy will
be pursued. Tumor and blood samples may undergo additional proteomic, genomic and
transcriptional analyses (both DNA and RNA analyses). This additional biomarker or
genomic research may be conducted to identify factors important for pembrolizumab therapy
and subject response to therapy (for example, to identify risk factors for AEs or who might
best respond to treatment).
4.2.3.4 Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on DNA (blood) or tumor tissue
specimens collected during this clinical trial.  This research may include genetic analyses
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere
in the protocol (as part of the main trial) and will only be conducted on specimens from
appropriately consented subjects. The objective of collecting specimens for Future
Biomedical Research is to explore and identify biomarkers that inform the scientific
understanding of diseases and/or their therapeutic treatments. For instance, exploratory
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events
are identified.  Genomic markers of disease may also be investigated.  Such retrospective
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to
outcome would require validation in future clinical trials. The overarching goal is to use such
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects
receive the correct dose of the correct drug/vaccine at the correct time.  The details of this
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and
Management of Specimens for Future Biomedical Research.  Additional informational
 
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material for institutional review boards/ethics committees (IRBs/ERCs) and investigational
site staff is provided in Section 12.3.
5.0 METHODOLOGY
Entry Criteria
5.1 
Diagnosis/Condition for Entry into the Trial
5.1.1 
Male/Female subjects with NSCLC who do not have an EGFR sensitizing mutation AND are
ALK  translocation  negative, whose tumors demonstrate PD-L1 strong expression as
determined by a central laboratory, have received no systemic anti-cancer therapy for their
metastatic NSCLC, and are at least 18 years of age will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2 
In order to be eligible for participation in this trial, the subject must:
1. Have a histologically or cytologically confirmed diagnosis of NSCLC, is stage IV,
does not have an EGFR sensitizing (activating) mutation or ALK translocation, and has
not received prior systemic chemotherapy treatment for their metastatic NSCLC.
2. Have measurable disease based on RECIST 1.1 as determined by the site.
3. Be ≥18 years of age on day of signing informed consent.
4. Have a life expectancy of at least 3 months
5. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group
(ECOG) Performance Status
6. Have adequate organ function as indicated by the following laboratory values in
Table 1:
 
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Table 1 
Adequate Organ Function Lab Values
System  
Laboratory Value
Hematological
Absolute neutrophil count (ANC) 
≥1,500 /mcL
Platelets 
≥100,000 / mcL
Hemoglobin  
≥9 g/dL or ≥5.6 mmol/L–  without transfusions within 2
weeks of first dose
Renal
Creatinine  OR  
calculated creatinine clearance (CrCl)a 
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subjects with creatinine levels > 1.5 X
institutional ULN
Hepatic
Total bilirubin  
≤  ULN
AST (SGOT) and ALT (SGPT) 
≤ 1.5 X ULN
Alkaline Phosphatase 
≤ 2.5 X ULN
Endocrine
Thyroid stimulating hormone (TSH) 
Within normal limits. Please note: If TSH is not within
normal limits at baseline, the subject may still be eligible
if T3 and free T4 are within the normal limits.
Coagulation
International Normalized Ratio (INR) 
or Prothrombin Time (PT) 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless the subject is receiving anticoagulant
therapy
≤1.5 X ULN unless the subject is receiving anticoagulant
therapy
a 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 * creatinine)
7. Subject has no history of prior malignancy, with the exception of basal cell carcinoma
of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ
cervical cancer, or has undergone potentially curative therapy with no evidence of
that disease recurrence for 5 years since initiation of that therapy.
8. Have provided a formalin fixed tumor tissue sample from a biopsy of a tumor lesion
either at the time of or after the diagnosis of metastatic disease has been made AND
from a site not previously irradiated to assess for PD-L1 status. Biopsies obtained
PRIOR to the administration of any systemic therapy administered for the treatment
of a subject’s tumor (such as neoadjuvant/adjuvant therapy) will not be permitted for
analysis. The tissue sample must be received by the central vendor prior to
randomization. Fine needle aspirates, Endobronchial Ultrasound (EBUS) or cell
blocks are not acceptable. Needle or excisional biopsies, or resected tissue is required.
 
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9. The subject’s tumor does not harbor an  EGFR sensitizing (activating) mutation or
ALK translocation. EGFR sensitizing mutations are those mutations that are
amenable to treatment with tyrosine kinase inhibitors including erlotinib, gefitinib, or
afatanib.  Investigators must be able to produce the source documentation of the
EGFR  mutation and ALK  translocation  status in all subjects with non-squamous
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 unable to test
for these molecular changes, formalin fixed paraffin embedded tumor tissue of any
age should be submitted to a central laboratory designated by the Sponsor for such
testing. Subjects with non-squamous histologies will not be randomized until the
EGFR  mutation  status and/or ALK translocation status is available in source
documentation at the site. For patients enrolled who are known to have a tumor of
predominantly squamous histology, molecular testing for EGFR and ALK
translocation will not be required as this is not SOC  and is not part of current
diagnostic guidelines.
10. Have a PD-L1 strong tumor as determined by IHC at a central laboratory. 
11. Female subjects must have a negative urine or serum pregnancy test at screening
(within 72 hours of first dose of study medication) if of childbearing potential or be of
non-child bearing potential. If the urine test is strong or cannot be confirmed as
negative, a serum pregnancy test will be required. The serum pregnancy test must be
negative for the subject to be eligible. Non-childbearing potential is defined as (by
other than medical reasons):
a. ≥45 years of age and has not had menses for greater than 1 year,
b. Amenorrheic for <2 years without a hysterectomy and oophorectomy and an
FSH value in the postmenopausal range upon pretrial (screening) evaluation,
c. Whose status is post hysterectomy, oophorectomy or tubal ligation.
Documented hysterectomy or oophorectomy must be confirmed with medical
records of the actual procedure or confirmed by an ultrasound. Tubal ligation
must be confirmed with medical records of the actual procedure otherwise the
subject must be willing to use two adequate barrier methods throughout the
study, starting with the screening visit through 120 days after the last dose of
study therapy and up to 180 days after last dose of chemotherapeutic agents as
specified in the protocol. Please see Section 5.7.2 for a list of acceptable birth
control methods. Information must be captured appropriately within the site's
source documents.
 
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12. If of childbearing potential, female subjects must be willing to use two adequate
barrier methods throughout the study, starting with the screening visit through 120
days after the last dose of study therapy and up to 180 days after last dose of
chemotherapeutic agents as specified in the protocol. Please see Section 5.7.2 for a
list of acceptable birth control methods.
Note: Abstinence is acceptable if this is the established and preferred contraception
for the subject.
13. Male subjects with a female partner(s) of child-bearing potential must agree to use
two adequate barrier methods throughout the trial starting with the screening visit
through 120 days after the last dose of pembrolizumab is received. Such methods of
contraception, or abstinence from heterosexual activity, are required from the
screening visit (Visit 1) through 180 days after the last dose of chemotherapy. Males
with pregnant partners must agree to use a condom; no additional method of
contraception is required for the pregnant partner.
Note: Abstinence is acceptable if this is the established and preferred contraception
for the subject.
14. Subject has voluntarily agreed to participate by giving written informed
consent/assent for the trial. The subject may also provide consent/assent for Future
Biomedical Research. However, the subject may participate in the main trial without
participating in Future Biomedical Research.
Subject Exclusion Criteria
5.1.3 
The subject must be excluded from participating in the trial if the subject:
1. Has an EGFR sensitizing mutation and/or an ALK translocation.
2. Has received systemic therapy for the treatment of their stage IV NSCLC.
Completion of 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.
3. Is currently participating and receiving study therapy or has participated in a study of
an investigational agent and received study therapy or used an investigation
device within 4 weeks of the first dose of treatment.
4. Tumor specimen is not evaluable for PD-L1 expression by the central laboratory. If
an additional tumor specimen is submitted AND evaluable for PD-L1 expression, the
subject will be eligible to participate if PD-L1 expression is assessed as “strong” by
the central laboratory.
 
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5. Is receiving systemic steroid therapy < 3 days prior to the first dose of trial treatment
or receiving any other form of immunosuppressive medication (corticosteroid use on
study for management of ECIs, as pre-medication for the control chemotherapies,
and/or a pre-medication for IV contrast allergies/reactions is allowed). Subjects who
are receiving daily steroid replacement therapy serve as an exception to this rule.
Daily prednisone at doses of 5-7.5 mg is an example of replacement therapy.
Equivalent hydrocortisone doses are also permitted if administered as a replacement
therapy.
6. Is expected to require any other form of systemic or localized antineoplastic therapy
while on trial (including maintenance therapy  with another agent for NSCLC,
radiation therapy, and/or surgical resection).
7. Has received prior systemic cytotoxic chemotherapy, biological therapy, OR major
surgery within 3 weeks of the first dose of trial treatment; received thoracic radiation
therapy of > 30 Gy within 6 months of the first dose of trial treatment.
8. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137,
or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways).
9. Has untreated central nervous system (CNS) metastases and/or carcinomatous
meningitis identified either on the baseline brain imaging (please see Brain Imaging
in Section 7 and Site Imaging Manual for additional details on the imaging modality)
obtained during the screening period OR identified prior to signing the ICF. Subjects
whose brain metastases have been treated may participate provided they show
radiographic stability  (defined as 2 brain images, both  of which are obtained after
treatment to the brain metastases. These imaging scans should both be obtained at
least four weeks apart and show no evidence of intracranial progression). In addition,
any neurologic symptoms that developed either as a result of the brain metastases or
their treatment must have returned to baseline or resolved. Any steroids administered
as part of this therapy must be completed at least three days prior to study medication.
10. 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 (i.e., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment. 
11. Has had an allogeneic tissue/solid organ transplant.
12. Has interstitial lung disease (ILD) OR has had a history of pneumonitis that has
required oral or IV steroids.
 
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13. Has received or will receive a live vaccine within 30 days prior to the first
administration of study medication. Seasonal flu vaccines that do not contain a live
virus are permitted.
14. Has an active infection requiring IV systemic therapy.
15. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
16. Has known active Hepatitis B, Hepatitis C or tuberculosis. Active Hepatitis B is
defined as a known positive HBsAg result. Active Hepatitis C is defined by a known
positive Hep C Ab result and known quantitative HCV RNA results greater than the
lower limits of detection of the assay.
17. 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.
18. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
19. 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).
20. 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 180 days after the last dose of SOC
chemotherapy.
21. Is or has an immediate family member (spouse or children) who is investigational site
or sponsor staff directly involved with this trial, unless prospective IRB approval (by
chair or designee) is given allowing exception to this criterion for a specific subject.
Trial Treatment(s)
5.2 
The treatments to be used in this trial are outlined below in Table 2.  For the control
chemotherapy options, the choice of platinum doublet and the respective dose of each
chemotherapeutic agent must be made and recorded prior to randomization. If a subject
received a platinum doublet as part of neoadjuvant/adjuvant therapy that doublet may not be
chosen as a SOC  chemotherapy control option for this trial unless a contraindication
precludes treatment with an alternate regimen. Pemetrexed is not permitted as a treatment for
subjects with squamous histologies.
 
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Table 2 
Trial Treatment
Drug 
Dose/Potency
Dose
Frequency
Route of
Administration
Regimen/
Treatment Regimen
Pembrolizumab 
200 mg IV  
Q3W  
IV
Day 1 of each 21 day
cycle
Paclitaxel 
200 mg/m2 
Q3W  
IV
Day 1 of each 21 day
cycle
Carboplatin  
AUC 5 or 6 
Q3W  
IV
Day 1 of each 21 day
cycle
Pemetrexed 
500 mg/m2
Q3W  
IV
Day 1 of each 21 day
cycle
Cisplatin  
75 mg/m2
Q3W  
IV
Day 1 of each 21 day
cycle
Gemcitabine 
1250 mg/m2
Q3W  
IV
Day 1 and 8 of each
21 day cycle
Trial treatment should begin on the day of randomization or as close as possible to the date
on which the subject is allocated/assigned.
All supplies indicated in Table 2 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 will be responsible for recording the lot number, manufacturer and expiry date
of any locally purchased 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 trial
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1 
5.2.1.1 Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.
This study will use a fixed dose of 200 mg of pembrolizumab. Details on the dose
calculation, preparation and administration are provided in the Pharmacy Manual.
Gemcitabine, carboplatin, cisplatin, paclitaxel and pemetrexed will be prepared and
administered as per the approved product label.
 
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5.2.1.2 Dose Modification (Escalation/Titration/Other)
Gemcitabine/Carboplatin or Cisplatin Chemotherapy Regimen
Refer to approved product labels for subjects receiving this regimen
Subjects have the option, in the event of toxicity, to change the choice of platinum
(carboplatin and cisplatin) administered. Changes may not occur with the other
chemotherapeutic agents provided in this trial.
Pemetrexed/Carboplatin or Cisplatin Chemotherapy Regimen
Refer to approved product labels for subjects receiving this regimen.
Subjects have the option, in the event of toxicity, to change the choice of platinum
(carboplatin and cisplatin) administered. Changes may not occur with the other
chemotherapeutic agents provided in this trial.
Paclitaxel/Carboplatin and Optional Pemetrexed Chemotherapy Regimen
Refer to approved product labels for subjects receiving this regimen.
Pembrolizumab
If a dose of pembrolizumab is withheld for toxicity, then subjects may resume dosing with
pembrolizumab if that is appropriate at their next scheduled appointment or when toxicity
has improved as described below. 
Pembrolizumab will be withheld for ≥ Grade 3 drug-related toxicity including laboratory
abnormalities, and severe or life-threatening AEs as per Table 3 below.
 
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Table 3 
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated With Pembrolizumab
General instructions:
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid
has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be
reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be
initiated if irAEs cannot be controlled by corticosteroids.
Immune-related
AEs
Toxicity grade or
conditions
(CTCAEv4.0)
Action taken to
pembrolizumab
irAE management with corticosteroid
and/or other therapies
Monitor and follow-up
Pneumonitis 
Grade 2 
Withhold
 Administer corticosteroids (initial
dose of 1-2 mg/kg prednisone or
equivalent) followed by taper
 
Monitor 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 (ie, diarrhea, abdominal pain,
blood or mucus in stool with or without fever)
and of bowel perforation (ie, 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
 
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Immune-related
AEs
Toxicity grade or
conditions
(CTCAEv4.0)
Action taken to
pembrolizumab
irAE management with corticosteroid
and/or other therapies
Monitor and follow-up
AST / ALT
elevation or
Increased
bilirubin
Grade 2
Withhold
 Administer corticosteroids (initial
dose of 0.5- 1 mg/kg prednisone or
equivalent) followed by taper
 
Monitor with liver function tests (consider
weekly or more frequently until liver enzyme
value returned to baseline or is stable)
Grade 3 or 4 
Permanently
discontinue
 Administer corticosteroids (initial
dose of 1-2 mg/kg prednisone or
equivalent) followed by taper
Type 1 diabetes
mellitus (T1DM)
or Hyperglycemia
Newly 
onset 
T1DM or
Grade 
3 
or 4
hyperglycemia
associated 
with
evidence of -cell
failure
Withhold
 Initiate insulin replacement therapy
for subjects with T1DM
 Administer anti-hyperglycemic 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
discontinue1
Hyperthyroidism 
Grade 2 
Continue
 Treat 
with 
non-selective 
beta-
blockers 
(eg, 
propranolol) 
or
thionamides as appropriate
 
Monitor for signs and symptoms of thyroid
disorders.
Grade 3 or 4 
Withhold or
permanently
discontinue1
Hypothyroidism  
Grade 2-4
Continue
 Initiate 
thyroid 
replacement
hormones (eg, levothyroxine or
liothyronine) per standard of care
 
Monitor for signs and symptoms of thyroid
disorders.
Nephritis and 
Renal dysfunction
Grade 2
Withhold
 Administer 
corticosteroids
(prednisone 
1-2 
mg/kg 
or
equivalent) followed by taper.
 
Monitor changes of renal function
Grade 3 or 4 
Permanently
discontinue
 
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Immune-related
AEs
Toxicity grade or
conditions
(CTCAEv4.0)
Action taken to
pembrolizumab
irAE management with corticosteroid
and/or other therapies
Monitor and follow-up
Myocarditis 
Grade 1 or 2 
Withhold
 Based on severity of AE administer
corticosteroids
 
Ensure adequate evaluation to confirm
etiology and/or exclude other causes
Grade 3 or 4 
Permanently
discontinue
All other immune-
related AEs
Intolerable/ 
persistent Grade 2
Withhold
 Based on type and severity of AE
administer corticosteroids
 
Ensure adequate evaluation to confirm
etiology and/or exclude other causes
Grade 3
Withhold 
or
discontinue 
based
on the type of event. 
Events that require
discontinuation
include 
and 
not
limited to:  Guillain-
Barre 
Syndrome,
encephalitis
Grade 
4 
or
recurrent Grade 3
Permanently
discontinue
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. 
NOTE:
For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE
resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM). 
 
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In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial
treatment should be discontinued after consultation with the Sponsor. Subjects who require
corticosteroids to manage drug-related AEs must be at an equivalent dose of ≤10mg per day
of prednisone to resume dosing with pembrolizumab. Furthermore, an inability to reduce the
corticosteroid dose for managing a drug-related AE to the equivalent of ≤10 mg prednisone
per day within 12 weeks of last pembrolizumab dose should prompt discussion between the
investigator and Sponsor regarding the subject’s ability to continue on treatment in the trial.
With investigator and Sponsor agreement, subjects with a laboratory AE still at Grade 2 after
12 weeks may continue treatment in the trial only if asymptomatic and controlled. This
includes subjects who experience drug induced hypothyroidism requiring replacement
therapy. Resumption of pembrolizumab may occur once the subject is stable on adequate
doses of replacement therapy and is clinically asymptomatic.
For information on the management of AEs, see Section 5.6.1. 
Subjects who experience Grade 3 or 4 pneumonitis, or recurrent persistent (>4 weeks) Grade
2 drug-related pneumonitis after rechallenge from a prior episode of persistent (>4 weeks)
Grade 2 drug-related pneumonitis, pembrolizumab MUST be permanently discontinued.
For subjects who experience a recurrence of the same AE(s) at the same grade or greater with
rechallenge of pembrolizumab, a consultation between the Sponsor and investigator should
occur to determine whether the subject should continue in the trial. However, for a subject
who experiences a recurrence of the same SAE at the same grade or greater with rechallenge
of pembrolizumab, the subject MUST discontinue study medication.
Dose increase or decrease of pembrolizumab will not be permitted in individual subjects.
Timing of Dose Administration
5.2.2 
Trial treatment may be administered up to 3 days after randomization for Cycle 1 Day 1 due
to administrative reasons unless the subject requires pemetrexed premedications. For these
subjects, the required premedications should be administered as close to randomization as
possible. After cycle 1 there is a 3 day window for all trial treatment. 
The specific time of pembrolizumab administration (e.g., time of the week for first
administration; time of the day for each administration) should take into consideration study
visit procedures.
All trial treatments will be administered on an out-patient basis.
Pembrolizumab: pembrolizumab 200 mg 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.
 
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Carboplatin: Carboplatin AUC 5 or 6 will be administered as an IV infusion over 30-60
minutes day 1 of every three week cycle following paclitaxel or pemetrexed infusions.
Cisplatin: Cisplatin 75 mg/m2 will be administered as an IV infusion over 6-8 hours OR as
outlined in local standard practices on day 1 of every 3 week cycle following pemetrexed.
Pemetrexed: Pemetrexed 500 mg/m2 will be administered as an IV infusion over 10 minutes
every three weeks. All subjects should be pre-medicated with steroids as per approved label
and local standard practices. In addition, all subjects assigned to pemetrexed must take a folic
acid preparation or multivitamin with folic acid containing between 350 to 1000 mcg daily.
At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first
dose of pemetrexed and dosing should continue during the full course of therapy and for 21
days after the last dose of pemetrexed.
Subjects must also receive one intramuscular injection of vitamin B12 1000 mcg during the
week preceding the first dose of pemetrexed and every 3 cycles thereafter. Subsequent
vitamin B12 injections may be given the same day as pemetrexed.
Initiation of the folic acid and vitamin B12 should occur as close to randomization as
possible. Pemetrexed will be administered on Cycle 1, day 1 and every 21 days thereafter. 
Gemcitabine: Gemcitabine 1250 mg/m2 will be administered as an IV infusion over 30
minutes on days 1 and 8 of every 3 week cycle.
Paclitaxel: Paclitaxel 200 mg/m2 will be administered as an IV infusion over 3 hrs. (or per
local standard practice) on day 1 of every 3 week cycle and should precede infusion with
carboplatin.
For additional details, refer to approved product labels for details regarding dose calculation,
reconstitution, preparation of the infusion fluid, and administration for each of the standard
of care chemotherapies. 
Trial Blinding/Masking
5.2.3 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the
treatment administered.
Randomization or Treatment Allocation
5.3 
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 and SOC, respectively.  The specific SOC
platinum doublet as well as the dose to be administered must be identified prior to
randomization.
 
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Stratification
5.4 
Randomization will be stratified according to the following factors:
1. Geography: East Asia vs non-East Asia
2. ECOG PS: 0 vs 1.
3. Histology: squamous vs non-squamous
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5 
Acceptable Concomitant Medications
5.5.1 
All treatments that the investigator considers necessary for a subject’s welfare may be
administered at the discretion of the investigator in keeping with the community standards of
medical care. All concomitant medication will be recorded on the case report form (CRF)
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications
and fluids. If changes occur during the trial period, documentation of drug dosage, frequency,
route, and date will also be included on the CRF.
Palliative and supportive care is permitted during the course of the trial for underlying
medical conditions and management of symptoms. Surgery for tumor control or symptom
management is not permitted during the study. Palliative radiotherapy is permitted to a single
lesion if considered medically necessary by the treating physician.  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. The specifics of the radiation treatment,
including the location, will be recorded.
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.
Prohibited Concomitant Medications and/or Treatments
5.5.2 
Subjects are prohibited from receiving the following therapies during the Screening,
Treatment, Crossover Phase, and Second Course Phases of this trial.
 Immunotherapy not specified in this protocol.
 Chemotherapy not specified in this protocol.
 Investigational agents other than pembrolizumab.
 Surgery for symptom management or tumor control
 Radiation therapy for tumor control
 
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 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, chicken pox, yellow fever, seasonal flu  (that
contain a live virus), H1N1 flu, rabies, BCG, and typhoid vaccine.
 Glucocorticoids for any purpose other than to modulate symptoms from an event of
clinical interest, use as a pre-medication for chemotherapeutic agents specified in the
protocol, or for use as a pre-medication in subjects with a known history of an IV
contrast allergy administered as part of CT radiography. Replacement doses of
steroids (for example, prednisone 5-7.5 mg daily) are permitted while on study.
 For subjects assigned to the control arm, concomitant meds should be prohibited as
per local standard of care practices and/or the respective package insert details.
Subjects who, in the assessment by the investigator, require the use of any of the
aforementioned treatments for clinical management should be removed from the trial.
Subjects may receive other medications that the investigator deems to be medically
necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-treatment Follow-up Phase.
Rescue Medications & Supportive Care
5.6 
Supportive Care Guidelines
5.6.1 
Pembrolizumab
Pembrolizumab subjects should receive appropriate supportive care measures as deemed
necessary by the treating investigator including but not limited to the items outlined below. 
For additional guidance and/or treatment recommendation please refer to the separate Events
of Clinical Interest Guidance Document. For guidelines for continuing treatment with
pembrolizumab, see Section 5.2.
 Diarrhea: Subjects should be carefully monitored for signs and symptoms of
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or
without fever) and of bowel perforation (such as peritoneal signs and ileus). In
symptomatic subjects, infectious etiologies should be ruled out, and if symptoms
are persistent and/or severe, endoscopic evaluation should be considered. All
subjects who experience diarrhea should be advised to drink liberal quantities of
clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes
should be substituted via IV infusion.
 
