Conditions: Non-Small-Cell Lung Carcinoma
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1) Non-Small-Cell Lung Cancer (NSCLC) PD1 PD-1 PDL1 PD-L1 Non-Small-Cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

Brief summary:
This is a Japan Extension Study of Global Study MK-3475-189 (NCT02578680). This is an efficacy and safety study of pembrolizumab (MK-3475) combined with pemetrexed/platinum chemotherapy versus pemetrexed/platinum chemotherapy alone in adult Japanese participants with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) who have not previously received systemic therapy for advanced disease. Participants will be randomly assigned to receive pembrolizumab combined with pemetrexed/platinum (Investigators choice of cisplatin or carboplatin), OR pemetrexed/platinum (Investigators choice of cisplatin or carboplatin).

With Amendment 11 (effective date 31-Jan-2022), once the study objectives have been met or the study has ended, participants will be discontinued from this study and will be enrolled in an extension study to continue protocol-defined assessments and treatment.

The primary hypothesis is that pembrolizumab in combination with pemetrexed/platinum chemotherapy prolongs Progression-Free Survival (PFS) and Overall Survival (OS) compared to pemetrexed/platinum chemotherapy alone.

Detailed description:
The MK-3475-189-Japan Extension Study will be identical to the global study (e.g. inclusion and exclusion criteria, study primary and secondary outcome measures and study procedures).

The MK-3475-189-Japanese Extension Study enrolled a total of 30 participants and the analyses included 10 participants (pembrolizumab =4; control = 6) that had been previously enrolled in the MK-3475-189 global study (NCT02578680), resulting in a total of 40 participants.

Arms:
arm 1: Participants receive pembrolizumab 200 mg intravenously (IV) PLUS pemetrexed 500 mg/m\^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m\^2 IV OR carboplatin Area Under the Curve (AUC) 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by pembrolizumab 200 mg IV PLUS pemetrexed 500 mg/m\^2 IV Q3W until progression. Participants who receive pembrolizumab 200 mg IV Q3W for up to 2 years, but experience disease progression, are eligible to receive a second course of pembrolizumab monotherapy 200 mg IV Q3W, at the investigator's discretion, for up to another year. arm 2: Participants receive saline placebo IV PLUS pemetrexed 500 mg/m\^2 IV (with vitamin supplementation) PLUS cisplatin 75 mg/m\^2 IV OR carboplatin AUC 5 IV on Day 1 of every 3-week cycle (Q3W) for 4 cycles followed by saline placebo IV PLUS pemetrexed 500 mg/m\^2 IV Q3W until progression. Participants who receive saline placebo, but experience disease progression, can switch over to pembrolizumab monotherapy 200 mg IV Q3W, at the investigator's discretion, for up to 2 years. The participants who switch over to pembrolizumab 200 mg IV Q3W, but experience disease progression, are eligible to receive a second course of pembrolizumab monotherapy 200 mg IV Q3W, at the investigator's discretion, for up to another year.

Interventions: intervention 1: Pembrolizumab 200 mg intervention 2: Cisplatin intervention 3: Carboplatin intervention 4: Pemetrexed intervention 5: Folic acid 350-1000 μg intervention 6: Vitamin B12 1000 μg intervention 7: Dexamethasone 4 mg intervention 8: Saline solution
Intervention descriptions: intervention 1: IV infusion intervention 2: IV infusion intervention 3: IV infusion intervention 4: IV infusion intervention 5: Orally; at least 5 doses of folic acid must be taken during the 7 days preceding the first dose of pemetrexed, and folic acid dosing must continue during the full course of therapy and for 21 days after the last dose of pemetrexed. intervention 6: Intramuscular injection in the week preceding the first dose of pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as pemetrexed administration. intervention 7: For prophylaxis; orally twice per day (or equivalent). Taken the day before, day of, and day after pemetrexed administration. intervention 8: IV infusion

Protocol document:
Prot_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03950674
06-Nov-2017
Document Date: 
A Randomized, Double-Blind, Phase III Study of Platinum+ 
Pemetrexed Chemotherapy with or without Pembrolizumab 
(MK-3475) in First Line Metastatic Non-squamous Non-small
Cell Lung Cancer Subjects (KEYNOTE-189)


Product:  MK-3475 
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Protocol/Amendment No.: 189-08 
MK-3475-189-08 Final Protocol
6-Nov-2017
Confidential
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, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Randomized, Double-Blind, Phase III Study of Platinum+ Pemetrexed Chemotherapy with 
or without Pembrolizumab (MK-3475) in First Line Metastatic Non-squamous Non-small 
Cell Lung Cancer Subjects (KEYNOTE-189)
IND NUMBER:  116,833
EudraCT NUMBER:  2015-003694-15 
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 16
2.0
TRIAL DESIGN........................................................................................................ 17
Trial Design ........................................................................................................... 17
2.1
Trial Diagram........................................................................................................ 20
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 20
Primary Objective(s) & Hypothesis(es) .............................................................. 20
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 21
3.2
Exploratory Objectives......................................................................................... 21
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 22
Background ........................................................................................................... 22
4.1
Pharmaceutical and Therapeutic Background .................................................... 22
4.1.1
Pre-clinical and Clinical Trials ........................................................................... 23
4.1.2
Ongoing Clinical Trials....................................................................................... 24
4.1.3
Information on Other Trial-related Therapy....................................................... 24
4.1.4
Rationale................................................................................................................ 24
4.2
Rationale for the Trial and Selected Subject Population .................................... 24
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 25
4.2.2
4.2.2.1
Rationale for Pembrolizumab Dose............................................................. 25
4.2.2.2
Rationale for the Use of Placebo ................................................................. 26
Rationale for Endpoints ...................................................................................... 27
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 27
4.2.3.2
Immune-related RECIST (irRECIST) ......................................................... 27
4.2.3.3
Rationale for Safety Endpoints .................................................................... 28
4.2.3.4
Patient Reported Outcomes.......................................................................... 28
EORTC QLQ-C30 and EORTC QLQ-LC13........................................ 28
4.2.3.4.1
EuroQoL (EQ)-5D ................................................................................ 28
4.2.3.4.2
4.2.3.5
Pharmacokinetic Endpoints ......................................................................... 29
4.2.3.6
Planned Exploratory Biomarker Research................................................... 29
 
 
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4.2.3.7
Future Biomedical Research........................................................................ 30
Benefit/Risk ........................................................................................................... 31
4.3
5.0
METHODOLOGY ................................................................................................... 31
Entry Criteria........................................................................................................ 31
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 31
5.1.1
Subject Inclusion Criteria.................................................................................... 31
5.1.2
Subject Exclusion Criteria .................................................................................. 33
5.1.3
Trial Treatment(s) ................................................................................................ 35
5.2
Dose Selection/Modification .............................................................................. 36
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 36
5.2.1.2
Dose Modification ....................................................................................... 36
Dose Modification and Toxicity Management Guidelines for 
5.2.1.2.1
Pembrolizumab ..................................................................................... 37
Dose Modification for Chemotherapy .................................................. 42
5.2.1.2.2
Timing of Dose Administration .......................................................................... 43
5.2.2
5.2.2.1
Pembrolizumab/Placebo .............................................................................. 43
5.2.2.2
Pemetrexed................................................................................................... 44
5.2.2.3
Cisplatin....................................................................................................... 44
5.2.2.4
Carboplatin................................................................................................... 44
5.2.2.5
Antiemetic Therapy ..................................................................................... 44
Trial Blinding/Masking....................................................................................... 44
5.2.3
Randomization ...................................................................................................... 45
5.3
Stratification.......................................................................................................... 45
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 45
5.5
Acceptable Concomitant Medications ................................................................ 45
5.5.1
Prohibited Concomitant Medications.................................................................. 46
5.5.2
Rescue Medications & Supportive Care............................................................. 47
5.6
Supportive Care Guidelines ................................................................................ 47
5.6.1
Pemetrexed-Related Toxicity.............................................................................. 47
5.6.2
Diet/Activity/Other Considerations..................................................................... 47
5.7
Diet...................................................................................................................... 47
5.7.1
Contraception...................................................................................................... 48
5.7.2
 
 
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Use in Pregnancy ................................................................................................ 49
5.7.3
Use in Nursing Women....................................................................................... 49
5.7.4
Subject Withdrawal/Discontinuation Criteria................................................... 49
5.8
Subject Replacement Strategy............................................................................. 51
5.9
Beginning and End of the Trial ........................................................................... 52
5.10
Clinical Criteria for Early Trial Termination ................................................... 52
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 53
Initial Treatment Phase........................................................................................ 53
6.1
Pharmacokinetic Collection Schedule for Pemetrexed, Carboplatin and 
6.1.1
Cisplatin .............................................................................................................. 57
Second Course Phase (Retreatment)................................................................... 58
6.2
Crossover Phase .................................................................................................... 60
6.3
7.0
TRIAL PROCEDURES ........................................................................................... 63
Trial Procedures ................................................................................................... 63
7.1
Administrative Procedures.................................................................................. 63
7.1.1
7.1.1.1
Informed Consent......................................................................................... 63
General Informed Consent.................................................................... 63
7.1.1.1.1
Consent and Collection of Specimens for Future Biomedical 
7.1.1.1.2
Research................................................................................................ 63
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 64
7.1.1.3
Subject Identification Card .......................................................................... 64
7.1.1.4
Medical History ........................................................................................... 64
7.1.1.5
Prior and Concomitant Medications Review ............................................... 64
Prior Medications.................................................................................. 64
7.1.1.5.1
Concomitant Medications..................................................................... 64
7.1.1.5.2
Subsequent Anti-Cancer Therapy Status .............................................. 65
7.1.1.5.3
7.1.1.6
Assignment of Screening Number............................................................... 65
7.1.1.7
Assignment of Treatment/Randomization Number ..................................... 65
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other) ................................... 65
Clinical Procedures/Assessments........................................................................ 65
7.1.2
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 65
7.1.2.2
Physical Exam.............................................................................................. 66
 
 
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Full Physical Exam ............................................................................... 66
7.1.2.2.1
Directed Physical Exam........................................................................ 66
7.1.2.2.2
7.1.2.3
Vital Signs.................................................................................................... 66
7.1.2.4
12-Lead Electrocardiogram (ECG).............................................................. 66
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 66
7.1.2.6
Pulse Oximetry (SpO2)................................................................................ 67
7.1.2.7
Tumor Imaging and Assessment of Disease................................................ 67
Initial Tumor Imaging........................................................................... 67
7.1.2.7.1
Tumor Imaging During the Trial .......................................................... 68
7.1.2.7.2
End of Treatment and Follow-up of Tumor Imaging ........................... 68
7.1.2.7.3
Second Course (Retreatment) and Crossover Tumor Imaging ............. 68
7.1.2.7.4
RECIST 1.1 Assessment of Disease ..................................................... 69
7.1.2.7.5
irRECIST Assessment of Disease......................................................... 70
7.1.2.7.6
7.1.2.8
Tumor Tissue Collection: PD-L1 Status...................................................... 72
Laboratory Procedures/Assessments .................................................................. 73
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 73
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 75
Blood Collection for Serum Pembrolizumab........................................ 75
7.1.3.2.1
Blood Collection for Pemetrexed, Carboplatin or Cisplatin................. 76
7.1.3.2.2
Blood Collection for Anti- pembrolizumab Antibodies ....................... 76
7.1.3.2.3
7.1.3.3
Patient Reported Outcomes (PROs)............................................................. 76
7.1.3.4
Blood for Correlative and Biomarker Studies ............................................. 77
7.1.3.5
Planned Genetic Analysis Sample Collection.............................................. 77
7.1.3.6
Future Biomedical Research Sample Collection ......................................... 77
Other Procedures................................................................................................. 78
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 78
Withdrawal From Future Biomedical Research ................................... 78
7.1.4.1.1
7.1.4.2
Blinding/Unblinding .................................................................................... 78
7.1.4.3
Calibration of Critical Equipment................................................................ 79
Visit Requirements.............................................................................................. 79
7.1.5
7.1.5.1
Screening...................................................................................................... 79
7.1.5.2
Treatment Phase........................................................................................... 80
 
 
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7.1.5.3
Post-Treatment............................................................................................. 80
Safety Follow-up Visit.......................................................................... 80
7.1.5.3.1
Follow-up Visits ................................................................................... 81
7.1.5.3.2
Survival Follow-up ............................................................................... 81
7.1.5.3.3
7.1.5.4
Survival Status ............................................................................................. 81
7.1.5.5
Second Course Phase (Retreatment Period) ................................................ 81
7.1.5.6
Crossover for Subjects With Documented Disease Progression Who 
Received Placebo......................................................................................... 82
7.1.5.7
Crossover Assessments and Procedures ...................................................... 83
Assessing and Recording Adverse Events .......................................................... 83
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 84
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 85
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 85
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 85
7.2.3.2
Events of Clinical Interest............................................................................ 86
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting ............ 87
Evaluating Adverse Events................................................................................. 87
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 90
7.2.5
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 90
7.3
Scientific Advisory Committee........................................................................... 90
7.3.1
Data Monitoring Committee ............................................................................... 90
7.3.2
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 90
Statistical Analysis Plan Summary ..................................................................... 91
8.1
Responsibility for Analyses/In-House Blinding ................................................. 92
8.2
Hypotheses/Estimation ......................................................................................... 93
8.3
Analysis Endpoints ............................................................................................... 93
8.4
Efficacy Endpoints.............................................................................................. 93
8.4.1
Safety Endpoints ................................................................................................. 94
8.4.2
Analysis Populations............................................................................................. 94
8.5
Efficacy Analysis Populations ............................................................................ 94
8.5.1
Safety Analysis Populations ............................................................................... 94
8.5.2
Statistical Methods................................................................................................ 95
8.6
 
 
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Statistical Methods for Efficacy Analyses .......................................................... 95
8.6.1
8.6.1.1
Progression-free Survival (PFS) .................................................................. 95
8.6.1.2
Overall Survival (OS) .................................................................................. 96
8.6.1.3
Objective Response Rate (ORR) and Duration of Response (DOR)........... 97
Statistical Methods for Safety Analyses ............................................................. 98
8.6.2
Summaries of Demographic and Baseline Characteristics and Other 
8.6.3
Analysis............................................................................................................. 100
Interim Analyses ................................................................................................. 100
8.7
Multiplicity .......................................................................................................... 101
8.8
Sample Size and Power Calculations ................................................................ 103
8.9
Subgroup Analyses and Effect of Baseline Factors ......................................... 104
8.10
Extent of Exposure.............................................................................................. 104
8.11
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 104
Investigational Product ...................................................................................... 104
9.1
Packaging and Labeling Information ............................................................... 105
9.2
Clinical Supplies Disclosure............................................................................... 105
9.3
Storage and Handling Requirements................................................................ 106
9.4
Discard/Destruction/Returns and Reconciliation ............................................ 106
9.5
Standard Policies................................................................................................. 106
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 106
Confidentiality..................................................................................................... 106
10.1
Confidentiality of Data ..................................................................................... 106
10.1.1
Confidentiality of Subject Records ................................................................... 106
10.1.2
Confidentiality of Investigator Information...................................................... 107
10.1.3
Confidentiality of IRB/IEC Information........................................................... 107
10.1.4
Compliance with Financial Disclosure Requirements..................................... 107
10.2
Compliance with Law, Audit and Debarment ................................................. 108
10.3
Compliance with Trial Registration and Results Posting Requirements ...... 109
10.4
Quality Management System............................................................................. 110
10.5
Data Management............................................................................................... 110
10.6
Publications ......................................................................................................... 110
10.7
 
 
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11.0
LIST OF REFERENCES....................................................................................... 112
12.0
APPENDICES......................................................................................................... 116
Merck Code of Conduct for Clinical Trials...................................................... 116
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research............................................................................................................... 118
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 122
List of Abbreviations .......................................................................................... 133
12.4
Calculated Creatinine Clearance ...................................................................... 135
12.5
MASCC corticosteroid dosing guidelines (2013 guidelines or more current 
12.6
guidelines, if available) ....................................................................................... 136
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 137
12.7
ECOG Performance Status................................................................................ 138
12.8
13.0
SIGNATURES......................................................................................................... 139
Sponsor's Representative ................................................................................... 139
13.1
Investigator.......................................................................................................... 139
13.2
 
 
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LIST OF TABLES
    
Table 1
Adequate Organ Function Laboratory Values ................................................... 32
Table 2
Trial Treatment .................................................................................................. 35
Table 3
Dose Modifications for Trial Medications......................................................... 37
Table 4
Dose Modification and Toxicity Management Guidelines for 
Immune-related Adverse Events Associated With Pembrolizumab.................. 38
Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines .......................................................................................................... 41
Table 6
Recommended Dose Modifications for Chemotherapy 
Hematological Toxicity ..................................................................................... 42
Table 7
Recommended Dose Modifications for Chemotherapy Non-
Hematological Toxicity ..................................................................................... 43
Table 8
Imaging and Treatment after Radiologic Evidence of PD................................. 72
Table 9
Laboratory Tests ................................................................................................ 74
Table 10
Evaluating Adverse Events................................................................................ 88
Table 11
Censoring Rules for Primary and Sensitivity Analyses of PFS......................... 96
Table 12
Analysis Strategy for Key Efficacy Endpoints.................................................. 98
Table 13
Analysis Strategy for Safety Parameters............................................................ 99
Table 14
Analyses Planned, Endpoints Evaluated, and Drivers of Timing.................... 100
Table 15
Boundary properties for planned analyses of PFS based on potential 
alpha-levels to be used for testing.................................................................... 102
Table 16
Boundary properties for planned analyses of OS ............................................ 102
Table 17
Product Descriptions........................................................................................ 105
 
 
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LIST OF FIGURES
          
Figure 1
Study Schema..................................................................................................... 20
Figure 2
Type I Error Reallocation Strategy.................................................................. 101
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
2.1
4.2.3.1
8.1
8.4.1
8.5.1
8.6.1
8.7
8.8
8.9
8.10
Trial Design
Efficacy Endpoints
Statistical Analysis Plan 
Summary
Efficacy Endpoints
Efficacy Analysis Populations
Statistical Methods for Efficacy 
Analyses
Interim Analyses
Multiplicity
Sample Size and Power 
Calculations
Subgroup Analyses and Effect of 
Baseline Factors
Timing of interim analysis 1 (IA1) was 
changed to occur after approximately 370 
progression-free survival (PFS) events have 
been observed. The total type I error allocated 
to PFS is subject to rollover to overall survival 
(OS) if the PFS test is positive. The type I error 
allocated to OS is subject to rollover to PFS if 
the OS test is positive. The total type I error 
(from PFS and OS) is subject to rollover to 
objective response rate (ORR) at IA1 if the 
PFS and OS tests are both positive. Interim 
analysis 2 (IA2) will be performed after 
approximately 468 PFS events have occurred 
and will evaluate PFS and OS. The final 
analysis will be performed after approximately 
416 deaths have occurred and will evaluate 
OS. 
To provide a more robust 
analysis of the data, focusing on 
OS and adjust the alpha spending 
to most inform the clinical 
meaningfulness of the data. In 
addition, subject accrual was 
greater than originally expected 
and estimated timing of interim 
analyses can now be calculated 
based on actual enrollment 
(N=616), rather than the planned 
enrollment (N=570). 
 