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 Nausea/vomiting: Administration of prophylaxis for nausea and vomiting should
be administered per institutional guidelines and local standard practices for the
standard of care chemotherapies offered for the control arm.  For pembrolizumab,
the therapy is considered to be of low to moderate emetogenic potential. 
Consideration for chemo induced nausea and vomiting prophylaxis should be
given in subsequent cycles of the administration according to standard
institutional practice and should not be routinely administered prior to the initial
trial treatment of pembrolizumab. Subjects should be strongly encouraged to
maintain liberal oral fluid intake.
 Anemia: Transfusions and/or erythropoietin may be utilized as clinically indicated
for the treatment of anemia, but should be clearly noted as concurrent
medications. Consider a potential immunologic etiology.
 Neutropenia: Prophylactic use of colony-stimulating factors including
Granulocyte Colony-Stimulating Factor (G-CSF), pegylated G-CSF or
Granulocyte Macrophage Colony-Stimulating Factor GM CSF is not allowed in
this trial. Therapeutic use of G-CSF is allowed in subjects with Grade 3-4 febrile
neutropenia. Consider a potential immunologic etiology.
 Thrombocytopenia: Transfusion of platelets may be used if clinically indicated.
ITP should be ruled out before initiation of platelet transfusion.
 Anti-infectives: Subjects with a documented infectious complication should
receive oral or IV antibiotics or other anti-infective agents as considered
appropriate by the treating Investigator for a given infectious condition, according
to standard institutional practice.
 Events of Clinical Interest with a potential immunologic etiology (ECI): Please
see the separate guidance document in the administrative binder regarding
identification, evaluation and management of adverse experiences of a potential
immunologic etiology. Depending on the type and severity of an ECI, oral or IV
treatment with a corticosteroid should be considered, in addition to appropriate
symptomatic treatment of a given condition.
 
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5.6.1.1 Supportive Care Guidelines for Events of Clinical Interest and Immune-related
Adverse Events
Immune-related Adverse Events
Adverse events (both non-serious and serious) associated with drug exposure and consistent
with an immune phenomenon  may represent an immunologic etiology.  These immune
related adverse events (irAEs) may be predicted based on the nature of the pembrolizumab
compound, its mechanism of action, and reported experience with immunotherapies that have
a similar mechanism of action. An irAE can occur shortly after the first dose or several
months after the last dose of treatment.  Particular attention should be paid to AEs that may
be suggestive of potential irAEs as outlined in 7.2.3.2.  Information on how to identify and
evaluate irAEs has been developed and is included in the Event of Clinical Interest Guidance
Document located in the Administrative Binder.
Events of Clinical Interest (ECI)
Events of clinical interest are non-serious and SAEs that may or may not be irAEs. ECIs
must be reported to Merck within 24 hours regardless of attribution to study treatment. Of
note, the requirement for reporting of ECIs applies to all arms, including comparators, of
pembrolizumab clinical trials. Information on how to identify  and report ECIs can  be
referenced in both Section 7.2.3.2 and the Event of Clinical Interest Guidance Document. 
Overview of Guidelines for Managing Suspected Pneumonitis from
5.6.2 
Pembrolizumab
Please consult the Event of Clinical Interest Guidance document in the Administrative Binder
for this study for a more in depth discussion of pneumonitis.
Guidelines for Infusion Reactions
5.6.3 
Pembrolizumab
Acute infusion reactions (which can include cytokine release syndrome, angioedema, or
anaphylaxis) are different from allergic/hypersensitive reactions, although some of the
manifestations are common to both AEs. Signs and symptoms usually develop during or
shortly after drug infusion and generally resolve completely within 24 hours of completion of
infusion. Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of
breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; Hypotension;
Myalgia (muscle pain); Nausea; Pruritus/itching; Rash/desquamation; Rigors/chills;
Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to
treatment); Urticaria (hives, welts, wheals); Vomiting.
Table 4 below shows treatment guidelines for subjects who experience an infusion reaction
associated with administration of pembrolizumab:
 
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Table 4 
Pembrolizumab Infusion Reaction 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 infusion interruption 
but 
responds 
promptly 
to 
symptomatic treatment (e.g., 
antihistamines, 
NSAIDS, 
narcotics, 
IV 
fluids); 
prophylactic 
medications 
indicated for < =24 hrs 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines
NSAIDS  
Acetaminophen  
Narcotics 
Increase monitoring of vital signs as
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of
stopping drug infusion, the infusion may
be restarted at 50% of the original infusion
rate (e.g. from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held until
symptoms resolve and the subject should
be premedicated for the next scheduled
dose.
Subjects who develop Grade 2 toxicity
despite adequate premedication should be
permanently discontinued from further
trial treatment administration.
Subject may be premedicated
1.5h (± 30-minutes) prior to
infusion of pembrolizumab
with:
Diphenhydramine 50 mg po
(or 
equivalent 
dose 
of
antihistamine).
Acetaminophen 500-1000 mg
po (or equivalent dose of
analgesic).
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:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
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.
Subject is permanently discontinued from
further trial treatment administration.
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
 
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Diet/Activity/Other Considerations
5.7 
Diet
5.7.1 
Subjects should maintain a normal diet unless modifications are required to manage an AE
such as diarrhea, nausea or vomiting.
Contraception
5.7.2 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if
pembrolizumab has transient adverse effects on the composition of sperm. Chemotherapy can
cause fetal harm if administered to pregnant women. Therefore, non-pregnant, non-
breastfeeding women may be enrolled if they are considered highly unlikely to conceive.
Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a
woman who is ≥45 years of age and has not had menses for greater than 1 year will be
considered postmenopausal), or 3) amenorrheic for <2 years without a hysterectomy and
oophorectomy and with a documented FSH value in the postmenopausal range, or 4) not
heterosexually active for the duration of the study, or 5) heterosexually active and willing to
use two methods of birth control (which is also recommended for the female partners of male
subjects). The two birth control methods can be either two barrier methods or a barrier
method plus a hormonal method to prevent pregnancy. Subjects should start using birth
control from study Visit 1 throughout the study period up to 120 days after the last dose of
pembrolizumab and up to 180 days after last dose of chemotherapeutic agents as specified in
the protocol.
The following are considered adequate barrier methods of contraception: diaphragm, condom
(by the partner), copper intrauterine device, sponge, or spermicide, as per local regulations
and guidelines. Appropriate hormonal contraceptives will include any registered and
marketed contraceptive agent that contains an estrogen and/or a progestational agent
(including oral, subcutaneous, intrauterine, or intramuscular agents). 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 they
must adhere to the contraception requirement (described above) for the duration of the study
and during the follow-up period defined in Section 7.2.2-Reporting of Pregnancy and
Lactation to the Sponsor. If there is any question that a subject will not reliably comply with
the requirements for contraception, that subject should not be entered into the study.
Use in Pregnancy
5.7.3 
If a female subject inadvertently becomes pregnant while on treatment in this study, the
subject will immediately be removed from the study. The site will contact the subject at least
monthly and document the subject’s status until the pregnancy has been completed or
terminated. The outcome of the pregnancy will be reported to the Sponsor without delay and
within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion,
congenital anomaly, or other disabling or life-threatening complication to the mother or
newborn). The study investigator will make every effort to obtain permission to follow the
 
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outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor. If
a male subject impregnates his female partner the study personnel at the site must be
informed immediately and the pregnancy reported to the Sponsor and followed as described
above and in Section 7.2.2.
Use in Nursing Women
5.7.4 
It is unknown whether pembrolizumab 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 breast-feeding are not eligible for enrollment.
Subject Withdrawal/Discontinuation Criteria
5.8 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the
discretion of the investigator should any untoward effect occur.  In addition, a subject may be
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the
trial plan is violated, or for administrative and/or other safety reasons.  Specific details
regarding discontinuation or withdrawal procedures; including specific details regarding
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 –  Other
Procedures.
In this trial, a subject may discontinue from treatment but continue to participate in the
regularly scheduled activities, as long as the subject does not withdraw consent. 
Discontinuation from treatment is permanent.  Once a subject has discontinued treatment,
even though he/she continues to be monitored in the trial, he/she shall not be allowed to
begin treatment again.
A subject must be discontinued from the trial for any of the following reasons:
● The subject or legal representative (such as a parent or legal guardian) withdraws
consent.
A subject must be discontinued from treatment (but may continue to be monitored in the
trial) for any of the following reasons:
 The subject or legal representative (such as a parent or legal guardian) withdraws
consent
 Disease progression unless the subject is considered to be deriving clinical benefit by
the investigator and is clinically stable.
Clinical Stability is defined as:
1) Absence of symptoms and signs indicating clinical significant progression of
disease (including worsening of laboratory values) indicating disease progression.
2) No decline in ECOG performance status.
 
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3) Absence of rapid progression of disease or progressive tumor at critical
anatomical sites (e.g., cord compression) requiring urgent alternative medical
intervention.
 Note: Tumor assessments should continue every 9 weeks (+/- 7 days) until RECIST
1.1-defined disease progression has been established by investigator assessment.
 Unacceptable adverse experiences as described in Section 5.2.1.2.
 Two years of uninterrupted delivery of pembrolizumab Q3W and no documented
progression of disease, or 35 administrations of study medication, whichever is later
 Inter-current illness that prevents further administration of treatment
 Investigator’s decision to withdraw the subject
 The subject has a confirmed strong serum pregnancy test
 Noncompliance with trial treatment or procedure requirements
 The subject is lost to follow-up
 Administrative reasons
If a pembrolizumab treated subject attains a CR, has been treated for at least six months with
pembrolizumab, and has at least two treatments with pembrolizumab beyond the date when
the initial CR was declared OR the subject has received the maximum administrations of
pembrolizumab as outlined above, the subject and Investigator may consider stopping
therapy with pembrolizumab. Subjects who discontinue pembrolizumab and then experience
radiographic disease progression according to RECIST 1.1 may be eligible for re-treatment
with pembrolizumab in the Second Course Phase at the discretion of the Investigator as
described in Section 7.1.5.5. Subjects will resume therapy at the dose and schedule they
previously received prior to stopping trial treatment.
 
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Chemotherapy may be discontinued when a subject has received the maximum number of
cycles as outlined in the protocol.
 The End of Treatment and Follow-up visit procedures are listed in Section 6 – Trial
Flow Chart and Section 7.1.5 - Visit Requirements. After the end of treatment, each
subject will be followed for a minimum of 30 days for AE monitoring (SAEs/ECIs
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, as
described in Section 7.2.3.1). Subjects will have post-treatment follow-up for disease
status until disease progression, initiating a non-study cancer treatment, withdrawing
consent, becoming lost to follow-up or 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 or withdrawal of consent.
Subject Replacement Strategy
5.9 
A subject that discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10 
The overall trial begins when the first subject signs the informed consent form.  The overall
trial ends when the last subject completes the last trial visit, discontinues 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 enrolled in a pembrolizumab extension trial.
Clinical Criteria for Early Trial Termination
5.11 
The trial will be stopped early if the risk/benefit ratio to the trial population as a whole is
unacceptable.
Statistical criteria for stopping the trial are provided in Section 8.0 – Statistical Analysis Plan.
Further recruitment in the trial or at (a) particular trial site(s) may be stopped due to
insufficient compliance with the protocol, GCP, Good Post-Marketing Study Practices,
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
Pembrolizumab Arm: Treatment and Follow-up Phase
6.1 
Screening
(Visit 1)
Treatment Cycles1 
End of Treatment
Phase
Observation
Phase22
(pre-PD)
Follow up Phase
24
Survival
Follow
up27
Treatment 
Cycle /
Scheduled
Time
-42 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinu
ation
Visit20
Safety
Follow
up
Visit21
Observation
Visit
Follow
up
Visit 1
Follow
up
Visit 2
Follow
up
Visit 3
and
Be-
yond
Survival
Follow
up
Visit 1
and
Beyond
Scheduling
Window
(Days):2
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At Study
Drug
Discontinu
ation +/- 3
30 days
from
Last
Dose
+/- 3
± 3 
3
Months
from
Last
Dose
+/- 7
6
Months
from
Last
Dose +/-
7
Every 3
Months
after
Visit
2+/- 7
Approx.
Every 2
Months
+/- 14
Administrative Procedures
Informed 
Consent
X
Informed 
Consent for
Future
Biomedical
Research
(optional)
X
Inclusion/Exclusi 
on Criteria
X
Subject ID 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 
X
NSCLC Disease
Details and Prior
Treatment
X
 
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Screening
(Visit 1)
Treatment Cycles1 
End of Treatment
Phase
Observation
Phase22
(pre-PD)
Follow up Phase
24
Survival
Follow
up27
Treatment 
Cycle /
Scheduled
Time
-42 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinu
ation
Visit20
Safety
Follow
up
Visit21
Observation
Visit
Follow
up
Visit 1
Follow
up
Visit 2
Follow
up
Visit 3
and
Be-
yond
Survival
Follow
up
Visit 1
and
Beyond
Scheduling
Window
(Days):2
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At Study
Drug
Discontinu
ation +/- 3
30 days
from
Last
Dose
+/- 3
± 3 
3
Months
from
Last
Dose
+/- 7
6
Months
from
Last
Dose +/-
7
Every 3
Months
after
Visit
2+/- 7
Approx.
Every 2
Months
+/- 14
Subsequent
antineoplastic
therapy status
X 
X 
X 
X 
X 
X 
X
Survival Status27
< ------------------------------------------------------------------------------------------------------------------------------------------------------------------------->  
X
Clinical
Procedures /
Assessments
Review Adverse
Events25 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
X 
X 
X
Full Physical
Examination  
X
X
Directed Physical
Examination
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
X 
X
Vital Signs and
Weight 14 
X 
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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
X
X 
X
EuroQol EQ-5D
18
X 
X X
X
X
X 
X
X
X
X
EORTC QLQ-
C30 18
X 
X X
X
X
X 
X
X
X
X
EORTC QLQ
LC-13 18
X 
X X
X
X
X 
X
X
X
X
 
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Screening
(Visit 1)
Treatment Cycles1 
End of Treatment
Phase
Observation
Phase22
(pre-PD)
Follow up Phase
24
Survival
Follow
up27
Treatment 
Cycle /
Scheduled
Time
-42 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinu
ation
Visit20
Safety
Follow
up
Visit21
Observation
Visit
Follow
up
Visit 1
Follow
up
Visit 2
Follow
up
Visit 3
and
Be-
yond
Survival
Follow
up
Visit 1
and
Beyond
Scheduling
Window
(Days):2
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At Study
Drug
Discontinu
ation +/- 3
30 days
from
Last
Dose
+/- 3
± 3 
3
Months
from
Last
Dose
+/- 7
6
Months
from
Last
Dose +/-
7
Every 3
Months
after
Visit
2+/- 7
Approx.
Every 2
Months
+/- 14
Oncology Health
Economic 
Assessment
(HEA)19
X X 
X 
X 
X 
X 
X
X 
X 
X 
X 
X
X
Central Laboratory Procedures/Assessments
Blood for Future
Biomedical 
Research
(optional)11
X
Pharmacokinetics
15
X 
X 
X
X
X
X
X 
X
Anti-
pembrolizumab
Antibodies16
X 
X 
X
X
X
X
X 
X
Blood for
Genetics13
X
Study Drug Administration
Pembrolizumab 
10
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Local Laboratory Procedures / Assessments
Pregnancy
Test - Urine or 
Serum β-HCG
3
X
 
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Screening
(Visit 1)
Treatment Cycles1
End of Treatment
Phase
Observation
Phase22
(pre-PD)
Follow up Phase
24
Survival
Follow
up27
Treatment 
Cycle /
Scheduled
Time
-42 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinu
ation
Visit20
Safety
Follow
up
Visit21
Observation
Visit
Follow
up
Visit 1
Follow
up
Visit 2
Follow
up
Visit 3
and
Be-
yond
Survival
Follow
up
Visit 1
and
Beyond
Scheduling
Window
(Days):2
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At Study
Drug
Discontinu
ation +/- 3
30 days
from
Last
Dose
+/- 3
± 3 
3
Months
from
Last
Dose
+/- 7
6
Months
from
Last
Dose +/-
7
Every 3
Months
after
Visit
2+/- 7
Approx.
Every 2
Months
+/- 14
PT/INR 
and
aPTT 4
X5
CBC 
 
with
Differential17
X5
X 
X 
X 
X 
X 
X 
X
X 
X
X 
X
X
X
X23
Comprehensive 
Chemistry
Panel17
X5
X 
X 
X 
X 
X 
X
X
X 
X
X 
X
X
X
X23
Urinalysis6
X5
X
X
X
X
X
X23
T3,FT4 
and
TSH7
X5
X 
X 
X
X
X
X 
X
X
X
X23
ALK
Translocation
Testing 9
X
EGFR Mutation
Testing9
X
Efficacy Measurements
Tumor Imaging8
X
X 
X 
X 
X 
X 
X 
X 
X 
X26
X26
X26
Brain Imaging28 
X
 
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Screening
(Visit 1)
Treatment Cycles1 
End of Treatment
Phase
Observation
Phase22
(pre-PD)
Follow up Phase
24
Survival
Follow
up27
Treatment 
Cycle /
Scheduled
Time
-42 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinu
ation
Visit20
Safety
Follow
up
Visit21
Observation
Visit
Follow
up
Visit 1
Follow
up
Visit 2
Follow
up
Visit 3
and
Be-
yond
Survival
Follow
up
Visit 1
and
Beyond
Scheduling
Window
(Days):2
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At Study
Drug
Discontinu
ation +/- 3
30 days
from
Last
Dose
+/- 3
± 3 
3
Months
from
Last
Dose
+/- 7
6
Months
from
Last
Dose +/-
7
Every 3
Months
after
Visit
2+/- 7
Approx.
Every 2
Months
+/- 14
Tumor Biopsies / Archival Tissue Collection
Tumor 
tissue
collection 
for
PD-L1 
expression 12
X
1 
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose oftrial 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 9 weeks (± 7 days) from
the date of randomization regardless of any treatment delays.
2 
In general, the window for each visit is  +/- 3 days unless otherwise specified.
3 
For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to first dose of trial treatment. If urine pregnancy results cannot be confirmed as negative, a
serum pregnancy test, performed by the local study site laboratory, will be required. Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
4 
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
5 
Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment. See Section 7.1.3 for details regarding laboratory tests.
6 
After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing. See Section 7.1.3 for details regarding
laboratory tests. Perform every 4 cycles after Cycle 13.
7 
Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service. After Cycle 1, lab samples can be collected up to 48 hours prior to the
scheduled time point. Laboratory results must be known and acceptable prior to dosing. See Section 7.1.3 for details regarding laboratory tests. Performed every 2 cycles after Cycle 13.
8 
Sponsor will collect radiological assessments for analysis by a central vendor. The initial tumor imaging will be performed within  30 days prior to randomization.   Scans performed as part of
routine clinical management are acceptable for use as the screening scan  if they are of diagnostic quality. On study imaging will be performed every 9 weeks (63 ± 7 days) calculated from the
randomization date or more frequently if clinically indicated and submitted for central radiology review. The timing for imaging studies should follow calendar days and should not be adjusted
for delays in  cycle starts. The same imaging technique should be used in a subject throughout the trial. Imaging assessments should be performed every 9 weeks (+/- 7 days from randomization.
Additional imaging at Discontinuation Visit and Safety Follow-up Visit is not required provided that imaging assessments have been performed per schedule. Imaging will continue at the protocol
defined interval until the time of PD, pregnancy, or the start of a new cancer treatment
9 
Site must be able to provide documentation of the subject’s tumor EGFR mutation and/or ALK translocation mutation status in patients with non-squamous histologies OR if clinically indicated.  If the
site is unable to provide this source documentation, or site level testing, then the Sponsor will offer this molecular testing of the tumor.
10 Pembrolizumab can be administered for up to 35 treatments.
11 Informed consent for Future Biomedical Research (FBR) samples must be obtained before the DNA sample is drawn.  DNA sample for analysis should be obtained predose, on Cycle 1 (or with the
next scheduled blood draw), as the last sample drawn, on allocated subjects only, or at a later date as soon as the informed consent is obtained. This sample should only be taken once from each
subject.  See Section 12.2 for guidance regarding the collection and management of specimens for FBR.
12 Tumor tissue for biomarker analysis from a biopsy of a tumor lesion not previously irradiated must be provided. Only biopsies obtained at the time of or after the diagnosis of metastatic disease will be
 
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Screening
(Visit 1)
Treatment Cycles1
End of Treatment
Phase
Observation
Phase22
(pre-PD)
Follow up Phase
24
Survival
Follow
up27
Treatment 
Cycle /
Scheduled
Time
-42 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinu
ation
Visit20
Safety
Follow
up
Visit21
Observation
Visit
Follow
up
Visit 1
Follow
up
Visit 2
Follow
up
Visit 3
and
Be-
yond
Survival
Follow
up
Visit 1
and
Beyond
Scheduling
Window
(Days):2
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At Study
Drug
Discontinu  
ation +/- 3 
30 days 
from 
Last 
Dose 
+/- 3 
± 3 
3 
Months 
from 
Last 
Dose 
+/- 7 
6 
Months 
from 
Last 
Dose +/- 
7
Every 3 
Months 
after 
Visit 
2+/- 7
Approx.
Every 2
Months
+/- 14
evaluated for PD-L1 expression.  Any leftover tumor tissue will be stored for future research if the subject signs the optional FBR consent. If a tumor biopsy was obtained from a target lesion during
eligibility assessment, it is preferred to obtain a new baseline scan. Biopsy of lesions on study should be limited to non-target lesions or new lesions if their pathologic etiology is ambiguous.
13 Blood for genetics sample will be collected to explore host genetics and to identify genetic predictors which may have a role in therapeutic response to pembrolizumab. This sample should be drawn
for planned, exploratory genetic analysis of DNA unless there is either a documented law or regulation prohibiting collection, or unless the IRB/IEC does not approve of the collection.
14 Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at screening only
15 Pre-dose (trough) samples at cycle 1, 2, 4, 8 and every 8 cycles thereafter while the subject is receiving pembrolizumab. Once the subject discontinues taking pembrolizumab additional samples
should be obtained at 1, 3 and 6 months after last dose of study medication. All trough samples should be drawn within 24 hours before infusion of pembrolizumab and at the same time as blood
collection for anti-pembrolizumab antibodies. Post-dose samples at cycle 1 should be drawn within 30 minutes after end of infusion, and one sample between 72 and 168 hr post-infusion.
16 Pre-dose (trough) samples at cycle 1, 2, 4, 8 and every 8 cycles thereafter while the subject is receiving pembrolizumab. Once the subject discontinues taking pembrolizumab additional samples should
be obtained at 1, 3 and 6 months after last dose of study medication. All trough samples should be drawn within 24 hours before infusion of pembrolizumab.
17 After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing. See Section 7.1.3 for details regarding
laboratory tests. CBC and chemistry will be performed every cycle up to cycle 10, then every other cycle thereafter.
18 PROs are assessed every cycle for the first three cycles and every third cycle (every 9 weeks) thereafter until PD while the subject is receiving study treatment. PROs will also be obtained at the
Treatment Discontinuation Visit and 30-day Safety Follow-up Visit.  If the Treatment Discontinuation Visit occurs 30 days from the last dose of study treatment, at the time of the mandatory Safety
Follow up Visit, PROs do not need to be repeated. During the Observation phase, PROs should continue to be assessed every 9 weeks until PD.  PROs are to be administered by trained site personnel
and completed electronically by subjects prior to all other study procedures and receiving results of any tests (including disease status).  The PROs should be administered in the following order:
EuroQol EQ-5D followed by EORTC QLQ-C30 and then EORTC QLQ-LC13. 
19  The Oncology HEA will be completed every cycle between cycles 2 to 8 and then every other cycle thereafter until PD while the subject is receiving study treatment.  The Oncology HEA will also be
obtained at the Treatment Discontinuation Visit and 30-day Safety Follow-up Visit.  If the Treatment Discontinuation Visit occurs 30 days from the last dose of study treatment, at the time of the
mandatory Safety Follow up Visit, the HEA does not need to be repeated. During the Observation phase, the HEA should continue to be assessed every 6 weeks until PD.  The Oncology HEA will be
administered and completed by qualified site personnel after the subject completes all other questionnaires and prior to all other study procedures. 
20 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. Imaging assessments should be performed every 9 weeks (+/- 7 days from randomization. Additional imaging at
Discontinuation Visit and Safety Follow-up Visit is not required provided that imaging assessments have been performed per schedule. Imaging will continue at the protocol defined interval until the
time of PD, pregnancy, or the start of a new cancer treatment
21 The mandatory Safety Follow-up Visit for all subjects should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of 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 0-1 or until beginning of a new antineoplastic therapy, whichever occurs first.
Subjects who are eligible for treatment with pembrolizumab during the Second Course Phase may have up to three Safety Follow-up Visits, one after the Treatment Phase, Crossover Phase and the
Second Course Phase. If the Discontinuation Visit occurs approximately 30 days (+/- 3 days) from last dose trial treatment the same procedures do not need to be repeated for the Safety Follow-up
Visit. Imaging assessments should be performed every 9 weeks (+/- 7 days from randomization. Additional imaging at Discontinuation Visit and Safety Follow-up Visit is not required provided that
imaging assessments have been performed per schedule. Imaging will continue at the protocol defined interval until the time of PD, pregnancy, or the start of a new cancer treatment
22 The Observation Phase is for any subject that discontinued study treatment for reasons other than pregnancy or PD (i.e., toxicity). Pembrolizumab subjects remain in the Observation Phase until the
 