 
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Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
3.1
3.2
8.4.1
8.6.1.3
Primary Objective(s) & 
Hypothesis(es)
Secondary Objective(s) & 
Hypothesis(es)
Efficacy Endpoints
Objective Response Rate and 
Duration of Response
Promoted OS objective to primary and ORR 
objective to key secondary.
To provide a more robust 
analysis of the data, focusing on 
OS and adjust the alpha spending 
to most inform the clinical 
meaningfulness of the data.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
3.0
3.1
3.2
3.3
Objectives
Primary Objective(s) & 
Hypothesis(es)
Secondary Objective(s) & 
Hypothesis(es)
Exploratory Objectives
Deleted duplicated objectives and revised 
wording of remaining objectives for clarity 
and consistency with current pembrolizumab 
development program standards.
To remove redundancies.
1.0
2.1
3.2
8.1
Trial Summary
Trial Design
Secondary Objective(s) & 
Hypothesis(es)
Statistical Analysis Plan Summary
Made the terminology for the chemotherapy 
regimen consistent throughout the protocol: 
pemetrexed/platinum
To correct typographical errors 
and clarify intended meaning.
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.2
5.2.1.2
5.2.1.2.1
5.5.2
5.8
6.1
6.2
6.3
7.1.2.6.4
7.1.3.2.2
7.1.5.4
7.1.5.5
7.1.5.6
Trial Treatment(s)
Dose Modification
Dose Modification and Toxicity 
Management Guidelines for 
Pembrolizumab
Prohibited Concomitant 
Medications
Subject Withdrawal/ 
Discontinuation Criteria
Initial Treatment Phase
Second Course (Retreatment) Phase
Crossover Phase
Second Course (Retreatment) and 
Crossover Tumor Imaging
Blood Collection for Pemetrexed, 
Carboplatin, or Cisplatin
Second Course Phase (Retreatment 
Period)
Crossover for Subjects With 
Documented Disease Progression
Who Received Placebo
Crossover Assessments and 
Procedures
Made typographical corrections and minor 
administrative edits.
To correct typographical errors 
and clarify intended meaning.
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
8.4.1
8.6.1.1
8.6.1.2
8.6.1.3
8.6.3
Efficacy Endpoints
Progression-free Survival (PFS)
Overall Survival (OS)
Objective Response Rate (ORR) 
and Duration of Response (DOR)
Summaries of Demographic and 
Baseline Characteristics and Other 
Analysis
5.2.1.2.1
Dose Modification and Toxicity 
Management Guidelines for 
Pembrolizumab
Updated the dose modification and toxicity 
management guidelines for pembrolizumab 
to include new information on myocarditis.
To align with the 
pembrolizumab development 
program current standards.
6.1
6.2
6.3
7.1.2.6.3
7.1.2.6.4
Initial Treatment Phase
Second Course (Retreatment) Phase
Crossover Phase
End of Treatment and Follow-up of 
Tumor Imaging
Second Course (Retreatment) and 
Crossover Tumor Imaging
Revised description of imaging at treatment 
discontinuation and beyond for clarity.
To align with the 
pembrolizumab development 
program current standards.
6.1
7.1.3.2
Initial Treatment Phase
Pharmacokinetic/Pharmacodynamic 
Evaluations
Revised details regarding pharmacokinetic 
and anti-pembrolizumab antibody sample 
collection and analysis for clarity.
To provide subjects and trial 
site personnel more accurate 
information regarding planned 
PK sample collection and 
analysis.
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.4.2
9.3
Blinding/Unblinding
Clinical Supplies Disclosure
Specified that if a subject’s treatment must be 
unblinded, the principal investigator, site 
personnel, and Sponsor personnel will be 
unblinded in order to provide appropriate 
medical care.
To 
clarify 
expectations 
regarding 
an 
unblinding 
incident. 
2.1
6.1
6.2
6.3
7.1.5.3.3
7.1.5.4 (new)
Trial Design
Initial Treatment Phase
Second Course (Retreatment) Phase
Crossover Phase
Survival Follow-up
Survival Status (new)
Specified that sites may be required to assess 
survival status at additional time points 
during the study.
To 
clarify 
survival 
status 
reporting requirements.
7.1.5.3.1
Safety Follow-up Visit
Specified that there may be a total of 2 safety 
follow-up visits for subjects who participate 
in the Crossover Phase.
To 
align
with 
the 
pembrolizumab 
development 
program current standards.
8.5.1
Efficacy Analysis Populations
Specified that efficacy analyses may be 
conducted using the Full Analysis Set (FAS).
To address a situation in which 
an 
unexpected 
number 
of 
randomized subjects are not 
treated.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase 
III 
study 
of 
Pemetrexed+Platinum 
with 
or 
without 
Pembrolizumab in first line (1L) metastatic non-squamous NSCLC
Trial Phase
Phase 3
Clinical Indication
Treatment of Non-Small Cell Lung Cancer
Trial Type
Interventional
Type of control
Placebo with Active control
Route of administration
Intravenous 
Trial Blinding
Double-blind
Treatment Groups
There are 2 treatment arms:

Pembrolizumab plus pemetrexed and carboplatin or cisplatin

Saline placebo plus pemetrexed and carboplatin or cisplatin
Number of trial subjects
Global Study: Approximately 570 subjects will be enrolled.  
Extension Study in Japan: Approximately 40 Japanese subjects overall 
will be enrolled in the global study and the extension study.
Estimated duration of trial
Global Study: The Sponsor estimates that the trial will require 
approximately 4 years from the time the first subject signs the 
informed consent until the last subject’s last study-related phone call 
or visit.
Extension Study in Japan: The Sponsor estimates that the trial will 
require approximately an additional 9 months from the time the first 
subject signs the informed consent until the last subject’s last study-
related phone call or visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final contact.  After a 
screening phase of up to 28 days, eligible subjects will receive 
assigned treatment on Day 1 of each 3-week (Q3W) dosing cycle.  
Treatment with pembrolizumab will continue until 35 treatment 
administrations of pembrolizumab therapy have been administered, 
documented disease progression, unacceptable adverse event(s), 
intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the subject, subject withdraws 
consent, pregnancy of the subject, noncompliance with the trial 
treatment or procedure requirements or administrative reasons.  
Subjects who experience documented disease progression will have 
treatment assignment unblinded and be able to continue on open-label 
pembrolizumab monotherapy in the Crossover Phase.  Pembrolizumab
treated subjects who have been on therapy for ≥ 6 months and who 
attain a complete response may consider stopping trial treatment. 
These subjects, as well as subjects assigned to the pembrolizumab arm 
who stop trial therapy after 35 treatment administrations for reasons 
other than disease progression or intolerability, may be eligible for re-
treatment with pembrolizumab
(Second Course Phase)
upon 
experiencing radiographic disease progression.  Participation in the 
Second Course Phase is at the discretion of the investigator according 
to the criteria in Section 7.1.5.4. After the end of treatment, each 
subject will be followed for a minimum of 30 days for adverse event 
monitoring even if the patient started new antineoplastic treatment 
(serious adverse events will be collected for up to 90 days following 
 
 
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cessation of Sponsor’s product, 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 radiographic imaging every 12 weeks, until initiating a non-
study cancer treatment, experiencing disease progression, death, 
withdrawing consent, or becoming lost to follow-up.
A list of abbreviations used in this document can be found in Section 12.4.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a worldwide, randomized, active-controlled, parallel-group, multi-site, double-blind 
trial of intravenous (IV) pembrolizumab (also known as MK-3475) combined with 
pemetrexed/platinum
chemotherapy 
versus 
saline 
placebo 
combined 
with 
pemetrexed/platinum chemotherapy in subjects with advanced or metastatic nonsquamous 
non-small cell lung cancer (NSCLC) who have not previously received systemic therapy for 
advanced disease and in whom EGFR or ALK-directed therapy is not indicated.  
Approximately 570 subjects will be enrolled in this trial to examine the efficacy of 
pembrolizumab combined with chemotherapy compared to chemotherapy alone. Subjects
will be randomized 2:1 to either receive pembrolizumab 200 mg combined with pemetrexed 
and platinum (investigator’s choice of cisplatin or carboplatin), or saline placebo, pemetrexed 
and platinum (investigator’s choice of cisplatin or carboplatin) as indicated below:

Arm 1: Pembrolizumab
200
mg + pemetrexed 500
mg/m2
(with vitamin 
supplementation) + cisplatin 75 mg/m2 OR carboplatin AUC 5, all on Day 1 every 
3 weeks (Q3W) for 4 cycles followed by pembrolizumab 200 mg + pemetrexed 
500 mg/m2 Q3W until progression.

Arm 2: Saline placebo + pemetrexed 500 mg/m2 (with vitamin supplementation) + 
cisplatin 75 mg/m2 OR carboplatin AUC 5, all on Day 1 Q3W for 4 cycles followed 
by saline placebo + pemetrexed 500 mg/m2 Q3W until progression.
Subjects who received adjuvant or neoadjuvant therapy are permitted onto the study if the 
therapy was completed at least 12 months prior to the development of metastatic disease.
Subjects will be stratified by smoking status (never vs former/current), cisplatin vs 
carboplatin, and programmed cell death ligand-1 (PD-L1) status (Tumor Proportion Score 
[TPS] ≥1% vs <1%) prior to randomization. PD-L1 inevaluable subjects will be included 
with the TPS <1% group.
Subjects will be evaluated at 6 weeks (42 ± 7 days) and 12 weeks (84 ± 7 days) and then 
every 9 weeks (63 ± 7 days) with radiographic imaging to assess response to treatment for 
the first 48 weeks and every 12 weeks (84 ± 7 days) subsequently; treatment-based decisions 
should be based on the immune-related RECIST criteria (irRECIST) (details are provided in 
the Procedure Manual).  All imaging obtained on study will be submitted without indication 
Randomization Ratio
Randomized 2:1 to either receive pembrolizumab combined with 
pemetrexed and platinum (investigator’s choice of cisplatin or 
carboplatin), or saline placebo with pemetrexed and platinum 
(investigator’s choice of cisplatin or carboplatin)
 
 
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of treatment assignment to a central imaging review vendor, ie, blinded independent central 
review (BICR), who will assess the images using Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST 1.1) for determination of progression-free survival (PFS) and
objective response rate (ORR). Adverse Event (AE) monitoring will be ongoing throughout 
the trial and graded in severity according to the guidelines outlined in the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
Treatment with pembrolizumab or saline placebo will continue until 35 trial treatments have 
been administered, documented disease progression, unacceptable adverse event(s), 
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, or administrative reasons. 
Treatment with pemetrexed will continue until documented disease progression, 
unacceptable adverse event(s), 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, or 
administrative reasons.
At the time of documented disease progression as confirmed by BICR using RECIST 1.1, 
subjects will have treatment assignment unblinded and may be able to continue therapy in the 
Crossover Phase as indicated below until subsequent documented progression, unacceptable 
adverse event(s), 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, or administrative 
reasons:
1. Subjects who had received saline placebo in combination with chemotherapy will be 
able to receive open-label pembrolizumab monotherapy for a total of 35 treatments.
2. Subjects who had received pembrolizumab in combination with chemotherapy, but 
are deemed to be benefiting clinically despite progression, will be able to receive 
open-label pembrolizumab monotherapy to complete a total of 35 treatments.
Subjects who attain a confirmed complete response (CR) per irRECIST may consider 
stopping trial treatment. These subjects, as well as subjects assigned to the pembrolizumab 
arm who stop trial therapy after 35 treatment administrations for reasons other than disease 
progression or intolerability, may be eligible for the Second Course Phase. The Second 
Course Phase is re-treatment with open-label pembrolizumab monotherapy after radiographic 
disease progression and participation is at the discretion of the investigator according to 
defined criteria in Section 7.1.5. Response or progression in the Second Course Phase will 
not count towards the PFS and ORR endpoints in this trial.
After the end of treatment, each subject will be followed for a minimum of 30 days for AE 
monitoring. Serious adverse events (SAEs) will be collected for up to 90 days after the end of 
treatment or 30 days following cessation of treatment if the subject initiates new cancer 
therapy, whichever is earlier. Subjects will have post-treatment follow-up for disease status, 
until initiating a non-study cancer treatment, experiencing disease progression, death, 
withdrawing consent, or becoming lost to follow-up.
 
 
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The Sponsor may request survival status to be assessed at additional time points and entered 
into the database during the course of the trial.  For example, survival status may be 
requested prior to, but not limited to, an external Data Monitoring Committee (eDMC)
review.
The primary endpoints of the trial are PFS (BICR/RECIST 1.1) and overall survival (OS). 
The key secondary endpoint is ORR (BICR/RECIST 1.1); other endpoints include duration 
of response (DOR) (BICR/RECIST 1.1) and safety as assessed by a variety of AE 
parameters. Exploratory analyses include PFS, OS, and ORR by PD-L1 expression levels and 
PFS, ORR, and DOR by investigator-assessed RECIST 1.1 and irRECIST. Drug-drug 
interaction studies and quality of life assessments are further exploratory endpoints. 
Participation in this trial will be dependent upon supplying tumor tissue from locations not 
radiated prior to biopsy; formalin-fixed specimens used to confirm diagnosis or collected 
after the subject has been diagnosed with metastatic disease will be preferred for 
determination of PD-L1 status prior to randomization. Biopsies obtained prior to receipt of 
adjuvant/neoadjuvant chemotherapy will be permitted if recent biopsy is not feasible.  
Subjects who received adjuvant/neoadjuvant therapy are permitted onto the trial as long as 
therapy was completed at least 12 months prior to the diagnosis of metastatic disease.
Subjects whose submitted tissue is inevaluable for PD-L1 status can still be eligible to 
participate in the study.
The specimen will be evaluated at a central laboratory facility for expression status of PD-L1 
in a prospective manner to enable stratification.
In terms of stratification, PD-L1 non-
evaluable subjects will be grouped with the TPS <1% group.
Two interim analyses will be conducted during the course of the trial with review by the 
eDMC. The first interim analysis (IA1) will be performed after approximately 370 PFS 
events have been observed. The second interim analysis (IA2) will be performed after 
approximately 468 PFS events have been observed. The final analysis (FA) will be 
performed after approximately 416 deaths have been observed. In addition, the trial may be 
stopped early at the recommendation of the eDMC if the risk/benefit ratio to the trial 
population as a whole is unacceptable. Details are described in Section 8.0 Statistical 
Analysis Plan.
Extension Study
Approximately 40 Japanese subjects overall will be enrolled in the global study and the 
extension study.  After the enrollment period of the global study is closed, subjects from 
Japan will continue to be enrolled in an extension study mainly to collect additional Japanese 
safety data.  The extension study will be identical to the global study (eg, inclusion and 
exclusion criteria, study endpoints, primary and secondary objectives, study procedures), 
with the exception of an additional Statistical Analysis Plan (SAP) for Japanese subjects.  
Details of the analysis will be provided in a separate Japan-specific SAP document.
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.
 
 
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Trial Diagram
2.2
The trial design is depicted in Figure 1.
Figure 1  Study Schema
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Pembrolizumab in combination with chemotherapy will be compared with saline placebo in 
combination with chemotherapy in subjects with advanced or metastatic nonsquamous, non-
small cell lung cancer (NSCLC) who have not previously received systemic therapy based on 
the following primary, secondary, and exploratory objectives:
Primary Objective(s) & Hypothesis(es)
3.1
1. To evaluate the antitumor activity of pembrolizumab in combination with 
chemotherapy compared with saline placebo in combination with chemotherapy using 
PFS per RECIST 1.1 as assessed by BICR of imaging.
Hypothesis:  Pembrolizumab in combination with chemotherapy prolongs PFS 
(BICR/RECIST 1.1) compared to saline placebo in combination with chemotherapy.
2. To evaluate the antitumor activity of pembrolizumab in combination with 
chemotherapy compared with saline placebo in combination with chemotherapy using 
OS.
 
 
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Hypothesis: Pembrolizumab in combination with chemotherapy prolongs OS 
compared to saline placebo in combination with chemotherapy.
Secondary Objective(s) & Hypothesis(es)
3.2
1. To evaluate the antitumor activity of pembrolizumab in combination with 
chemotherapy compared with saline placebo in combination with chemotherapy using 
ORR per RECIST 1.1 as assessed by BICR.
Hypothesis: Pembrolizumab in combination with chemotherapy improves ORR 
(BICR/RECIST 1.1)
compared with saline placebo
in combination
with 
chemotherapy.
2. To evaluate the antitumor activity of pembrolizumab in combination with 
chemotherapy compared with saline placebo in combination with chemotherapy using
DOR per RECIST 1.1 as assessed by BICR.
3. To evaluate the safety and tolerability profile of pembrolizumab in combination with 
pemetrexed/platinum chemotherapy.
Exploratory Objectives
3.3
1. To evaluate the effect of PD-L1 expression levels on the efficacy endpoints of PFS, OS,
and ORR.
2. To evaluate the antitumor activity of pembrolizumab in combination with 
chemotherapy compared with saline placebo in combination with chemotherapy using 
PFS, ORR, and DOR assessed by the investigator using RECIST 1.1.
3. To evaluate the antitumor activity of pembrolizumab in combination with 
chemotherapy compared with saline placebo in combination with chemotherapy using 
PFS, ORR, and DOR per investigator-assessed irRECIST response criteria.  
4. To investigate the relationship between pembrolizumab treatment and biomarkers 
predicting response (eg, PD-L1, genetic variation, serum sPD-L1) utilizing newly 
obtained or archival FFPE tumor tissue and blood, including serum and plasma.
5. To evaluate changes in health-related quality-of-life assessments from baseline in the 
biomarker-positive strata and in the overall study population using the EORTC QLQ-
C30 and EORTC QLQ-LC13.
6. To characterize utilities in subjects treated with pembrolizumab in combination with
chemotherapy compared with saline placebo in combination with chemotherapy using 
the EuroQoL(EQ)-5D.
7. To characterize the pharmacokinetic characteristics of pemetrexed/platinum treatment 
and pembrolizumab.
 
 
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8. To explore the relationship between genomic variation and response to the treatment(s) 
administered.
Variation across the human genome (germline and tumor) will be 
analyzed for association with clinical data collected in this study.
9. To evaluate PFS and OS following crossover to pembrolizumab in subjects initially 
treated with saline placebo in combination with chemotherapy.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
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]. In particular, the presence of CD8+ T -cells 
and the ratio of CD8+ effector T -cells / FoxP3+ regulatory T-cells seems to correlate with 
improved prognosis and long -term survival  in  solid  malignancies such  as  ovarian,  
colorectal and  pancreatic  cancer, hepatocellular carcinoma, malignant melanoma and renal 
cell carcinoma (RCC). TILs can be expanded ex vivo and re-infused, inducing durable 
objective tumor responses in cancers such as melanoma [9] [10].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T -
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[11] [12]. 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 [13] [14]. 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 [15] [16]. 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 [14]
[17] [18] [19]. 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 [17]. 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 
 
 
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prognosis and survival in various cancer types, including RCC 17 [20], pancreatic carcinoma 
[21], hepatocellular carcinoma [22], and ovarian carcinoma [23]. Furthermore, PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma [24].
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 KEYNOTE-001 and KEYNOTE-010, the Phase 2/3
trial of 
pembrolizumab vs docetaxel in previously treated subjects with advanced or metastatic 
NSCLC.
Pre-clinical and Clinical Trials
4.1.2
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, melanoma
and colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted CD8+ T-cell 
infiltration into the tumor and the presence of IFN-gamma, granzyme B and perforin, 
indicating that the mechanism of action involved local infiltration and activation of effector 
T-cell function in vivo [23] [25] [26] [27] [28] [29]. In addition, the combination of 
gemcitabine and anti-PD-L1 mAb demonstrated synergy in the rejection of pancreatic mouse 
tumors [23]. In-house experiments have confirmed the in vivo efficacy of PD-1 blockade as a 
monotherapy as well as in combination with chemotherapy in syngeneic mouse tumor 
models (see the IB).
Recent clinical data of pembrolizumab suggest high sustained rates of tumor regression in 
patients with advanced melanoma and NSCLC. In an ipilimumab-refractory cohort of 
melanoma patients who received pembrolizumab 10 mg/kg or 2 mg/kg IV Q3W, the ORR 
was 24% (95% CI 15-34) in the 2 mg/kg arm, consisting of 1 CR and 20 PRs. Among the 
21 subjects with an objective response, 3 (14%) had PD 2.8, 2.9, and 8.2 months after initial 
response. The remaining 18 subjects (86%) had ongoing responses with durations ranging 
from 1.4+ to 8.5+ months, which included 8 subjects with ongoing responses of 6 months or 
longer. Furthermore, the toxicity profile was manageable with the majority of the toxicities at 
Grade 1 or 2 [30].
In the same open-label multi-cohort Phase 1 trial (KEYNOTE-001), a total of 495 NSCLC 
subjects were treated with at least 1 dose of pembrolizumab. The ORR was 19.4% (18.0% in 
the 394 previously treated subjects and 24.8% in the 101 previously untreated subjects). The 
response rate was similar regardless of dose, schedule, and histologic analysis. Current or 
former smokers had a response rate of 22.5%, as compared with 10.3% among subjects who 
had never smoked cigarettes. 
Subjects were required to submit a newly obtained tumor biopsy prior to initiating therapy 
with pembrolizumab to evaluate the tumors for expression of PD-L1. After evaluation of 
several methods for pathological assessment, in a training set, membranous PD-L1 
expression in at least 50% of tumor cells (tumor proportion score [TPS] ≥50%) was selected 
as the cutoff point defining PD-L1 high. In a validation set of 313 subjects, the response rate 
was 45.2% in the 73 subjects with a TPS of at least 50%, including 43.9% in previously 
treated subjects and 50.0% in previously untreated subjects, values that numerically exceeded 
the response rate in the training group [31].
 
 
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Ongoing Clinical Trials
4.1.3
A number of clinical trials are exploring the value of pembrolizumab monotherapy compared 
to standard chemotherapy in a PD-L1-enriched population, both as second-line therapy 
(KEYNOTE-010) and first-line therapy (KEYNOTE-024 and KEYNOTE-042) with results 
expected in 2015-2016.  Chemotherapy combinations with pembrolizumab are being 
explored in a Phase1B/2 study (KEYNOTE-021); preliminary data presented at ASCO 2015 
suggest a manageable toxicity profile and an encouraging response rate of 58% with the 
combination of pembrolizumab and carboplatin-pemetrexed as first-line therapy.
Information on Other Trial-related Therapy
4.1.4
Platinum doublet chemotherapy is the standard of care for the treatment of patients with good 
performance status (ECOG 0 or 1), advanced or metastatic, previously untreated NSCLC in 
whom EGFR or ALK-directed therapy is not indicated. Treatments include cisplatin or 
carboplatin in combination with either paclitaxel, gemcitabine, pemetrexed or docetaxel [32].  
Multiple Phase 3 studies have demonstrated similar efficacy for most platinum doublets in 
NSCLC patients; study ECOG 1594 being the most cited [33].
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% CI 0.99-1.15, p=0.100). These data support the interchangeable use of carboplatin or 
cisplatin in combination with standard of care antineoplastic agents [34]. 
In a non-inferiority, Phase 3 trial, overall survival in 1725 subjects with previously untreated 
NSCLC was found to be non-inferior after treatment with cisplatin and pemetrexed compared 
to cisplatin combined with gemcitabine (median survival 10.3 months vs 10.3 months; HR 
0.94; 95% CI 0.84–1.05%) [35]. However, in a planned subgroup analysis, cisplatin and 
pemetrexed was found to be superior in subjects with nonsquamous NSCLC (n = 1000; HR 
0.81; 95% CI, 0.7 – 0.94; p = 0.005). In contrast, subjects with squamous cell histology did
better with cisplatin and gemcitabine (n = 473; 10.8 months versus 9.4 months, respectively, 
p = 0.05). Pemetrexed and platinum therapy has become a significant treatment of choice for 
advanced nonsquamous NSCLC. Continuation of pemetrexed after initial four cycles of 
pemetrexed cisplatin demonstrated a survival benefit in a randomized double-blind, placebo-
controlled study: median overall survival 13.9 months (CI 12.8-16.0) for pemetrexed 
compared to 11.0 months (CI 10.0-12.5) for placebo and a hazard ratio of 0.78 (CI 0.64-0.96)
[36].
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
Lung cancer accounted for an estimated 13% of total cancer diagnoses, representing 
1.8 million new cases in 2012. Mortality from lung cancer in 2012 amounted to 1.6 million 
 
 
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deaths globally: the leading cause of cancer death in men and the second leading cause in 
women [37]. NSCLC accounts for approximately 85% of all lung cancer cases, with the 
majority being nonsquamous.
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%
[38]
the treatment of NSCLC remains a highly unmet medical need. Cytotoxic 
chemotherapies as single agents or in combination have served as the mainstay of treatment 
for decades with platinum containing doublets conferring the greatest advances in overall 
survival gains. As noted in Section 4.1.4, platinum and pemetrexed therapy has become a 
relative standard option for nonsquamous NSCLC.
Molecular profiling has, however, established a definite role for EGFR and ALK directed 
therapy in a small subset of NSCLC patients. The EGFR tyrosine kinase inhibitors gefitinib, 
erlotinib and afatinib have demonstrated marked superiority over chemotherapy in patients 
with activating EGFR mutations. In addition, agents that overcome resistance to initial 
therapy are also in development. Similarly, ALK inhibitors crizotinib and ceritinib have 
shown significant activity in ALK-rearranged NSCLC with more agents in development. 
Interestingly, the ALK inhibitors are also active in a rare subgroup of ROS-1 rearranged 
NSCLC patients. 
This study will, therefore, be restricted to nonsquamous NSCLC subjects in whom EGFR or 
ALK directed therapy is not indicated. Importantly, subjects will not be selected by PD-L1 
expression status, although this is a stratification factor.
Rationale for Dose Selection/Regimen/Modification
4.2.2
4.2.2.1
Rationale for Pembrolizumab Dose
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W.  The dose 
recently approved in the United States and several other countries for treatment of melanoma 
subjects is 2 mg/kg Q3W.  Information on the rationale for selecting 200 mg Q3W is 
summarized below.
KEYNOTE-001, an open-label Phase 1 study is being conducted to evaluate the safety, 
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), and anti-tumor 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) and dose 
expansion cohorts evaluated 2 mg/kg Q3W and 10 mg/kg Q3W in subjects with advanced 
solid tumors.  All dose levels were well tolerated and no dose-limiting toxicities were 
observed.  This first-in-human study of pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels.  No maximum 
tolerated dose (MTD) has been identified.  In addition, two randomized cohort evaluations of 
melanoma subjects receiving pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W 
have been completed, and one randomized cohort evaluating 10 mg/kg Q3W versus 
 
 
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10 mg/kg Q2W has also been completed.  The clinical efficacy and safety data demonstrate a 
lack of important differences in efficacy or safety profile across doses. 
An integrated body of evidence suggests that 200 mg every 3 weeks (Q3W) is expected to 
provide similar response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg Q2W.  Previously, 
a flat pembrolizumab exposure-response relationship for efficacy and safety has been found 
in subjects with melanoma in the range of doses between 2 mg/kg and 10 mg/kg.  Exposures 
for 200 mg Q3W are expected to lie within this range and will be close to those obtained with 
2 mg/kg Q3W dose.
A population pharmacokinetic (PK) model, which characterized the influence of body weight 
and other patient covariates on exposure, has been developed.  The PK profile of 
pembrolizumab is consistent with that of other humanized monoclonal antibodies, which 
typically have a low clearance and a limited volume of distribution.  The distribution of 
exposures from the 200 mg fixed dose are predicted to considerably overlap those obtained 
with the 2 mg/kg dose and importantly will maintain individual patient exposures within the 
exposure range established in melanoma as associated with maximal clinical response.  
Pharmacokinetic properties of pembrolizumab, and specifically the weight-dependency in 
clearance and volume of distribution are consistent with no meaningful advantage to weight-
based dosing relative to fixed dosing.   
In translating to other tumor indications, similarly flat exposure-response relationships for 
efficacy and safety as observed in subjects with melanoma can be expected, as the anti-tumor 
effect of pembrolizumab is driven through immune system activation rather than through a 
direct interaction with tumor cells, rendering it independent of the specific tumor type.  In 
addition, available PK results in subjects with melanoma, NSCLC, and other tumor types 
support a lack of meaningful difference in pharmacokinetic exposures obtained at tested 
doses among tumor types.  Thus, the 200 mg Q3W fixed-dose regimen is considered an 
appropriate fixed dose for other tumor indications as well.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage.  The existing data suggest 
200 mg Q3W as the appropriate dose for pembrolizumab.
4.2.2.2
Rationale for the Use of Placebo
The use of saline placebo in combination with standard chemotherapy will ensure the 
objectivity 
of 
investigator-assessed 
progression 
as 
well 
as 
any 
decisions 
to 
interrupt/discontinue therapy. Since randomization and placebo use can be a perceived 
barrier to subject enrollment, a 2:1 randomization will be used to enhance subject accrual.
 
 
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Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
Primary
PFS is an acceptable measure of clinical benefit for a randomized Phase 3 trial that 
demonstrates superiority of a new antineoplastic therapy, especially if the magnitude of 
effect is large and the therapy has an acceptable risk-benefit profile. Furthermore, it is an 
endorsed regulatory endpoint for first-line NSCLC trials with recent FDA and EMA 
approvals including the EGFR inhibitors afatinib and erlotinib. PFS will be assessed per 
RECIST 1.1 by central imaging vendor that will be blinded to the treatment assignment to 
minimize any bias in the response assessments.  In addition, final determination of radiologic 
progressive disease (PD) will be based on the central imaging vendor assessment of 
progression, rather than local site investigator/radiology assessment.  Expedited assessment 
by the central imaging vendor in instances of suspected radiological progression identified at 
the site (verification of PD) will be communicated to the study team. Approval of nivolumab 
in the second line setting as well as multiple clinical trial opportunities will make subject
crossover to a PD-1/PD-L1 agent from the control group almost certain and negate any 
ability to measure overall survival reliably.
OS has been recognized as the gold standard for the demonstration of superiority of a new 
antineoplastic therapy in randomized clinical studies.
Secondary
ORR based on RECIST 1.1 and assessed by BICR is an endpoint commonly accepted by 
both regulatory authorities and the oncology community.
DOR based on RECIST 1.1 and assessed by BICR is an endpoint commonly accepted by 
both regulatory authorities and the oncology community.
4.2.3.2
Immune-related RECIST (irRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with treatment of pembrolizumab.  Immunotherapeutic agents such as pembrolizumab may 
produce antitumor effects by potentiating endogenous cancer-specific immune responses.  
The response patterns seen with such an approach may extend beyond the typical time course 
of responses seem with cytotoxic agents, and can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions.
Standard RECIST 1.1 may, thus, not provide a complete response assessment of 
immunotherapeutic agents such as pembrolizumab.  Based on an analysis of patients with 
melanoma enrolled in KEYNOTE-001, 7% of evaluable subjects experienced delayed or 
early tumor pseudo-progression.  Of note, subjects who had progressive disease by RECIST 
1.1 but not by immune-related Response Criteria had longer OS than subjects with 
progressive disease by both criteria.  Additionally, the data suggest that RECIST 1.1 may 
underestimate the benefit of pembrolizumab in approximately 15% of subjects.  These 
findings support the need to apply a modification to RECIST 1.1 that takes into account the 
unique patterns of atypical response in immunotherapy and enable treatment beyond initial 
radiographic progression. However, it is not clear whether the same pattern will be observed 
 
 
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in combination with chemotherapy, hence RECIST 1.1 will remain the primary assessment 
method.
Immune-related RECIST (irRECIST) is RECIST 1.1 adapted to account for the unique tumor 
response seen with immune-therapeutics as described in [39].  The assessment of 
unidimensional target lesions and response categories per irRECIST are identical to RECIST 
1.1.  However, Merck has implemented an adaptation related to new lesions, non-target and 
tumor burden assessment in order to confirm radiographic progression.  irRECIST will be 
used by local site investigators to assess tumor response and progression, and make treatment 
decisions.
4.2.3.3
Rationale for Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of,
causality, and outcome of adverse events (AEs)/serious adverse events (SAEs); and changes 
in vital signs and laboratory values. Adverse events will be assessed as defined by CTCAE, 
Version 4.0.
4.2.3.4
Patient Reported Outcomes
EORTC QLQ-C30 and EORTC QLQ-LC13
4.2.3.4.1
The EORTC QLQ-C30 was developed to assess the quality of life of cancer subjects and is 
the most widely used cancer-specific HRQoL instrument.  It contains 30 items and measures 
five functional dimensions (physical, role, emotional, cognitive, and social), three symptom 
items (fatigue, nausea/vomiting, and pain), six single items (dyspnea, sleep disturbance, 
appetite loss, constipation, diarrhea, and financial impact) and global health and quality of 
life.  The global health and quality of life scale uses a 7 point scale scoring with anchors 
(1=very poor and 7=excellent); the other items are scored on a 4 point scale (1=not at all, 2=a 
little, 3= quite a bit, 4=very much).
The EORTC QLQ-LC13, a supplemental lung cancer-specific module used in combination 
with QLQ-C30, comprises multi-item and single-item measures of lung cancer-associated 
symptoms (cough, hemoptysis, dyspnea, and site specific pain) and treatment-related 
symptoms  (sore mouth, dysphagia, peripheral neuropathy and alopecia) [40]. 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 more than 60 languages.
The EORTC QLQ-C30 and QLQ-LC13 are the most frequently utilized and reported patient-
reported outcome measures in lung cancer clinical trials. The reliability, validity and 
practicality of these instruments have been reported [40] [41]. 
EuroQoL (EQ)-5D
4.2.3.4.2
The EuroQol-5D (EQ-5D) is a standardized instrument for use as a measure of health 
outcome.  The EQ-5D 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.  Each dimension is rated on a three point scale from 1 (extreme problem) 
 
 
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to 3 (no problem).  The EQ-5D also includes a graded (0 to 100) vertical visual analog scale 
on which the subject rates his or her general state of health at the time of the assessment.  The 
EQ-5D will always be completed by subjects first before completing the EORTC QLQ-C30 
and EORTC QLQ-LC13. 
4.2.3.5
Pharmacokinetic Endpoints
Blood samples will be obtained to measure pharmacokinetics (PK) of pembrolizumab, 
pemetrexed and carboplatin (or cisplatin).  
The pembrolizumab serum maximum concentration (Cmax) and minimum concentration 
(Ctrough) at planned visits and times will be summarized.  Pharmacokinetic data will also be 
analyzed using nonlinear mixed effects modeling.  Based on PK data obtained in this study as 
well as PK data obtained from other studies, a population PK analysis will be performed to 
characterize pharmacokinetic parameters (Clearance (CL), Volume of distribution (V)) and 
evaluate the effect of extrinsic and intrinsic factors to support proposed dosing regimen. 
Pharmacokinetic data will also be used to explore the exposure-response relationships for 
pembrolizumab antitumor activity/efficacy as well as safety in the proposed patient 
population, if feasible.
The results of these analyses, if performed, will be reported 
separately.  
To estimate the effect of pembrolizumab on the pharmacokinetics of pemetrexed and 
carboplatin (or cisplatin), pharmacokinetic studies will be conducted in a subset of research 
participants enrolled on this protocol. See Section 7.1.3.2 for additional details.
4.2.3.6
Planned Exploratory Biomarker Research
Planned Genetic Analysis
Understanding genetic determinants of drug response is an important endeavor during 
medical research. This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation. If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
Additional biomarker research to identify factors important for pembrolizumab therapy may 
also be pursued. For example, tumor and blood samples (including serum and plasma) from 
this study may undergo proteomic, genomic, metabolomic and transcriptional analyses. 
Additional research may evaluate factors important for predicting responsiveness or 
resistance to pembrolizumab therapy and other immunologic targets.
Assays may include but are not be limited to:
Immunohistochemistry
PD-L1 expression in tumor tissue will be characterized by immunohistochemistry to explore 
the relationship between tumor PD-L1 expression and response to treatment with 
pembrolizumab. Other exploratory biomarkers (e.g. PD-1 expression, markers of T-cell 
phenotype) may also be evaluated.
 
 
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Transcriptional Analyses
Messenger RNA (mRNA) expression profiling in archival material (biopsy specimens, 
peripheral blood) will be completed to assess expression of approximately 700 genes and 
attempt to define a gene set critical for clinical response to pembrolizumab. The hypothesis 
to be tested is that pembrolizumab induces responses in tumors that reflect an inflamed/ 
immune phenotype based on gene expression signatures capturing PD-L1 & interferon-
gamma transcriptional programs.  Global profiling will also be pursued.  Expression of 
individual genes related to the immune system may also be evaluated such as immune 
signatures and critical cytokines (e.g., IL-10). microRNA profiling may also be pursued in 
serum samples.
Proteomic analysis
In addition to expression on the tumor tissue, PD-L1 can be shed from tumor and released 
into the blood. Enzyme-linked immunoassay can measure PD -L1 in serum and correlate this 
expression with response to pembrolizumab therapy, as well as levels of PD-L1 IHC or 
protein in the tumor. Blood would be a less invasive compartment compared to tumor from 
which to measure PD-L1 protein biomarker. In addition to this specific protein biomarker, 
both tissue and blood derivatives can be subjected to proteomic profiling studies using a 
variety of platforms that could include but are not limited to immunoassay, Liquid 
chromatography/Mass Spectrometry. This approach could identify novel protein biomarker 
that could aid in patient selection for pembrolizumab therapy.
Gene Analyses
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to define certain tumor types at the genetic level as being
‘hypermutated’ or can detect the presence of specific T-cell clones within the tumor 
microenvironment or in the peripheral blood. There is a potential that the hypermutated state 
and/or increased T-cell clonality may correlate with response to pembrolizumab therapy, 
and/or that the converse, ‘hypomutated’ state or lack of dominant T-cell clones may correlate 
with non-response.
In addition, understanding genetic determinants of drug response is an important endeavor 
during medical research. This research will evaluate whether genetic variation within a 
clinical trial population correlates with response to the treatment(s) under evaluation. If 
genetic variation is found to predict efficacy or adverse events, the data might inform optimal 
use of therapies in the patient population.
4.2.3.7
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
 
 
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understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of this Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
4.3
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 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with nonsquamous NSCLC who have not received prior systemic 
chemotherapy treatment for their advanced or metastatic NSCLC, are at least 18 years of age 
and in whom EGFR or ALK-directed therapy is not indicated 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-confirmed or cytologically confirmed diagnosis of stage IV
(M1a or M1b- AJCC 7th edition) nonsquamous NSCLC.
2. Have
confirmation that EGFR or ALK-directed therapy is not indicated 
(documentation of absence of tumor activating EGFR mutations AND absence of 
ALK gene rearrangements OR presence of a K-Ras mutation). 
3. Have measurable disease based on RECIST 1.1 as determined by the local site 
investigator/radiology assessment.  Target lesions situated in a previously irradiated 
area are considered measurable if progression has been demonstrated in such lesions.
4. Have not received prior systemic treatment for their advanced/metastatic NSCLC. 
Subjects who received adjuvant or neoadjuvant
therapy are eligible if the 
adjuvant/neoadjuvant therapy was completed at least 12 months prior to the 
development of metastatic disease.
5. Have provided tumor tissue from locations not radiated prior to biopsy; formalin-
fixed specimens after the subject has been diagnosed with metastatic disease will be 
preferred for determination of PD-L1 status prior to randomization. Biopsies obtained 
 
 
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prior to receipt of adjuvant/neoadjuvant chemotherapy will be permitted if recent 
biopsy is not feasible.
6. Be ≥18 years of age on day of signing informed consent.
7. Have a life expectancy of at least 3 months.
8. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Status.
9. Have adequate organ function as indicated by the following laboratory values
[Table 1]:
Table 1  Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L– 4 weeks without transfusions
Renal
calculated creatinine clearance (CrCl)a
≥50 mL/min 
Hepatic
Serum total bilirubin
≤1.5xULN OR
Direct bilirubin ≤ULN for subjects with total bilirubin levels 
>1.5xULN
AST (SGOT) and ALT (SGPT)
≤2.5xULN  OR
≤5xULN for subjects with liver metastases
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT) or Partial Thromboplastin Time 
(PTT)
≤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 using the Cockcroft-Gault Method: Refer to Appendix 12.5 for 
appropriate calculation 
10. If female of childbearing potential (Section 5.7.2), have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication.  
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required. 
11. If female of childbearing potential (Section 5.7.2), be willing to use an adequate 
method of contraception as outlined in Section 5.7.2-Contraception, for the course of 
the study through 120 days after the last dose of study medication or through 180 
days after last dose of chemotherapeutic agents as specified in the protocol. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
12. If male subject with a female partner(s) of child-bearing potential, must agree to use 
an adequate method of contraception as outlined in Section 5.7.2-Contraception, 
starting with the first dose of study therapy through 120 days after the last dose of 
 
 
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study therapy or through 180 days after last dose of chemotherapeutic agents as 
specified in the protocol. 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 usual lifestyle and preferred contraception for 
the subject.
13. 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 predominantly squamous cell histology NSCLC. Mixed tumors will be
categorized by the predominant cell type; if small cell elements are present, the 
subject is ineligible.
2. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks prior to administration of pembrolizumab.
3. Before the first dose of trial treatment:
a) Has received prior systemic cytotoxic chemotherapy for metastatic disease
b) Has received antineoplastic biological therapy (e.g., erlotinib, crizotinib, 
cetuximab) for metastatic disease
c) Had major surgery (<3 weeks prior to first dose)
4. Received radiation therapy to the lung that is > 30 Gy within 6 months of the first 
dose of trial treatment.
5. Completed palliative radiotherapy within 7 days of the first dose of trial treatment.
6. Is expected to require any other form of antineoplastic therapy while on study.
7. Has received a live-virus vaccination within 30 days of planned treatment start. 
Seasonal flu vaccines that do not contain live virus are permitted.
8. Has clinically active diverticulitis, intra-abdominal abscess, GI obstruction, peritoneal
carcinomatosis.
9. Has a known history of prior malignancy except if the subject has undergone 
potentially curative therapy with no evidence of that disease recurrence for 5 years 
since initiation of that therapy.  
Note: The time requirement for no evidence of disease for 5 years does not apply 
to the NSCLC tumor for which a subject is enrolled in the study.  The time 
requirement also does not apply to subjects who underwent successful definitive 
resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous 
cell carcinoma of the skin, in situ cervical cancer, or other in situ cancers.
 