04T748
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Product:  MK-3475 (SCH-900475)
63
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Screening
(Visit 1)
Treatment Cycles1 
End of Treatment
Phase
Observation
Phase22
(pre-PD)
Follow up Phase
24
Survival
Follow
up27
Treatment 
Cycle /
Scheduled
Time
-42 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinu
ation
Visit20
Safety
Follow
up
Visit21
Observation
Visit
Follow
up
Visit 1
Follow
up
Visit 2
Follow
up
Visit 3
and
Be-
yond
Survival
Follow
up
Visit 1
and
Beyond
Scheduling
Window
(Days):2
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At Study
Drug
Discontinu  
ation +/- 3 
30 days 
from 
Last 
Dose 
+/- 3 
± 3 
3 
Months 
from 
Last 
Dose 
+/- 7 
6 
Months 
from 
Last 
Dose +/- 
7
Every 3 
Months 
after 
Visit 
2+/- 7
Approx.
Every 2
Months
+/- 14
time of PD, pregnancy, or the start of a new antineoplastic therapy. Observation visits should begin 4 weeks (28 days +/- 7 days) from the Safety Follow-up Visit and follow a Q3W (21 days +/- 3
days) schedule thereafter. Tumor imaging for the Observation Visits should be maintained Q9W by following the same calendar day schedule that was initiated during Treatment Cycles. For subjects
who have received at least 15 treatment cycles of pembrolizumab, the frequency of tumor imaging may be reduced to every 12 weeks (84 +/- 7 days) during the Observation Visits.
23 During the Observation Phase, these laboratory assessments should be obtained every 12 weeks.
24 Subjects who stop pembrolizumab after 35 trial treatments and have achieved PR and/or SD OR have achieved CR (see section 7.1.5.5) will move to the Follow up Phase of the study. Follow up visit
1 should take place 3 months after the last dose of trial treatment. Follow up visit 2 should take place 6 months after last dose of trial treatment and additional Follow up visits should take place every 3
months thereafter. Subjects who experience disease progression (and do not continue into the Second Course Phase) or start a new antineoplastic therapy will move directly into Survival Follow up.
For subject convenience, all Follow up assessments may occur during the same visit as the imaging studies are obtained.  Subjects with an AE of Grade >1 will be further followed until the resolution
of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy, whichever occurs first.
25 Once a subject discontinues study treatment, report all SAEs (related and unrelated to trial treatment), ECIs, and irAEs occurring within 90 days following cessation of treatment or 30 days following
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. After this time, report only SAEs and ECIs that are considered related to trial treatment.
26 Tumor imaging is not needed for subjects who start another anti-cancer treatment regimen.
27 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 approximately every 2 months to assess for survival status.  Post-study treatments and the subject’s response to them will also be collected.  Updated survivalstatus 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 who have a death event previously recorded).
28 See Brain Imaging in Section 7.1.2.7 and the Site Imaging Manual for acceptable imaging modalities
 
04T748
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Product:  MK-3475 (SCH-900475)
64
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
SOC Arm: Treatment and Follow-up Phase
6.2 
Screening
(Visit 1)
Treatment Cycles1 
End of Treatment Phase 
Observation 
Phase20 (pre-PD) 
Survival
Follow up23
Treatment Cycle / 
Scheduled Time
-42 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinuati 
on Visit18 
Safety 
Follow Up
Visit19
Observation Visit 
Survival
Follow up
Visit 1 and
Beyond
Scheduling Window
(Days):2
± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At Study
Drug
Discontinuati
on +/- 3
30 Days
from Last
Dose +/- 3
± 3
Approx.
Every 2
Months +/-
14
Administrative Procedures
Informed Consent
X
Informed Consent for
Future Biomedical 
Research (optional)
X
Inclusion/Exclusion Criteria
X
Subject ID 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 
X
NSCLC Disease Details
and Prior Treatment
X
Subsequent antineoplastic
therapy status
X 
X 
X
X
Survival Status23
< --------------------------------------------------------------------------------------------------------------------------------------------------------------->
X
Clinical Procedures /
Assessments
Review Adverse Events22
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
X 
X
FullPhysical Examination
X
X
Directed Physical
Examination  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
Vital Signs and Weight 14
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
X
 
04T748 
07WZMS

Product:  MK-3475 (SCH-900475)
65
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Screening
(Visit 1)
Treatment Cycles1 
End of Treatment Phase 
Observation 
Phase20 (pre-PD) 
Survival
Follow up23
Treatment Cycle / 
Scheduled Time
-42 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinuati 
on Visit 
18 
Safety 
Follow Up
Visit19
Observation Visit 
Survival
Follow up
Visit 1 and
Beyond
Scheduling Window
(Days):2
± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At Study
Drug
Discontinuati
on +/- 3
30 Days
from Last
Dose +/- 3
± 3
Approx.
Every 2
Months +/-
14
12-Lead ECG
X
ECOG Performance Status
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
EuroQol EQ-5D16
X 
X 
X
X
X
X 
X
X
X
X
EORTC QLQ-C3016
X 
X 
X
X
X
X 
X
X
X
X
EORTC QLQ QLQ-LC1316
X 
X 
X
X
X
X 
X
X
X
X
Oncology Health Economic 
Assessment (HEA)
17
X 
X 
X 
X 
X 
X 
X
X
X 
X
X
X
X
Central Laboratory Procedures/Assessments
Blood for Future
Biomedical Research
(optional)11
X
Blood for Genetics13
X
Study Drug Administration
Carboplatin/Pemetrexed10
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Cisplatin/Pemetrexed10
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Paclitaxel/Carboplatin10
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Carboplatin/Gemcitabine
X 
X 
X 
X 
X 
X
Cisplatin/Gemcitabine
X 
X 
X 
X 
X 
X
 
04T748
07WZMS

Product:  MK-3475 (SCH-900475)
66
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Screening
(Visit 1)
Treatment Cycles1 
End of Treatment Phase 
Observation 
Phase20 (pre-PD) 
Survival
Follow up23
Treatment Cycle / 
Scheduled Time
-42 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinuati 
on Visit 
18 
Safety 
Follow Up
Visit19
Observation Visit 
Survival
Follow up
Visit 1 and
Beyond
Scheduling Window
(Days):2
± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At Study
Drug
Discontinuati
on +/- 3
30 Days
from Last
Dose +/- 3
± 3
Approx.
Every 2
Months +/-
14
Local Laboratory Procedures / Assessments
Pregnancy Test - Urine or
Serum β-HCG 3
X
PT/INR and aPTT 4
X5
CBC  with Differential15
X5
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
X
X
X
X21
Comprehensive  Chemistry
Panel15
X5
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
X
X
X
X21
Urinalysis6
X5
X 
X
X
X
X
X21
T3,FT4 and TSH7
X5
X 
X 
X 
X 
X
X 
X
X
X
X21
ALK 
Translocation
Testing9
X
EGFR Mutation Testing9
X
Efficacy Measurements
Tumor Imaging8
X
X 
X 
X 
X 
X 
X 
X 
X
Brain Imaging 24
X
Tumor Biopsies / Archival Tissue Collection
Tumor tissue collection
for PD-L1  expression
12
X
 
04T748
07WZMS

Product:  MK-3475 (SCH-900475)
67
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Screening
(Visit 1)
Treatment Cycles1
End of Treatment Phase 
Observation 
Phase20 (pre-PD) 
Survival
Follow up23
Treatment Cycle / 
Scheduled Time
-42 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinuati 
on Visit 
18
Safety 
Follow Up
Visit19
Observation Visit 
Survival
Follow up
Visit 1 and
Beyond
Scheduling Window 
(Days): 2
± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At Study 
Drug 
Discontinuati 
on +/- 3 
30 Days 
from Last 
Dose +/- 3 
± 3 
Approx.
Every 2
Months +/-
14
1 
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose oftrialtreatment 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 willbe performed every 9 weeks (± 7 days) from
the date of randomization regardless of any treatment delays.
2 
In general, the window for each visit is +/- 3 days unless otherwise specified.
3 
For women ofreproductive potential, a urine pregnancy test will be performed within 72 hours prior to first dose oftrial treatment. Ifurine pregnancy results cannot be confirmed as negative, a
serum pregnancy test, performed by the local study site laboratory, will be required. Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
4 
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
5 
Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment. See Section 7.1.3 for details regarding laboratory tests.
6 
After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing. See Section 7.1.3 for details regarding
laboratory tests. Perform every 4 cycles after Cycle 13.
7 
Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service. After Cycle 1, lab samples can be collected up to 48 hours prior to the
scheduled time point. Laboratory results must be known and acceptable prior to dosing. See Section 7.1.3 for details regarding laboratory tests. Performed every 2 cycles after Cycle 13.
8 
Sponsor will collect radiological assessments for analysis by  a central vendor. The initial tumor imaging will be performed within  30 days prior to randomization.   Scans performed as part
of routine clinical management are acceptable for use as the screening scan if they are of diagnostic quality. On study imaging will be performed every 9 weeks (63 ± 7 days) calculated from
the randomization date or more frequently  if clinically  indicated and submitted for central radiology review. The timing for imaging studies should follow calendar days and should not be
adjusted for delays in  cycle starts. The same imaging technique should be used in a subject throughout the trial.  Imaging assessments should be performed every 9 weeks (+/- 7 days from
randomization. Additional imaging at Discontinuation Visit and Safety Follow-up Visit is not required provided that imaging assessments have been performed per schedule. Imaging will continue
at the protocol defined interval until the time of PD, pregnancy, or the start of a new cancer treatment
9 
Site must be able to provide documentation of the subject’s tumor EGFR mutation and/or ALK translocation mutation status in patients with non-squamous histologies OR if clinically indicated.  If
the site is unable to provide this source documentation, or site level testing, then the Sponsor will offer this molecular testing of the tumor.
10 
This regimen to be administered up to a maximum of 6 cycles. Pemetrexed may be given after 4 cycles of Carboplatin/Pemetrexed, Cisplatin/Pemetrexed or  Paclitaxel/Carboplatin in subjects with
non-squamous histologies. 
11 
Informed consent for Future Biomedical Research (FBR) samples must be obtained before the DNA sample is drawn.  DNA sample for analysis should be obtained predose, on Cycle 1 (or with the
next scheduled blood draw), as the last sample drawn, on allocated subjects only, or at a later date as soon as the informed consent is obtained. This sample should only be taken once from each
subject.  See Section 12.2 for guidance regarding the collection and management of specimens for FBR.
12 
Tumor tissue for biomarker analysis from a biopsy of a tumor lesion not previously irradiated must be provided. Only biopsies obtained at the time of or after the diagnosis of metastatic disease will
be evaluated for PD-L1 expression.  Any leftover tumor tissue will be stored for future research if the subject signs the optional FBR consent. If a tumor biopsy was obtained from a target lesion
during eligibility assessment, it is preferred to obtain a new baseline scan. Biopsy of lesions on study should be limited to non-target lesions or new lesions if their pathologic etiology is ambiguous.
13 
Blood for genetics sample will be collected to explore host genetics and to identify genetic predictors which may have a role in therapeutic response to pembrolizumab. This sample should be drawn
for planned, exploratory genetic analysis of DNA unless there is either a documented law or regulation prohibiting collection, or unless the IRB/IEC does not approve of the collection.
14 
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at screening only
15 
After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing. See Section 7.1.3 for details regarding
laboratory tests. CBC and chemistry will be performed every cycle up to cycle 10, then every other cycle thereafter. Additional laboratory assessments required for the SOC platinum doublets
offered in this trial, but not included in the above Flowchart, should be obtained per local guidance and results recorded in the appropriate CRF. 
16 
PROs are assessed every cycle for the first three cycles and every third cycle (every 9 weeks) thereafter until PD while the subject is receiving study treatment. PROs will also be obtained at the
Treatment Discontinuation Visit and 30-day Safety Follow-up Visit.  If the Treatment Discontinuation Visit occurs 30 days from the last dose of study treatment, at the time of the mandatory Safety
Follow up Visit, PROs do not need to be repeated. During the Observation phase, PROs should continue to be assessed every 9 weeks until PD.  PROs are to be administered by trained site
 
04T748
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Product:  MK-3475 (SCH-900475)
68
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Screening
(Visit 1)
Treatment Cycles1
End of Treatment Phase 
Observation 
Phase20 (pre-PD) 
Survival
Follow up23
Treatment Cycle / 
Scheduled Time
-42 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinuati 
on Visit 
18
Safety 
Follow Up
Visit19
Observation Visit 
Survival
Follow up
Visit 1 and
Beyond
Scheduling Window 
(Days): 2
± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At Study 
Drug 
Discontinuati 
on +/- 3 
30 Days 
from Last 
Dose +/- 3 
± 3 
Approx.
Every 2
Months +/-
14
personnel and completed electronically by subjects prior to all other study procedures and receiving results of any tests (including disease status).  The PROs should be administered in the following
order: EuroQol EQ-5D followed by EORTC QLQ-C30 and then EORTC QLQ-LC13. 
17 
The Oncology HEA will be completed every cycle between cycles 2 to 8 and then every other cycle thereafter until PD while the subject is receiving study treatment.  The Oncology HEA will also
be obtained at the Treatment Discontinuation Visit and 30-day Safety Follow-up Visit. If the Treatment Discontinuation Visit occurs 30 days from the last dose of study treatment, at the time of the
mandatory Safety Follow up Visit, the HEA does not need to be repeated. During the Observation phase, the HEA should continue to be assessed every 6 weeks until PD.  The Oncology HEA will
be administered and completed by qualified site personnel after the subject completes all other questionnaires and prior to all other study procedures. 
18 
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. Imaging assessments should be performed every 9 weeks (+/- 7 days from randomization. Additional imaging at
Discontinuation Visit and Safety Follow-up Visit is not required provided that imaging assessments have been performed per schedule. Imaging will continue at the protocol defined interval until the
time of PD, pregnancy, or the start of a new cancer treatment
19 
The mandatory Safety Follow-up Visit for all subjects should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of 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 0-1 or until beginning of a new antineoplastic therapy, whichever occurs first.
Subjects who are eligible for treatment with pembrolizumab during the Second Course Phase may have up to three Safety Follow-up Visits, one after the Treatment Phase, Crossover Phase and the
Second Course Phase. If the Discontinuation Visit occurs approximately 30 days (+/- 3 days) from last dose trial treatment the same procedures do not need to be repeated for the Safety Follow-up
Visit. Imaging assessments should be performed every 9 weeks (+/- 7 days from randomization. Additional imaging at Discontinuation Visit and Safety Follow-up Visit is not required provided that
imaging assessments have been performed per schedule. Imaging will continue at the protocol defined interval until the time of PD, pregnancy, or the start of a new cancer treatment
20 
The Observation Phase is for any subject that discontinued study treatment for reasons other than pregnancy or PD (i.e., toxicity). Observation visits should begin 4 weeks (28 days +/- 7 days) from
the Safety Follow-up Visit and follow a Q3W (21 days +/- 3 days) schedule thereafter. Tumor imaging for the Observation Visits should be maintained Q9W by following the same calendar day
schedule that was initiated during Treatment Cycles.
21 
During the Observation Phase, these laboratory assessments should be obtained every 12 weeks.
22 
Once a subject discontinues study treatment, report all SAEs (related and unrelated to trial treatment), ECIs, and irAEs occurring within 90 days following cessation of treatment or 30 days following
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  After this time, report only SAEs and ECIs that are considered related to trial treatment.
23 
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 approximately every 2 months to assess for survival status.  Post-study treatments and the subject’s response to them will also be collected.  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 who have a death event previously recorded).
24 
See Brain Imaging in Section 7.1.2.7 and the Site Imaging Manual for acceptable imaging modalities
 
04T748
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Product:  MK-3475 (SCH-900475)
69
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Second Course Treatment and Follow-up Phase
6.3 
Second Course Treatment Cycles1 
End of Second Course
Treatment
Follow up Phase14
Survival Follow
up10
Treatment Cycle /
Scheduled Time
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 
13 
Discontinuation
Visit
Safety Follow
up Visit13
Follow up
Visit 1
Follow up
Visit 2
Follow up
Visit 3 and
beyond
Survival
Follow up
Visit 1 and
beyond
Scheduling
Window
(Days):2
±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 
±3 
At Study Drug
Discontinuation
+/- 3
30 Days
from Last
Dose +/- 3
3 Months from
Last Dose +/-
7
6 Months from
Last Dose +/-
7
Every 3
Months after
Visit 2
+/- 7
Approx. Every
2 Months +/-
14
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
Survival status10
<-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------->
X 
Study Drug Administration
Pembrolizumab12
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Clinical Procedures / Assessments
Review 
Adverse
Events11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
X 
X
Full 
Physical
Examination
X
X
Directed 
Physical
Examination
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
X
Vital 
Signs 
and
Weight15
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
X
X
ECOG Performance
Status
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
X
X
 
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Product:  MK-3475 (SCH-900475)
70
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Second Course Treatment Cycles1 
End of Second Course
Treatment
Follow up Phase14
Survival Follow
up10
Treatment Cycle /
Scheduled Time
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Discontinuation
Visit
Safety Follow
up Visit13
Follow up
Visit 1
Follow up
Visit 2
Follow up
Visit 3 and
beyond
Survival
Follow up
Visit 1 and
beyond
Scheduling
Window
(Days):2
±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 
±3 
At Study Drug
Discontinuation
+/- 3
30 Days
from Last
Dose +/- 3
3 Months from
Last Dose +/-
7
6 Months from
Last Dose +/-
7
Every 3
Months after
Visit 2
+/- 7
Approx. Every
2 Months +/-
14
Pregnancy 
Test 
-
Urine or Serum β-
HCG 3, 5 
X
PT/INR and aPTT 4, 5
X
CBC with
Differential5, 9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
X16
X 16
X16
Comprehensive
Chemistry Panel5 9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
X16
X16
X16
Urinalysis 5, 6
X 
X 
X 
X
X
X16
T3, FT4 and TSH5,7
X 
X 
X 
X 
X 
X 
X
X
X 16
X16 
X16
Efficacy Measurements
Tumor Imaging 8
X 
X 
X 
X 
X 
X 
X 
X 
X
X
1 
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 therapy.
2 
In general, the window for each visit is +/- 3 days unless otherwise specified.
3 
For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to the first Second Course dose. Ifurine pregnancy results cannot be confirmed as negative, a
serum pregnancy test, performed by the localstudy site laboratory, willbe required. Pregnancy tests (serum and/or urine tests) should be repeated ifrequired by local guidelines.
4 
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
5 
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 for details regarding laboratory
tests.
6 
After the first dose, lab samples can be collected up to 48 hours prior to the scheduled time point.  Laboratory results must be known and acceptable prior to dosing.  See Section 7.1.3 for details
regarding laboratory tests.  Perform every 4 cycles after cycle 13.
7 
After the first dose, lab samples can be collected up to 48 hours prior to the scheduled time point.  Laboratory results must be known and acceptable prior to dosing.  See Section 7.1.3 for details
regarding laboratory tests.  Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service. Thyroid function tests should be performed
every other cycle.
8 
Sponsor will collect radiological assessments for analysis by a central vendor. If the subject enters the Second Course Phase, Cycle 1 scan may be performed up to 30 days prior to the first dose of trial
treatment in the Second Course Phase.  Imaging will be performed every 9 weeks (63 +/-7 days) after the first dose of Second Course Phase trial treatment up until cycle 13 and every 12 weeks (84
+/- 7 days) thereafter. The timing of imaging should follow calendar days and should not be adjusted for delays in cycle starts. The same imaging technique should be used in a subject throughout the
 
04T748
07WZMS

Product:  MK-3475 (SCH-900475)
71
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Second Course Treatment Cycles1 
End of Second Course
Treatment
Follow up Phase14
Survival Follow
up10
Treatment Cycle /
Scheduled Time
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Discontinuation
Visit
Safety Follow
up Visit13
Follow up
Visit 1
Follow up
Visit 2
Follow up
Visit 3 and
beyond
Survival
Follow up
Visit 1 and
beyond
Scheduling
Window
(Days):2
±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 
±3 
At Study Drug
Discontinuation
+/- 3
30 Days
from Last
Dose +/- 3
3 Months from
Last Dose +/-
7
6 Months from
Last Dose +/-
7
Every 3
Months after
Visit 2
+/- 7
Approx. Every
2 Months +/-
14
trial. Subjects who discontinue trial treatment due to reasons other than disease progression, should continue to be assessed every 9 weeks (63 +/- 7 days) by radiologic imaging until the start of a new
antineoplastic therapy, documented disease progression, or death, whichever occurs first. If trial treatment is discontinued after cycle 13, tumor imaging should be performed every 12 weeks (84 days
+/- 7 days). Continued imaging is not needed for subjects who start another antineoplastic treatment. The same imaging technique should be used in a subject throughout the trial. Imaging
assessments should be performed every 9 weeks (+/- 7 days from randomization. Additional imaging at Discontinuation Visit and Safety Follow-up Visit is not required provided that imaging
assessments have been performed per schedule. Imaging will continue at the protocol defined interval until the time of PD, pregnancy, or the start of a new cancer treatment
9 
After the first dose, lab samples can be collected up to 48 hours prior to the scheduled time point.  Laboratory results must be known and acceptable prior to dosing.  See Section 7.1.3 for details
regarding laboratory tests.  CBC and chemistry will be performed every cycle up to cycle 10, then every other cycle thereafter.
10 Once a subject experiences disease progression or starts a new antineoplastic therapy, the subject moves into the Survival Follow-up Phase and should be contacted by telephone approximately every
2 months to assess for survival status and start of new antineoplastic therapy if applicable.  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 who have a death event previously recorded).
11 Record all AEs occurring within 30 days after the last dose of trial treatment. Report all SAEs (related and unrelated to trial treatment), ECIs, and irAEs occurring within 90 days following cessation
of treatment or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. After this time, report only SAEs and ECIs that are considered related to
trialtreatment.
12 Pembrolizumab can be administered up to 17 trial treatment in Second Course Phase.
13 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 0-1 or until beginning of a new antineoplastic therapy, whichever occurs first.  Subjects who
are eligible per the requirements in Section 7.1.5.5 for treatment with pembrolizumab during the Second Course Phase may have up to three Safety Follow-up Visits, one after the Treatment Phase,
Crossover Phase and the Second Course Phase. Imaging assessments should be performed every 9 weeks (+/- 7 days from randomization. Additional imaging at Discontinuation Visit and Safety
Follow-up Visit is not required provided that imaging assessments have been performed per schedule. Imaging will continue at the protocol defined interval until the time of PD, pregnancy, or the
start of a new cancer treatment
14 Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-up Phase and should be assessed every 9 weeks (63 ± 7 days) by radiologic imaging to
monitor disease status.  Follow-up Visit 1 should be scheduled 3 months after the last dose of trial treatment.  Follow-up Visit 2 should occur 6 months after the last dose of trial treatment. After
Follow-up Visit 2 subjects only need to be assessed every 9 weeks (63 ± 7 days) by radiologic imaging to monitor disease status, development of drug related SAEs and ECIs, and initiation of new
antineoplastic therapy.  Unless otherwise noted in the flow chart, every effort should be made to collect subject information until the start of new antineoplastic therapy, disease progression or death,
whichever occurs first.
15 Vital signs to include temperature, pulse, respiratory rate, blood pressure, and weight.
16 Every effort should be made to collect blood samples at the Safety Follow Up Visit, Follow Up Visit 1, and Follow Up Visit 2 until the start of new antineoplastic therapy, disease progression or
death, whichever comes first.
 