 
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10. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided they are clinically stable for at least 2 weeks and, have no evidence of new 
or enlarging brain metastases and also are off steroids 3 days prior to dosing with 
study medication.  Stable brain metastases by this definition should be established 
prior to the first dose of study medication. Subjects with known untreated, 
asymptomatic brain metastases (ie, no neurological symptoms, no requirements for 
corticosteroids, no or minimal surrounding edema, and no lesion >1.5 cm) may 
participate but will require regular imaging of the brain as a site of disease.
11. Previously had a severe hypersensitivity reaction to treatment with another mAb.
12. Has a known sensitivity to any component of cisplatin, carboplatin or pemetrexed
13. Has active autoimmune disease that has required systemic treatment in past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs).  Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.
14. Is on chronic systemic steroids. Subjects with asthma that require intermittent use of 
bronchodilators, inhaled steroids, or local steroid injections would not be excluded 
from the study. 
15. Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs 
(NSAIDs), other than an aspirin dose ≤ 1.3 g per day, for a 5-day period (8-day 
period for long-acting agents, such as piroxicam).
16. Is unable or unwilling to take folic acid or vitamin B12 supplementation.
17. Had prior treatment with any other anti-PD-1, or PD-L1 or PD-L2 agent or an 
antibody targeting other immuno-regulatory receptors or mechanisms.  Has 
participated in any other MK-3475 trial and has been treated with MK-3475.
Examples of such antibodies include (but are not limited to) antibodies against 
IDO, PD-L1, IL-2R, GITR
18. Has an active infection requiring therapy.
19. Has known history of Human Immunodeficiency Virus (HIV) (known HIV 1/2 
antibodies positive).
20. Has known active Hepatitis B or C. 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.
21. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation 
for the full duration of the study, or is not in the best interest of the subject to 
participate, in the opinion of the treating Investigator.
22. Has known psychiatric or substance abuse disorder that would interfere with 
cooperation with the requirements of the trial.
 
 
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23. Is, at the time of signing informed consent, a known regular user of any illicit drugs 
or had a recent history (within the last year) of substance abuse (including alcohol).
24. Has symptomatic ascites or pleural effusion. A subject who is clinically stable 
following treatment for these conditions (including therapeutic thoraco-
or 
paracentesis) is eligible.
25. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
26. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study.
Trial Treatment(s)
5.2
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which treatment is allocated.  The treatments to be used in this trial are outlined below in
[Table 2] and Section 5.2.2.
Table 2  Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment Period
Use
Pembrolizumab1
200 mg
Q3W
IV infusion
Day 1 of each 21 
day cycle
Experimental
Normal saline1
N/A
Q3W
IV infusion
Day 1 of each 21 
day cycle
Placebo
Cisplatin
75 mg/m 2
Q3W
IV infusion
Day 1 of each 21 
day cycle for 4 
cycles
Treatment of 
cancer 
(comparator)
Carboplatin
AUC 5
Q3W
IV infusion
Day 1 of each 21 
day cycle for 4 
cycles
Treatment of 
cancer 
(comparator)
Pemetrexed
500 mg/m 2
Q3W
IV infusion
Day 1 of each 21 
day cycle
Treatment of 
cancer 
(comparator)
1 Pembrolizumab/placebo to be administered prior to chemotherapy. 
All trial treatments will be administered on an out-patient basis.
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.
 
 
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Dose Selection/Modification
5.2.1
5.2.1.1
Dose Selection (Preparation)
Pembrolizumab: the dose amount required to prepare the pembrolizumab infusion solution 
will be based on a fixed dose of 200 mg.  Details on preparation and administration of 
pembrolizumab are provided in the Pharmacy Manual.
Concomitant standard chemotherapeutic agents will be prepared and administered as per the 
approved product label at the doses indicated below:

Pemetrexed: 500mg/m2

Cisplatin: 75mg/m2

Carboplatin: AUC 5 (using Calvert formula). Carboplatin dose not to exceed 750mg
Calvert Formula
Total Dose (mg) = (target AUC) x (CrCl + 25)
The estimated CrCl used in the Calvert formula should not exceed 125 mL/min
Maximum carboplatin dose (mg) = target AUC 5 (mg•min/mL) x (125 + 25) = 5 x 
150 mL/min = 750 mg
5.2.1.2
Dose Modification 
If appropriate, the Investigator may attribute each toxicity event to cisplatin/carboplatin, 
pemetrexed or pembrolizumab alone or to the combination and use a stepwise dose 
modification according to [Table 3] to [Table 7].  Dose modifications must be based on the 
maximum toxicity experienced during a cycle. Toxicity needs to resolve to Grade ≤1 or 
baseline prior to resuming subsequent cycle. For individual subjects requiring a dose 
modification, treatment for each new cycle may be delayed if the scheduled off-drug periods 
are not adequate to allow for recovery to Grade ≤1 or the baseline status of the subject.  
Pembrolizumab dose reductions are not permitted.  Pembrolizumab treatment may be 
interrupted or discontinued due to toxicity. If a dose reduction for toxicity occurs with any 
agent, the dose may not be re-escalated. Subjects can have a maximum of 2 dose 
modifications (if applicable) to each of the components of study therapy throughout the 
course of the study for toxicities.  If a subject experiences several toxicities and there are 
conflicting recommendations, the most conservative dose adjustment recommended should 
be followed (dose reduction appropriate to the most severe toxicity).  Subjects who require a 
3rd dose modification to any particular component will have that agent discontinued.
Reduction of one chemotherapy agent and not the other agent is appropriate if, in the opinion 
of the Investigator, the toxicity is clearly related to one of the treatments. If, in the opinion of 
the Investigator, the toxicity is related to the combination of both chemotherapy agents, both 
drugs should be reduced according to recommended dose modifications. If the toxicity is 
related to the combination of three agents, all three agents should be reduced (if applicable), 
interrupted or discontinued according to the recommended dose modifications. Subjects may 
have chemotherapy discontinued and continue on pembrolizumab/saline placebo alone.  
 
 
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Similarly subjects
may discontinue pembrolizumab/saline placebo and continue on 
chemotherapy alone if appropriate.
Chemotherapy may be interrupted for a maximum of 6 weeks from last dose; pembrolizumab 
may be interrupted for a maximum of 12 weeks from last dose.
The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) must be 
used to grade the severity of adverse events. All dose modifications should be based on the 
AE requiring the greatest dose modification. Dose modifications are detailed in [Table 3]
through [Table 7].
Table 3  Dose Modifications for Trial Medications
Dose Level 0
Dose Level -1
Dose Level -2
Dose Level -3
Cisplatin
75 mg/m2
56 mg/ m2
38 mg/ m2
Discontinue
Carboplatin
AUC 5
Maximum dose 
750mg
AUC 3.75
Maximum dose 
562.5mg
AUC 2.5
Maximum dose 
375mg
Discontinue
Pemetrexed
500mg/m2
375 mg/m2
250 mg/m2
Discontinue
Pembrolizumab/placebo
200 mg fixed dose
Dose reductions 
are not permitted
Dose reductions 
are not permitted
Dose reductions 
are not permitted
Dose Modification and Toxicity Management Guidelines for Pembrolizumab
5.2.1.2.1
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than on body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in [Table 4].
 
 
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Table 4
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated With 
Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and 
symptoms of pneumonitis

Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus).

Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis. 

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement 
therapy for participants with 
T1DM 

Administer anti-hyperglycemic in 
participants with hyperglycemia 

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
Renal 
dysfunction
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
 
 
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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:  
Gullain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in [Table 5]. 
Table 5 Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab
with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record.
Dose Modification for Chemotherapy
5.2.1.2.2
Recommended dose modifications for key chemotherapy toxicities are outlined in [Table 6]
and [Table 7]. These serve as a guide and do not replace investigator judgment and 
applicable local label recommendations if more stringent.
Table 6  Recommended Dose Modifications for Chemotherapy Hematological Toxicity
Pemetrexed
Cisplatin/Carboplatin
Platelets
ANC
Dose level (DL) from Table 3
≥50,000/mcL  AND
≥ 500/mcL
DL 0
DL 0
≥50,000/mcL  AND
< 500/mcL
DL -1
DL -1
<50,000/mcL without
bleeding AND
ANY
DL -1
DL -1
<50,000/mcL with Grade ≥ 2 
bleeding AND
ANY
DL -2
DL -2
ANY  AND
< 1,000/mcL + fever ≥ 
38.5°C (101°F)
DL -1
DL -1
 
 
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Table 7  Recommended Dose Modifications for Chemotherapy Non-Hematological Toxicity
Pemetrexed
Cisplatin
Carboplatin
Event
CTC Grade
Dose level (DL) from Table 3
Nausea or vomiting
Grade 3or 4
DL 0
DL 0
DL 0
Diarrhea
Grade 3or 4
DL -1
DL -1
DL 0
Mucositis
Grade 3or 4
DL -2
DL 0
DL 0
Neurotoxicity
Grade 2
DL 0
DL -2
DL 0
Grade 3or 4
DL -1
Discontinue
DL -1
Transaminase elevation
Grade 3
DL -1
DL -1
DL -1
Grade 4
Discontinue
Discontinue
Discontinue
Other non-hematological
toxicity
Grade 3or 4
DL -1
DL -1
DL -1
Creatinine clearance (CrCl):
CrCl will be based on the original weight-based Cockcroft and Gault formula (Section 12.5). 
CrCl must be ≥45mL/min prior to the administration of chemotherapy. Pemetrexed and/or 
platinum may be delayed for up to 42 days to allow the subject time to recover from the 
toxicity. If a subject’s CrCl value has not returned to ≥45 mL/min within 42 days after the 
previous dose, platinum and/or pemetrexed must be discontinued.
Timing of Dose Administration
5.2.2
Subjects will receive blinded pembrolizumab 200 mg or saline placebo together with 
pemetrexed 500mg/m2 (with vitamin supplementation) + cisplatin 75 mg/m2 OR carboplatin 
AUC 5  all on Day 1 Q3W for 4 cycles followed by blinded pembrolizumab 200 mg or saline 
placebo together with  pemetrexed 500 mg/m2 Q3W until progression/completion.
Trial treatment should be administered on Day 1 of each cycle after all procedures / 
assessments have been completed. Trial treatment can be administered 3 days of the 
targeted Day 1 for each cycle, except Cycle 1 when treatment can only be administered 
+3 days of the targeted Day 1.
All trial treatments will be administered on an out-patient basis.
For subjects who experience disease progression, investigators may elect to interrupt 
treatment by deferring the decision to continue/discontinue treatment in the trial until 
confirmation of disease progression per RECIST 1.1 at least 28 days from the date of 
imaging demonstrating disease progression confirmed by BICR.  Subjects for whom disease 
progression is not confirmed on subsequent imaging may resume treatment.  Please see 
Section 5.8 for other exceptions.
5.2.2.1
Pembrolizumab/Placebo
Pembrolizumab/saline placebo 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).  
 
 
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The Pharmacy Manual contains specific instructions for pembrolizumab reconstitution, 
preparation of the infusion fluid, and administration. 
5.2.2.2
Pemetrexed
Pemetrexed 500 mg/m2 will be administered as an IV infusion over 10 minutes Q3W until 
progression or unacceptable toxicity.  All subjects should receive the appropriate 
supplementation of vitamin B12 and folic acid and corticosteroid prophylaxis as listed below
(or as per local label):

Folic Acid 350-1000 μg oral: at least 5 doses of folic acid must be taken during the 
7 days preceding the first dose of pemetrexed, and folic acid dosing must continue 
during the full course of therapy and for 21 days after the last dose of pemetrexed.

Vitamin B12 1000 μg IM injection in the week preceding the first dose of pemetrexed 
and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be given 
the same day as pemetrexed administration.

Dexamethasone prophylaxis 4 mg, orally twice per day (or equivalent). Taken the day 
before, day of, and day after pemetrexed administration. Higher or additional doses 
are permitted for antiemetic prophylaxis during cycles 1-4 but not to exceed doses in 
MASCC guidelines (Section 12.6).
5.2.2.3
Cisplatin
Cisplatin 75mg/m2 should be infused approximately 30 minutes after the pemetrexed 
infusion for the first 4 cycles and should be immediately preceded and followed by hydration 
procedures and administered according to local practice and labels. 
5.2.2.4
Carboplatin
Carboplatin AUC 5 mg/mL/min will be administered as an IV infusion over 15-60 minutes 
Q3W for 4 cycles immediately after pemetrexed as per local practice and labels.  
5.2.2.5
Antiemetic Therapy
Antiemetic therapy should follow MASCC guidelines (http://www.mascc.org/antiemetic-
guidelines) and should, for the first four cycles, include a 5-HT3 receptor antagonist,
dexamethasone (or equivalent) and aprepitant (or equivalent) as per the MASCC guidelines.
Trial Blinding/Masking
5.2.3
This is a double-blinded trial; therefore, the subject, the investigator and Sponsor personnel 
or delegate(s) who are involved in the treatment administration or clinical evaluation of the 
subjects are unaware of the group assignments.  The chemotherapy agents will be open-label.  
The Sponsor, investigator and subject will not know whether the treatment administered 
contains pembrolizumab or saline placebo.  The study site’s unblinded pharmacist will obtain 
each subject’s study identification number and study drug assignment from the interactive 
voice response system (IVRS)/interactive web response system (IWRS) and prepare the 
solutions for infusion.  The unblinded pharmacist will provide the investigative staff with 
 
 
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ready-to-use blinded pembrolizumab/saline infusion solutions, packaged identically in order 
to maintain the blinding, for administration at scheduled infusion visits.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization
5.3
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 2 treatment arms.  
Subjects will be assigned randomly in a 2:1 ratio to pembrolizumab and chemotherapy or 
saline placebo and chemotherapy, respectively.  The choice of cisplatin or carboplatin 
treatment will be determined prior to randomization and documented in the IVRS/IWRS.  
The 2:1 ratio of pembrolizumab to chemotherapy is intended to enhance subject accrual.  
Stratification
5.4
Treatment allocation/randomization will be stratified according to the following factors:
1. PD-L1 expression: Tumor Proportion Score ≥1% vs <1%.  PD-L1 inevaluable 
subjects will be included with the TPS <1% group.
2. Platinum chemotherapy: cisplatin vs carboplatin 
3. Smoking status: never vs former/current
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy may be required.  
The investigator should discuss any questions regarding this with the Sponsor Clinical 
Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy schedule requires the mutual agreement of the investigator, the 
Sponsor and the subject.
Acceptable Concomitant Medications
5.5.1
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (eCRF) 
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 eCRF.
Palliative and supportive care is permitted during the course of the trial for underlying 
medical conditions and management of symptoms. Surgery or radiotherapy for tumor control 
is not permitted during the study; however, radiotherapy or procedures for symptom 
management is allowed.
 
 
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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.
Colony-Stimulating Factors
Routine use of colony-stimulating factors (CSFs) is not permitted. American Society of 
Clinical Oncology guidelines for use of CSFs should be followed [42].
Nonsteroidal Anti-Inflammatory Drugs
Subjects taking NSAIDs or salicylates will not take the NSAID or salicylate (other than an 
aspirin dose ≤1.3 grams per day) for 2 days before, the day of, and 2 days after receiving 
pemetrexed. Subjects taking NSAIDs or salicylates with a long half-life (for example, 
naproxen, piroxicam, diflunisal, or nabumetone) will not take the NSAIDs or salicylates for 5 
days before, the day of, and 2 days after pemetrexed.
Prohibited Concomitant Medications
5.5.2
Subjects are prohibited from receiving the following therapies during the Screening, 
Treatment, Crossover and Second Course Phases of this trial:

Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol.

Immunotherapy not specified in this protocol.

Chemotherapy not specified in this protocol.

Investigational agents other than pembrolizumab.

Radiation therapy; radiotherapy for symptom management is allowed.
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the Investigator’s discretion

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist ®) are 
live attenuated vaccines and are not allowed.

Prolonged therapy with systemic glucocorticoids (>7 days) for any purpose other than 
to modulate symptoms from an immune-related Adverse Event (as listed in 
Section 5.6.1) or for use as a pre-medication for chemotherapeutic agents specified in 
the protocol.  Brief, limited use of systemic corticosteroids (≤7 days) are permitted 
where such use is considered standard of care (e.g. as pre-medication for contrast 
allergy or for COPD exacerbation).  Replacement doses of steroids (for example, 
prednisone 10 mg daily) are permitted while on study.  The use of physiologic doses 
of corticosteroids may be approved after consultation with the Sponsor.

Phenytoin during therapy with cisplatin/carboplatin.
 
 
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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
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined in [Table 4]. Where appropriate, 
these guidelines include the use of oral or intravenous treatment with corticosteroids as well 
as additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab. 
Note: if after the evaluation the event is determined not to be related, the investigator does 
not need to follow the treatment guidance.  Refer to [Table 4] in Section 5.2.1 for guidelines 
regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Pemetrexed-Related Toxicity
5.6.2
Leucovorin is allowed: (1) for treatment of CTCAE Grade 4 leukopenia or Grade 4 
neutropenia lasting more than 3 days, beginning on the third day of Grade 4 
myelosuppression; or (2) immediately for treatment of Grade 4 thrombocytopenia, bleeding 
associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis.
The following doses and schedules are recommended for intravenous use:
•
leucovorin 100 mg/m2 intravenously once, followed by
•
leucovorin 50 mg/m2 intravenously every 6 hours for 8 days.
Appropriate doses of the oral formulation may also be used at the investigator’s discretion.
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.
 
 
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Contraception
5.7.2
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.
For this trial, male subjects will be considered to be of non-productive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).
Female subjects will be considered of non-reproductive potential if they are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug or 180 days after the last dose of chemotherapeutic agents by 
complying with one of the following:  
(1) practice abstinence† from heterosexual activity; 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):
•
intrauterine device (IUD)
•
vasectomy of a female subject’s male partner 
•
contraceptive rod implanted into the skin
Combination method (requires use of two of the following):
•
diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide)
•
cervical cap with spermicide (nulliparous women only)  
•
contraceptive sponge (nulliparous women only) 
•
male condom or female condom (cannot be used together)
 
 
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•
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy or through 180 days after the last dose of 
chemotherapeutic agents as specified in the protocol.  If there is any question that a subject of 
childbearing potential will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study.
Use in Pregnancy
5.7.3
If a female subject inadvertently becomes pregnant while on treatment in this study, the 
subject will immediately be discontinued from trial treatment. The site will contact the 
subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated. The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor. 
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 
 
 
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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.  Once a 
subject has discontinued treatment for CR or after receiving the maximum 35 treatments, 
even though he/she continues to be monitored in the trial, he/she may be allowed to begin 
treatment again if deemed medically appropriate.
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.

Investigator’s decision to withdraw the subject from the trial

The subject is lost to follow-up

Administrative reasons
A subject must be discontinued from trial treatment but continue to be followed for any of 
the following reasons:

The subject or legal representative (such as parent or legal guardian) requests to 
discontinue treatment.

Unacceptable adverse experiences as described in Section 7.2.

Intercurrent illness that prevents further administration of treatment

Confirmed radiographic disease progression outlined in Section 7.1.5 (exception if 
the Sponsor approves treatment continuation)
Note: If a subject has confirmed progression of disease by RECIST 1.1, the subject 
may be unblinded and have the opportunity to crossover to receive open-label 
pembrolizumab monotherapy if he/she was receiving saline placebo and meets all 
crossover criteria defined in Section 7.1.5.5; a subject who was receiving 
pembrolizumab and is deemed to be clinically benefiting despite progression will 
have the opportunity to continue open-label pembrolizumab monotherapy.  If a 
subject has unconfirmed progression of disease and is clinically stable, it is at the 
discretion of the investigator to continue treating the subject with the assigned 
treatment per protocol until progression of disease is confirmed at least 28 days from 
the date of the scan suggesting progression of disease.
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.
3) Absence of rapid progression of disease or progressive tumor at critical 
anatomical sites (eg, cord compression) requiring urgent alternative medical 
intervention.

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
 
 
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
Intercurrent illness other than another malignancy as noted above that prevents 
further administration of treatment

Recurrent Grade 2 pneumonitis

A confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

Investigator’s decision to withdraw the subject from trial treatment

Completion of 35 treatments (approximately 2 years) with pembrolizumab/placebo
Note: The number of treatments is calculated starting with the first dose.  Subjects 
who stop the combination or pembrolizumab after receiving 35 doses may be eligible 
for retreatment if they progress after stopping trial treatment provided they meet the 
requirements detailed in Section 7.1.5.4. Subjects may be retreated in the Second 
Course Phase (Retreatment) for up to an additional 17 cycles (approximately 1 year).

Discontinuation of treatment may be considered for subjects who have attained a
confirmed complete response (CR) and have been treated for at least 8 cycles (at 
least 24 weeks), receiving 2 cycles of the combination including 2 doses of 
pembrolizumab/placebo beyond the date when the initial CR was declared. 
Subjects who stop the combination with stable disease (SD), partial response (PR), or 
CR, may be eligible for up to 1 year (17 cycles) of pembrolizumab if they experience 
disease progression after stopping combination trial treatment.  This retreatment is 
termed the Second Course Phase (Retreatment) and is described in detail in Section 
7.1.5.4.
Chemotherapy may be discontinued when a subject has received the maximum number of 
cycles permitted by the local regulatory authority.

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 adverse event monitoring even 
if the subject started new antineoplastic treatment (serious adverse events will be 
collected for up to 90 days following cessation of Sponsor’s product, or 30 days 
following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier as described in Section 7.2.3.1). 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 each subject will either 
move into the Second Course Phase or be followed for overall survival until death or 
withdrawal of consent.
This study will be considered complete in terms of primary endpoint following the 
final analysis of PFS, after the pre-specified number of PFS events.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
 
 
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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 study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.11
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
 
 
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6.0 TRIAL FLOW CHART
Initial Treatment Phase
6.1
Details regarding the procedures listed in this table are outlined in Section 7.0.
Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
Post Treatment
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36 
+
Discon
Safety 
Follow-up
Follow-up 
Visits
Survival 
Follow-
up1
Scheduling Window (Days):2
-28 to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon
30 Days 
Post 
Discon
Every 6 
Weeks Post 
Safety 
Follow-up
±7 days
Every 12 
Weeks
±14 days
Administrative Procedures
Informed Consent 
X
Informed Consent for Future Biomedical 
Research (optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X19
X19
NSCLC Disease Details and Prior 
Treatment
X
Obtain allocation number using IVRS17
X
Subsequent antineoplastic therapy status
X
X
X
X
Survival Status1
X
Clinical Procedures / Assessments
Review Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
Directed Physical Examination
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weight 
X
X3
X
X
X
X
X
X
X
X
X
SpO2
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
ECOG Performance Status
X4
X18
X
X
X
X
X
X
X
X
X
X
 
 
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Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
Post Treatment
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36 
+
Discon
Safety 
Follow-up
Follow-up 
Visits
Survival 
Follow-
up1
Scheduling Window (Days):2
-28 to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon
30 Days 
Post 
Discon
Every 6 
Weeks Post 
Safety 
Follow-up
±7 days
Every 12 
Weeks
±14 days
Laboratory Procedures / Assessments: Analysis Performed by Local Laboratory6
Pregnancy Test - Urine or Serum β-HCG 5
X
PT/INR and aPTT/PTT
X4
CBC  with Differential 6
X4
X
X
X
X
X
X
X
X
X
Comprehensive Chemistry Panel6
X4
X
X
X
X
X
X
X
X
X
Creatinine Clearance Calculation
X4
X
X
X
X
X
X
X
X
X
Urinalysis6
X4
X7
X7
X7
X
X
T3 or FT3, FT4 and TSH 6
X4
X
X
X8
X8
X8
X
X
KL-6, SP-D
X
X
X
X
X
X
X
X
X
X
Analysis Performed by Central Laboratory
Pembrolizumab Pharmacokinetics 9
X
X
X
X
X
Anti-pembrolizumab Antibodies 9
X
X
X
X
X
Blood for Genetics (DNA)15
X
Pharmacokinetics for Pemetrexed, 
Carboplatin and Cisplatin14
X
X
X
Blood for Correlative Studies (DNA and 
RNA)
X
X
X
X16
Blood for Biomarker Studies (Plasma and 
Serum)
X
Tumor Tissue Collection
Newly Obtained Tissue Collection for PD-
L1 Biomarker Analysis
X
Efficacy Measurements
Tumor Imaging 
X
X10
X10
X10
X11
X11
X12
X12
Study Drug Administration
Cisplatin or carboplatin
X
X
X
X
 
 
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Screening 
Phase
Treatment Cycles  (3-Week Cycles)
End of 
Treatment
Post Treatment
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4
5
6 to 
17
18 to 
35
36 
+
Discon
Safety 
Follow-up
Follow-up 
Visits
Survival 
Follow-
up1
Scheduling Window (Days):2
-28 to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At Time of 
Discon
30 Days 
Post 
Discon
Every 6 
Weeks Post 
Safety 
Follow-up
±7 days
Every 12 
Weeks
±14 days
Pemetrexed
X
X
X
X
X
X
X
X
Pembrolizumab or Saline Placebo
X
X
X
X
X
X
X
Patient Reported Outcomes (PRO)
EuroQol (EQ)-5D13
X
X
X
X
X
X
X
X
X
X
EORTC QLQ-C3013
X
X
X
X
X
X
X
X
X
X
EORTC QLQ-LC1313
X
X
X
X
X
X
X
X
X
X
1.
After documented disease progression, or the start of new anti-cancer treatment; contacts are approximately every 12 weeks by telephone. Updated survival status may be 
requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants who do not/will not have a scheduled study visit or study 
contact during the Sponsor-defined time period will be contacted for their survival status (excluding participants who have a death event previously recorded).
2.
In general, the window for each visit is ± 3 days unless otherwise noted.  
3.
Height will be measured only at Visit 1.
4.
ECOG and laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment.
5.
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment. A serum test can be considered if 
urine is not appropriate. Monthly pregnancy testing should be conducted as per local regulations where applicable.
6.
After Cycle 1, lab samples can be collected up to 3 days prior to Day 1 of subsequent cycles.
7.
To be repeated every 6 cycles after beginning with Cycle 6.
8.
To be repeated every other Cycle beginning with Cycle 6.
9.
Pre-dose trough for both PK and anti-pembrolizumab antibody samples will be collected at Cycles 1, 2, 4, 6, 8 and every 4 cycles thereafter, and 30 days after 
discontinuation of study drug (or until the subject starts new anti-cancer therapy).  All pre-dose trough samples should be drawn within 24 hours before infusion of 
pembrolizumab/saline placebo.  Additional post-dose peak PK samples will be drawn within 30 minutes after end of pembrolizumab/saline placebo infusion at Cycles 1 
and 8.  An additional single PK sample should be drawn at 24 hours (Day 2), between 72 and 168 hours (Day 4-8) and 336 hours (Day 15) after Cycle 1 dosing. Collection 
windows are found in the Procedures Manual.
10. Imaging performed at 6 weeks (± 7 days) and 12 weeks (± 7 days) and then every 9 weeks (63 days ± 7 days) for the first 48 weeks in the treatment period.
11. Imaging performed every 12 weeks (84 days ± 7 days) subsequently.
12. If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not mandatory. Follow up scans to be 
performed using the same imaging schedule used while on treatment (that is, every 6 or 9 weeks in year 1 or 12 weeks after year 1).
13. In year 1 (Cycles 1 to 17), PROs are completed at Cycles 1 through 5 and then every 3rd cycle (every 9 weeks) while on treatment; in years 2 and 3 (Cycle 18 and beyond), 
PROs are completed every 4th cycle (every 12 weeks) while on treatment.  PROs are also completed at treatment discontinuation visit and 30-day safety follow-up visit. See 
 
 
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Section 7 for additional details.
14. Details on collection times are presented in Section 6.1.1.
15. This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is 
collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned genetic analysis is not approved, but 
FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
16. At treatment discontinuation if subject discontinues prior to Cycle 3.
17. Obtaining allocation number should be performed within 3 days prior to the first dose of trial treatment.
18. Does not have to be done if Screening ECOG was performed within 3 days prior to Cycle 1.
19. After the Safety Follow-up Visit record all medications taken for SAEs and ECIs as defined in Section 7.2.
 
 
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Pharmacokinetic Collection Schedule for Pemetrexed, Carboplatin and Cisplatin
6.1.1
Sample collection will be in a sub-set of subjects, see Section 7.1.3.2.2 for details.
Cycle 1
(21 Days)
Cycle 2
(21 Days)
Cycle 4
(21 Days)
Cycle Day
1
1
1
1
1
1
1
1
2
3
4
1
1
1
2
1
1
1
2
Time Points (hours)5
Pre
Post (end of 
infusion)
.5
1
2
4
6 
8
24
48
72
Pre
Post
2
24
Pre
Post
2
24
Pemetrexed
X1
X2
X
X
X
X
X
X3
X3
X3
Carboplatin
X1
X2
X4
X
X
X
X
X3
Cisplatin
X1
X2
X
X3
X1
X2
X
X3
X1
X2
X
X3
Please note: Actual drug dosing and PK/pharmacodynamic sampling times have to be documented by the sites and will be captured in the database.  
Sample collection must be from opposite arm to that used for study drug administration/infusion.  If drug was administered via a central venous catheter, sample collection for PK 
should be from a different site.
1.
Predose collection should be within 60 minutes of dosing (hour 0) each cycle PK is collected.
2.
Post-dose collection should be within 15 minutes after the end of infusion.  The infusion duration for pemetrexed is 10 minutes (0.17 hour), carboplatin is 15-60 minutes, and 
cisplatin is 30 minutes.  The detail of PK collection including time window is written in the Procedure Manual.   
3.
Window: ±2 hours.
4.
Carboplatin is planned to be administered as an IV infusion over 15 to 60 minutes Q3W for 4 cycles immediately after pemetrexed.  If infusion duration is 45-60 min, then 1 
hour sample can be eliminated as end of infusion sample collection (Post) would cover this 1 hour time point.   
5.
Time relative to initiation of each drug administration.   
 
 
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Second Course Phase (Retreatment)
6.2
Details regarding the procedures listed in this table are outlined in Section 7.0.  Second course retreatment subjects may receive up to 
17 cycles (approximately 1 year) of pembrolizumab therapy.  
Trial Period:
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
1
2
3
4
To be Repeated 
Beyond 6 Cycles
Discon
Safety 
Follow-
up
Follow 
Up Visits
Survival 
Follow-
up1
5
6
Scheduling Window (Days)2:
+3
± 3
± 3
± 3
± 3
± 3
At Time 
of Discon
30 Days 
Post 
Discon
Every 6 
Weeks 
Post 
Safety 
Follow up
±7 days
Every 
12 
Weeks
±14 
days
Administrative Procedures
Eligibility Criteria
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
X9
X9
Subsequent antineoplastic therapy status
X
X
X
X
Survival Status1
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
Directed Physical Examination
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
SpO2
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
Laboratory Procedures/Assessments:  analysis performed 
by LOCAL laboratory
Pregnancy Test – Serum or Urine3
X
Hematology4
X5
X
X
X
X
X
X
X
Chemistry Panel4
X5
X
X
X
X
X
X
X
Urinalysis4
X5
X6
X
X
T3 or FT3, FT4, TSH4
X5
X
X6
X
X
KL-6, SP-D
X
X
X
X
X
X
X
X
Efficacy Measurements
Tumor Imaging
X7
X8
X8
X8
X8
Study Drug Administration
Pembrolizumab 
X
X
X
X
X
X
 
 
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1. After documented disease progression, or the start of new anti-cancer treatment; contacts are approximately every 12 weeks by telephone. Updated survival status may be 
requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants who do not/will not have a scheduled study visit or study 
contact during the Sponsor-defined time period will be contacted for their survival status (excluding participants who have a death event previously recorded).
2. In general, the window for each visit is ± 3 days unless otherwise noted.
3. For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment. A serum test can be considered if urine
is not appropriate. Monthly pregnancy testing should be conducted as per local regulations where applicable.
4. After Cycle 1, lab samples can be collected up to 3 days prior to the scheduled time point.  
5. Laboratory tests for determining eligibility for retreatment are to be performed within 10 days prior to the first retreatment dose of pembrolizumab.  
6. To be repeated every 4 cycles after Cycle 5.
7. A scan must be performed within 30 days prior to restarting treatment with pembrolizumab.
8. Imaging performed every 12 weeks (84 ± 7 days).
9. After the Safety Follow-up Visit record all medications taken for SAEs and ECIs as defined in Section 7.2.
 
 
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Crossover Phase
6.3
Only applicable for subjects who are unblinded after verification of PD by BICR and deemed eligible for the crossover phase if 
initially in the placebo arm or for continued treatment despite PD in the pembrolizumab arm.  Subjects may receive up to a total of 
35 cycles (approximately 2 years) of pembrolizumab monotherapy. Details regarding the procedures listed in this table are outlined in 
Section 7.0.
Treatment Cycles1
End of Treatment 
Phase
Follow up Phase8
Survival 
Follow up11
Treatment Cycle / 
Scheduled Time
14
2
3
4
5
6
7
8
9
10
11
12
13
14 
throug
h 35
Discontin
uation 
Visit6
Safety 
Follow 
up 
Visit 7
Follow 
up Visit 
1
Follow 
up 
Visit 2
Follow 
up 
Visit 3 
and 
Beyond
Survival 
Follow up 
Visit 1 and 
Beyond
Scheduling 
Window (Days):
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 
3
± 3
± 
3
± 
3
± 3
± 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
Every 
3 
Months 
±14
Administrative Procedures
Prior and 
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X12
X12
Subsequent 
antineoplastic 
therapy status
X
X
X
X
X
X
Survival Status11
X
Clinical Procedures / Assessments
Review Adverse 
Events 9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical 
Examination
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and 
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SpO2
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 laboratory2
CBC  with 
Differential
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PT/INR and 
aPTT/PTT 
X
Comprehensive 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
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Treatment Cycles1
End of Treatment 
Phase
Follow up Phase8
Survival 
Follow up11
Treatment Cycle / 
Scheduled Time
14
2
3
4
5
6
7
8
9
10
11
12
13
14 
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Discontin
uation 
Visit6
Safety 
Follow 
up 
Visit 7
Follow 
up Visit 
1
Follow 
up 
Visit 2
Follow 
up 
Visit 3 
and 
Beyond
Survival 
Follow up 
Visit 1 and 
Beyond
Scheduling 
Window (Days):
+3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 
3
± 3
± 
3
± 
3
± 3
± 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
Every 
3 
Months 
±14
Chemistry Panel
Urinalysis
X
X
X
X
X
X
X
T3 or FT3, FT4 and 
TSH
X
X
X
X
X
X
X
X
X
X
KL-6, SP-D
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Efficacy Measurements
Tumor Imaging3
X
X
X
X
X
X10
X10
X10
X10
Study Drug Administration
Pembrolizumab5
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 ± 3 days).  If treatment cycles are adjusted all procedures except imaging will be completed according to the Cycle number and not weeks on 
treatment, imaging will be performed every 12 weeks (84 days ± 7 days) from the first dose of trial treatment regardless of any treatment delays.
2.
Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment. After Cycle 1, lab samples can be collected up to 72 hours prior to 
the scheduled time point. Laboratory results must be known prior to dosing. Urinalysis: perform every 6 cycles after Cycle 13. T3 or FT3, FT4, and TSH: perform every 2 
cycles after Cycle 14; thyroid function tests will be performed by a central lab only if the local laboratory is unable to perform this service. See Section 7.1.3 for details 
regarding laboratory tests.  
3.
Blinded 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 12 weeks (84 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., immune-related RECIST or standard RECIST v 1.1 on the 
discontinuation form. 
4.
Screening can initiate once progressive disease have been verified by the blinded central radiology review.  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. 
5.
Treatment with Pembrolizumab should not initiate until at least 21 days after the last dose of chemotherapy regardless of the time of progression.  Pembrolizumab can be 
administered for up to 2 years.
6.
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.
7.
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 
 
 
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days) from last dose trial treatment the same procedures do not need to be repeated for the Safety Follow-up Visit.
8.
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.
9.
Once a subject discontinues study treatment, report all SAEs (related and unrelated to trial treatment) 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, and ECIs occurring within 30 days following cessation of treatment.  
After this time, report only SAEs that are considered related to trial treatment.
10. Tumor imaging is not needed for subjects who start another anti-cancer treatment regimen.
11. Once the subject stops the imaging assessments for this protocol (eg, 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 12 weeks 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 participants who do not/will 
not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding participants who have a death 
event previously recorded).
12. After the Safety Follow-up Visit record all medications taken for SAEs and ECIs as defined in Section 7.2.
 
 
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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 
trial or 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.
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 
 
 
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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.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinical significant by the Investigator.  Details regarding the subject’s 
lung cancer will be recorded separately and not listed as medical history.  
The investigator or qualified designee will obtain prior and current details regarding the 
subject’s lung cancer.
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 
during the screening period (Day -30 through Day -1 of trial treatment start).  Prior anti-
cancer treatment for NSCLC will be recorded separately and not listed as a prior medication. 
The investigator or qualified designee will review and record all prior anti-cancer treatments 
including systemic treatments, radiation, and surgeries, regardless of the time prior to first 
dose of trial treatment.
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 Safety Follow-up Visit.  In addition, new medications started 
during the Crossover Phase and Second Course Phase through the Crossover Safety Follow-
up Visit and Second Course Phase Safety Follow-up Visit, respectively, should be recorded.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7.2.
 
 
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Subsequent Anti-Cancer Therapy Status
7.1.1.5.3
The investigator or qualified designee will review all new anti-cancer therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first new dose of the new therapy.  Once new anti-cancer therapy has been initiated the 
subject will move into survival follow-up. 
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
7.1.1.7
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
pembrolizumab doses for non-drug-related or administrative reasons (see Section 5.2.1.2 for 
drug-related modifications) require consultation between the investigator and the Sponsor 
and written documentation of the collaborative decision on subject management.
Trial medication will be administered by site and/or institution staff per local SOPs and 
guidelines.  The total volume of pembrolizumab infused will be compared to the total volume
prepared to determine compliance to each dose of pembrolizumab administered.
The instructions for preparing and administering pembrolizumab will be provided in the 
Pharmacy Manual.
Clinical Procedures/Assessments
7.1.2
7.1.2.1
Adverse Event (AE) 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 12.7). Toxicities 
 
 
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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 adverse event 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 adverse event immune related.  Immunological, serological and 
histological (biopsy) data should be used to support the diagnosis of an immune-related 
toxicity.  
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.
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
12-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 medical history.   
Additional ECGs may be performed as clinically necessary. 
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The Investigator or qualified designee will assess ECOG status (see Section 12.8) 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.
ECOG at Cycle 1 of Initial Treatment Phase does not have to be done if screening ECOG 
was performed within the prior 3 days.
 
 
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7.1.2.6
Pulse Oximetry (SpO2)
Pulse oximetry will be performed using local standard procedures once at screening, prior to 
the administration of each dose of trial treatment, at Discontinuation Visit, and at Safety 
Follow-up Visit as specified in the Trial Flow Chart.
7.1.2.7
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual (SIM).  Tumor imaging should be acquired by computed 
tomography (CT, strongly preferred).  Magnetic resonance imaging (MRI) should be used 
when CT is contraindicated or for imaging in the brain.  The same imaging technique 
regarding modality and use of contrast should be used in a subject throughout the trial to 
optimize the visualization of existing and new tumor burden.
Local site investigator/radiology assessment based on RECIST 1.1 will be used to determine 
subject eligibility. Although RECIST 1.1 references to maximum of 5 target lesions in total 
and 2 per organ, Merck allows maximum of 10 target lesions in total and 5 per organ.  All 
scheduled images for all study subjects from the sites will be submitted to the central 
imaging vendor. In addition, additional imaging (including other modalities) that are 
obtained at unscheduled time points to determine disease progression, as well as imaging 
obtained for other reasons but captures radiologic progression, should be submitted to the 
central imaging vendor.
The central imaging vendor will verify progressive disease (PD) upon request following local 
site investigator-assessed radiologic evidence of PD.  Verification of progression is one of 
the qualification criteria for Crossover Phase.  Expedited verification of radiologic PD by the 
central imaging vendor will be communicated to the study site and sponsor (See Section 
7.1.2.7.5).
Initial Tumor Imaging
7.1.2.7.1
Initial tumor imaging at screening must be performed within 28 days prior to the date of 
randomization.  The site study team must review screening images to confirm the subject has 
measurable disease per RECIST 1.1. The screening images must be submitted to the central 
imaging vendor for retrospective confirmation of eligibility.
Scans performed as part of routine clinical management are acceptable for use as screening
tumor imaging if they are of diagnostic quality and performed within 28 days prior to the 
date of randomization and can be assessed by the central imaging vendor. 
Subjects with previously treated brain metastases may participate provided they have stable 
brain metastases. Any neurologic symptoms must have returned to baseline and subjects 
must have no clinical evidence of new or enlarging brain metastases, and have not used 
steroids for brain metastases for at least 3 days prior to trial initiation as per local site 
assessment. This exception does not include carcinomatous meningitis, as subjects with 
carcinomatous meningitis are excluded regardless of clinical stability.
 