04T748
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Product:  MK-3475 (SCH-900475)
72
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Cross Over Phase
6.4 
(Only applicable for subjects randomized to SOC that have confirmation of PD by blinded independent central radiology review and
qualified for the Crossover Phase).
Treatment Cycles1
End of Treatment
Phase
Observa
tion
Phase14
(pre-
PD)
Follow up Phase16
Survival
Follow
up19
Treatment Cycle /
Scheduled Time
18 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13
14
through
35
Discontin
uation
Visit12
Safety
Follow
up
Visit 13
Observat
ion 
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):2 
± 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
± 3 
3
Months
from
Last
Dose
+/- 7
6
Month
s from
Last
Dose
+/- 7
Every 3
Months
after
Visit
2+/- 7
Approx.
Every 2
Months +/-
14
Administrative Procedures
Prior and 
Concomitant 
Medications
X 
X 
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
X
Survival Status19
< ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ >
X
Clinical Procedures / Assessments
Review Adverse
Events 17
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
X 
X 
X 
X
X
Full Physical
Examination
X
X
Directed Physical
Examination
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
X 
X 
X
Vital Signs and
Weight 7
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
X
ECOG
Performance Status
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
X
Laboratory Procedures / Assessments: analysis performed by local laboratory
CBC  with
Differential11
X
3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X15
 
04T748
07WZMS

Product:  MK-3475 (SCH-900475)
73
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Treatment Cycles1 
End of Treatment
Phase
Observa
tion
Phase14 
(pre-
PD)
Follow up Phase16
Survival
Follow
up19
Treatment Cycle /
Scheduled Time
18 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13
14
through
35
Discontin
uation
Visit12
Safety
Follow
up
Visit 13
Observat
ion 
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):2 
± 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
± 3 
3
Months
from
Last
Dose
+/- 7
6
Month
s from
Last
Dose
+/- 7
Every 3
Months
after
Visit
2+/- 7
Approx.
Every 2
Months +/-
14
PT/INR and aPTT
X
3
Comprehensive
Chemistry Panel11
X
3
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
X
X15
Urinalysis4
X
3
X
X
X 
X
X
X
X15
T3, FT4 and TSH 5
X
3
X 
X 
X
X 
X 
X
X
X
X
X15
Patient Reported Outcomes (PRO)
EuroQol EQ-5D  
9
X 
EORTC QLQ-C30
9 
X
EORTC 
QLQ-
LC13 9
X
Oncology 
Health
Economic
Assessment 9
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
X
X 
X 
X
Efficacy Measurements
Tumor Imaging6
x 
x 
x 
x 
x 
X 
X 
X 
X18
X18 
X18
Study Drug Administration
Pembrolizumab 
10
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
1 
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 9 weeks (± 7 days) from
the first dose of trial treatment regardless of any treatment delays.
2 
In general, the window for each visit is 3 days unless otherwise specified.
3 
Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment. See Section 7.1.3 for details regarding laboratory tests. 
4 
After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point.  Laboratory results must be known and acceptable prior to dosing.  See Section 7.1.3 for details regarding
laboratory tests; perform every 6 cycles after cycle 14.
 
04T748
07WZMS

Product:  MK-3475 (SCH-900475)
74
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Treatment Cycles1 
End of Treatment
Phase
Observa
tion
Phase14
(pre-
PD)
Follow up Phase16
Survival
Follow
up19
Treatment Cycle / 
Scheduled Time
1 8
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13
14 
through 
35 
Discontin  
uation 
Visit 12
Safety 
Follow 
up 
Visit 13 
Observat 
ion  
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): 2 
± 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 
± 3 
3 
Months 
from  
Last 
Dose 
+/- 7 
6 
Month  
s from 
Last 
Dose 
+/- 7
Every 3 
Months 
after 
Visit 
2+/- 7
Approx.
Every 2
Months +/-
14
5 
After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point.  Laboratory results must be known and acceptable prior to dosing.  See Section 7.1.3 for details regarding
laboratory tests; perform every 2 cycles after Cycle 13. Thyroid function tests will be performed by a centrallaboratory only if the local laboratory is unable to perform this service.
6 
Blinded independent central review verifying progressive disease is: 1) required for crossover, without exception, and 2) is based on RECIST 1.1. Tumor response assessment is required every 9
weeks (63 days±7 days) until the subject starts another anti-cancer treatment.  Assessment of disease response or progression will be determined by the investigator.  The treating physician will
record a physician assessed tumor response and the criteria used i.e.  modified RECIST 1.1 or standard RECIST v 1.1 on the discontinuation form. Imaging assessments should be performed every 9
weeks (+/- 7 days from crossover. Additional imaging at Discontinuation Visit and Safety Follow-up Visit is not required provided that imaging assessments have been performed per schedule.
Imaging will continue at the protocol defined interval until the time of PD, pregnancy, or the start of a new cancer treatment.
7 
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. 
8 
Screening can initiate once progressive disease have been verified by the blinded independent centralradiology review.  Treatment with Pembrolizumab should not initiate until at least 30 days from
the date of last dose of chemotherapy. Screening procedures may be completed during these 30 days.  All procedures and assessments completed at the time of withdrawal from the main study may
be used as appropriate for the start of the Crossover Phase of the study.
9 
PROs are to be administered by trained site personnel and completed electronically by subjects at cross-over treatment cycle 1 prior to all other study procedures and receiving results of any tests.
The PROs should be administered in the following order: EuroQol EQ-5D followed by EORTC QLQ-C30 and then EORTC QLQ-LC13.   The Oncology HEA will be completed every cycle between
cycles 1 to 8 and then every other cycle thereafter.  The Oncology HEA will also be obtained at the Treatment Discontinuation  Visit and 30-day Safety Follow-up Visit.  If the Treatment
Discontinuation Visit occurs 30 days from the last dose of study treatment, at the time of the mandatory Safety Follow up Visit, the HEA does not need to be repeated.  During the Observation phase,
the HEA should continue to be assessed every 6 weeks until PD.  The Oncology HEA will be administered and completed by qualified site personnel after the subject completes all other
questionnaires and prior to all other study procedures. 
10 Treatment with Pembrolizumab should  not initiate until at least 30 days from the date of verified disease progression.  Pembrolizumab can be administered for up to 35 cycles.
11 After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point.  Laboratory results must be known and acceptable prior to dosing.  See Section 7.1.3 for details regarding
laboratory tests. CBC and chemistry will be performed every cycle up to cycle 10, then every other cycle.
12 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. Imaging assessments should be performed every 9 weeks (+/- 7 days from crossover. Additional imaging at
Discontinuation Visit and Safety Follow-up Visit is not required provided that imaging assessments have been performed per schedule. Imaging will continue at the protocol defined interval until the
time of PD, pregnancy, or the start of a new cancer treatment.
13 The mandatory Safety Follow-up Visit for all subjects should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of 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 0-1 or until beginning of a new antineoplastic therapy, whichever occurs
first. Subjects who are eligible for treatment with pembrolizumab during the Second Course Phase may have up to three Safety Follow-up Visits, one after the Treatment Phase, Crossover Phase and
the Second Course Phase. If the Discontinuation Visit occurs approximately 30 days (+/- 3 days) from last dose trial treatment the same procedures do not need to be repeated for the Safety Follow-
up Visit. Imaging assessments should be performed every 9 weeks (+/- 7 days from crossover. Additional imaging at Discontinuation Visit and Safety Follow-up Visit is not required provided that
imaging assessments have been performed per schedule. Imaging will continue at the protocol defined interval until the time of PD, pregnancy, or the start of a new cancer treatment
14 The Observation Phase is for any subject that discontinued study treatment for reasons other than pregnancy or PD (i.e., toxicity). Pembrolizumab subjects remain in the Observation Phase until the
time of PD, pregnancy, or the start of a new antineoplastic therapy. Observation visits should begin 4 weeks (28 days +/- 7 days) from the Safety Follow-up Visit and follow a Q3W (21 days +/- 3
 
04T748
07WZMS

Product:  MK-3475 (SCH-900475)
75
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Treatment Cycles1 
End of Treatment
Phase
Observa
tion
Phase14
(pre-
PD)
Follow up Phase16
Survival
Follow
up19
Treatment Cycle /
Scheduled Time
1 8
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
through 
35 
Discontin  
uation 
Visit 12
Safety 
Follow 
up 
Visit 13 
Observat 
ion  
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): 2 
± 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 
± 3 
3 
Months 
from  
Last 
Dose 
+/- 7 
6 
Month  
s from 
Last 
Dose 
+/- 7
Every 3 
Months 
after 
Visit 
2+/- 7
Approx.
Every 2
Months +/-
14
days) schedule thereafter. Tumor imaging for the Observation Visits should be maintained Q9W by following the same calendar day schedule that was initiated during Treatment Cycles. For
subjects who have received at least 15 treatment cycles of pembrolizumab, the frequency of tumor imaging may be reduced to every 12 weeks (84 +/- 7 days) during the Observation Visits.
15 During the Observation Phase, these laboratory assessments should be obtained every 12 weeks.
16 Subjects who stop pembrolizumab after 35 trial treatments and have achieved PR and/or SD OR have achieved a CR (see section 7.1.5.5) will move to the Follow up Phase of the study. Follow up
visit 1 should take place 3 months after the last dose of trial treatment. Follow up visit 2 should take place 6 months after last dose of trial treatment and additional Follow up visits should take place
every 3 months thereafter. Subjects who experience disease progression (and do not continue into the Second Course Phase) or start a new antineoplastic therapy will move directly into Survival
Follow up. For subject convenience, all Follow up assessments may occur during the same visit as the imaging studies are obtained.  Subjects with an AE of Grade >1 will be further followed until
the resolution of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy, whichever occurs first.
17 Once a subject discontinues study treatment, report all SAEs (related and unrelated to trial treatment), ECIs, and irAEs occurring within 90 days following cessation of treatment or 30 days
following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  After this time, report only SAEs and ECIs that are considered related to trial treatment.
18 Tumor imaging is not needed for subjects who start another anti-cancer treatment regimen.
19 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 approximately every 2 months to assess for survival status.  Post-study treatments and the subject’s response to them will also be collected.  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 who have a death event previously recorded).
 
04T748
07WZMS

Product:  MK-3475 (SCH-900475)
76
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Amendment 08, Pembrolizumab Arm: Treatment and Follow-up Phase
6.5 
Treatment Cycles1
End of Treatment
Phase
Follow up Phase
11
Survival
Follow
up13
Treatment 
Cycle /
Scheduled
Time
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinua
tion Visit9
Safety
Follow
up
Visit10
Follow
up Visit 1
Follow up
Visit 2
Follow
up Visit
3 and
Beyond
Survival
Follow up
Visit 1 and
Beyond
Scheduling 
Window
(Days):2
± 3 
± 3 ± 3 
± 3 
± 3 ± 3 ± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At Study
Drug
Discontinua
tion
+/- 3
30 days
from
Last
Dose +/-
3
3
Months
from
Last
Dose +/-
7
6 Months
from Last
Dose
+/- 7
Every 3
Months
after
Visit 2
+/- 7
Approx.
Every 2
Months
+/- 14
Administrative Procedures
Review Prior and
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 Status13
< --------------------------------------------------------------------------------------------------------------------------------------------------------------------- >
X
Clinical Procedures / Assessments
Review Adverse
Events12
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X
X
X
X
Directed Physical
Examination
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
X
X
Vital Signs and
Weight 7
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X
X
ECOG
Performance
Status
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X
X
Study Drug Administration
Pembrolizumab 
6
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Product:  MK-3475 (SCH-900475)
77
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Treatment Cycles1
End of Treatment
Phase
Follow up Phase
11
Survival
Follow
up13
Treatment 
Cycle /
Scheduled
Time
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinua
tion Visit9
Safety
Follow
up
Visit10
Follow
up Visit 1
Follow up
Visit 2
Follow
up Visit
3 and
Beyond
Survival
Follow up
Visit 1 and
Beyond
Scheduling 
Window
(Days):2
± 3 
± 3 ± 3 
± 3 
± 3 ± 3 ± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At Study
Drug
Discontinua
tion
+/- 3
30 days
from
Last
Dose +/-
3
3
Months
from
Last
Dose +/-
7
6 Months
from Last
Dose
+/- 7
Every 3
Months
after
Visit 2
+/- 7
Approx.
Every 2
Months
+/- 14
Local Laboratory Procedures / Assessments
CBC 
with
Differential8
X
X
X
X 
X
X
X
Comprehensive 
Chemistry Panel8
X
X
X
X 
X
X
X
Urinalysis3
X
X
X
X
X
T3,FT4 and TSH4
X 
X 
X 
X 
X
X 
X
X
X
Efficacy Measurements
Tumor Imaging5
X 
X 
X 
X 
X 
X 
X 
X14
X14
X14
1 
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose oftrialtreatment 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 9 weeks (± 7 days) from the date of randomization regardless of any treatment delays.
2 
In general, the window for each visit is  +/- 3 days unless otherwise specified.
3 
After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing. See Section 7.1.3 for
details regarding laboratory tests. Perform every 4 cycles after Cycle 13.
4 
Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service. After Cycle 1, lab samples can be collected up to 48 hours
prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing. See Section 7.1.3 for details regarding laboratory tests. Performed every 2 cycles
after Cycle 13.
5 
On study imaging will be performed every 9 weeks (63 ± 7 days) calculated from the randomization date or more frequently if clinically indicated. The timing for imaging studies
should follow calendar days and should not be adjusted for delays in cycle starts. The same imaging technique should be used in a subject throughout the trial. Imaging assessments
should be performed every 9 weeks (+/- 7) days from randomization. Additional imaging at Discontinuation Visit and Safety Follow-up Visit is not required provided that imaging
assessments have been performed per schedule. Imaging will continue at the protocol defined interval until the time of PD, pregnancy, or the start of a new cancer treatment.
6 
Pembrolizumab can be administered for up to 35 treatments.
 
04T748
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Product:  MK-3475 (SCH-900475)
78
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Treatment Cycles1
End of Treatment
Phase
Follow up Phase
11
Survival
Follow
up13
Treatment 
Cycle /
Scheduled
Time
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinua
tion Visit9
Safety
Follow
up
Visit10
Follow
up Visit 1
Follow up
Visit 2
Follow
up Visit
3 and
Beyond
Survival
Follow up
Visit 1 and
Beyond
Scheduling 
Window
(Days):2
± 3 
± 3 ± 3 
± 3 
± 3 ± 3 ± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At Study
Drug
Discontinua
tion
+/- 3
30 days
from
Last
Dose +/-
3
3
Months
from
Last
Dose +/-
7
6 Months
from Last
Dose
+/- 7
Every 3
Months
after
Visit 2
+/- 7
Approx.
Every 2
Months
+/- 14
7 
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at screening only.
8 
After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing. See Section 7.1.3 for
details regarding laboratory tests. CBC and chemistry will be performed every3 cycles.
9 
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.
10 The mandatory Safety Follow-up Visit for all subjects should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of 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 0-1 or until beginning of a new antineoplastic
therapy, whichever occurs first. Subjects who are eligible for treatment with pembrolizumab during the Second Course Phase may have up to three Safety Follow-up Visits, one after
the Treatment Phase, Crossover Phase and the Second Course Phase. If the Discontinuation Visit occurs approximately 30 days (+/- 3 days) from last dose trial treatment the same
procedures do not need to be repeated for the Safety Follow-up Visit.
11 Subjects who stop pembrolizumab after 35 trial treatments and have achieved PR and/or SD OR have achieved CR (see section 7.1.5.5) will move to the Follow up Phase of the study.
Follow up visit 1 should take place 3 months after the last dose of trial treatment. Follow up visit 2 should take place 6 months after last dose of trial treatment and additional Follow up
visits should take place every 3 months thereafter. Subjects who experience disease progression (and do not continue into the Second Course Phase) or start a new antineoplastic therapy
will move directly into Survival Follow up. For subject convenience, all Follow up assessments may occur during the same visit as the imaging studies are obtained.  Subjects with an
AE of Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy, whichever occurs first.
12 Once a subject discontinues study treatment, report all SAEs (related and unrelated to trial treatment), ECIs, and irAEs occurring within 90 days following cessation of treatment or 30
days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. After this time, report only SAEs and ECIs that are considered related to trial
treatment.
13 During the Survival Follow-up Phase, the subject should be contacted by telephone approximately every 2 months to assess for survival status.  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 who have a death event previously recorded).
14 Tumor imaging is not needed for subjects who start another anti-cancer treatment regimen.
 
04T748
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Product:  MK-3475 (SCH-900475)
79
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Amendment 08, SOC Arm: Treatment and Follow-up Phase
6.6 
Treatment Cycles1
End of Treatment Phase 
Survival Follow
up11
Treatment Cycle /
Scheduled Time
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinuation
Visit8
Safety Follow
up Visit9
Survival Follow
up Visit 1 and
beyond
Scheduling Window 
(Days):2
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At Study Drug
Discontinuation
+/- 3
30 Days from
Last Dose
+/- 3
Approx. Every 2
Months
+/- 14
Administrative Procedures
Review Prior and Concomitant
Medications
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
Subsequent antineoplastic
therapy status
X
X
X
Survival Status11
< --------------------------------------------------------------------------------------------------------------------------------------------------------------------- >
X
Clinical Procedures /
Assessments
Review Adverse Events10
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
X
Directed Physical Examination
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
Vital Signs and Weight 5
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
ECOG Performance Status
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
Study Drug Administration
Carboplatin/Pemetrexed4
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
X 
X
Cisplatin/Pemetrexed4
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
X 
X
Paclitaxel/Carboplatin4
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
X 
X
Carboplatin/Gemcitabine 
X 
X 
X 
X 
X 
X
Cisplatin/Gemcitabine 
X 
X 
X 
X 
X 
X
Local Laboratory Procedures / Assessments
CBC  with Differential6 
X 
X 
X 
X 
X 
X
X
 
04T748
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Product:  MK-3475 (SCH-900475)
80
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Treatment Cycles1
End of Treatment Phase 
Survival Follow
up11
Treatment Cycle /
Scheduled Time
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and
Beyond 
Discontinuation
Visit8
Safety Follow
up Visit9
Survival Follow
up Visit 1 and
beyond
Scheduling Window 
(Days):2
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At Study Drug
Discontinuation
+/- 3
30 Days from
Last Dose
+/- 3
Approx. Every 2
Months
+/- 14
Comprehensive  Chemistry
Panel6
X
X
X
X 
X
X
X
T3,FT4 and TSH3
X 
X
X
X
X
X 
X
X
X
Efficacy Measurements
Tumor Imaging7
X 
X 
X 
X 
X 
X 
X
1 
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 9 weeks
(± 7 days) from the date of randomization regardless of any treatment delays.
2 
In general, the window for each visit is +/- 3 days unless otherwise specified.
3 
Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service. After Cycle 1, lab samples can be collected up to 48 hours prior to
the scheduled time point. Laboratory results must be known and acceptable prior to dosing. See Section 7.1.3 for details regarding laboratory tests. Performed every 2 cycles after Cycle 13.
4 
This regimen to be administered up to a maximum of 6 cycles. Pemetrexed may be given after 4 cycles of Carboplatin/Pemetrexed, Cisplatin/Pemetrexed or  Paclitaxel/Carboplatin in subjects
with non-squamous histologies. 
5 
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at screening only
6 
After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing. See Section 7.1.3 for details
regarding laboratory tests. CBC and chemistry will be performed every 3 cycles, and every 4 cycles after Cycle 13. Additional laboratory assessments required for the SOC platinum doublets
offered in this trial, but not included in the above Flowchart, should be obtained per local guidance and results recorded in the appropriate CRF. 
7 
On study imaging will be performed every 9 weeks (63 ± 7 days) calculated from the randomization date or more frequently if clinically indicated. The timing for imaging studies should
follow calendar days and should not be adjusted for delays in  cycle starts. The same imaging technique should be used in a subject throughout the trial. Imaging assessments should be
performed every 9 weeks (+/- 7) days from randomization. Additional imaging at Discontinuation Visit and Safety Follow-up Visit is not required provided that imaging assessments have been
performed per schedule. Imaging will continue at the protocol defined interval until the time of PD, pregnancy, or the start of a new cancer treatment.
8 
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.
9 
The mandatory Safety Follow-up Visit for all subjects should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of 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 0-1 or until beginning of a new antineoplastic therapy, whichever
occurs first. Subjects who are eligible for treatment with pembrolizumab during the Second Course Phase may have up to three Safety Follow-up Visits, one after the Treatment Phase,
Crossover Phase and the Second Course Phase. If the Discontinuation Visit occurs approximately 30 days (+/- 3 days) from last dose trial treatment the same procedures do not need to be
repeated for the Safety Follow-up Visit
10 
Once a subject discontinues study treatment, report all SAEs (related and unrelated to trial treatment), ECIs, and irAEs occurring within 90 days following cessation of treatment or 30 days
following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  After this time, report only SAEs and ECIs that are considered related to trial treatment.
11 During the Survival Follow-up Phase, the subject should be contacted by telephone approximately every 2 months to assess for survival status.  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 who have a death event previously recorded).
 
04T748
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Product:  MK-3475 (SCH-900475)
81
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Amendment 08, Second Course Treatment and Follow-up Phase
6.7 
Second Course Treatment Cycles1 
End of Second Course Treatment
Survival Follow up9
Treatment 
Cycle 
/
Scheduled Time
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Discontinuation Visit 
Safety Follow up
Visit12
Survival Follow
up Visit 1 and
Beyond
Scheduling Window
(Days):2
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
At Study Drug
Discontinuation +/- 3
30 Days from
Last Dose
+/- 3
Approx. Every
2 Months
+/- 14
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
Survival status9 
< ---------------------------------------------------------------------------------------------------------------------------------------------------- >
X
Study Drug Administration
Pembrolizumab 11
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Clinical Procedures / Assessments
Review Adverse Events10
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
X
Directed 
Physical
Examination
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
Vital Signs and Weight13
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
ECOG Performance Status
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
 
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Product:  MK-3475 (SCH-900475)
82
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Second Course Treatment Cycles1 
End of Second Course Treatment
Survival Follow up9
Treatment 
Cycle 
/
Scheduled Time
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Discontinuation Visit 
Safety Follow up
Visit12
Survival Follow
up Visit 1 and
Beyond
Scheduling Window
(Days):2
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
At Study Drug
Discontinuation +/- 3
30 Days from
Last Dose
+/- 3
Approx. Every
2 Months
+/- 14
Pregnancy Test -Urine or
Serum β- HCG 3, 5
X 
PT/INR and aPTT 4, 5
X
CBC with Differential5, 8
X
X
X
X
X
X
X14
Comprehensive Chemistry
Panel5 8 
X
X
X
X
X
X
X14
T3, FT4 and TSH5,6
X 
X
X 
X 
X
X 
X
X
X14
Efficacy Measurements
Tumor Imaging 7
X 
X 
X 
X 
X 
X 
X
1 
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).
Iftreatment cycles are adjusted all procedures except imaging will be completed according to the Cycle number and not weeks on therapy.
2 
In general, the window for each visit is +/- 3 days unless otherwise specified.
3 
For women  of reproductive potential, a urine pregnancy test will be performed within  72 hours prior to the first Second Course dose. If urine pregnancy results cannot be confirmed as
negative, a serum pregnancy test, performed by the localstudy site laboratory, willbe required. Pregnancy tests (serum and/or urine tests) should be repeated ifrequired by local guidelines.
4 
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
5 
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 for details regarding
laboratory tests.
6 
After the first dose, lab samples can be collected up to 48 hours prior to the scheduled time point.  Laboratory results must be known and acceptable prior to dosing.  See Section 7.1.3 for details
regarding laboratory tests.  Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service. Thyroid function tests should be
performed every other cycle.
7 
If the subject enters the Second Course Phase, Cycle 1 scan may be performed up to 30 days prior to the first dose of trial treatment in the Second Course Phase.  Imaging will be performed
every 9 weeks (63 +/-7 days) after the first dose of Second Course Phase trial treatment up until cycle 13 and every 12 weeks (84 +/- 7 days) thereafter. The timing of imaging should follow
calendar days and should not be adjusted for delays in cycle starts. The same imaging technique should be used in a subject throughout the trial. Subjects who discontinue trial treatment due to
reasons other than disease progression, should continue to be assessed every 9 weeks (63 +/- 7 days) by radiologic imaging until the start of a new antineoplastic therapy, documented disease
progression, or death, whichever occurs first. If trial treatment is discontinued after cycle 13, tumor imaging should be performed every 12 weeks (84 days +/- 7 days). Continued imaging is not
needed for subjects who start another antineoplastic treatment. The same imaging technique should be used in a subject throughout the trial. Imaging assessments should be performed every 9
weeks (+/- 7 days from randomization. Additional imaging at Discontinuation Visit and Safety Follow-up Visit is not required provided that imaging assessments have been performed per
schedule. Imaging will continue at the protocol defined interval until the time of PD, pregnancy, or the start of a new cancer treatment
 
04T748
07WZMS

Product:  MK-3475 (SCH-900475)
83
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Second Course Treatment Cycles1 
End of Second Course Treatment
Survival Follow up9
Treatment 
Cycle 
/
Scheduled Time
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Discontinuation Visit 
Safety Follow up
Visit12
Survival Follow
up Visit 1 and
Beyond
Scheduling Window
(Days):2
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
At Study Drug
Discontinuation +/- 3
30 Days from
Last Dose
+/- 3
Approx. Every
2 Months
+/- 14
8 
After the first dose, lab samples can be collected up to 48 hours prior to the scheduled time point.  Laboratory results must be known and acceptable prior to dosing.  See Section 7.1.3 for details
regarding laboratory tests.  CBC and chemistry will be performed every 3rd cycle.
9 
Once a subject experiences disease progression or starts a new antineoplastic therapy, the subject moves into the Survival Follow-up Phase and should be contacted by telephone approximately
every 2 months to assess for survival status and start of new antineoplastic therapy if applicable.  During the Survival Follow-up Phase, the subject should be contacted by telephone
approximately every 2 months to assess for survival status.  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 who have a death
event previously recorded).
10 Record all AEs occurring within 30 days after the last dose of trial treatment. Report all SAEs (related and unrelated to trial treatment), ECIs, and irAEs occurring within 90 days following
cessation of treatment or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. After this time, report only SAEs and ECIs that are
considered related to trial treatment.
11 Pembrolizumab can be administered up to 17 trial treatment in Second Course Phase.
12 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 0-1 or until beginning of a new antineoplastic therapy, whichever occurs first. 
Subjects who are eligible per the requirements in Section 7.1.5.5 for treatment with pembrolizumab during the Second Course Phase may have up to three Safety Follow-up Visits, one after the
Treatment Phase, Crossover Phase and the Second Course Phase.
13 Vital signs to include temperature, pulse, respiratory rate, blood pressure, and weight.
14 Every effort should be made to collect blood samples at the Safety Follow Up Visit until the start of new antineoplastic therapy, disease progression or death, whichever comes first.
 