 
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Tumor Imaging During the Trial
7.1.2.7.2
The first on-study imaging assessment should be performed at 6 weeks (42 days ±7 days) and
again at 12 weeks (84 days ±7 days) from the date of randomization. Subsequent tumor 
imaging should be performed every 9 weeks (63 days ±7 days) or more frequently if 
clinically indicated.  After 48 weeks, subjects who remain on treatment will have imaging 
performed every 12 weeks (84 days ±7 days).  Imaging timing should follow calendar days 
and should not be adjusted for delays in cycle starts. Imaging should continue to be 
performed until disease progression verified by central imaging vendor (unless site PI elects 
to continue treatment and follow irRECIST), the start of new anti-cancer treatment, 
withdrawal of consent, or death, whichever occurs first. All supplemental imaging must be 
submitted to the central imaging vendor.
Per RECIST 1.1, partial and complete response should be confirmed by a repeat tumor
imaging assessment not less than 4 weeks from the date the response was first documented.  
The tumor imaging for confirmation of response may be performed at the earliest 4 weeks 
after the first indication of response, or at the next scheduled scan (i.e. 6, 9 or 12 weeks 
later), whichever is clinically indicated.  Subjects will then return to regular scheduled 
imaging, starting with the next scheduled imaging time point. Subjects who obtain a 
confirmation scan do not need to undergo the next scheduled tumor imaging if it is < 4 weeks 
later; tumor imaging may resume at the subsequent scheduled imaging time point.
Per irRECIST (Section 7.1.2.7.6), disease progression should be confirmed by the site at least 
4 weeks after central verification of site-assessed 1st radiologic evidence of PD in clinically 
stable subjects.  Subjects who have unconfirmed disease progression may continue on 
treatment at the discretion of the site investigator until progression is confirmed by the site
provided they have met the conditions detailed in Section 7.1.2.7.6. Subjects who obtain a 
confirmation scan do not need to undergo the next scheduled tumor imaging if it is < 4 weeks 
later; tumor imaging may resume at the subsequent scheduled imaging time point if clinically 
stable. Subjects who have confirmed disease progression as assessed by the site will 
discontinue the treatment. Exception is detailed in Section 7.1.2.7.6.
End of Treatment and Follow-up of Tumor Imaging
7.1.2.7.3
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (± 4 week window).  If a previous scan was obtained within 4 
weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not
mandatory. In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, tumor 
imaging using the same imaging schedule used while on treatment (every 6 or 9 weeks in 
year 1 or 12 weeks after year 1) to monitor disease status until (1) the start of new anti-cancer 
treatment, (2) disease progression, (3) death, or (4) the end of the study, whichever occurs 
first, should be used.
Second Course (Retreatment) and Crossover Tumor Imaging
7.1.2.7.4
A scan must be performed within 30 days prior to starting/restarting treatment with 
pembrolizumab.  Local reading (investigator assessment with site radiology reading) will be 
 
 
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used to determine eligibility.  Imaging should be submitted to the central imaging vendor for 
retrospective verification.
The first on-study imaging assessment should be performed at 12 weeks (84 days ±7 days) 
after the start/restart of treatment.  Subsequent tumor imaging should be performed every
12 weeks (84 days ±7 days) or more frequently if clinically indicated.
Per RECIST 1.1, partial or complete response should be confirmed by a repeat tumor 
imaging assessment not less than 4 weeks from the date the response was first documented.  
The tumor imaging for confirmation of response may be performed at the earliest 4 weeks 
after the first indication of response, or at the next scheduled scan, whichever is clinically 
indicated. Subjects will then return to regular scheduled imaging every 12 weeks (84 days ±7 
days), starting with the next scheduled imaging time point. Subjects who obtain a 
confirmation scan do not need to undergo scheduled tumor imaging if it is < 4 weeks later 
and may wait until the next scheduled imaging time point.
Per irRECIST (Section 7.1.2.7.6), if tumor imaging shows initial PD, tumor assessment 
should be repeated ≥ 4 weeks later in order to confirm PD with the option of continuing 
treatment while awaiting radiologic confirmation of progression. Subjects who obtain a 
confirmation scan do not need to undergo scheduled tumor imaging if it is < 4 weeks later 
and may wait until the next scheduled imaging time point if clinically stable.
Imaging should continue to be performed until disease progression, the start of new anti-
cancer treatment, withdrawal of consent, death, or notification by the Sponsor, whichever 
occurs first.  Disease progression may be confirmed at least 4 weeks after the first tumor 
imaging indicating progressive disease in clinically stable subjects.
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (± 4 week window).  If a previous scan was obtained within 4 
weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not
mandatory. In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by radiologic imaging every 
12 weeks (84 days ± 7 days) until (1) the start of new anti-cancer treatment, (2) disease 
progression, (3) death, or (4) the end of the study, whichever occurs first.
RECIST 1.1 Assessment of Disease
7.1.2.7.5
RECIST 1.1 will be applied by the central imaging vendor as the primary measure for 
assessment of tumor response, date of disease progression, and as a basis for all protocol 
guidelines related to disease status (e.g., discontinuation of study therapy). Initial tumor 
imaging showing site-assessed PD should be submitted to the central imaging vendor 
immediately
only if the investigator intends to cross over without hesitation to 
pembrolizumab monotherapy. The site will be notified if the central imaging vendor verifies 
progressive disease (PD) using RECIST 1.1.
 
 
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irRECIST Assessment of Disease
7.1.2.7.6
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic
drugs. irRECIST
will be used by site 
investigator/local radiology review to assess tumor response and progression, and make 
treatment decisions. This data will be collected in the clinical database. Treatment efficacy 
based on irRECIST as assessed by central imaging vendor review will be evaluated 
retrospectively.
When feasible, subjects should not be discontinued until progression is confirmed by the 
local site investigator/radiology assessment.  This allowance to continue treatment despite 
initial radiologic progressive disease (PD) takes into account the observation that some 
subjects can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response.  Subjects that are deemed 
clinically unstable are not required to have repeat tumor imaging for confirmation of PD.  
Tumor flare includes any of the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing non-target lesion(s)

Development of new lesions(s)
In subjects who have initial evidence of radiological PD by RECIST 1.1, it is at the discretion 
of the PI whether to continue a subject on study treatment until repeat imaging is obtained 
(using irRECIST for subject management, see [Table 8]).  This clinical judgment decision by 
the site should be based on the subject’s overall clinical condition, including performance 
status, clinical symptoms, and laboratory data.
Subjects may receive study treatment and 
tumor assessment should be repeated ≥ 4 weeks later in order to confirm PD by irRECIST 
per site assessment.  If PD is confirmed by irRECIST, a request should be submitted to the 
central imaging vendor to verify PD.  Clinical stability is defined as the following: 
1) Absence of symptoms and signs indicating clinically significant progression of disease, 
including worsening of laboratory values
2) No decline in ECOG performance status 
3) Absence of rapid progression of disease 
4) Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
Any subject deemed clinically unstable should be discontinued from trial treatment at 
central verification of site-assessed first radiologic evidence of PD and is not required to have 
repeat imaging for PD confirmation.  
In determining whether or not the tumor burden has increased or decreased per irRECIST,
the local site investigator should consider all target and non-target lesions as well as any 
incremental new lesion(s).
 
 
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Scenarios where PD is not confirmed at repeat imaging if ALL of the following occur by 
irRECIST:

Target lesion sum of diameters is <20% or <5 mm absolute increase compared to nadir

Non-target disease resulting in initial PD is stable or qualitatively improved

New lesion resulting in initial PD is stable or qualitatively improved

No new incremental new lesion(s) since last evaluation

No incremental new non-target lesion progression since last evaluation
If repeat imaging does not confirm PD per irRECIST as assessed by the local site 
investigator and the subject continues to be clinically stable, treatment may continue and 
follow the regular imaging schedule. 
Disease progression will be considered to be “confirmed” at repeat imaging if ANY of the 
following occur (as assessed by irRECIST): 

Target lesion sum of diameters remains ≥20 % and at least 5 mm absolute increase 
compared to nadir

Non-target disease resulting in initial PD is qualitatively worse

New lesion resulting in initial PD is qualitatively worse

Additional new lesion(s) since last evaluation

Additional new non-target lesion progression since last evaluation
If repeat imaging confirms PD due to any of the scenarios listed above, subject will be 
discontinued from study therapy.
NOTE: If a subject has confirmed radiographic progression (i.e. 2 scans at least 4 weeks 
apart demonstrating progressive disease) per irRECIST, but the subject is achieving a 
clinically meaningful benefit, and there is no further increase in the tumor burden at the 
confirmatory tumor imaging, an exception to continue treatment may be considered
following consultation with the Sponsor. In this case, if treatment is continued, tumor 
imaging should continue to be performed following the intervals as outlined in Section 6.0
Study Flowchart and be submitted to the central imaging vendor.
Additional details about irRECIST are referenced in Merck TIP Sheet for RECIST 1 1 and 
irRECIST.
 
 
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Table 8 Imaging and Treatment after Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st 
radiologic 
evidence of PD 
by RECIST 1.1 
which has been 
verified by the 
central 
imaging 
vendor
No 
additional 
imaging required
Discontinue treatment 
(for 
placebo 
-
transition to Crossover 
Phase if qualification 
criteria 
met; 
for 
pembrolizumab 
–
exception is possible 
upon 
consultation 
with sponsor)
Repeat imaging at 
>
4 
weeks 
to 
confirm PD per 
physician 
discretion only
Discontinue 
treatment
Repeat 
tumor 
imaging 
confirms PD by 
irRECIST at the 
local site
and 
PD verified by 
central imaging 
vendor
No 
additional 
imaging required
Discontinue treatment
(for 
placebo 
–
transition to Crossover 
Phase if qualification 
criteria 
met; 
for 
pembrolizumab 
-
exception is possible 
upon 
consultation 
with sponsor)
At 
physician 
discretion
N/A
Repeat 
tumor 
imaging shows 
SD, PR or CR 
by 
irRECIST 
by the local site
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue 
study 
treatment 
at 
the 
local 
site 
Investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart study 
treatment 
if 
condition 
has 
improved 
and/or 
clinically stable per 
Investigator’s 
discretion. 
Next 
tumor image should 
occur according to 
the regular imaging 
schedule outlined in 
the protocol
CR=complete response; irRECIST=immune-related response evaluation criteria in solid tumors; PD=progressive disease; 
PFS=progression-free survival; PR=partial response; SD=stable disease
7.1.2.8
Tumor Tissue Collection: PD-L1 Status
All subjects should submit either a newly obtained core or excisional biopsy or archival 
tissue (FNA is not adequate for both archival and new tissue samples) to a central lab for 
characterization of PD-L1 status prior to treatment allocation.
Note: Submission of formalin-fixed paraffin embedded tumor tissue sample blocks are 
preferred; if submitting unstained slides, the slides should be freshly cut and submitted 
to the testing laboratory within 14 days from the site slide section date, otherwise a 
new specimen will be requested.
If the sample is determined to be non-evaluable prior to testing by the central laboratory, a 
new sample should be submitted if available.  This may include additional cut slides that are 
outside of the 14 day window noted above.
Individual subject PD-L1 status will not be disclosed to investigative sites, study subjects or 
Sponsor personnel. Analyses by PD-L1 biomarker status will be limited and documented.
 
 
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If the subject signs the Future Biomedical Research consent, any leftover samples that would 
be ordinarily discarded at the end of the main study will be retained for Future Biomedical 
Research. 
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 9].
 
 
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Table 9  Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum 
β-human 
chorionic 
gonadotropin (β-hCG)a
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)d
Platelet count
Alanine aminotransferase (ALT)
Protein
aPTT/PTT d
White Blood Cell 
- WBC (total and 
differential)
Aspartate 
aminotransferase 
(AST)
Specific gravity 
Total triiodothyronine (T3)e
Red Blood Cell 
Count
Carbon 
dioxide 
(CO2
or 
Bicarbonate) b
Microscopic 
exam, if abnormal 
results are noted 
Free thyroxine (FT4)
Absolute 
Neutrophil Count
Calcium
Urine 
pregnancy 
testa
Thyroid stimulating hormone 
(TSH)
Absolute 
Lymphocyte 
Count
Chloride
Follicle Stimulating Hormone 
(FSH)f
Creatinine
Blood for correlative studies
Glucose
Blood for genetics
Lactate Dehydrogenase
Sialylated 
carbohydrate 
antigen KL-6  (KL-6)g
Phosphorus
Surfactant Protein D (SP-D)g
Potassium
Sodium
Total Bilirubin
Direct Bilirubin, if total bilirubin 
is elevated above the upper limit 
of normal
Total protein
Blood Urea Nitrogen
Uric acid
Ureac
a. Perform on women of childbearing potential only. Urine pregnancy test is preferred. If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required. 
b. If these tests are not done as part of standard of care in your region then these tests do not need to be performed.
c. Blood Urea Nitrogen is preferred; if not available urea may be tested.
d. Coagulation factors (PT/INR and aPTT/PTT) should be tested as part of the screening procedures for all 
subjects.
Any subject receiving anticoagulant therapy should have coagulation factors monitored closely 
throughout the trial.
e. Total T3 is preferred; if not available free T3 may be tested.
f. As needed, FSH to be performed at Screening to confirm post-menopausal status.
g. Serological biomarkers for interstitial lung disease; to be performed at every cycle; required in Japan only
Laboratory tests for screening 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 3 days 
prior to Day 1 of subsequent cycles.  
Results must be reviewed by the investigator or qualified designee and found to be 
acceptable prior to each dose of trial treatment.  Unresolved abnormal labs that are drug 
related AEs should be followed until resolution.  Labs do not need to be repeated after the 
end of treatment if labs are within normal range.
 
 
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7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
The following analyses may only be performed if required.
Pembrolizumab
To further evaluate pembrolizumab immunogenicity and pembrolizumab exposure in this 
indication, and also to evaluate exposure of the proposed dosing regimen, sample collections 
for analysis of anti-drug antibodies (ADA) and PK are currently planned as shown in the 
Trial Flowchart (Sections 6.1).  Blood samples will be obtained to measure pharmacokinetics 
of serum pembrolizumab in combination with pemetrexed and carboplatin (or cisplatin).  The 
pembrolizumab serum maximum concentration (Cmax) and minimum concentration (Ctrough) 
at planned visits and times will be summarized.  If ongoing ADA and/or PK results continue 
to be consistent with existing ADA and/or PK data from other pembrolizumab clinical trials, 
it may be decided to discontinue or reduce further sample collection in this study.  
Pharmacokinetic data may be analyzed using nonlinear mixed effects modeling.  Based on 
pharmacokinetic (PK) data obtained in this study as well as PK data obtained from other 
studies, a population PK analysis may performed to characterize pharmacokinetic parameters 
(Clearance (CL), Volume of distribution (V)) and evaluate the effect of extrinsic and intrinsic 
factors to support proposed dosing regimen. Pharmacokinetic data will also be used to 
explore the exposure-response relationships for pembrolizumab antitumor activity/efficacy as 
well as safety in the proposed patient population, if feasible. The results of these analyses, if 
performed, will be reported separately.  
Exploratory drug-drug interaction analysis 
To estimate the effect of pembrolizumab on the pharmacokinetics of pemetrexed and 
carboplatin (or cisplatin) and, conversely, to estimate the effects of pemetrexed and 
carboplatin (or cisplatin) on the pharmacokinetics of pembrolizumab, pharmacokinetic 
studies will be conducted in a subset of research participants enrolled on this protocol.  
Since this protocol does not have a pembrolizumab monotherapy arm, the data from other 
studies can be pooled together to assess the effect of pemetrexed and carboplatin (or 
cisplatin) on the pharmacokinetics of pembrolizumab. In addition, the pharmacokinetics of 
pemetrexed and carboplatin (or cisplatin) may be extracted from other studies to confirm 
results if sample size is too small given variability and imbalanced sample size due to the 
randomized trial.   
The pharmacokinetic parameters, namely the maximum plasma drug concentration (Cmax), 
the time to reach Cmax (Tmax), the area under the plasma concentration-time curve (AUC) of 
pemetrexed, carboplatin or cisplatin would be estimated for each patient by standard 
noncompartmental methods, if feasible. Population pharmacokinetic approach may be used if 
needed.  The observed pharmacokinetics data at planned visits and times will be summarized.  
Blood Collection for Serum Pembrolizumab 
7.1.3.2.1
Pre-dose trough PK and anti-pembrolizumab antibody samples will be collected at Cycles 1, 
2, 4, 6, 8 and every 4 cycles thereafter, 30 days after discontinuation of study drug (or until 
the subject starts new anti-cancer therapy). All pre-dose trough samples should be drawn 
within 24 hours before infusion of pembrolizumab/saline placebo.
 
 
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Additional post-dose peak PK samples will be drawn within 30 minutes after end of 
pembrolizumab/saline placebo infusion at Cycles 1 and 8.  An additional single PK sample 
should be drawn at 24 hours (Day 2), between 72 and 168 hours (Day 4-8) and 336 hours 
(Day 15) after Cycle 1 dosing. 
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Procedure Manual.  PK samples should be drawn according to the PK collection schedule 
for subjects who receive pembrolizumab.  Every effort should be taken to collect samples at 
30 days after end of pembrolizumab treatment.  
Blood Collection for Pemetrexed, Carboplatin or Cisplatin
7.1.3.2.2
Pemetrexed
Blood samples for pemetrexed measurement will be collected during Cycle 1 before dosing,
at 0.17 h (within 15 minutes after the end of infusion), and at 0.5, 1, 2, 4, 8, 24, 48, and 72 h 
after the start of the drug infusion. The exact time of sample collection and time of 
pemetrexed administration will be recorded.  Sample collection, storage and shipment 
instructions for plasma samples will be provided in the Procedure Manual.
Carboplatin
Blood samples for carboplatin measurement will be collected at Cycle 1 before dosing, at the 
end of the carboplatin infusion, and at 1, 2, 4, 6, 8, 12 and 24 h after the start of the 
carboplatin administration. The exact time of sample collection and time of carboplatin
administration will be recorded.  Sample collection, storage and shipment instructions for 
plasma samples will be provided in the Procedure Manual.
Cisplatin
Pharmacokinetic studies of unbound and total cisplatin will be performed in consenting 
subjects enrolled on this protocol with the first infusion on Cycle 1, 2, and 4 (three total 
occasions, if possible).  Blood samples will be drawn for pharmacokinetic analyses at the 
following time points: Pre-dose, immediately at end of infusion (EOI), 2 hours, and 24 hours 
(±2) after the start of the cisplatin administration.  The exact time of sample collection and 
time of cisplatin administration will be recorded.  Sample collection, storage and shipment 
instructions for plasma samples will be provided in the Procedure Manual.
Blood Collection for Anti- pembrolizumab Antibodies
7.1.3.2.3
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Procedure Manual. Anti- pembrolizumab antibody samples should be drawn according to 
the ADA collection schedule (Section 6.1). Every effort should be taken to collect samples 
at 30 days after end of pembrolizumab/saline placebo treatment for ADA.  Simultaneous PK 
sampling is required for interpretation of ADA analysis.
7.1.3.3
Patient Reported Outcomes (PROs)
The EuroQol (EQ)-5D, EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires will be 
administered by trained study site personnel and completed electronically by the subjects 
themselves.  
 
 
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It is strongly recommended that ePROs are administered prior to drug administration, 
adverse event evaluation and disease status notification. The ePROs are completed in the 
following order: EuroQol e(EQ)-5D first, then EORTC eQLQ-C30, and lastly the EORTC 
eQLQ-LC13 at the time points specified in the Trial Flow Charts and briefly summarized 
below. The Patient Reported Outcomes (PROs) are assessed as follows (does not include 
HEA):

At Cycles 1, 2, 3, 4 and 5

After the fifth cycle and until the end of year 1 (Cycle 17) they will be assessed every 
third  cycle (every 9 weeks) 

During years 2 and 3 they will be assessed every fourth cycle (every 12 weeks) until 
PD, while the subject is receiving study treatment. 