04T748
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Product:  MK-3475 (SCH-900475)
84
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Amendment 08, Cross Over Phase
6.8 
(Only applicable for subjects randomized to SOC that have not started new anti-neoplastic therapy).
Treatment Cycles1 
End of Treatment
Phase
Follow up Phase13
Survival
Follow
up15
Treatment Cycle /
Scheduled Time
18 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13
14
through
35
Discontin
uation
Visit11
Safety
Follow
up
Visit 12
Follow
up Visit
1
Follow
up
Visit 2
Follow
up
Visit 3
and
Beyond
Survival
Follow up
Visit 1 and
Beyond
Scheduling
Window (Days):2 
± 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
3
Months
from
Last
Dose
+/- 7
6
Month
s from
Last
Dose
+/- 7
Every 3
Months
after
Visit 2
+/- 7
Approx.
Every 2
Months
+/- 14
Administrative Procedures
Prior and 
Concomitant 
Medications
X 
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 Status15
< ----------------------------------------------------------------------------------------------------------------------------------------------------------------- >
X
Clinical Procedures / Assessments
Review Adverse
Events 14
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
X
X
Directed Physical
Examination
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
X 
X
Vital Signs and
Weight 7
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X
ECOG
Performance Status
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X
Laboratory Procedures / Assessments: analysis performed by local laboratory
CBC  with
Differential10
X
3
X 
X 
X 
X 
X 
X
X
PT/INR and aPTT
X
3
Comprehensive
Chemistry Panel10
X
3
X 
X 
X 
X 
X 
X 
X
 
04T748
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Product:  MK-3475 (SCH-900475)
85
Protocol/Amendment No.: 024-11
MK-3475-024-11 FinalProtocol
20-Dec-2017
Confidential
Treatment Cycles1 
End of Treatment
Phase
Follow up Phase13
Survival
Follow
up15
Treatment Cycle /
Scheduled Time
18 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13
14
through
35
Discontin
uation
Visit11
Safety
Follow
up
Visit 12
Follow
up Visit
1
Follow
up
Visit 2
Follow
up
Visit 3
and
Beyond
Survival
Follow up
Visit 1 and
Beyond
Scheduling
Window (Days):2 
± 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
3
Months
from
Last
Dose
+/- 7
6
Month
s from
Last
Dose
+/- 7
Every 3
Months
after
Visit 2
+/- 7
Approx.
Every 2
Months
+/- 14
T3, FT4 and TSH 5 
X
3 
X 
X
X
X 
X
X
X
X
X
Efficacy Measurements
Tumor Imaging6
x
x
x
x
x 
X
X 
X16 
X16 
X16
Study Drug Administration
Pembrolizumab 
9
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
1 
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.
2 
In general, the window for each visit is 3 days unless otherwise specified.
3 
Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment. See Section 7.1.3 for details regarding laboratory tests. 
4 
After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point.  Laboratory results must be known and acceptable prior to dosing.  See Section 7.1.3 for
details regarding laboratory tests; perform every 6 cycles after cycle 14.
5 
After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point.  Laboratory results must be known and acceptable prior to dosing.  See Section 7.1.3 for
details regarding laboratory tests; perform every 2 cycles after Cycle 13. Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform
this service.
6 
Blinded independent centralreview verifying progressive disease is: 1) required for crossover, without exception, and 2) is based on RECIST 1.1. Tumor response assessment is required
every 9 weeks (63 days±7 days) until the subject starts another anti-cancer treatment.  Assessment of disease response or progression will be determined by the investigator.  The treating
physician will record a physician assessed tumor response and the criteria used i.e.  modified RECIST 1.1 or standard RECIST v 1.1 on the discontinuation form. Imaging assessments
should be performed every 9 weeks (+/- 7 days from crossover. Additional imaging at Discontinuation Visit and Safety Follow-up Visit is not required provided that imaging assessments
have been performed per schedule. Imaging will continue at the protocol defined interval until the time of PD, pregnancy, or the start of a new cancer treatment.
7 
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. 
8 
Treatment with Pembrolizumab should not initiate until at least 30 days from the date of last dose of chemotherapy. Screening procedures may be completed during these 30 days.  All
procedures and assessments completed at the time of withdrawal from the main study may be used as appropriate for the start of the Crossover Phase of the study.
9 
Pembrolizumab can be administered for up to 35 cycles.
10 After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point.  Laboratory results must be known and acceptable prior to dosing.  See Section 7.1.3 for
details regarding laboratory tests. CBC and chemistry will be performed every 3rd cycle.
11 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.
12 The mandatory Safety Follow-up Visit for all subjects should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of new antineoplastic
 
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Treatment Cycles1 
End of Treatment
Phase
Follow up Phase13
Survival
Follow
up15
Treatment Cycle / 
Scheduled Time
1 8
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13
14 
through 
35 
Discontin  
uation 
Visit 11
Safety 
Follow 
up 
Visit 12 
Follow 
up Visit 
1 
Follow 
up 
Visit 2 
Follow
up
Visit 3
and
Beyond
Survival
Follow up
Visit 1 and
Beyond
Scheduling 
Window (Days): 2 
± 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 
3 
Months 
from 
Last 
Dose 
+/- 7 
6 
Month  
s from 
Last 
Dose 
+/- 7
Every 3 
Months 
after 
Visit 2 
+/- 7
Approx.
Every 2
Months
+/- 14
treatment, whichever comes first. Subjects with an AE of Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy,
whichever occurs first. Subjects who are eligible for treatment with pembrolizumab during the Second Course Phase may have up to three Safety Follow-up Visits, one after the
Treatment Phase, Crossover Phase and the Second Course Phase. If the Discontinuation Visit occurs approximately 30 days (+/- 3 days) from last dose trial treatment the same
procedures do not need to be repeated for the Safety Follow-up Visit.
13 Subjects who stop pembrolizumab after 35 trial treatments and have achieved PR and/or SD OR have achieved a CR (see section 7.1.5.5) will move to the Follow up Phase of the study.
Follow up visit 1 should take place 3 months after the last dose of trial treatment. Follow up visit 2 should take place 6 months after last dose of trial treatment and additional Follow up
visits should take place every 3 months thereafter. Subjects who experience disease progression (and do not continue into the Second Course Phase) or start a new antineoplastic therapy
will move directly into Survival Follow up. For subject convenience, all Follow up assessments may occur during the same visit as the imaging studies are obtained.  Subjects with an
AE of Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy, whichever occurs first.
14 Once a subject discontinues study treatment, report all SAEs (related and unrelated to trial treatment), ECIs, and irAEs occurring within 90 days following cessation of treatment or 30
days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  After this time, report only SAEs and ECIs that are considered related to trial
treatment.
15 Once a subject experiences disease progression or starts a new antineoplastic therapy, the subject moves into the Survival Follow-up Phase and should be contacted by telephone
approximately every 2 months to assess for survival status and start of new antineoplastic therapy if applicable.  During the Survival Follow-up Phase, the subject should be contacted by
telephone approximately every 2 months to assess for survival status.  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 who have a death event previously recorded).
16 Tumor imaging is not needed for subjects who start another anti-cancer treatment regimen.
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each
visit.  Individual trial procedures are described in detail below.  It may be necessary to
perform these procedures at unscheduled time points if deemed clinically necessary by the
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations
may require that additional informed consent be obtained from the subject.  In these cases,
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1 
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
trialor Future Biomedical Research.
General Informed Consent
7.1.1.1.1 
Consent must be documented by the subject’s dated signature or by the subject’s legally
acceptable representative’s dated signature on a consent form along with the dated signature
of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the subject before
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form
and any written information provided to the subject must receive the IRB/ERC’s
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable
representative should be informed in a timely manner if new information becomes available
that may be relevant to the subject’s willingness to continue participation in the trial.  The
communication of this information will be provided and documented via a revised consent
form or addendum to the original consent form that captures the subject’s dated signature or
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at
the protocol level. 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations
and Sponsor requirements.
 
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Consent and Collection of Specimens for Future Biomedical Research
7.1.1.1.2 
The investigator or qualified designee will explain the Future Biomedical Research consent
to the subject, answer all of his/her questions, and obtain written informed consent before
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the
informed consent will be given to the subject.
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.
7.1.1.4 Medical History
A medical history will be obtained by the investigator or qualified designee. 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 NCSLC even if diagnosed greater than 10 years prior to Visit 1.  NSCLC
history will be recorded separately and not listed as Medical History.  Medical history will
also include an assessment of smoking history.
7.1.1.5 Prior and Concomitant Medications Review
Prior Medications
7.1.1.5.1 
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. In addition, record all treatments for a prior cancer
other than NSCLC even if taken greater than 30 days prior to Visit 1.  Prior treatments for
NSCLC will be recorded separately and not listed as a prior medication.
Concomitant Medications
7.1.1.5.2 
The investigator or qualified designee will record medication, if any, taken by the subject
during the trial through the 30-day Safety Follow-up Visit. After the Safety Follow-up Visit
record all medications related to reportable SAEs and ECIs as defined in Section 7.2.
 
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7.1.1.6 Non-small cell lung cancer Disease Details and Treatments
Disease Details
7.1.1.6.1 
The investigator or qualified designee will obtain prior and current NSCLC disease details.
Prior Treatment
7.1.1.6.2 
The investigator or qualified designee will review all prior treatments for NSCLC including
systemic treatments, radiation and surgeries.
Subsequent Antineoplastic Therapy Status
7.1.1.6.3 
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 allocation.  Each subject
will be assigned only one screening number.  Screening numbers must not be re-used for
different subjects. 
Any subject who is screened multiple times will retain the original screening number
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in
Section 7.1.5.1.
7.1.1.8 Assignment of Randomization Number
All eligible subjects will be randomly allocated and will receive a randomization number. 
The randomization number identifies the subject for all procedures occurring after
randomization.  Once a 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 randomization number.
7.1.1.9 Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between
pembrolizumab doses due to toxicity require consultation between the investigator and the
Sponsor and written documentation of the collaborative decision on subject management.
 
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Administration of trial medication will be witnessed by the investigator and/or trial staff. The
total volume of trial treatment infused will be compared to the total volume prepared to
determine compliance with each dose administered.
Clinical Procedures/Assessments
7.1.2 
7.1.2.1 Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically
indicated. Adverse experiences will be graded and recorded throughout the study and during
the follow-up period according to NCI CTCAE Version 4.0 (see Section 12.6). Toxicities
will be characterized in terms including seriousness, causality, toxicity grading, and action
taken with regard to trial treatment.
An immune related adverse event (irAE) may be defined as an AE of unknown etiology,
associated with drug exposure and is consistent with an immune phenomenon. Efforts should
be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic causes prior to
labeling an AE immune related. Immunological, serological and histological (biopsy) data
should be used to support the diagnosis of an immune-related toxicity. Following the
guidance described in Section 7.2.3.2., certain irAEs should also be reported to the Sponsor
as ECIs. (See the separate guidance document in the administrative binder regarding the
identification, evaluation and management of irAEs and ECIs).
Please refer to Section 7.2 for detailed information regarding the assessment and recording of
AEs.
7.1.2.2 Physical Exam
Full Physical Exam
7.1.2.2.1 
The investigator or qualified designee will perform a complete physical exam during the
screening period. Clinically significant abnormal findings should be recorded as medical
history. The time points for full physical exam are described in Section 6 - Trial Flow Chart.
After the first dose of trial treatment new clinically significant abnormal findings should be
recorded as AEs.
Directed Physical Exam
7.1.2.2.2 
For cycles that do not required a full physical exam per the Trial Flow Chart, the investigator
or qualified designee will perform a directed physical exam as clinically indicated prior to
trial treatment administration. New clinically significant abnormal findings should be
recorded as AEs.
 
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7.1.2.3 Vital Signs
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
the Trial Flow Chart. Vital signs include temperature, pulse, respiratory rate, weight and
blood pressure. Height will be measured at Visit 1 only.
7.1.2.4 Lead Electrocardiogram (ECG)
A standard 12-lead ECG will be performed using local standard procedures once at
screening. Clinically significant abnormal findings should be recorded as medicalhistory.
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 12.5) at
screening, prior to the administration of each dose of trial treatment and during the Follow-up
period as specified in the Trial Flow Chart.
7.1.2.6 Tumor Imaging
The process for image collection and transmission to the central vendor can be found in the
Site Imaging Manual.  Tumor imaging may be performed by computed tomography (CT)
(preferred) or magnetic resonance imaging (MRI), but the same imaging technique should be
used in a subject throughout the trial.  CT scan is the more commonly used modality and is
strongly encouraged for images of the thorax, abdomen and pelvis.  An MRI with contrast is
suggested if a pelvis CT scan is not considered SOC. See Section 7.1.2.7 Brain Imaging for
brain scan details.
The initial tumor imaging will be performed within 30 days of randomization date.  Scans
performed as part of routine clinical management are acceptable for use as the screening scan
if they are of diagnostic quality and performed within 30 days of randomization date.  The
subject must have at least one radiographically measurable lesion per RECIST 1.1 per local
reading.  On-study imaging will be performed every 9 weeks (63 ± 7 days) from the date of
randomization  or more frequently if clinically indicated.  Tumor timing should follow
calendar days and should not be adjusted for delays in cycle starts.  It must be emphasized
that subjects continue to receive all assessments as outlined in the Flowchart until RECIST
1.1 defined progression is documented by blinded independent central radiology, including
instances of study therapy discontinuation due to toxicity.
 
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If RECIST 1.1 defined progression is documented by blinded independent central radiology
review, then the subject may be discontinued from trial treatment unless, in the opinion of the
investigator, the subject is deriving clinical benefit from the therapy and the subject does not
have any signs or symptoms of clinically instability. Clinical stability is defined as following:
1) Absence of symptoms and signs indicating clinical significant progression of disease
(including worsening of laboratory values) indicating disease progression.
2) No decline in ECOG PS.
3) Absence of rapid progression of disease or progressive tumor at critical anatomical
sites (e.g., cord compression) requiring urgent alternative medical intervention.
Immune related response criteria assessed by the blinded independent radiology review will
be provided to the investigator at the time of RECIST 1.1 defined progression in order to aid
in decisions regarding treatment continuation.  If treatment is continued beyond RECIST 1.1
defined tumor progression, subsequent imaging assessments should be based upon modified
RECIST criteria. Modified RECIST 1.1 is an adapted form of RECIST 1.1 to account for the
unique tumor response seen in this class of therapeutics. 
In modified RECIST 1.1, if imaging shows PD, tumor assessment may be repeated 4 weeks
later at the site in order to confirm PD with the option of continuing treatment for clinically
stable subjects (see Table 5 below).
In determining whether or not the tumor burden has increased or decreased, investigators
should consider all target lesions as well as non-target lesions. Subjects that are deemed
clinically unstable are not required to have repeat imaging for confirmation. If radiologic
progression is confirmed at the subsequent scan then the subject will be discontinued from
trial treatment unless, if in the opinion of the investigator, the subject is deriving clinical
benefit and upon consultation with the Sponsor.  If radiologic progression is not confirmed,
then the subject should resume/continue trial treatment and have their next scan according to
the every 9 weeks (63 ± 7 days) schedule. 
 
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Table 5 
Imaging and Treatment Determinations After First Radiological Evidence of PD
Clinically Stable 
Clinically Unstable
Imaging 
Treatment 
Imaging 
Treatment
1st radiologic
evidence 
of
PD
Repeat
imaging at 4
weeks 
to
confirm PD
May continue
study treatment
at 
the
investigator’s
discretion
while awaiting
confirmatory
scan
Repeat
imaging at 4
weeks 
to
confirm PD if
possible.
Discontinue
treatment
Repeat 
scan
confirms PD
No additional
imaging
required 
if
investigator
does not see
benefit.  If
Investigator
sees 
benefit,
continue
regularly
scheduled
imaging
assessments
every 9 weeks
(63 ± 7 days)
while 
on
treatment.
May continue
treatment 
if
investigator
considers
subject
deriving
clinical benefit
No additional 
imaging
required
N/A
Repeat 
scan
shows 
SD,
PR or CR
Continue
regularly
scheduled
imaging
assessments
every 9 weeks
(63 ± 7 days)
while 
on
treatment.a
Continue study
treatment 
at
the
investigator’s
discretion.
Continue
regularly
scheduled
imaging
assessments
every 9 weeks
(63 ± 7 days)
while 
on
treatment.a
May restart study
treatment 
if
condition 
has
improved 
and/or
clinically stable per
investigator’s
discretion.
There is no requirement for PD to be confirmed ≥4 weeks later for subjects in the control arm (e.g. those not
receiving pembrolizumab).
a Tumor imaging will be assessed first at 9 weeks (63 ± 7 days). Subsequent tumor imaging will be performed every 9
weeks (63 ± 7 days) until end of treatment for all subjects.
SD does not need to be confirmed ≥4 weeks later. Schedule of 9 weeks (63 ± 7 days) should be followed as per
protocol.
 
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Imaging during the Observation Phase should be obtained every 9 weeks (63 ± 7 days) until
the subject experiences disease progression that has been confirmed by blinded independent
central radiology review or starts a new antineoplastic therapy. 
Subjects who move into the Second Course Phase will continue to have scans performed
every 9 weeks (63 7 days) after the first dose of Second Course Phase trial treatment for
Year 1 and every 3 months thereafter. 
The same imaging technique should be used in a subject throughout the trial.  The processes
for image collection, processing and transmission to the central vendor are in the Site
ImagingManual.
For Amendment 08, tumor imaging will no longer be required for RECIST v1.1 assessments
in accordance with the end points of this trial.  Imaging should still be conducted every 9
weeks to assess for tumor response, but will no longer be required to be submitted to the
blinded independent central radiology review.
7.1.2.7 Brain Imaging
For patients with no previous history of brain metastases, screening brain imaging will need
to be obtained. MRI is the preferred imaging modality however CT is acceptable if an MRI is
clinically contraindicated. If lesions are identified, the lesions must be treated, regardless of
symptoms. Two additional scans, obtained at least 4 weeks apart, should be obtained to
document disease stability AFTER local treatment administration to the brain metastases has
been completed.  Subjects with previously treated brain metastases may participate provided
they are stable, which is defined as lack of progression on two sets of imaging obtained at
least four weeks prior.  Stability as defined above should be documented prior to the first
dose of trial treatment.  In addition, any neurologic symptoms must have returned to baseline
or resolved and the subject is not using steroids for at least three days prior to trial treatment.
The screening brain scan may be collected up to 42 days prior to randomization.
7.1.2.8 Patient Reported Outcomes (PROs)
The EuroQol EQ-5D, EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires will be
administered by trained site personal and completed electronically by the subjects prior to all
other study procedures and receiving results of any tests. Every effort should be made to
withhold any information regarding disease progression from the subject until AFTER the
ePRO assessments have been obtained.  The PROs are completed in the following order:
EuroQol EQ-5D first, then EORTC QLQ-C30, and lastly the EORTC QLQ-LC13 at the time
points specified in the Trial Flow Charts. The ePRO must be completed by the subject,
themselves.
The Oncology Health Economic Assessment (HEA) form captures non-study related
healthcare visits, including healthcare provider visits, emergency room (ER) visits, and
hospitalizations (including admission and discharge dates and primary discharge diagnosis).
It will be administered and completed by qualified site personnel after the subject completes
 
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all other questionnaires and before other study procedures.  HEA collection time points are
specified in the Trial Flow Charts.
It is most relevant and strongly recommended that ePROs and HEAs are administered prior
to drug administration, AE evaluation and disease status notification.
Following Amendment 08, PRO and HEA assessments will no longer be required.
7.1.2.9 Tumor Tissue Collection
Tumor tissue for biomarker analysis from formalin fixed paraffin embedded tumor tissue
sample or newly obtained formalin fixed biopsy of a tumor lesion not previously irradiated
must be provided in the form of a tissue block or unstained slides and received by the central
vendor before randomization. If new scientific data emerge that indicate that an existing
biopsy or surgical specimen is suboptimal for identification of subjects, then only new
biopsies will be acceptable for determination of PD-L1 status. Only subjects whose tumors
demonstrate strong PD-L1 expression are eligible for enrollment. A fine needle aspirate,
EBUS  or cytologic specimen will not be acceptable. Needle or excisional biopsies, or
resected tissue is required. Newly obtained formalin fixed specimens are encouraged.
If the subject signs the Future Biomedical Research (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
operations/laboratory Manual. Older biopsy material or surgical specimens may be used to
assess EGFR mutation status and ALK translocation status, if not already documented when
the subject signs informed consent.
Laboratory Procedures/Assessments
7.1.3 
Details regarding specific laboratory procedures/assessments to be performed in this trial are
provided below. The total amount of blood/tissue to be drawn/collected over the course of
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes
drawn/collected by visit and by sample type per subject can be found in the Procedures
Manual.
7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 6.
 
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Table 6 
Laboratory Tests
Hematology  
Chemistry
Urinalysis
Other
Hematocrit 
Albumin
Blood
Follicle 
Stimulating
Hormone (FSH)
Hemoglobin  
Alkaline phosphatase
Glucose
Serum β-human chorionic
gonadotropin (β-hCG)
Platelet count 
Alanine 
aminotransferase 
(ALT)
Protein
Total 
Triiodothyronine(T3)
It is acceptable to use
FT3 in place of T3 if that
is considered standard of
care at your site.
WBC (total and
differential)
Aspartate 
aminotransferase 
(AST)
Specific gravity 
Free thyroxine (FT4)
Carbon Dioxide (CO2 or
Bicarbonate If these tests are
not done as part of standard
of care in your region then
these tests do not need to be
performed.)
Microscopic exam, if
abnormal results are
noted
Thyroid 
stimulating
hormone (TSH)
Calcium
PT (INR)
Chloride
aPTT
Creatinine
PK
Glucose
Blood for FBR
Magnesium
Anti-pembrolizumab
Antibodies
Phosphorus
Blood for Genetics
Potassium
Sodium
Total Bilirubin 
Direct Bilirubin, if total
bilirubin is elevated above the
upper limit of normal
Total protein
Blood Urea Nitrogen (BUN):
BUN  or Urea should be
collected 
per 
institutional
standard. It is not required to
perform 
both 
of 
these
laboratory tests
Urea:
BUN or Urea should be
collected 
per 
institutional
standard. It is not required to
perform 
both 
of 
these
laboratory tests
Uric Acid
 
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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, pre-dose laboratory
procedures can be conducted up to 48 hours prior to dosing.
Results must be reviewed by the investigator or qualified designee and found to be
acceptable prior to each dose of trial treatment.
All screening tests (both local and central) must be known and acceptable prior to
randomization. All labs performed locally must be known and acceptable prior to dosing in
Cycle 1 and beyond. Any non-screening test performed for Cycle 1 and beyond by central lab
should be evaluated by the treating investigator when results are available.
Additional laboratory assessments required for the SOC platinum doublets offered in this
trial, but not included in the Flowcharts, should be obtained per local guidance and results
recorded in the appropriate CRF. 
7.1.3.2 Pharmacokinetic Evaluations
Blood Collection for Serum Pembrolizumab
7.1.3.2.1 
Sample collection, storage and shipment instructions for serum samples will be provided in
the Procedures manual.
The time points for PK blood sampling are described in Section 6 - Trial Flow Chart. Blood
samples for PK will be collected and stored only at this time. Further analysis may be
performed if required.
Following Amendment 08, blood samples for PK measurements are no longer required.
7.1.3.3 Anti-Pembrolizumab Antibodies
Sample collection, storage and shipment instructions will be provided in the Procedures
manual.
The time points for anti-pembrolizumab antibody blood sampling are described in Section 6 -
Trial Flow Chart. Blood samples for anti-pembrolizumab antibodies will be collected and
stored only at this time.  Further analysis may be performed if required.
Following Amendment 08, blood samples for anti-pembrolizumab antibodies is no longer
required.
7.1.3.4 Molecular Testing
Site must be able to provide documentation of subject’s tumor EGFR mutation and ALK
translocation status. If the site is unable to provide this source documentation, then the
Sponsor will offer this molecular testing of the tumor. Detailed instructions for tissue
collection, processing and shipment are provided in the operations/laboratory Manual.
 