At the Treatment Discontinuation Visit.* 

At 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.
7.1.3.4
Blood for Correlative and Biomarker Studies
Blood for correlative studies (RNA and DNA) should be collected pre-dose for each of the 
following:  Day 1, Cycle 1; Day 1 Cycle 2; Day 1 Cycle 3 and at treatment discontinuation if 
subject discontinues prior to Cycle 3.  Blood for biomarker studies (Plasma and Serum) 
should be collected pre-dose only at Cycle 1 Day 1. Detailed instructions with specific time 
points per sample are provided in the Procedures Manual. Any leftover samples from the
correlative blood studies and biomarker studies will be stored for future biomedical research 
if the subject signs the FBR consent.
7.1.3.5
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual. Samples should be collected for planned analysis 
of associations between genetic variants in germline/tumor DNA and drug response.  If a
documented law or regulation prohibits (or local IRB/Independent Ethics Committee [IEC]
does not approve) sample collection for these purposes, then such samples should not be
collected at the corresponding sites.  Leftover DNA extracted from planned genetic analysis 
samples will be stored for future biomedical research only if subject signs the Future
Biomedical Research consent.
7.1.3.6
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA for future research

Leftover DNA and RNA from correlative studies
 
 
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
Leftover plasma and serum from biomarker studies

Leftover main study tumor
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the end of treatment visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.  Subjects who a) attain a CR or b) complete 35 administrations of 
pembrolizumab (approximately 2 years) may discontinue treatment with the option of 
restarting treatment if they meet the criteria specified in Section 7.1.5.4.  After discontinuing 
treatment following assessment of CR or 35 administrations of pembrolizumab, these 
subjects should return to the site for a Safety Follow-up Visit (described in Section 7.1.5.3) 
and then proceed with assessments (described in Section 7.1.5.3).
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 
, 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
When the investigator or sub-investigator needs to identify the blinded therapy used by a 
subject and the dosage administered in case of emergency e.g., the occurrence of serious 
adverse experiences, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding.  As requested by the investigator or sub-
investigator the emergency unblinding call center will provide the information to him/her 
 
 
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promptly and report unblinding to the sponsor.  The emergency unblinding call center will 
make a record promptly however, the investigator or sub-investigator must enter the toxicity 
grade of the adverse experiences observed,   their relation to study drug, the reason thereof, 
etc., in the medical chart etc., before unblinding is performed.  
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject. Every effort should be made not to unblind the subject unless necessary.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Once an emergency unblinding has taken place, the principal investigator,
site personnel, and Sponsor personnel are unblinded so that appropriate follow-up medical 
care can be provided to the subject.  
At the end of the trial, unblinding logs are to be returned to the Sponsor or designee.
7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Laboratory equipment – as required for inclusion labs and trial assessments

Imaging equipment – as required for study objectives
See protocol-specified guidance in the Administrative Binder, Procedures 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 28 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.
 
 
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Written consent must be obtained prior to performing any protocol specific procedure. 
Screening procedures (i.e., vital signs and full physical exam) and 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 28 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.

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 the first dose of
trial treatment.
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.
7.1.5.3
Post-Treatment 
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 will be followed for up 
to 2 years. If the subject experienced a CR, PR, or SD during the Treatment Phase on
pembrolizumab, and then experiences PD at any time during that two year follow-up period,
he/she will be eligible to receive up to 12 months of therapy with pembrolizumab in the 
Second Course Phase according to the criteria in Section 7.1.5.4. After the Second Course
Phase, subjects should be followed for up to two years, with no option for retreatment with 
pembrolizumab on study.
Subjects who discontinue trial treatment for a reason other than disease progression
will still be considered as on study and should continue with regularly scheduled 
assessments (also refer to Section 7.1.2.7.3), including collecting subject information on the
start of new antineoplastic therapy, disease progression, and death.
Safety Follow-up Visit
7.1.5.3.1
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. 
All AEs that occur prior to the Safety Follow-up Visit should be recorded.  Subjects with an
AE of Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or until
 
 
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the beginning of a new anticancer therapy, whichever occurs first. Serious AEs that occur 
within 90 days of the end of treatment or before initiation of a new anticancer treatment 
should also be followed and recorded.
Subjects who are eligible per the requirements in Section 7.1.5.4 for treatment with
pembrolizumab during the Second Course Phase (retreatment) may have up to 2 safety
follow-up visits, one after the Initial Treatment Phase and the second after the Second Course 
Phase.  Subjects who are eligible per the requirements in Section 7.1.5.5 for treatment with
pembrolizumab during the Crossover Phase may have up to 2 safety follow- up visits, one 
after the Crossover Phase and another after the Second Course Phase.
Follow-up Visits
7.1.5.3.2
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 6 weeks after the Safety 
Follow-up Visit to monitor disease status.  Every effort should be made to collect 
information regarding disease status until the start of new anti-cancer therapy, disease 
progression, death, or end of trial.  Information regarding post-trial anticancer treatment will 
be collected if new treatment is initiated.
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.5.4 will move from the Follow-Up Phase to the Second Course Phase when 
they experience disease progression.  Details are provided in the Trial Flow Chart (Section 6) 
for retreatment with pembrolizumab.
Survival Follow-up
7.1.5.3.3
Once a subject experiences PD or starts a new anti-cancer therapy, the subject moves into the 
Survival Follow-Up Phase and should be contacted by telephone approximately every 
12 weeks to assess for survival status until death, withdrawal of consent, or the end of the 
study, whichever occurs first. Post-study treatments and the subject’s response to them will 
also be collected.
7.1.5.4
Survival Status
To ensure current and complete survival data is available at the time of any database lock, 
updated survival status may be requested during the course of the study by the Sponsor.  For 
example, updated survival status may be requested prior to, but not limited to, an eDMC 
review.  Upon Sponsor notification, all participants who do not/will not have a scheduled 
study visit or study contact during the sponsor-defined time period will be contacted for their 
survival status (excluding participants who have a previously recorded death event in the 
collection tool).  
7.1.5.5
Second Course Phase (Retreatment Period)
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
All subjects who stop trial treatment with SD or better may be eligible for up to an additional 
17 cycles (approximately 1 year) of pembrolizumab treatment if they progress after stopping 
trial treatment from the initial treatment phase.  This retreatment is termed the Second Course 
 
 
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Phase of this trial and is only available if the trial remains open and the subject meets the 
following conditions:
Either

Stopped 
initial 
treatment 
with 
trial 
treatment 
after 
attaining 
an 
investigator-determined confirmed CR based on RECIST 1.1, and
o
Was treated with at least 8 cycles of trial treatment before discontinuing 
treatment, and
o
Received at least 2 treatments with pembrolizumab/placebo beyond the date when 
the initial CR was declared
OR

Had SD, PR, or CR and stopped trial treatment after completion of 35 administrations 
(approximately 2 years) of trial treatment for reasons other than disease progression 
or intolerability
AND

Experienced an investigator-determined radiographic disease progression by 
RECIST 1.1 after stopping initial treatment, and
o
Upon unblinding at the time of centrally verified disease progression were found 
to have received pembrolizumab, and
o
No new anticancer treatment was administered after the last dose of trial 
treatment, and
o
The subject meets all of the safety parameters listed in the inclusion criteria and 
none of the safety parameters listed in the exclusion criteria, and the trial is 
ongoing.
An objective response or progression of disease 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 With Documented Disease Progression Who Received 
Placebo
Subjects who are randomized into the placebo with chemotherapy arm will have the 
opportunity to crossover to receive pembrolizumab monotherapy after they experience
disease progression on placebo with chemotherapy and are unblinded. Subjects who
permanently discontinue chemotherapy due to an AE, withdrawn consent, or any reason
other than progressive disease, will not be eligible for crossover. Crossover subjects must
not initiate treatment with pembrolizumab monotherapy any earlier than 21 days after their 
last dose of chemotherapy regardless of the time of progression.
Crossover Qualifications:
Subjects who received placebo will be considered for crossover to pembrolizumab
monotherapy after documented, progressive disease assessed based on RECIST 1.1 by 
BICR. Crossover is optional and is at the discretion of the Investigator (with the Sponsor’s
agreement). Subjects who meet the following criteria are eligible for crossover:
 
 
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
Documented verification of progressive disease by BICR

Adverse events (except alopecia) due to therapy must have improved to CTCAE 
(Version 4.0) Grade ≤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

Subject has not received any
systemic anti-cancer therapies other than the
chemotherapy administered during the treatment phase.

If required, completed palliative radiotherapy (30Gy or less) ≥7 days before the first 
dose of crossover trial treatment.

If progressive disease is centrally verified but subject does not qualify for Crossover, 
unblinding may be considered after consulting with Sponsor.
7.1.5.7
Crossover Assessments and Procedures
Crossover subjects must not initiate treatment with pembrolizumab monotherapy any earlier
than 21 days after their last dose of chemotherapy regardless of the time of progression. The
subject will then start the crossover phase as outlined in Crossover Flow Chart in Section 6.3. 
Screening procedures need to be completed within 28 days of centrally verified progressive 
disease (or up to 42 days from last dose if recovering from adverse event). 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. The tumor image used to
determine progressive disease can be used as the new baseline image for the Crossover 
phase if 1) 30 days prior to receiving the first dose of pembrolizumab monotherapy and
2) No study treatment between the image and first dose of pembrolizumab monotherapy,
otherwise a new baseline image must be performed prior to pembrolizumab monotherapy 
treatment. Subjects who crossover and then achieve a CR per RECIST 1.1 have the option to
hold pembrolizumab while continuing in the trial. Additional details are provided in
Second Course Phase Section 7.1.5.4.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
 
 
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Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Adverse events will not be collected for subjects during pre-screening (for determination of 
archival tissue status) as long as that subject has not undergone any protocol-specified 
procedure or intervention.  If the subject requires a blood draw, fresh tumor biopsy etc., the 
subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab by ≥1000 mg (5 times the dose).. No specific information is 
available on the treatment of overdose of pembrolizumab. In the event of overdose, 
pembrolizumab should be discontinued and the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reportin g 
procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product or 180 
days after last dose of chemotherapeutic agents or 30 days following cessation of treatment if 
the subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator.  All reported pregnancies must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
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 another important medical event. 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.

Is a new cancer (that is not a condition of the study);

Is associated with an overdose.
Refer to [Table 10] for additional details regarding each of the above criteria.
 
 
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For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
 
 
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than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3 - Immediate Reporting of Adverse Events to the Sponsor.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
 
 
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Table 10
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or 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) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events and Patient Events and Incidents will be reported to regulatory 
authorities, IRB/IECs and investigators in accordance with all applicable global laws and 
regulations, i.e., per ICH Topic E6 (R1) Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Scientific Advisory Committee
7.3.1
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Data Monitoring Committee
7.3.2
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the Sponsor per the DMC Charter regarding steps 
to ensure both subject safety and the continued ethical integrity of the trial.  Also, the DMC 
will review interim trial results, consider the overall risk and benefit to trial participants (see 
Section 8.7 - Interim Analyses) and recommend to the Sponsor if the trial should continue in 
accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in 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 executive committee and/or protocol team regarding steps 
to ensure both subject safety and the continued ethical integrity of the trial.
A DMC recommendation will be communicated to the Sponsor as agreed to in the DMC 
Charter.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, changes made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended 
(consistent with ICH Guideline E-9).  Changes to exploratory or other non-confirmatory 
analyses made after the protocol has been finalized, but prior to the conduct of any 
analysis, will be documented in a supplemental SAP (sSAP) and referenced in the Clinical 
 
 
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Product:  MK-3475 
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Protocol/Amendment No.:  189-08 
MK-3475-189-08 Final Protocol
6-Nov-2017
Confidential
central radiologist(s) will perform the central imaging review without knowledge of 
treatment assignment.
The study team at the Sponsor consisting of clinical, statistical, statistical programming and 
data management personnel, will be blinded to subject-level PD-L1 biomarker results. An 
unblinded data management personnel, unblinded Sponsor statistician and unblinded Sponsor 
statistical programmer will have access to the subject-level PD-L1 results for the purpose of 
data review and will have no other responsibilities associated with the study. A summary of 
PD-L1 biomarker prevalence may be provided to the study team at the Sponsor by the IVRS 
vendor or the unblinded Sponsor statistician.
An external data monitoring committee (eDMC) will be convened to review accumulating 
safety to provide an opportunity to terminate the study early if there are concerns regarding 
safety. The eDMC will also review the unblinded efficacy results at the planned interim 
analysis. The eDMC responsibilities and review schedules will be outlined in the eDMC 
charter. The recommendation of the eDMC will be communicated to an executive oversight 
committee of the Sponsor and, in the event of a recommendation to halt the trial early due to 
safety concerns, to the appropriate regulatory agencies.
If the eDMC recommends 
modifications to the design of the protocol or discontinuation of the study, this executive 
oversight committee may be unblinded to results at the treatment level in order to act on 
these recommendations.
Limited numbers of additional Sponsor personnel may be unblinded, if required, in order to 
act on the recommendations of the eDMC. The extent to which individuals are unblinded 
with respect to the results will be documented. Additional logistical details, revisions to the 
above plan and data monitoring guidance will be provided in the eDMC Charter.
Hypotheses/Estimation
8.3
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
8.4
Efficacy Endpoints
8.4.1
Primary
Progression-free survival (PFS) – RECIST 1.1 assessed by BICR
PFS is defined as the time from randomization to the first documented disease progression 
per RECIST 1.1 based on BICR or death due to any cause, whichever occurs first. See
Section 8.6.1 for definition of censoring.
Overall Survival
OS is defined as the time from randomization to death due to any cause.  Subjects without
documented death at the time of analysis will be censored at the date of last known contact.
 
 
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Secondary
Objective Response Rate (ORR) – RECIST 1.1 assessed by BICR
ORR is defined as the proportion of subjects who have a CR or a PR. Responses are based on 
confirmed assessments by BICR per RECIST 1.1. 
Duration of Response (DOR) – RECIST 1.1 assessed by BICR
For subjects who demonstrated confirmed CR or PR, DOR is defined as the time from first 
documented evidence of CR or PR until disease progression or death. DOR for subjects who 
have not progressed or died at the time of analysis will be censored at the date of their last 
tumor assessment.
Safety Endpoints
8.4.2
Safety measurements are described in Section 7.
Analysis Populations
8.5
Efficacy Analysis Populations
8.5.1
The Intention-to-Treat (ITT) population will serve as the population for primary efficacy 
analysis. All randomized subjects will be included in this population. Subjects will be 
included in the treatment group to which they are randomized.
If an unexpectedly large number of randomized subjects are not treated, analyses may be 
performed using the Full Analysis Set (FAS), including all randomized subjects who 
received at least 1 dose of study treatment and did not have a major protocol violation.
Details on the approach to handling missing data are provided in Section 8.6 Statistical 
Methods.
Extension Study
After the sample size required for the global study is reached, the study will continue to 
randomize subjects in Japan until the sample size for the Japanese subjects meets the target.  
The Japanese subjects randomized in the extension study will not be included in the above 
primary efficacy analysis population.  The ITT Japanese subjects as well as the entire ITT 
population consisting of the primary efficacy population and subjects randomized in the 
extension will be analyzed separately per local regulatory requirement.
Safety Analysis Populations
8.5.2
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be included in the treatment group corresponding 
to the study treatment they actually received for the analysis of safety data using the ASaT 
population.  For most subjects this will be the treatment group to which they are randomized.  
Subjects who take incorrect study treatment for the entire treatment period will be included in 
 
 
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the treatment group corresponding to the study treatment actually received. Any subject who 
receives the incorrect study medication for one cycle but receives the correct treatment for all 
other cycles will be analyzed according to the correct treatment group and a narrative will be 
provided for any events that occur during the cycle for which the subject is incorrectly dosed. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in 
Section 8.6 Statistical Methods.
Extension Study
The Japanese subjects randomized and treated in the extension study will not be included in 
the above primary safety analysis population.  The ASaT Japanese subjects as well as the 
entire ASaT population consisting of the primary safety population and subjects randomized 
and treated will be analyzed per local regulatory requirements.
Statistical Methods
8.6
Statistical Methods for Efficacy Analyses
8.6.1
This section describes the statistical methods that address the primary and secondary 
objectives.  Methods related to exploratory objectives will be described in the sSAP.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 8.8, Multiplicity. Nominal p-values will 
be computed for other efficacy analyses, but should be interpreted with caution due to 
potential issues of multiplicity.
All statistical tests, unless otherwise specified, will be stratified for treatment and 
stratification factors.  
8.6.1.1
Progression-free Survival (PFS)
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 (based on the stratification factors defined in Section 5.4). A stratified Cox proportional 
hazard model with Efron's method of tie handling will be used to assess the magnitude of the 
treatment difference (ie, hazard ratio) between the treatment arms. The hazard ratio and its 
95% confidence interval from the stratified Cox model with Efron's method of tie handling 
and with a single treatment covariate will be reported. The stratification factors used for 
randomization (See Section 5.4) will be applied to both the stratified log-rank test and the 
stratified Cox model. 
Since disease progression is assessed periodically, 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 by BICR, regardless of discontinuation of study 
 
 
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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 per RECIST 1.1 by central imaging 
vendor, we will perform 2 sensitivity analyses with different sets of censoring rules. The first 
sensitivity analysis 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. The second sensitivity analysis is the same as the primary analysis except 
that it considers discontinuation of treatment or initiation of an anticancer treatment 
subsequent to discontinuation of study-specified treatments, whichever occurs later, to be a 
PD event for subjects without documented PD or death. The censoring rules for primary and
sensitivity analyses are summarized in [Table 11]. In case there is an imbalance between the 
treatment groups on disease assessment schedules or censoring patterns, we will perform an 
additional PFS sensitivity analysis using time from randomization to scheduled tumor 
assessment time instead of actual tumor assessment.
Table 11  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
In case the proportional hazards assumption is not valid, Restricted Mean Survival Time 
(RMST) method may be conducted for PFS to account for the possible non-proportional 
hazards effect.
An exploratory analysis of PFS2, defined as the time from randomization to
second/subsequent disease progression after initiation of new anti-cancer therapy, or death 
from any cause, whichever first, will be carried out. Patients alive and for whom a second 
objective disease progression has not been observed will be censored at the last time known 
to be alive and without second objective disease progression.
Further details of sensitivity analyses will be described in sSAP as needed.
8.6.1.2
Overall Survival (OS)
The non-parametric 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 (based on the 
 
 
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Product:  MK-3475 
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Protocol/Amendment No.:  189-08 
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6-Nov-2017
Confidential
stratification factor defined in Section 5.4). A stratified Cox proportional hazard model with 
Efron's method of tie handling will be used to assess the magnitude of the treatment 
difference (ie, the hazard ratio). The hazard ratio and its 95% confidence interval from the 
stratified Cox model with a single treatment covariate will be reported. The stratification 
factors used for randomization (See Section 5.4) will be applied to both the stratified log-
rank test and the stratified Cox model. Restricted Mean Survival Time (RMST) method may 
be conducted for OS to account for the possible non-proportional hazards effect.
Since subjects in the control arm are allowed to switch to the pembrolizumab treatment after 
progressive disease, adjustment for the effect of crossover on OS may be performed based on 
recognized methods, eg, a two-stage method or the Rank Preserving Structural Failure Time 
(RPSFT) model proposed by Robins and Tsiatis [43], based on an examination of the 
appropriateness of the data to the assumptions required by the methods.
Further details of sensitivity analyses will be described in sSAP as needed.
8.6.1.3
Objective Response Rate (ORR) and Duration of Response (DOR)
Stratified Miettinen and Nurminen’s method will be used for comparison of the ORR 
between 2 treatment groups. The difference in ORR and its 95% confidence interval from the 
stratified Miettinen and Nurminen’s method with strata weighting by sample size with a 
single treatment covariate will be reported. The stratification factors used for randomization 
(See Section 5.4) will be applied to the analysis.
If sample size permits, duration of response will be summarized descriptively using Kaplan-
Meier medians and quartiles. Only the subset of patients who show a complete response or 
partial response will be included in this analysis.
[Table 12] summarizes the primary analysis approach for primary and key secondary efficacy 
endpoints. Sensitivity analysis methods are described above for each endpoint as applicable.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, and 
interim analyses is described in Section 8.7 Interim Analyses and in Section 8.8 Multiplicity.
 