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7.1.3.5 Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:
 Blood for genomics use
 Leftover tumor tissue
Other Procedures
7.1.4 
7.1.4.1 Withdrawal/Discontinuation
When a subject discontinues/withdraws from participation in the trial, all applicable activities
scheduled for the final trial visit should be performed at the time of discontinuation.  Any
adverse events which are present at the time of discontinuation/withdrawal should be
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and
Recording Adverse Events.
Withdrawal From Future Biomedical Research
7.1.4.1.1 
Subjects may withdraw their consent for Future Biomedical Research and have their
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by
contacting the principal investigator for the main trial.  If medical records for the main trial
are still available, the investigator will contact the Sponsor using the designated mailbox
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to
obtain appropriate information to complete specimen withdrawal.  Subsequently, the
subject's specimens will be removed from the biorepository and be destroyed.  A letter will
be sent from the Sponsor to the investigator confirming the destruction. It is the
responsibility of the investigator to inform the subject of completion of destruction.  Any
analyses in progress at the time of request for destruction or already performed prior to the
request being received by the Sponsor will continue to be used as part of the overall research
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the
investigator is no longer required by regulatory authorities to retain the main trial records) or
the specimens have been completely anonymized, there will no longer be a link between the
subject’s personal information and their specimens.  In this situation, the request for
specimen destruction cannot be processed.
7.1.4.2 Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
 
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7.1.4.3 Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be
suitably calibrated and maintained to ensure that the data obtained is reliable and/or
reproducible.  Documentation of equipment calibration must be retained with the study
documentation as source documentation at the trial site.
Critical Equipment for this trial includes:
 Laboratory equipment – as required for inclusion labs and trial assessments
 Imaging equipment – as required for study objectives
 Safety equipment- as required for safety assessments
 Drug administration equipment- as required for storage, preparation and
administration of study drugs
See protocol-specific Administrative Binder, Procedures Manual, Pharmacy Manual,
operations/laboratory Manual and Site Imaging Manual.
Visit Requirements
7.1.5 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1 Screening
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related
details are provided above in Section 7.1 - Trial Procedures.
Approximately 42 days prior to randomization, potential subjects will be evaluated to
determine that they fulfill the entry requirements as set forth in Section 5.1.  Screening
procedures may be repeated after consultation with the Sponsor.
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 42 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.
 
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 For women of reproductive potential, a urine pregnancy test will be performed within
72 hours prior to first dose of trial treatment.  If urine pregnancy results cannot be
confirmed as negative, a serum pregnancy test, performed by the local study site
laboratory, will be required.
 Tumor imaging must be performed within 30 days prior to 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 Phase
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related
details are provided above in Section 7.1 - Trial Procedures.
Subject should continue to receive all assessments as defined in the Treatment phase of the
Flowchart while they are actively receiving treatment, which includes both SOC and
pembrolizumab. This includes those subjects who are treated beyond RECIST v1.1 PD.
Please note there is no difference in the frequency of assessments for those subjects who are
treated beyond RECIST v1.1 defined PD.
7.1.5.3 End of Treatment Visits
Discontinuation Visit
7.1.5.3.1 
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 7.1.5.3.2 Mandatory Safety Follow up
Visit
Mandatory Safety Follow up Visit
7.1.5.3.2 
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 0-1 or until beginning of a new antineoplastic therapy,
whichever occurs first. Subjects who are eligible per the requirements in Section 7.1.5.5 for
treatment with pembrolizumab during the Second Course Phase may have up to two Safety
Follow-up Visits, one after the Treatment Phase and the second after the Second Course
Phase.
 
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Observation Visit
7.1.5.3.3 
Subjects who complete their fixed number of 4 - 6 cycles of SOC or who stop either SOC
(including pemetrexed maintenance) or pembrolizumab for reasons other than PD or
pregnancy, should move into the Observation Phase of the study and complete the
assessments in the Observation Visits schedule as outlined in the study flow chart in Section
6.
Subjects randomized to pembrolizumab who discontinue therapy due to a PR and/or SD after
35 trial treatments should follow procedures in the End of Treatment Phase and Follow-up
Phase of the study. If PD is established by the site during the assessments obtained during the
Follow-up Phase of the study, the subject may be eligible for the Second Course Phase.
Laboratory tests including CBC, thyroid function tests, comprehensive chemistry panel and
urinalysis should be obtained every 3 months during the Observation Visit Phase.
Following Amendment 08, the Observation Visits will no longer be required.  Subjects
receiving SOC may proceed directly to Crossover if they meet the requirements outlined in
section 7.1.5.6 below and will otherwise proceed directly to survival follow-up upon
discontinuing SOC therapy.  Subjects receiving pembrolizumab who would have previously
continued with Observation Visits will now move directly into Survival Follow-up.
7.1.5.4 Follow up Phase
All 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.
Follow-up Visits
7.1.5.4.1 
Subjects who are randomized to pembrolizumab, or are receiving pembrolizumab on the
Crossover Phase, and have received the maximum  administrations of pembrolizumab OR
who have achieved a CR (see criteria outlined in Section 7.1.5.5), should be followed as
indicated in the Follow up Phase of the study outlined in Section 6.0. Follow-up Visit 1
should be scheduled 3 months after the last dose of trial treatment. Assessment for drug-
related immune-related AEs should occur at Follow-up Visit 1. Follow-up Visit 2 should
occur 6 months after the last dose of trial treatment. Unless otherwise noted in the flowchart,
every effort should be made to collect subject information on the start of new antineoplastic
therapy, disease progression and death.
Subjects who are eligible to receive re-treatment with pembrolizumab according to the
criteria in Section 7.1.5.5 will move to the Second Course Phase when they experience
disease progression.  Imaging should be performed every 9 weeks to assess tumor response.
 
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Survival Follow-up
7.1.5.4.2 
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 approximately every 2 months to assess for survival status. Post-
study treatments and the subject’s response to them will also be collected.
7.1.5.5 Second Course Phase
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 who were randomized
to receive pembrolizumab may be eligible to receive pembrolizumab for 17 cycles in the
Second Course Phase of this study if the subject:
o Stopped their initial treatment with pembrolizumab after attaining a confirmed CR
according to RECIST 1.1, was treated for at least six months with
pembrolizumab, and received at least two treatments with pembrolizumab beyond
the date when the initial CR was declared. A CR by RECIST 1.1 means that all
index lesions have resolved (none have bidimensional measurements), all non-
index lesions have disappeared, and no new lesions have been identified. These
findings must be confirmed on subsequent imaging at least 4 weeks later for the
call of CR by RECIST 1.1  to be appropriate. As such, the subject will have no
evidence of metastatic cancer in order for the subject and his/her physician to
consider the subject’s participation in this Second Course Phase.
o Experience an investigator assessed radiographic disease progression according to
RECIST 1.1 after stopping their initial treatment with pembrolizumab due to
achievement of a confirmed CR.
o Did not receive any anti-cancer treatment since the last dose of pembrolizumab.
OR
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of
study therapy for reasons other than disease progression or intolerability.
o Experienced PD during treatment, yet continued to receive pembrolizumab
beyond progression and attained subsequent benefit, completing 24 months
without further disease progression or intolerability.
AND
o Continues to meet inclusion criteria 4, 5, 6, 11, 12, and 13. 
o Continues to meet exclusion criteria 4, 5, 8 to 17 and/or 18.
 
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Subjects will be re-treated at the same dose as when they last received pembrolizumab. An
objective response or progression of disease assessed by investigator reviewed RECIST 1.1
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.
7.1.5.6 Crossover for Subjects in the Chemotherapy Arm
Subjects on the SOC arm with documented disease progression following chemotherapy, are
eligible to participate in the crossover arm of this trial. Subjects who permanently discontinue
chemotherapy due to an AE, withdraw consent, or for any reason other than progressive
disease, will not be eligible for crossover. Crossover subjects may not initiate treatment with
pembrolizumab any earlier than 30 days after their last dose of chemotherapy regardless of
the time of progression. Of note, the 30 day safety follow up visit may occur on the same day
as the first dose of pembrolizumab in the Crossover Phase. Subjects who are being observed
for progression in the Observation Phase should not initiate therapy with pembrolizumab
until PD has been verified by blinded independent central review.
Crossover Qualifications:
Subjects on the SOC arm will be considered for crossover to pembrolizumab after
documented, progressive disease per RECIST 1.1 guidelines (based on centrally reviewed
assessment). Crossover is optional and is at the discretion of the Investigator (with the
SPONSORs agreement). Imaging must be completed to establish a new baseline for the
Crossover Phase.
Subjects who meet the following criteria are eligible for crossover:
 Chemotherapy induced AEs (except alopecia) must have improved to CTCAE
(Version 4.0) ≤Grade 1
 Have adequate organ function as indicated by the laboratory values in Table 1.
 If a subject is unstable as a result of a new or progressing brain metastasis(es), the
subject will not be eligible for crossover.
 ECOG Performance Status 0-1
 Documentation of progressive disease per RECIST v1.1 by a blinded independent
centralreview
 Subject has not received any other systemic anticancer therapies other than the SOC
platinum doublet administered during the treatment phase.
 Subject has not received palliative radiotherapy of 30Gy or less within 7 days of the
first dose of trial treatment.
 
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Subjects who crossover and then achieve a CR per RECIST 1.1 have the option to hold
pembrolizumab. Additional details are provided in Second Course Phase Section 7.1.5.5.
Subjects who permanently discontinue the Crossover Phase will follow the same Survival
Follow-up assessments outlined in   Section 6.
Following Amendment 08, documented progressive disease per RECIST 1.1 is no longer a
requirement for Crossover.  Subjects randomized to SOC and who have not received an anti-
PD-1 therapy may crossover to pembrolizumab.  All other criteria remain in effect to ensure
subject safety.
7.1.5.7 Survival Status
To ensure current and complete survival data are available at the time of database locks,
updated survival data may be requested during the course of the trial by the Sponsor.  For
example, updated survival status may be requested prior to but not limited to an external Data
Monitoring Committee (eDMC) review, interim, and/or final analysis.  Upon Sponsor
notification, all 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 who have a previously recorded death event in the collection tool).
Assessing and Recording Adverse Events
7.2 
An adverse event is defined as any untoward medical occurrence in a patient or clinical
investigation subject administered a pharmaceutical product and which does not necessarily
have to have a causal relationship with this treatment. An adverse event can therefore be any
unfavourable and unintended sign (including an abnormal laboratory finding, for example),
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in
frequency and/or intensity) of a preexisting condition that is temporally associated with the
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in
frequency or severity from expected levels are not to be considered adverse events. 
Examples of this may include, but are not limited to, teething, typical crying in infants and
children and onset of menses or menopause occurring at a physiologically appropriate time.
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 the course of the use of the Sponsor's product in clinical
trials or within the follow-up period specified by the protocol, or prescribed in clinical
practice, from overdose (whether accidental or intentional), from abuse and from withdrawal.
 
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Adverse events may also occur in screened subjects during any pre-allocation baseline period
as a result of a protocol-specified intervention, including washout or discontinuation of usual
therapy, diet, placebo treatment or a procedure.
Progression of the cancer under study is not considered an adverse event unless it is
considered to be drug related by the investigator.
All adverse events will be recorded from the time the consent form is signed through 30 days
following cessation of treatment and 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.
Definition of an Overdose for This Protocol and Reporting of Overdose to the
7.2.1 
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed
dose for any of the treatments: five times the pembrolizumab dose or more than 20% of the
chemotherapy regimen. No specific information is available on the treatment of overdose of
pembrolizumab. In the event of overdose, pembrolizumab or the chemotherapy regimen
should be discontinued and the subject should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken
without any associated clinical symptoms or abnormal laboratory results, the overdose is
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours
to the Sponsor either by electronic media or paper.  Sponsor Contact information can be
found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of
investigators or their designees to report any pregnancy or lactation in a subject
(spontaneously reported to them) that occurs during the trial or within 120 days of
completing the trial or 30 days following cessation of treatment if the subject initiates new
anticancer therapy, whichever is earlier.  All subjects who become pregnant 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.
 
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Such events must be reported within 24 hours to the Sponsor either by electronic media or
paper.  Sponsor Contact information can be found in the Investigator Trial File Binder (or
equivalent).
Immediate Reporting ofAdverse Events to the Sponsor
7.2.3 
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 a new cancer (that is not a condition of the study);
●
Is associated with an overdose;
●
Is an other important medical event
Refer to Table 7 for additional details regarding each of the above criteria.
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 information) that occurs to any subject from the time the consent is signed through
90 days following cessation of treatment or 30 days following cessation of treatment if the
subject initiate new anticancer therapy, whichever is earlier, whether or not related to the
Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic
media or paper.  Sponsor Contact information 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 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 recorded as such on the Adverse Event case report forms/worksheets and
reported within 24 hours to the Sponsor either by electronic media or paper.  Sponsor Contact
information can be found in the Investigator Trial File Binder (or equivalent).
 
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Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not
associated with clinical symptoms or abnormal laboratory results.
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that
is less than 2X the upper limit of normal, as determined by way of protocol-specified
laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require
an additional evaluation for an underlying etiology.  The trial site guidance for
assessment and follow up of these criteria can be found in the Investigator Trial File
Binder (or equivalent).
3. Additional adverse events:
A separate guidance document has been provided entitled “Event of Clinical Interest
Guidance Document” (previously entitled, “Event of Clinical Interest and Immune-
Related Adverse Event Guidance Document”).  This document can be found in the
administrative binder and provides guidance regarding identification, evaluation and
management of ECIs and irAEs. 
ECIs (both non-serious and serious adverse events) identified in this guidance document
from the date of first dose through 90 days following cessation of treatment, or 30 days
after the initiation of a new anticancer therapy, whichever is earlier, need to be reported
to the SPONSOR within 24 hours of the event, regardless of attribution to study
treatment, consistent with standard SAE reporting guidelines and either by electronic
media or paper.  Sponsor Contact information can be found in the administrative binder.
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be
evaluated and subjects should be asked for signs and symptoms suggestive of an
immune-related event.  Subjects who develop an ECI thought to be immune-related
should have additional testing to rule out other etiologic causes.  If lab results or
symptoms indicate a possible immune-related ECI, then additional testing should be
performed to rule out other etiologic causes.  If no other cause is found, then it is
assumed to be immune-related.
 
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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, unless there is
evidence suggesting a causal relationship between the drug and the event. Any such event
will be submitted to the Sponsor within 24 hours either by electronic or paper media.
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
7.2.4 
An investigator who is a qualified physician will evaluate all adverse events according to the
NCI Common Terminology for Adverse Events (CTCAE), version 4. 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
fullattribution of the adverse experience to the single agent.
 
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Table 7 
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 mild 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 of 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) or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. 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 
test drug 
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 there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.)
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in
accordance with all applicable global laws and regulations.
TRIAL GOVERNANCE AND OVERSIGHT
7.3 
Scientific Advisory Committee
7.3.1 
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific
publications.
Executive Oversight Committee
7.3.2 
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior
Management.  The EOC will receive and decide upon any recommendations made by the
Data Monitoring Committee (DMC) regarding the trial.
Data Monitoring Committee
7.3.3 
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 include 3 clinicians experienced in Lung Cancer and 1 external statistician; this is in
addition to the unblinded trial statistician who will be a non-voting member of the
committee.
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 8.1.5 - Interim
Analyses) and recommend to the EOC  if the trial should continue in accordance with the
protocol.
Specific details regarding 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 a separate charter that is
reviewed and approved by the DMC.  The DMC will monitor the trial at an appropriate
frequency, as described in the detailed DMC charter.  The DMC will also make
recommendations to the Sponsor protocol team regarding steps to ensure both subject safety
and the continued ethical integrity of the trial.
 
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A DMC recommendation will be communicated to the Sponsor as agreed to in the DMC
Charter.
7.3.3.1 Post Final Analysis Activities
If the DMC recommends crossover of patients from standard of care to pembrolizumab based
upon positive OS observed at either the interim PFS analysis or final OS analysis, all patients
with a randomization number in this study, if they still meet certain inclusion criteria, may be
offered further therapy with pembrolizumab; the details of which will be discussed in a future
communication.
8.0 STATISTICAL ANALYSIS PLAN
Statistical Analysis Plan Summary
8.1 
This section contains a brief summary of the statistical analyses for this trial. Full detail is in
the Statistical Analysis Plan (SAP) (Section 8.2).
Efficacy Analyses
8.1.1 
The intention-to-treat (ITT) population that includes all randomized subjects will serve as the
primary population for the analyses of efficacy data in this trial. The primary efficacy
endpoint is PFS (i.e., time from randomization to documented progressive disease or death
due to any cause, whichever occurs first) per RECIST 1.1 based on blinded independent
radiologists’ review. The secondary efficacy endpoints for this trial are OS  and ORR per
RECIST 1.1 based on blinded independent radiologists’ review. An outline of the analysis
strategy for key efficacy endpoints is presented in Table 8 below. The analysis plan for PROs
will be provided in a separate document before the final PFS analysis.
Table 8 
Analysis Strategy for Key Efficacy Endpoints
Endpoint
(Description, Time Point)
Statistical Method
Analysis
Population
Missing Data Approach
Primary
PFS
(RECIST 1.1 by blinded
independent central
radiology review)
Testing: Stratified Log-rank test
Estimation: Stratified Cox model with 
Efron's tie handling method
ITT
Model based
Secondary
OS
Testing: Stratified Log-rank test
Estimation: Stratified Cox model with
Efron's tie handling method for
estimation
ITT  
Model based
ORR
(RECIST 1.1 by blinded
independent central
radiology review)
Stratified Miettinen & Nurminen
method 
ITT  
Subjects with missing
data are considered
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Safety Analyses
8.1.2 
The All Subjects as Treated (ASaT) population will be used for the primary analysis of safety
data in this study. Investigators will be asked to report adverse experiences at every visit on
this study (at least every three weeks during treatment) using Common Terminology Criteria
for Adverse Events, Version 4.0. The attribution to drug, time-of-onset, duration of the event,
its resolution, and any concomitant medications administered will be reported. AEs will be
analyzed and reported for between arm differences in various parameters, including but not
limited to Events of Clinical Interest outlined in the separate ECI and irAE guidance
document, all AEs, SAEs, fatal AEs, and laboratory changes. Safety analyses will follow a
tiered approach.
In the primary safety comparison between pembrolizumab and control, subjects who cross
over to pembrolizumab are censored at time of crossover (i.e., AEs occurring during
treatment with pembrolizumab are excluded for control-arm subjects). An exploratory safety
analysis will be conducted for the crossover population including all safety events starting
from the date of first dose of pembrolizumab.
Multiplicity
8.1.3 
The overall type I error rate for this study is strictly controlled at 2.5% (one-sided). There are
one planned analysis of ORR, one planned analysis of PFS and two planned analyses of OS.
The ORR analysis will occur when the first 191 randomized subjects have a minimum of 6
months of follow up, and will be tested at the 0.5% (one-sided) alpha level. PFS will be
tested only once at the planned PFS analysis after ~175 PFS events are observed, and will be
tested at the 2.5% (one-sided) level if ORR is positive or at the 2.0% (one-sided) level if
ORR is negative. OS will be tested only if PFS is positive and at the same level as PFS (i.e.,
step-down).
For OS, a Hwang-Shih-DeCani alpha-spending function with the gamma parameter -0.4 and
beta-spending function with gamma -35 are constructed to implement group sequential
boundaries that control the type I error rate as well as allow for non-binding futility analysis.
If at least 110 OS events are observed at the planned PFS analysis after ~175 PFS events are
observed, an interim OS analysis will be conducted at the level determined by the spending
function and the actual number of OS events at the PFS analysis. The final OS analysis will
occur when ~170 OS events are observed at the level determined by the spending function
and the actual number of OS events observed at the PFS analysis.
However, if there are less than 110 OS events at the planned PFS analysis, a nominal alpha
of 0.01% (negligible impact on overall type I error rate) will be spent on the OS hypothesis at
the time of the planned PFS analysis to prevent the study from premature stopping. The next
interim and final OS analyses will be conducted after ~110 and ~170 OS events are observed,
respectively, at the alpha level determined by the spending function boundaries and actual
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Based on emerging external data, the above testing strategy may be modified to improve the
efficiency of the design. Should this happen, the change will be documented elsewhere, if not
in a protocol amendment, at the earliest time before any unblinding of the data.
Following Amendment 08, the final OS analysis is no longer required and will not be
performed as described above. This is due to the study hypothesis for OS being supported at
the interim analysis with database cutoff of May 9, 2016.
Power and Sample Size
8.1.4 
The study is event-driven and plans to randomize approximately 300 subjects with 1:1 ratio
into the pembrolizumab arm and the SOC arm.
The planned ORR analysis will be conducted after the first 191 subjects have a minimum of
6 months of follow up. This analysis has ~95% power to detect a 30% difference in ORR
(e.g., 32% in SOC versus 62% in pembrolizumab) at alpha=0.5%. An observed ORR
difference of approximately 19% is needed to achieve a positive ORR outcome (e.g., 32% in
SOC versus 51% in pembrolizumab).
The planned PFS analysis will be conducted after approximately  175 PFS events are
observed between the pembrolizumab arm and control. If there are less than 110 OS events at
the time, then the analysis may be delayed for up to two months or when the target OS
number is reached, whichever occurs first. With ~175 PFS events, the study has ~98%/97%
power to detect a HR of 0.55 at alpha = 2.5%/2% (one-sided) at the final PFS analysis. A
p-value less than 2.5%/2% (one-sided) for PFS approximately corresponds to an empirical
HR  of <0.744/0.738 (or approximately at least 7.4/7.5 months of median PFS in
pembrolizumab vs. 5.5 months of median PFS in SOC).
With ~110 OS events at interim OS analysis, the study has ~90% power to observe a HR <1
when the true HR is 0.7, assuming that half of the subjects in the control arm cross over to
pembrolizumab at the time of analysis. The final OS analysis will be conducted after
approximately 170 deaths have occurred between the pembrolizumab arm and control. With
170 OS events at final OS analysis, the study has ~75% power to observe a HR <1 assuming
that ~70% of the subjects in the control arm cross over to pembrolizumab. With two planned
OS analyses, i.e., ~110 OS events at final PFS analysis and ~170 OS events at the final OS
analysis, the study has approximately 60%/57% power to detect a HR of 0.7 at the level of
2.5%/2.0% (one-sided). However, due to the anticipated high crossover rate, the actual power
could be substantially lower. A 95% CI will be provided for HR to characterize the OS effect
in case superiority is not demonstrated and the rank-preserving structural failure time model
will be used for crossover adjustment. More details are provided in Section 8.2.7.
ORR, PFS and OS Analyses
8.1.5 
There is one planned analysis of ORR, one planned analysis of PFS and two planned
analyses of OS. Table 9 provides the summary of the interim analysis strategy assuming that
~110 OS events are observed at the time of the final PFS analysis.
 
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Table 9 
Summary of PFS and OS Analysis Strategies
ORR, PFS and
OS Analyses
Key Endpoints
Expected Timing
of Analysis
Sample size expected
at time of analysis
Primary Purpose
of Analysis
ORR analysis 
 ORR
~16 months from 
study start
 First
191   
subjects have at
least 
6 
months
follow up
 Demonstrate
superiority 
of
pembrolizumab 
in
ORR
Final PFS analysis
Interim OS analysis
 PFS (primary) 
 OS  
~20 months from
study start
 ~ 175 PFS (~110
OS) events between
the pembrolizumab
arm 
and 
the
chemotherapy arm
 Demonstrate
superiority 
of
pembrolizumab in
PFS
 Examine OS  effect
ofpembrolizumab
Final OS analysis 
 OS  
~28 months from
study start
 ~170 OS  events
between 
the
pembrolizumab
arm 
and 
the
chemotherapy arm
 Examine OS effect
of pembrolizumab
Following Amendment 08, the final OS analysis is no longer required and will not be
performed as described above. This is due to the study hypothesis for OS being supported at
the interim analysis with database cutoff of May 9, 2016.
Statistical Analysis Plan
8.2 
Responsibility for Analyses/In-House Blinding
8.2.1 
The statistical analysis of the data obtained from this study will be the responsibility of the
Clinical Biostatistics department of the SPONSOR.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for
study treatment assignment for this protocol, and the randomization will be implemented in
IVRS.
Although the trial is open label, analyses or summaries generated by randomized treatment
assignment, actual treatment received, will be limited and documented. In addition, the
independent radiologist(s) will perform the central imaging review without knowledge of
treatment group assignment.
Treatment-level results ofthe planned ORR and PFS analyses will be provided by an external
unblinded statistician to the eDMC. 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 eDMC or facilitate regulatory filing after the ORR/ PFS analysis.
The extent to which individuals are unblinded with respect to results of interim analyses will
be documented by the unblinded statistician.
The eDMC will serve as the primary reviewer of the results of the planned ORR and PFS
analyses and the interim OS analysis, and will make recommendations for discontinuation of
 
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the study or modification to an executive committee of the SPONSOR. If the eDMC
recommends modifications to the design of the protocol or discontinuation of the study, this
executive committee may be unblinded to results at the treatment level in order to act on
these recommendations. Additional logistical details and data monitoring guidance will be
provided in the eDMC 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 violators, or data validation efforts after the PFS analyses.
Hypotheses/Estimation
8.2.2 
Objectives and hypotheses of the study are stated in Section 3. The study is considered to
have met its primary objective if pembrolizumab is superior to SOC in PFS.
Analysis Endpoints
8.2.3 
8.2.3.1 Efficacy Endpoints
Primary
Progression-free survival - RECIST 1.1
Progression-free-survival is defined as the time from randomization to the first documented
disease progression per RECIST 1.1 based on blinded independent central radiologists’
review or death due to any cause, whichever occurs first. See Section 8.2.5.1.1 for definition
of censoring.
Secondary
Overall Survival
Overall Survival is defined as the time from randomization to death due to any cause.
Subjects without documented death at the time of the final analysis will be censored at the
date of the last follow-up.
Objective response rate
Objective response rate is defined as the proportion of the subjects in the analysis population
who have a complete response (CR) or partial response (PR). Responses are based upon
blinded independent centralradiologists’ review per RECIST 1.1.
 
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Exploratory
Exploratory endpoints of this study  include PFS2, time to response, response duration,
disease control rate as well as ORR, response duration, disease control rate, PFS and OS
following crossover to pembrolizumab. Patient-reported outcomes (PROs) while on
treatment and post-discontinuation will be examined.
An exploratory analysis of PFS2, defined as the time from randomization to subsequent
disease progression after initiation of new anti-cancer therapy, or death from any cause,
whichever first, will be carried out. If progression after next-line therapy cannot be measured,
a PFS  event is defined as end or discontinuation of next-line treatment or death from any
cause, whichever occurs first. Subjects alive and for whom a PFS event has not been
observed will be censored at the last time known to be alive and without second disease
progression.
Time to progression following crossover to pembrolizumab is defined as the time from the
first dose of crossover therapy to the earliest documented disease progression (with respect to
the last available tumor assessment prior to crossover). OS following crossover to
pembrolizumab is defined as the time from the first dose of crossover therapy to death due to
any cause.
8.2.3.2 Safety Endpoints
Safety measurements are described in Section 7.
Analysis Population
8.2.4 
8.2.4.1 Efficacy Analysis Population
The analysis of primary efficacy endpoints are based on the intention -to-treat (ITT)
population, i.e., 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 8.2.5
Statistical Methods.
8.2.4.2 Safety Analysis Populations
The All Subject 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
one dose of study treatment. Subjects will be included in the treatment group corresponding
to the trial treatment they actually received for the analysis of safety data. Subjects who take
incorrect trial treatment for the entire treatment period will be included in the treatment group
corresponding to the trial treatment actually received. At least one laboratory or vital sign
measurement obtained subsequent to at least one dose of trial treatment is required for
inclusion in the analysis of each specific parameter. To assess change from baseline, a
baseline measurement is also required.
 
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Details on the approach to handling missing data for safety analyses are provided in Section
8.2.5 Statistical Methods.
Statistical Methods
8.2.5 
Statistical testing and inference for safety analyses are described in Section 8.2.5.2. Efficacy
results that will be considered to be statistically significant after consideration of the strategy
for controlling the Type I error are described in Section 8.2.6, Multiplicity. Nominal p-values
may be computed for other efficacy analyses as a measure of strength of association between
the endpoint and the treatment effect rather than formal tests of hypotheses.
8.2.5.1 Statistical Methods for Efficacy Analyses
The overall type I error rate for this study is strictly controlled at 2.5% (one -sided) that
allows the trial to declare positive in ORR, PFS or OS  (if PFS is significant) in the ITT
population.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints and
multiple analyses is described in Section 8.2.6 and Section 8.2.9.
Progression-Free Survival
8.2.5.1.1 
The non-parametric 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., HR) between the treatment
arms. The HR and its 95% CI from the stratified Cox model with Efron's method of tie
handling and with a single treatment covariate will be reported. The same stratification
factors used for randomization (see Section 5.4) will be applied to both the stratified log-rank
test and the stratified Cox model.
Since disease progression is assessed periodically, progressive disease (PD) can occur any
time in the time interval between the last assessment where PD was not documented and the
assessment when PD is documented. For the primary analysis, for the subjects who have PD,
the true date of disease progression will be approximated by the date of the first assessment
at which PD is objectively documented per RECIST 1.1, regardless of discontinuation of
study drug. Death is always considered as a confirmed PD event. Sensitivity analyses will be
performed for comparison of PFS based on investigator's assessment.
In order to evaluate the robustness of the PFS endpoint, two sensitivity analyses will be
performed with a different set of censoring rules. Sensitivity analysis 1 is the same as the
primary analysis except that it censors at the last disease assessment without PD when PD or
death is documented after more than one missed disease assessment. Sensitivity analysis 2 is
the same as the primary analysis except that it considers discontinuation of treatment or
initiation of new anticancer treatment, whichever occurs later, to be a PD event for subjects
without documented PD or death. The censoring rules for primary and sensitivity analyses
are summarized in Table 10. In case there is an imbalance between the treatment groups on
 
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disease assessment schedules or censoring patterns, we will also perform the following two
additional PFS sensitivity analyses: 1) a PFS analysis using time to scheduled tumor
assessment visit from randomization as opposed to actual tumor assessment time; 2)
Finkelstein’s likelihood-based score test for  interval-censored data, which modifies the Cox
proportional hazard model for interval censored data, will be used as a supportive analysis
for the PFS endpoint. The interval will be constructed so that the left endpoint is the date of
the last disease assessment without documented PD and the right endpoint is the date of
documented PD or death, whichever occurs earlier.
Table 10 
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and no death;
new 
anticancer
treatment is not initiated
Censored at last disease
assessment
Censored at last disease
assessment
Censored at last disease
assessment if still on
study 
therapy;
progressed at treatment
discontinuation
otherwise
No PD and no death;
new 
anticancer
treatment is initiated
Censored at last disease
assessment before new
anticancer treatment
Censored at last disease
assessment 
before 
new
anticancer treatment
Progressed at date of
new 
anticancer
treatment
PD 
or 
death
documented after ≤ 1
missed 
disease
assessment
Progressed at date of
documented PD or death
Progressed 
at 
date 
of
documented PD or death
Progressed at date of
documented 
PD 
or
death
PD 
or 
death
documented after ≥ 2
missed 
disease
assessments
Progressed at date of
documented PD or death
Censored at last disease
assessment prior to the  ≥ 2
missed disease assessment
Progressed at date of
documented 
PD 
or
death
Overall Survival
8.2.5.1.2 
The Kaplan-Meier method will be used to estimate the survival curves. 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 HR). The HR  and its 95% CI from the
stratified Cox model with a single treatment covariate will be reported. The same
stratification factors used for randomization (see Section 5.4) will be applied to both the
stratified log-rank test and the stratified Cox model.
Since subjects in the control arm are expected to discontinue from the study earlier compared
to subjects in the pembrolizumab arm because of earlier onset of PD and they may switch to
the pembrolizumab treatment after the confirmed progressive disease, the Rank Preserving
Structural Failure Time (RPSFT) model will be used to adjust for the effect of crossover on
OS. The RPSFT model provides a randomization-based estimate of treatment effect (RBEE)
corrected for the bias induced by crossover. The 95% CIs of the HR for OS after adjustment
of the cross-over effect will be provided. The Kaplan-Meier estimates of the OS rate at time
points of interest will also be compared between the two treatment groups to explore the
 
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confounding effect of subsequent treatments. To further account for the possible confounding
effect, a sensitivity analysis of OS that censors subjects at the time of initiation of new
therapy will be performed and an OS analysis that treats initiation of new therapy as a time-
dependent binary covariate will also be conducted. In case the proportional hazards
assumption doesn’t hold, Fleming and Harrington’s weighted log-rank test or other methods,
as appropriate, will be conducted, after proper adjustment of the crossover effect over time.
Objective response rate
8.2.5.1.3 
Stratified Miettinen and Nurminen’s method will be used for comparison of the ORRs
between the treatment groups. A 95% CI for the difference in response rates between the
pembrolizumab arm and the control as well as the p-value will be provided. The same
stratification factors used for randomization (see Section 5.4) will be applied to the analysis.
Sensitivity analyses will be performed for comparison of ORR based on investigator's
assessment.
Exploratory analyses
8.2.5.1.4 
If the number of responders permits, response duration will be summarized descriptively
using Kaplan-Meier medians and quartiles. Only the combined subset of subjects who show a
complete or partial response will be included in this analysis.
The same approaches as previously described for primary analysis and secondary analysis
will be applied to subjects who crossover to pembrolizumab after disease progression on the
control arm (chemotherapy) in this study. The reference start time of PFS and OS is the time
of first dose crossover therapy.
For subjects who cross over to pembrolizumab after disease progression on the control arm,
time to progression  while on the control arm will be compared to the time to progression
following crossover, where the time to progression following crossover is defined as the time
from time of crossover to the earliest documented disease progression. The last available
tumor assessment before crossover will serve as the baseline for disease assessment post
crossover. If the number of events permits, time to progression  before and after crossover
will be summarized descriptively using the Kaplan-Meier method.
An exploratory analysis of PFS2, defined as the time from randomization to subsequent
disease progression after initiation of new anti-cancer therapy, or death from any cause,
whichever first, will be carried out. If progression after next-line therapy cannot be measured,
a PFS  event is defined as end or discontinuation of next-line treatment or death from any
cause, whichever occurs first. Subjects alive and for whom a PFS event has not been
observed should be censored at the last time known to be alive and without second disease
progression.
EORTC QLQ-C30, EORTC QLQ-LC13, EuroQoL EQ-5D, Oncology Health Economic
Assessment (HEA) and tumor volumetric changes will be summarized as part of the
exploratory analysis. Longitudinal and descriptive data analysis will be used to evaluate
 
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patient-reported outcomes (PRO). Several approaches will be considered to address the issue
of informative missing data, for example, (i) truncating the analysis observation period at the
visit closest to median duration of treatment in the comparator arm, and (ii) hierarchical
pattern mixture models incorporating reason for missingness (a model that treats disease
progression as a time-varying covariate). The difference in PRO score for progressed
subjects compared to subjects with no radiographic evidence of tumor progression will be
evaluated within each treatment arm. For HEA, descriptive statistics by treatment group will
include total counts of each type of healthcare contact, as well as the total number of hospital
days. The detailed PRO analysis plan will be included in a separate document.
8.2.5.2 Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including
adverse experiences (AEs), laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 11). The tiers differ with
respect to the analyses that will be performed. Safety parameters or adverse experiences of
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be
subject to inferential testing for statistical significance with p-values and 95% CIs provided
for between-group comparisons. Other safety parameters will be considered Tier 2 or Tier 3.
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for between-
group comparisons; only point estimates by treatment group are provided for Tier 3 safety
parameters. There are no Tier 1 safety analyses in this study. No p-values would be provided
for safety comparison.
Adverse experiences (specific terms as well as system organ class terms) and predefined
limits of change in laboratory, vital signs, and ECG parameters that are not pre-specified as
Tier-1 endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on the number
of events observed. Membership in Tier 2 requires that at least 4 subjects in any treatment
group exhibit the event; all other adverse experiences and predefined limits of change will
belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% CI for the between-group
difference in percent incidence will always include zero when treatment groups of equal size
each have less than 4 events and thus would add little to the interpretation of potentially
meaningful differences. Because many 95% CIs may be provided without adjustment for
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in
review, not a formal method for assessing the statistical significance of the between-group
differences in adverse experiences and predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG
parameters that are not pre-specified as Tier-1 endpoints will be considered Tier 3 safety
parameters. Summary statistics for baseline, on-treatment, and change from baseline values
will be provided by treatment group in table format. In addition, summary statistics for the
difference between treatment groups will also be provided, along with nominal p-values for
 
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between-group differences. Mean change from baseline over time will be plotted with the
corresponding standard errors.
Detailed kinetics and characteristics of immune mediated adverse events occur in subjects
treated with pembrolizumab will be summarized in the study.
Table 11 
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
p-Value 
95% CI for
Treatment
Comparison
Descriptive
Statistics
Tier 2
Any AE
X
X
Any Grade 3-5 AE
X
X
Any Serious AE
X
X
Onset of First Grade 3-5 AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade3-5 and Drug-Related AE
X
X
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
X
X
Specific AEs, SOCs (including ≥4 of subjects
in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs (incidence <4 of subjects
in all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs,
Vital Signs)
X
8.2.5.3 Summaries of Baseline Characteristics, Demographics, and Other Analyses
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 reason
for discontinuation will be displayed. Demographic variables (such as age) and baseline
characteristics will be summarized by treatment either by descriptive statistics or categorical
tables. The reasons for exclusion from the ITT population (if any) will be summarized.
Multiplicity
8.2.6 
The overall type I error rate for this study is strictly controlled at 2.5% (one-sided). There are
one planned analysis of ORR, one planned analysis of PFS and two planned analyses of OS.
The ORR analysis will occur when the first 191 randomized subjects have a minimum of 6
months of follow up, and will be tested at the 0.5% (one-sided) alpha level. PFS will be
tested only once at the planned PFS analysis after ~175 PFS events are observed, and will be
tested at the 2.5% (one-sided) level if ORR is positive or at the 2.0% (one-sided) level if
ORR is negative. OS will be tested only if PFS is positive and at the same level as PFS (i.e.,
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For OS, a Hwang-Shih-DeCani alpha-spending function with the gamma parameter -0.4 and
beta-spending function with gamma -35 are constructed to implement group sequential
boundaries that control the type I error rate as well as allow for non-binding futility analysis.
If at least 110 OS events are observed at the planned PFS analysis after ~175 PFS events are
observed, an interim OS analysis will be conducted at the level determined by the spending
function boundaries and the actual number of OS events at the PFS analysis time of the final
PFS analysis. The final OS analysis will occur when ~170 OS events are observed at the
level determined by the spending function and the actual number of OS events observed at
the PFS analysis.
However, if there are less than 110 OS events at the planned PFS analysis, a nominal alpha
of 0.01% (negligible impact on overall type I error rate) will be spent on the OS hypothesis at
the time of the planned PFS analysis to prevent the study from premature stopping. The next
interim and final OS analyses will be conducted after ~110 and ~170 OS events are observed,
respectively, at the alpha level determined by the spending function boundaries and actual
number of OS events
Following Amendment 08, the final OS analysis is no longer required and will not be
performed as described above. This is due to the study hypothesis for OS being supported at
the interim analysis with database cutoff of May 9, 2016.
Sample Size and Power Calculation
8.2.7 
The study is event-driven and plans to randomize approximately 300 subjects with 1:1 ratio
into the pembrolizumab arm and the SOC arm.
The planned ORR analysis will be conducted after first 191 subjects have a minimum of 6
months of follow up. This analysis has ~95% power to detect a 30% difference in ORR (e.g.,
32% in SOC vs. 62% in pembrolizumab) at alpha=0.5%. An observed ORR difference of
approximately 19% of an observed ORR difference is needed to achieve a positive ORR
outcome (e.g., an observed ORR of approximately 32% in SOC versus 51% in
pembrolizumab).
The planned PFS analysis will be conducted after approximately  175 PFS events are
observed between the pembrolizumab arm and control. If there are less than 110 OS events at
the time, the analysis may be delayed for up to 2 months or when the target OS number is
reached, whichever occurs first. With ~175 PFS events, the study has ~98%/97% power to
detect a HR 0.55 at alpha = 2.5%/2% (one-sided) at the PFS analysis. A p-value less than 2%
(one-sided) for PFS approximately corresponds to an empirical HR  of <0.744/0.738 (or
approximately at least 7.4/7.5 months of median PFS in  pembrolizumab vs. 5.5 months of
median PFS in SOC). With ~110 OS events at the interim OS analysis, the study has ~90%
power to demonstrate a numerically positive OS effect when the true HR is 0.7 assuming that
half of the subjects in the control arm cross over to pembrolizumab at the time of analysis.
The sample size calculation is based on the following assumptions: 1) PFS  follows an
exponential distribution with a median of 5.5 months in the control arm, 2) HR between
 
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pembrolizumab and control is 0.55, 3) an enrollment period of 14  months and at least 6
months PFS  follow-up after enrollment completion, and 4) a dropout rate of 10% per year.
The assumption for the median PFS of 5.5 months in the control arm does not take into
account potential prognostic implications in a biomarker selected population.  As such, the
control median may be more or less than 5.5 months. 
The final OS analysis will be conducted after approximately 170 deaths have occurred
between the pembrolizumab arm and control. The final OS analysis is expected to occur 14
months after enrollment completion. With 170 deaths at final OS analysis, the study has
~75% power to observe a HR <1 assuming that ~70% of the subjects in the control arm cross
over to pembrolizumab. With two planned OS analyses, i.e., ~110 OS events at final PFS
analysis and ~170 OS events at final OS analysis, the study has approximately 60%/57%
power to detect a HR of 0.7 with the overall alpha controlled at 2.5%/2.0%  (one-sided).
However, due to the anticipated high crossover rate, the actual power could be substantially
lower. A 95% CI will be provided for HR to characterize the OS effect in case superiority is
not demonstrated. The details on the boundaries and nominal alpha levels at the final PFS
and OS analyses are given in Section 8.2.9. The calculation is based on the following
assumptions: 1) OS  follows an exponential distribution with a median of 13 months in the
control arm, 2) HR between pembrolizumab and control is 0.7, 3) an enrollment period of 14
months and 14-15 months follow-up after enrollment completion, and 4) a dropout rate of
0.005 per month. The assumption for the median OS of 13 months in the control arm does
not take into account potential prognostic implications in a biomarker selected population. 
As such, the control median may be greater or less than 13 months. 
Following Amendment 08, the final OS analysis is no longer required and will not be
performed as described above. This is due to the study hypothesis for OS being supported at
the interim analysis with database cutoff of May 9, 2016.The sample size and power
calculation were performed in the software EAST and R (package “gsDesign”).
Subgroup Analyses and Effect of Baseline Factors
8.2.8 
To determine whether the treatment effect is consistent across various subgroups, the
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary
endpoint will be estimated and plotted within each category of the following classification
variables:
 Age category (≤65, >65 years)
 Sex (female, male)
 Race (white, non-white)
 ECOG status (0, 1)
 Geographic region of enrolling site (East Asia, non-East Asia)
 Histology (squamous, non-squamous)
 Smoking status (never, former, current)
 
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 Brain metastasis status (baseline brain metastasis, no baseline brain metastasis)
 Investigators’ choice of standard of care chemotherapy
The consistency of the treatment effect will be assessed descriptively via summary statistics
by category for the classification variables listed above.
ORR, PFS and OS analyses
8.2.9 
One planned analysis of ORR, one planned analysis of PFS and two planned analyses of OS
are currently planned.  In this study, the futility bounds are non-binding, which means the
bounds are considered guidance rather than strict bounds.
Following Amendment 08, only one analysis of OS is planned.
8.2.9.1 ORR, PFS analysis and interim OS analysis
The planned ORR analysis will take place when the first 191 subjects have at least 6 months
of follow up, i.e., approximately 16 months after study start. ORR will be tested at alpha
level of 0.5%. Only the first 191 subjects with at least 6 moths follow up will be included in
the ORR analysis. An observed ORR difference of approximately 19% is needed to achieve a
positive ORR outcome (e.g., an observed ORR of approximately 32% in SOC versus 51% in
pembrolizumab). The trial will continue irrespective of the outcome.
The planned PFS analysis will take place when approximately 175 PFS events have been
observed between the pembrolizumab arm and the control arm, which is expected to occur
about 20 months after study start. If there are less than 110 OS events between two arms at
the time, the analysis may be delayed for up to 2 months or until when the target OS number
is reached, whichever occurs first. The primary objective of this analysis is to demonstrate
superiority of pembrolizumab in PFS  and exclude detrimental effect of pembrolizumab on
OS.
The pembrolizumab arm will be compared to the SOC arm. An observed HR of ~0.738 or
less would demonstrate PFS superiority at α = 2% (one-sided) assuming ORR is negative at
the first interim analysis, or an observed HR of ~0.744 or less if α = 2.5% (one-sided)
assuming ORR is positive at the first interim analysis. This HR approximately corresponds to
at least 1.9-2.0 month improvement of the median PFS from 5.5 months in the SOC arm. The
trial will be discontinued if the PFS superiority is not demonstrated.
The study will also examine OS at the planned PFS analysis. It is expected that
approximately 110 deaths will be observed at this analysis.  With ~110 OS events at the
planned PFS analysis, the study has ~90% power to observe a HR <1 when the true HR on
OS is 0.7, assuming that half of the subjects in the control arm cross over to pembrolizumab
at the time of analysis. Via the group sequential approach with the predefined alpha-spending
function  (assuming that PFS is statistically significant), the superiority hypothesis will be
tested at the type I error of 1.5% with ~110 deaths. An empirical HR < ~0.661, i.e., at least
6.7-month improvement in median OS, would demonstrate OS superiority. A futility analysis
 
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will be conducted at the same time and an observed HR on OS >1.7 will approximately meet
the criterion for futility. The boundaries for OS hypothesis testing will be re-calculated if
actual monitoring schedule is altered.
However, if less than 110 OS events are observed at the planned PFS analysis, OS hypothesis
will be tested at one-sided 0.01% level (negligible impact on overall type I error rate) to
prevent premature stopping. For instance, with 80 OS events, an alpha level 0.01%
approximately corresponds to an empirical HR of 0.44, i.e., 16.9-months improvement in
median OS.  A futility analysis will be conducted at level 0.01% at the same time and an
observed HR on OS  >2.3 will approximately meet the criterion for futility. The next OS
interim analysis will then be conducted after ~110 OS events are observed with the
boundaries calculated via the group sequential approach as presented in the previous
paragraph.
8.2.9.2 Final OS Analysis
The final analysis will take place when approximately 170 deaths have occurred between the
pembrolizumab arm and the SOC arm which is expected to occur approximately 28 months
after study start.
Assuming PFS is statistically significant and the trial is not terminated at the interim OS
analysis, the OS hypothesis at the final analysis will be tested at α = 1.65%. The empirical
HR for OS  superiority is < ~0.72, which corresponds to at least ~5-month improvement in
median OS. The boundary for OS hypothesis testing will be re-calculated if actual
monitoring schedule is altered. A 95% CI will be provided for HR to characterize the OS
effect in case the superiority is not demonstrated. As an exploratory analysis, RPSFT model
will be used to adjust for the crossover effect.
Following Amendment 08, the final OS analysis is no longer required and will not be
performed as described in this section. This is due to the study hypothesis for OS being
supported at the interim analysis with database cutoff of May 9, 2016. 
Compliance (Medication Adherence)
8.2.10 
Drug accountability data for trial treatment will be collected during the study. Compliance
with trial treatment administration will be measured by subjects: 1) receiving unscheduled
study agent infusions/injections; 2) missing an infusion/injection. Numbers and percentages
of subjects and infusion/injection visits with any deviation in these measures will be reported
for the ITT population.
Extent of Exposure
8.2.11  
The extent of exposure will be summarized as duration of treatment in cycles. Dose intensity
will also be summarized as appropriate.
 
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9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL
SUPPLIES
Investigational Product
9.1 
The investigator shall take responsibility for and shall take all steps to maintain  appropriate
records and ensure appropriate supply, storage, handling, distribution and usage of
investigational product in accordance with the protocol and any applicable laws and
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 12.
Table 12 
Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab (MK-3475)
25 mg / mL
Solution for infusion
Pemetrexed
Lyophilized powder for infusion
Paclitaxel6 mg / mL
Solution for infusion
Carboplatin 10 mg / mL
Solution for infusion
Cisplatin 1 mg / mL
Solution for infusion
Gemcitabine
Lyophilized powder for infusion
The pemetrexed, paclitaxel, carboplatin, cisplatin and gemcitabine will be provided centrally by
the Sponsor or locally by the trial site, subsidiary or designee, depending on local country
operational or regulatory requirements. All other products will be provided locally by the trial
site, subsidiary or designee.
The trial site will be responsible for recording the lot number, manufacturer and expiry date
of any locally purchased product.
After the time of the marketing approval of pembrolizumab, “clinical trial drug” of
pembrolizumab will be replaced with “post-marketing clinical trial drug”. The subjects can
receive treatment of pembrolizumab as post-marketing clinical trial drug.
Packaging and Labeling Information
9.2 
Clinical supplies will be affixed with a clinical label in accordance with regulatory
requirements.
All supplies will be provided open label. Pembrolizumab (MK-3475) will be provided as
non-kitted single vials or as single vials in a kit box. The Pemetrexed will be supplied as a
single vial. All other products will be provided as a kit with a single vial.
 
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Clinical Supplies Disclosure
9.3 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or
designee are not blinded. Treatment (name, strength or potency) is included in the label text;
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
9.4 
Clinical supplies must be stored in a secure, limited-access location under the storage
conditions specified on the label. 
Receipt and dispensing of trial medication must be recorded by an authorized person at the
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Returns and Reconciliation
9.5 
The investigator is responsible for keeping accurate records of the clinical supplies received
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the
amount remaining at the conclusion of the trial.
For all trial sites, the local country Sponsor personnel or designee will provide appropriate
documentation that must be completed for drug accountability and return.
Standard Policies
9.6 
Trial site personnel will have access to a central electronic 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
10.1 
Confidentiality of Data
10.1.1 
By signing this protocol, the investigator affirms to the Sponsor that information furnished to
the investigator by the Sponsor will be maintained in confidence, and such information will
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar
or expert committee; affiliated institution and employees, only under an appropriate
understanding of confidentiality with such board or committee, affiliated institution and
employees.  Data generated by this trial will be considered confidential by the investigator,
except to the extent that it is included in a publication as provided in the Publications section
of this protocol.
 
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Confidentiality of Subject Records
10.1.2 
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative),
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in
order to verify worksheet/case report form data.  By signing the consent form, the subject
agrees to this process.  If trial documents will be photocopied during the process of verifying
worksheet/case report form information, the subject will be identified by unique code only;
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in
connection with this trial in accordance with all applicable privacy laws, rules and
regulations.
Confidentiality of Investigator Information
10.1.3 
By signing this protocol, the investigator recognizes that certain personal identifying
information with respect to the investigator, and all subinvestigators and trial site personnel,
may be used and disclosed for trial management purposes, as part of a regulatory
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other
countries, including countries that do not have laws protecting such information. 
Additionally, the investigator’s name and business contact information may be included
when reporting certain serious adverse events to regulatory authorities or to other
investigators.  By signing this protocol, the investigator expressly consents to these uses and
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor
may share an investigator’s name and contact information with other participating
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4 
The Sponsor is required to record the name and address of each IRB/IEC member 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.
 
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Compliance with Financial Disclosure Requirements
10.2 
Financial Disclosure requirements are outlined in the US Food and Drug Administration
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the
Sponsor's responsibility to determine, based on these regulations, whether a request for
Financial Disclosure information is required.  It is the investigator's/subinvestigator's
responsibility to comply with any such request. 
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by
the Sponsor or through a secure password-protected electronic portal provided by the
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this
information to the Sponsor in the United States for these purposes.  This may involve the
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3 
By signing this protocol, the investigator agrees to conduct the trial in an efficient and
diligent manner and in conformance with this protocol; generally accepted standards of Good
Clinical Practice (e.g., International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice:
Consolidated Guideline and other generally accepted standards of good clinical practice);
Good Post-marketing Study Practice, and all applicable federal, state and local laws, rules
and regulations relating to the conduct of the clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory
authority inspection of trial-related documents and procedures and provide for direct access
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or
from government programs for procedures included as part of the trial reimbursed to the
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in
compliance with Good Clinical Practice standards, Good Post-marketing Study Practice, and
applicable federal, state and local laws, rules and regulations; and, for each subject
participating in the trial, provide all data, and, upon completion or termination of the clinical
trial, submit any other reports to the Sponsor as required by this protocol or as otherwise
required pursuant to any agreement with the Sponsor.
 
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Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator
upon request and also shall be made available at the trial site upon request for inspection,
copying, review and audit at reasonable times by representatives of the Sponsor or any
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This
documentation includes, but is not limited to, the protocol, worksheets/case report forms,
advertising for subject participation, adverse event reports, subject source data,
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or
quality control procedures and laboratory director curriculum vitae.  By signing this protocol,
the investigator agrees that documentation shall be retained until at least 2 years after the last
approval of a marketing application in an ICH region or until there are no pending or
contemplated marketing applications in an ICH region or until at least 2 years have elapsed
since the formal discontinuation of clinical development of the investigational product. 
Because the clinical development and marketing application process is variable, it is
anticipated that the retention period can be up to 15 years or longer after protocol database
lock. The Sponsor will determine the minimum retention period and notify the investigator
when documents may be destroyed.  The sponsor 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 discarding
trial and/or subject files. 
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s
primary physician about the subject’s participation in the trial if the subject has a primary
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator
will immediately disclose in writing to the Sponsor if any person who is involved in
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating
investigator for a multi-center trial (including multinational).  When more than one trial site
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national
 
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principal coordinator (Protocol CI), responsible for coordinating the work of the principal
investigators at the different trial sites in that Member State, according to national
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In
addition, the Sponsor must designate a principal or coordinating investigator to review the
trial report that summarizes the trial results and confirm that, to the best of his/her
knowledge, the report accurately describes the conduct and results of the trial (Clinical Study
Report (CSR) CI).  The Sponsor may consider one or more factors in the selection of the
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the
anticipated review process, thorough understanding of clinical trial methods, appropriate
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely
responsible for determining whether the trial and its results are subject to the requirements
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  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 FDAMA/FDAAA 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
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this
trial or its results to the Clinical Trials Data Bank.
Quality Management System
10.5 
By signing this protocol, the Sponsor agrees to be responsible for implementing and
maintaining a quality management system with written development procedures and
functional area standard operating procedures (SOPs) to ensure that trials are conducted and
data are generated, documented, and reported in compliance with the protocol, accepted
standards of Good Clinical Practice, Good Post-marketing Study Practice, and all applicable
federal, state, and local laws, rules and regulations relating to the conduct of the clinical trial.
Data Management
10.6 
The investigator or qualified designee is responsible for recording and verifying the accuracy
of subject data.  By signing this protocol, the investigator acknowledges that his/her
electronic signature is the legally binding equivalent of a written signature. By entering
his/her electronic signature, the investigator confirms that all recorded data have been
verified as accurate.
 
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Detailed information regarding Data Management procedures for this protocol will be
provided separately.
Publications
10.7 
This trial is intended for publication, even if terminated prematurely. Publication may include
any or all of the following: posting of a synopsis online, abstract and/or presentation at a
scientific conference, or publication of a full manuscript.  The Sponsor will work with the
authors to submit a manuscript describing trial results within 12 months after the last data
become available, which may take up to several months after the last subject visit in some
cases such as vaccine trials.  However, manuscript submission timelines may be extended on
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees
to delay publication of the trial results until the Sponsor notifies the investigator that all
relevant regulatory authority decisions on the trial drug have been made with regard to
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the
primary outcome, 12 months after the decision to discontinue development, or product
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is
needed for analysis, to protect intellectual property, or to comply with confidentiality
agreements with other parties.  Authors of the primary results manuscript will be provided
the complete results from the Clinical Study Report, subject to the confidentiality agreement.
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also
include the protocol and statistical analysis plan to facilitate the peer and editorial review of
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will
allow the journal, if it so desires, to post on its website the key sections of the protocol that
are relevant to evaluating the trial, specifically those sections describing the trial objectives
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures,
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an
investigator and his/her colleagues may publish their data independently.  In most cases,
publication of individual trial site data does not add value to complete multicenter results,
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main
paper may be of value.  Limitations of single trial site observations in a multicenter trial
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design,
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising
it critically for important intellectual content; and 3) final approval of the version to be
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial
execution may also be taken into account to determine authorship, provided that
contributions have also been made to all three of the preceding authorship criteria.  Although
 
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publication planning may begin before conducting the trial, final decisions on authorship and
the order of authors’ names will be made based on participation and actual contributions to
the trial and writing, as discussed above. The first author is responsible for defending the
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or
presentations regarding this trial 45 days prior to submission for publication/presentation.
Any information identified by the Sponsor as confidential must be deleted prior to
submission; this confidentiality does not include efficacy and safety results. Sponsor review
can be expedited to meet publication timelines.
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Shirabe K, Motomura T, Muto J, Toshima T, Matono R, Mano Y, et al.
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Al-Shibli K, Al-Saad S, Andersen S, Donnem T, Bremnes RM, Busund L-T.
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1 
Merck*
Code of Conduct for Clinical Trials
I. Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code
does not apply to investigator-initiated trials which are not under the control of Merck.
II.  Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine
subject preferences, etc. 
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial.
2.  Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3.  Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud,
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary,
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and
data disclosed accordingly.
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In  such cases, publication of
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial,
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to
defend the trialresults and conclusions.  Merck funding of a trialwill 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, trialparticipation. 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 trialprotocol, and in signing
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
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Collection and Management of Specimens for Future Biomedical Research
12.2 
1. Definitions
a. Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease.  A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics
as related to drug/vaccine response.2
c. Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e. RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The DNA and tumor specimen(s) collected in the current trial will be used to study
various causes for how subjects may respond to a drug/vaccine.  The DNA and tumor
specimen(s) will be stored to provide a resource for future trials conducted by Merck
focused on the study of biomarkers responsible for how a drug/vaccine enters and is
removed by the body, how a drug/vaccine works, other pathways a drug/vaccine may
interact with, or other aspects of disease.  The specimen(s) may be used for future assay
development and/or drug/vaccine development.
It is now well recognized that information obtained from studying and testing clinical
specimens offers unique opportunities to enhance our understanding of how individuals
respond to drugs/vaccines, enhance our understanding of human disease and ultimately
improve public health through development of novel treatments targeted to populations
with the greatest need.  All specimens will be used by Merck or designees and research
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a. Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained
during screening for protocol enrollment from all subjects or legal guardians, at a trial
visit by the investigator or his or her designate.  Informed consent for Future
Biomedical Research should be presented to the subjects on Visit 1.  If delayed,
present consent at next possible Subject Visit. Informed consent must be obtained
prior to collection of all Future Biomedical Research specimens.  Consent forms
signed by the subject will be kept at the clinical trial site under secure storage for
regulatory reasons.  Information contained on the consent form alone cannot be traced
 
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to any specimens, test results, or medical information once the specimens have been
rendered de-identified.
Subjects are not required to participate in the Future Biomedical Research sub-trial in
order to participate in the main trial. Subjects who decline to sign the Future
Biomedical Research informed consent will not have the specimen collected nor will
they be discontinued from the main trial.
A template of each trial site’s approved informed consent will be stored in the
Sponsor’s clinical document repository.  Each consent will be assessed for
appropriate specimen permissions. 
Each informed consent approved by an ethics committee is assigned a unique tracking
number.  The tracking number on this document will be used to assign specimen
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c. eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research
specimens will be captured in the electronic Case Report Forms (eCRFs). 
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when
the subject is having blood drawn for other trial purposes. Specimens like tissue and
bone marrow will usually be obtained at a time when the subject is having such a
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an
objective to the main trial, this analysis is detailed in the main body of this protocol
(Section 8.0 –  Statistical Analysis Plan).  These specimens will be processed,
analyzed, and the remainder of the specimen will be destroyed.  The results of these
analyses will be reported along with the other trial results.  A separate specimen will
be obtained from properly-consented subjects in this protocol for storage in the
biorepository for Future Biomedical Research.
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.
 
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To maintain privacy of information collected from specimens obtained for Future
Biomedical Research, Merck has developed secure policies and procedures.  All
specimens will be de-identified as described below.
At the clinical trial site, unique codes will be placed on the Future Biomedical Research
specimens for transfer to the storage facility.  This first code is a random number which
does not contain any personally identifying information embedded within it. The link (or
key) between subject identifiers and this first unique code will be held at the trial site.  No
personal identifiers will appear on the specimen tube. 
This first code will be replaced with a second code at a Merck designated storage/lab
facility.  The second code is linked to the first code via a second key. The specimen is
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and
privacy protection for subjects over the use of a single code.  Access to both keys would
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal
specimen identifiers.  A secure link, the second key, will be utilized to match the second
code to the first code to allow clinical information collected during the course of the trial
to be associated with the specimen.  This second key will be transferred under secure
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The
second code will be logged into the primary biorepository database at Merck and, in this
database, this identifier will not have identifying demographic data or identifying clinical
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen
will be stored in a designated biorepository site with secure policies and procedures for
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future
biomedical research and the clinical information, at the time of analysis.  This linkage
would not be possible for the scientist conducting the analysis, but can only be done by
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck
Entrusted Keyholder will link the information and then issue a de-identified data set for
analysis.  The only other circumstance by which future biomedical research data would
be directly linked to the full clinical data set would be those situations mandated by
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good
scientific practices.  However, exploratory analyses will not be conducted under the
highly validated conditions usually associated with  regulatory approval of diagnostics. 
The scope of research performed on these specimens is limited to the investigation of the
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by
Merck, or an additional third party (e.g., a university investigator) designated by Merck. 
The investigator conducting the analysis will be provided with double coded specimens. 
 
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Re-association of analysis results with corresponding clinical data will only be conducted
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research
specimens remaining with the third party after the specific analysis is performed will be
returned to the sponsor or destroyed and documentation of destruction will be reported to
Merck.
6. Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by
contacting the principal investigator for the main trial.  If medical records for the main
trial are still available, the investigator will contact Merck using the designated mailbox
(clinical.specimen.management@merck.com) and a form will be provided by Merck to
obtain appropriate information to complete specimen withdrawal.  Subsequently, the
subject's specimens will be removed from the biorepository and be destroyed. A letter
will be sent from Merck to the investigator confirming the destruction. It is the
responsibility of the investigator to inform the subject of completion of destruction.  Any
analyses in progress at the time of request for destruction or already performed prior to
the request being received by the Sponsor will continue to be used as part of the overall
research trial data and results. No new analyses would be generated after the request is
received.
In the event that the medical records for the main trial are no longer available (e.g., if the
investigator is no longer required by regulatory authorities to retain the main trial
records) or the specimens have been completely anonymized, there will no longer be a
link between the subject’s personal information and their specimens. In this situation, the
request for specimen destruction can not be processed.
7. Retention of Specimens
Future Biomedical Research specimens will be stored in the biorepository for potential
analysis for up to 20 years from acquisition.  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 Merck 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 Merck policies and procedures and
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical
Research sub-trial will be maintained by Merck.  This is done to separate the future
exploratory test results (which include genetic data) from the clinical trial database
thereby maintaining a separation of subject number and these results.  The separate
databases are accessible only to the authorized Sponsor and the designated trial
 
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administrator research personnel and/or collaborators.  Database user authentication is
highly secure, and is accomplished using network security policies and practices based in
international standards (e.g., ISO17799) to protect against unauthorized access.  The
Merck Entrusted Keyholder maintains control over access to all specimen data.  These
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant
laws/regulations globally that research results have to be, in all circumstances, returned to
the trial participant.  Some guidelines advocate a proactive return of data in certain
instances.  No information obtained from exploratory laboratory studies will be reported
to the subject or family, and this information will not be entered into the clinical database
maintained by Merck on subjects.  Principle reasons not to inform or return results to the
subject include: lack of relevance to subject health, limitations of predictive capability,
concerns of misinterpretation and absence of good clinical practice standards in
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects
while the clinical trial is still ongoing, investigators will be contacted with information as
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and
will be advised that counseling should be made available for all who choose to participate
in this diagnostic testing.
If any exploratory results are definitively associated with clinical significance after
completion of a clinical trial, Merck will publish the results without revealing specific
subject information, inform all trial sites who participated in the Merck clinical trial and
post anonymized results on our website or other accredited website(s) that allow for
public access (e.g., disease societies who have primary interest in the results) in order that
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender,
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical
trials for future biomedical research.  When trials with specimens are conducted and
subjects identified to serve as controls, every effort will be made to group specimens
from subjects and controls to represent the ethnic and gender population representative of
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the subject have been minimized. Risks include
those associated with venipuncture to obtain the whole blood specimen.  This specimen
will be obtained at the time of routine blood specimens drawn in the main trial.
Merck 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.
 
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It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage,
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data
analysis.  These subject data will be kept in a separate, secure Merck database, and all
specimens will be stripped of subject identifiers.  No information concerning results
obtained from future biomedical research will be entered into clinical records, nor will it
be released to outside persons or agencies, in any way that could be tied to an individual
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to
clinical.specimen.management@merck.com.
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
- 
E15;
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for
12.3 
IRBs/IECs and Investigational Site Staff
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List of Abbreviations
12.4 
Abbreviation/Term
Definition
1L
First Line
AE
Adverse event
ADA
Anti-Drug Antibodies
ALT
Alanine aminotransferase
ALK
anaplastic lymphoma kinase
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
AUC
Area Under Curve
AST
Aspartate aminotransferase
ᵝ-HCG
Beta human chorionic gonadotropin
BSC
best supportive care
CBC
Complete blood count
CI
confidence interval
CNS
Central nervous system
CR
Complete response
CrCl
Calculated creatinine clearance
CRF
Case report form
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic acid
DMC
Data Monitoring Committee DMC
EBUS
Endobronchial Ultrasound
ECI
Events of clinical interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
ERC
Ethics review committee
FBR
Future Biomedical Research
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
Hb
Hemoglobin
HBV
Hepatitis B
HCV
Hepatitis C
HIV
Human immunodeficiency virus
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
irRC
immune-related response criteria
INR
International normalized ratio
irAEs
Immune-related adverse events
IRB
Institutional Review Board
ITT
intent-to-treat
IV
Intravenous
Kg
Kilogram
LDH
lactate dehydrogenase
mcL
Millimeters
MEL
Melanoma
MG
Milligram
Mg/kg
Milligram per kilogram
 
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Abbreviation/Term
Definition
MRI
Magnetic resonance imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MTD
Maximum tolerated dose
NA or N/A
Not Applicable
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
OTC
Over-the-counter
PD
Progressive disease
PD-L1
Programmed Cell Death Ligand 1
PD-L2
Programmed Cell Death Ligand 2
PET
Positron emission tomography
PFS
Progression free survival
PFS2
next line of therapy PFS2
PGt
Pharmacogenetic
PK
Pharmacokinetic
PK-PD
Pharmacokinetic-Pharmacodynamic
PRO
patient reported outcome
PR
Partial response
PT
Prothrombin time
Q-TWiST
Quality-adjusted Time without Symptoms or Toxicity
RCC
renal cell carcinoma
RNA
Ribonucleic acid
RECIST
Response Evaluation Criteria in Solid Tumors RECIST 1.1
RR
Response rate
Q3W
Every 3 weeks
SAE
Serious adverse events
SAP
Statistical Analysis Plan
SFU
Survival follow-up
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOC
Standard of Care
TIL
Tumor-infiltrating lymphocytes
TKI
tyrosine kinase inhibitors
TSH
Thyroid stimulating hormone
TTP
Time To Progression
ULN
Upper limit of normal
WHO
World Health Organization
 
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ECOG Performance Status
12.5 
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease
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:  OkenMM, CreechRH, TormeyDC, Horton J, DavisTE, McFadden
ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J
Clin Oncol 1982;5:649-55. Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair.
 
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
12.6 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting.
(http://ctep.cancer.gov/reporting/ctc.html)
 
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for
12.7 
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response.  While
either CT or MRI may be used utilized, as per RECIST 1.1, CT is the preferred imaging
technique in this study. 
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S.
Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J Cancer. 2009
Jan;45(2):228-47.
 
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Immune Related Response Criteria
12.8 
For all subjects who experience disease progression on study, the date noted for of disease
progression is the time of the scan where it is originally detected, and not the following date
of the confirmatory scan.
Definitions of measurable and non-measurable disease
Measurable disease: Neoplastic masses that can be precisely measured in 2 in-plane
perpendicular diameters. Both its longest diameter and its longest perpendicular must be
greater than or equal to 10 mm or 2 times the axial slice thickness. Lymph nodes must have a
short-axis line-length of ≥ 15 mm.  Malignant lymph nodes must be measurable in 2
perpendicular diameters. Both its longest diameter and its longest perpendicular must be
greater than or equal to 15 mm or 2 times the axial slice thickness.  The quantitative endpoint
will be defined as the product of the longest diameter with its longest perpendicular.
Non-measurable disease: Non-measurable lesions are those that are not suitable for
quantitative assessment over time. These include:
1) Neoplastic masses that are too small to measure, because their longest uninterrupted
diameter or longest perpendicular are less than 10 mm or two times the axial slice
thickness.
2) Neoplastic masses whose boundaries cannot be distinguished.  This includes masses
which cannot be demarcated from surrounding tissue because of inadequate contrast,
masses with overly complex morphology, or those with highly heterogeneous tissue
composition. 
3) Other types of lesions that are confidently felt to represent neoplastic tissue, but
difficult to quantify in a reproducible manner. These include bone metastases,
leptomeningeal metastases, malignant ascites, pleural/pericardial effusions,
inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, ill-defined
abdominal masses, etc.
For irRC, only target lesions selected at baseline and measurable new lesions are taken
into account.
At the baseline tumor assessment, the sum of the products of the two largest perpendicular
diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions and
five cutaneous index lesions) is calculated. 
At each subsequent tumor assessment, the SPD of the index lesions and of new, measurable
lesions (≥ 5 X 5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral
lesions) are added together to provide the total time-point tumor burden.
 
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Overall response using irRC:
 Complete Response (irCR): Complete disappearance of all tumor lesions (whether
measureable or not, and no new lesions).  CR must be confirmed by repeated,
consecutive assessments made no less than 4 weeks from the date first documented.
 Partial Response (irPR): Decrease in SPD of 50% or greater by a consecutive
assessment at least 4 weeks after first documentation.
 Stable Disease (irSD): Failure to meet criteria for irCR or irPR, in absence of irPD. 
 Progressive Disease (irPD): At least 25% increase in SPD relative to nadir
(minimum recorded tumor burden) Confirmation by a repeat, consecutive assessment
no less than 4 weeks from the data first documented. 
Please note other key differences between irRC and the original WHO criteria:
New measurable lesions will be incorporated into the SPD
New non measurable lesions do not define progression but preclude irCR
Non-index lesions contribute to defining irCR (complete disappearance required).
See the Site Imaging Manual for more details.
REFERENCE
IrRC for the current protocol is adopted from the following reference:
Wolchok  JD, Hoos A, O’Day S et al. Guidelines for the evaluation of immune therapy
activity in solid tumors: immune-related response criteria. Clinical Cancer Research  2009
Dec 1;15(23):7412-20.  Epub 2009 Nov 24.
 
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13.0 SIGNATURES
Sponsor's Representative
13.1 
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2 
I agree to conduct this clinical trial in accordance with the design outlined in this protocol
and to abide by all provisions of this protocol (including other manuals and documents
referenced from this protocol).  I agree to conduct the trial in accordance with generally
accepted standards of Good Clinical Practice and Good Post-marketing Study 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 –  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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