 
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Table 12  Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical Method†
Analysis 
Population
Missing Data Approach
Primary Endpoints
PFS per RECIST 1.1 by central 
imaging vendor
Test: Stratified Log-rank test 
to assess the treatment 
difference
Estimation: Stratified Cox 
model with Efron’s tie 
handling method to assess 
the magnitude of treatment 
difference
ITT
Primary censoring rule
Sensitivity analysis 1
Sensitivity analysis 2
OS
Test: Stratified Log-rank test 
to assess the treatment 
difference
Estimation: Stratified Cox 
model with Efron’s tie 
handling method to assess 
the magnitude of treatment 
difference
ITT
Model based
(censored at last known 
alive date)
Secondary Endpoint
ORR per RECIST 1.1 by 
central imaging vendor
Stratified M&N method with 
sample size weights††
ITT
Subjects without assessments 
are considered non-
responders and 
conservatively included in 
denominator
 † Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used 
for randomization (Section 5.4) will be applied to the analysis.
†† Miettinen and Nurminen method
Statistical Methods for Safety Analyses
8.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, vital signs, etc.
Adverse Events
Adverse events (AEs) will be coded using the standard MedDRA and grouped system organ 
class. Adverse events (AEs) will be graded by the investigator according to the Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.0.
Tiered Approach
The analysis of safety results will follow a tiered approach [Table 13]. The tiers differ with 
respect to the analyses that will be performed. “Tier 1” safety endpoints that will be subject 
to inferential testing for statistical significance with p -values and 95% confidence intervals 
provided for between-group comparisons. For this protocol, there are no Tier 1 events. Other 
safety parameters will be considered Tier 2 or Tier 3. Tier 2 parameters will be assessed via 
point estimates with 95% confidence  intervals provided for between-group comparisons; 
only point estimates by treatment group are provided for Tier 3 safety parameters. 
Adverse experiences (specific terms as well as system organ class terms) 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 event s observed. Membership in Tier 2 requires that at least 4 subjects in any 
 
 
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Product:  MK-3475 
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Protocol/Amendment No.:  189-08 
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6-Nov-2017
Confidential
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% confidence interval 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% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences 
and predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, 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, the broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, any drug related AE, any Grade 3-5 AE, any serious AE, any AE 
which is both drug-related and Grade 3-5, any AE which is both serious and drug-related, 
dose modification due to AE, and who discontinued due to an AE, and death will be 
considered Tier 2 endpoints. 95% confidence intervals (Tier 2) will be provided for between-
treatment differences in the percentage of subjects with events; these analyses will be 
performed using the Miettinen and Nurminen method (1985), an unconditional, asymptotic 
method.
Table 13  Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Serious AE 
X
X
Any Grade 3-5 AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade 3-5 and Drug-Related AE
X
X 
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
Specific AEs, SOCs, or PDLCs‡ (incidence ≥4 of subjects 
in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <4 of subjects 
in all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, Vital Signs)
X
 
 
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Summaries of Demographic and Baseline Characteristics and Other Analysis
8.6.3
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of subjects randomized, and the primary reasons 
for discontinuation will be displayed.  Demographic variables (eg, age, gender) and baseline 
characteristics will be summarized by treatment either by descriptive statistics or categorical 
tables.
Interim Analyses
8.7
Two interim efficacy analyses are planned in addition to the final analysis.

The first interim analysis (IA1) will evaluate PFS and OS. It will be performed after 
enrollment is complete and approximately 370 PFS events have been observed, 
approximately 19 months after first patient enrolled. It is estimated that approximately 
242 deaths will be observed. ORR will be tested at this interim analysis if both the PFS 
and OS test results are significant.

The second interim analysis (IA2) is the final analysis for PFS and will be performed 
after approximately 468 PFS events have been observed, approximately 26 months after 
first patient enrolled. An interim analysis of OS will be performed; it is estimated that 
approximately 332 deaths will be observed.

The final analysis (FA) will evaluate OS only and will be performed after approximately 
416 deaths have been observed. It is estimated that this will occur approximately 
35 months after enrollment begins.
The analyses planned, endpoints evaluated and drivers of the timing are summarized in
[Table 14]. 
Table 14 Analyses Planned, Endpoints Evaluated, and Drivers of Timing
Analysis
Endpoint(s)
Timing
IA1
PFS; OS; ORR if both PFS 
and OS are positive
~370 PFS events (~242 OS 
events expected at this time)
IA2
PFS; OS
~468 PFS events (~332 OS 
events expected at this time)
FA
OS
~416 OS events
Decisions to stop the trial early will be based on DMC recommendations with review by the 
Executive Oversight Committee.
Type I error control for the efficacy analyses as well as efficacy bounds are described in the 
next section.
 
 
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Multiplicity
8.8
The trial uses the graphical method of Maurer and Bretz [44] to provide strong multiplicity 
control for multiple hypotheses as well as interim analyses. 
Figure 2 shows the initial one-sided α-allocation for each hypothesis in the ellipse
representing the hypothesis. The weights for reallocation from each hypothesis to the others 
are represented in the boxes on the lines connecting hypotheses. This is further explained 
below.
See Figure 2 for the type I error reallocation strategy for endpoints PFS, OS, and ORR.
Figure 2 Type I Error Reallocation Strategy
PFS
PFS hypothesis will be tested at α=0.0095. When OS test is significant, the PFS hypothesis 
may be tested at α=0.025 (re-allocated α). The Lan-DeMets O'Brien-Fleming spending 
function was used to control the type I error in the interim analysis. [Table 15] below 
demonstrates the bounds and boundary properties for PFS hypothesis testing. The table will 
be updated using the actual number of PFS events at the interim and final PFS analyses.
 
 
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Table 15 Boundary properties for planned analyses of PFS based on potential alpha-levels to 
be used for testing
Analysis
Value
α=0.0095
α=0.025
IA 1: 79%
Z
2.6946
2.2676 
N: 616
p (1-sided)
0.0035
0.0117 
Events: 370
HR at bound
0.7427
0.7790 
Month: 19.2
P(Cross) if HR=1
0.0035
0.0117 
P(Cross) if HR=0.7
0.7160
0.8439 
IA2*
Z
2.3895
2.0222 
N: 616
p (1-sided)
0.0084
0.0216 
Events: 468
HR at bound
0.7910
0.8204 
Month: 26
P(Cross) if HR=1
0.0095
0.0250 
P(Cross) if HR=0.7
0.9040
0.9550 
*The final analysis of PFS will be performed at IA2.
If the OS superiority null hypotheses are rejected at an interim or final analysis, each PFS 
interim analysis test may be compared to its updated rejection boundary for formal testing.
OS
The OS hypothesis will be tested at α=0.0155. When PFS test is significant, the OS 
hypothesis may be tested at α=0.025 (re-allocated α). [Table 16] demonstrates the bounds 
and boundary properties for OS hypothesis testing. The HR of OS between the experimental 
group and control group is assumed to be 0.7. The table will be updated using the actual 
number of OS events at the interim and final OS analyses. The Lan-DeMets O'Brien-Fleming 
spending function was used to derive the design in α columns.
Table 16 Boundary properties for planned analyses of OS 
Analysis
Value
α=0.0155
α=0.025
IA 1: 58% 
Z 
2.9715 
2.7215 
N: 616
p (1-sided) 
0.0015 
0.0032 
Events: 242
HR at bound 
0.6662 
0.6893 
Month: 19.3 
P(Cross) if HR=1 
0.0015 
0.0032 
P(Cross) if HR=0.7 
0.3711 
0.4695 
IA 2: 80% 
Z 
2.4926 
2.2831 
N: 616
p (1-sided) 
0.0063 
0.0112 
Events: 332
HR at bound 
0.7482 
0.7666 
Month: 26.2 
P(Cross) if HR=1 
0.0068 
0.0122 
P(Cross) if HR=0.7 
0.7332 
0.7991 
Final 
Z 
2.2155 
2.0300 
N: 616 
p (1-sided) 
0.0134 
0.0212 
Events: 416 
HR at bound 
0.7940 
0.8095 
Month: 35 
P(Cross) if HR=1 
0.0155 
0.0250 
P(Cross) if HR=0.7 
0.9000 
0.9300 
 
 
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A sensitivity analysis for OS will be pre-specified in the supplemental statistical analysis 
plan to account for any multiplicity concerns raised by not formally testing the OS null 
hypothesis such as DMC requests. This analysis will be performed if requested by regulators. 
However, there is no plan to do formal testing at these analyses or to declare a positive 
efficacy finding based on these results.
If the PFS superiority null hypotheses are rejected at any interim analyses, each OS interim 
and final analysis test may be compared to its updated rejection boundary for formal testing.
ORR
When both PFS and OS tests are significant, =0.025 will be allocated to the ORR test. If the 
OS test does not achieve statistical significance at IA1, the p value of the ORR test from IA1 
will be compared to 2.5% if the null hypotheses for PFS and OS are rejected at a later time. 
Sample Size and Power Calculations
8.9
This trial is well-powered for the primary and key secondary endpoints. Enrollment of 
570 subjects is assumed to occur over 12 months at 2:1 ratio between the experimental and 
control groups. The actual enrollment is 616 subjects within 13 months. With 370 PFS events 
at IA1, the study has ~72% power for detecting a HR of 0.7 at 0.0095 (one-sided) and ~84% 
power for detecting a HR of 0.7 at 0.025 (one-sided). With 468 PFS events at IA2, the study 
has ~90% power for detecting a HR of 0.7 at 0.0095 (one-sided) and ~96% power for 
detecting a HR of 0.7 at 0.025 (one-sided). The duration of PFS in the control group is 
assumed to follow an exponential distribution with a median of 6.5 months based on 
historical data. The assumed follow-up time after last patient enrolled is 13 months for IA2. 
An exponential dropout rate of 0.35% per month is assumed.
With 242 deaths at IA1, the study has ~37% power for detecting a HR of 0.7 at 0.0155 (one-
sided) and ~47% power for detecting a HR of 0.7 at 0.025 (one-sided) when the PFS test is
significant. With 332 deaths at IA2, the study has ~73% power for detecting a HR of 0.7 at 
0.0155 (one-sided) and ~80% power for detecting a HR of 0.7 at 0.025 (one-sided) when the 
PFS test is significant. With 416 deaths at FA, the study has ~90% power for detecting a HR 
of 0.7 at 0.0155 (one-sided) and ~93% power for detecting a HR of 0.7 at 0.025 (one-sided) 
when the PFS test is significant. The duration of OS in the control group is assumed to follow 
an exponential distribution with a median of 13 months based on historical data. The 
exponential dropout rate assumed for OS is 0.1% per month. 
The sample size of 616 yields 89% (α=0.025) power to detect an ORR difference from an 
underlying 45% response rate in the control group to 60% in the experimental group, when 
both PFS and OS tests are significant.  The approximate treatment difference required to 
reach the bound (Δ ORR) is 0.0575.
Power and interim analysis calculations were performed using EAST 5 and the gsDesign R 
package.
Extension Study
After the enrollment for the global study has completed, the study will continue to randomize 
subjects in a 2:1 ratio into the pembrolizumab/pemetrexed/platinum arm or saline 
placebo/pemetrexed/platinum arm in Japan until the sample size for the Japanese subjects 
 
 
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reaches approximately 30.  The sample size for the overall Japanese subjects is projected to 
be approximately 40.  Japanese subjects randomized after completion of enrollment in the 
global study will not be included in the analysis of the global study.
Subgroup Analyses and Effect of Baseline Factors
8.10
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for OS, PFS, and ORR (with a nominal 95% CI) will be 
estimated and plotted within each category of the following classification variables (a 
subgroup will not be analyzed if it includes <10% of the ITT population): 

Age category (<65, 65 years)

ECOG Performance Scale (0, 1)

Sex (female, male)

Race (white, non-white)

Geographic region (US, Ex US)

Geographic region (EU, Ex EU)

Smoking status (never, former/current)

Brain metastasis status at baseline (yes, no)

PD-L1 expression (unknown, TPS <1%, or TPS ≥1%) 

PD-L1 expression (unknown, TPS <50%, or TPS ≥50%)

PD-L1 expression (unknown, TPS <1%, 1%≤TPS≤49%, or TPS ≥50%)

Platinum chemotherapy (cisplatin, carboplatin)
Extent of Exposure
8.11
The extent of exposure will be summarized as duration of treatment in cycles.
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 17].
 
 
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Table 17 Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 25 mg/mL
Solution for infusion
Pemetrexed* 500 mg/vial
Lyophilized powder for infusion
Carboplatin 10 mg/mL
Solution for infusion
Cisplatin 1 mg/mL
Solution for infusion
*Pemetrexed disodium
All other supplies not indicated in [Table 17] 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, as per local guidelines unless otherwise instructed by the 
Sponsor.
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 will be provided as non-kitted 
single vials or as single vials in a kit box. Pemetrexed will be supplied as a single vial.  All 
other products will be provided as a kit with a single vial.
Clinical Supplies Disclosure
9.3
This trial is blinded but provided open label; therefore, an unblinded pharmacist or qualified 
trial site personnel will be used to blind supplies. Treatment identity (name, strength or 
potency) is included in the label text; random code/disclosure envelopes or lists are not 
provided.
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind subjects and to unmask treatment identity. In the event that the emergency 
unblinding call center is not available for a given site in this trial, the central electronic 
treatment allocation/randomization system (IVRS/IWRS) should be used in order to unblind 
subjects and to unmask treatment identity.  The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Once an emergency unblinding has taken place, the principal investigator, 
 
 
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site personnel, and Sponsor personnel are unblinded so that appropriate follow-up medical 
care can be provided to the subject.
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.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
9.6
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
 
 
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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.
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 
 
 
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allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
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, 
 
 
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the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must 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 
 
 
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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, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
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 
 
 
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the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
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11.0 LIST OF REFERENCES
[1]
Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8.
[2]
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune 
evasion. Nat Med 2002;8(8):793-800.
[3]
Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, et al. Tumor cell 
expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant 
melanoma. Cancer 2010;116:1757-66.
[4]
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. 
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 
2012;366(26):2443-54.
[5]
Patnaik A, Kang SP, Tolcher AW, Rasco DW, Papadopoulos KP, Beeram M, et al.  
2012 ASCO Annual Meeting:  Phase I study of MK-3475 (anti-PD-1 monoclonal 
antibody) in patients with advanced solid tumors.
[6]
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. 
Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J 
Med 2010;363(8):711-23.
[7]
Chapman PB, Hauschild A, Robert C, Hannen JB, Ascierto P, Larkin J, et al. Improved 
survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 
2011;364(26):2507-16.
[8]
Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab plus 
dacarbazine for previously untreated metastatic melanoma. N Engl J Med 
2011;364(26):2517-26.
[9]
Sasaki A, Tanaka F, Mimori K, Inoue H, Kai S, Shibata K, et al. Prognostic value of 
tumor-infiltrating FOXP3+ regulatory T cells in patients with hepatocellular carcinoma. 
EJSO 2008;34:173-9.
[10]
Shen Z, Zhou S, Wang Y, Li R, Zhong C, Liang C, et al. Higher intratumoral infiltrated 
Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in 
resectable gastric cancer. J Cancer Res Clin Oncol 2010;136:1585-95.
[11]
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26(3-4):373-400.
[12]
Usubütün A, Ayhan A, Uygur MC, Özen H, Toklu C, Ruacan S. Prognostic factors in 
renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.
[13]
Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive lymphocyte 
and dendritic cell infiltration after interleukin-2 immunotherapy. Report of a case. 
Tumori 2008;94(3):426-30.
[14]
Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15(6):544-51.
 
 
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[15]
Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J 
Cutan Pathol 2010;37(Suppl 1):48-53.
[16]
Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet Oncol. 
2009 Sep;10(9):840-1.
[17]
Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications 
of type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008;99(10):1704-11.
[18]
Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et 
al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and 
metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 
2009;58(3):449-59.
[19]
Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification of 
positive selection in the thymus of PD-1-deficient mice. J Exp Med. 2000 Mar 
6;191(5):891-8.
[20]
Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates 
with poor prognosis in renal cell carcinoma. BJU Int 2011;107(9):1500-6.
[21]
Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, et al. Intratumoral 
CD8+ T/FOXP3+ cell ratio is a predictive marker for survival in patients with 
colorectal cancer. Cancer Immunol Immunother 2010;59:653-61.
[22]
Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, et al. Inflammatory tumor 
microenvironment is associated with superior survival in hepatocellular carcinoma 
patients. J Hepatol 2010;52:370-9.
[23]
Pölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. Foxp3(+) 
cell infiltration and granzyme B(+)/Foxp3(+) cell ratio are associated with outcome in 
neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 
2010;59(6):909-19.
[24]
Oble DA, Loewe R, Yu P, Mihm MC Jr. Focus on TILs: prognostic significance of 
tumor infiltrating lymphocytes in human melanoma. Cancer Immun. 2009 Apr 2;9:3.
[25]
Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic value 
of 
tumour-infiltrating 
lymphocytes 
(TILs) 
in 
colorectal 
cancer. 
J 
Pathol 
1997;182(3):318-24.
[26]
Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin 
Oncol 2005;23(10):2346-57.
[27]
Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment 
of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J 
Med 2008;358(25):2698-703.
 
 
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[28]
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 
2001;98(24):13866-71.
[29]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 
2005;23:515-48.
[30]
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and Tumor 
Responses with Lambrolizumab (AntiΓÇôPD-1) in Melanoma. N Engl J Med 
2013;369(2):134-44.
[31]
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. 
Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 
May 21;372(21):2018-28.
[32]
Peters S, Adjei AA, Gridelli C, Reck M, Kerr K, Felip E, et al. Metastatic non-small-
cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment 
and follow-up. Annals Oncol 2012;23(Supplement 7):vii56-vii64.
[33]
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison 
of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 
2002;346:92-8.
[34]
Ardizzoni A, Boni L, Tiseo M, Fossella FV, Schiller JH, Paesmans M, et al. Cisplatin-
versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-
cell lung cancer: an individual patient data meta-analysis. J Natl Cancer Inst. 2007 Jun 
6;99(11):847-57.
[35]
Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. 
Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in 
chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin 
Oncol 2008;26(21):3543-51.
[36]
Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, et al. 
PARAMOUNT: Final overall survival results of the phase III study of maintenance 
pemetrexed versus placebo immediately after induction treatment with pemetrexed plus 
cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 
Aug 10;31(23):2895-902.
[37]
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer 
statistics, 2012. CA Cancer J Clin. 2015 Mar;65(2):87-108.
[38]
Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, et al. 
International Association for the Study of Lung Cancer International Staging 
Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: 
proposals for the revision of the TNM stage groupings in  the forthcoming (seventh) 
edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2007 
Aug;2(8):706-14. Erratum in: J Thorac Oncol. 2007 Oct;2(10):985.
 
 
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[39]
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. 
Developing a common language for tumor response to immunotherapy: immune-
related response criteria using unidimensional measurements. Clin Cancer Res. 2013 
Jul 15;19(14):3936-43.
[40]
Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M. The EORTC QLQ-
LC13: a modular supplement to the EORTC core quality of life questionnaire (QLQ-
C30) for use in lung cancer clinical trials. Eur J Cancer 1994;30A(5):635-42.
[41]
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The 
European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-
life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 
1993;85(5):365-76.
[42]
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 2006 
update of recommendations for the use of white blood cell growth factors: an evidence-
based clinical practice guideline. J Clin Oncol 2006;24(19):3187-205.
[43]
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models. Commun Stat-Theor M 1991;20(8):2609-31.
[44]
Maurer W, Bretz F. Multiple testing in group sequential trials using graphical 
approaches. Stat Biopharm Res 2013;5(4):311-20.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law,
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.6 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease. The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
 
 
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of patient consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
 
 
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mailbox 
 and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction cannot be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
 
 
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through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff
 
 
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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
BICR
Blinded independent central review
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
eDMC
external Data Monitoring Committee
DOR
Duration of response
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
FA
Final analysis
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
HR
Hazard ratio
IA1
Interim analysis (first)
IA2
Interim analysis (second)
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
irRC
immune-related response criteria
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
INR
International normalized ratio
irAEs
Immune-related adverse events
 
 
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Abbreviation/Term
Definition
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
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 (NSCLC)
ORR
Objective response rate
OS
Overall survival
OTC
Over-the-counter
PD
Progressive disease
PD-L1
Programmed cell death ligand-1
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
SD
Stable disease
SFU
Survival follow-up
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOC
Standard of Care
T1DM
Type 1 Diabetes Mellitus
TIL
Tumor-infiltrating lymphocytes
TKI
tyrosine kinase inhibitors
TPS
Tumor Proportion Score
TSH
Thyroid stimulating hormone
TTP
Time To Progression
ULN
Upper limit of normal
WHO
World Health Organization
 
 
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Calculated Creatinine Clearance
12.5
Original, Weight-Based Cockcroft and Gault Formula for Calculated Creatinine
Clearance for Men
For serum creatinine concentration in mg/dL:
CrCl =
(mL/min)
(140 – agea) (wtb) 1.0
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl =
(mL/min)
(140 – agea) (wtb) 1.0
0.81 serum creatinine (mol/L)
a
Age in years.
b
Weight (wt) in kilograms.
Source: Cockcroft and Gault 1976.
Original, Weight-Based Cockcroft and Gault Formula for Calculated Creatinine
Clearance for Women
For serum creatinine concentration in mg/dL:
CrCl =
(mL/min)
(140 – agea) (wtb) 0.85
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl =
(mL/min)
(140 – agea) (wtb) 0.85
0.81 serum creatinine (mol/L)
a
Age in years.
b
Weight (wt) in kilograms.
Source: Cockcroft and Gault 1976.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16:31–41
 
 
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MASCC corticosteroid dosing guidelines (2013 guidelines or more current 
12.6
guidelines, if available)
 
 
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
12.7
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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ECOG Performance Status
12.8
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.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair.
 
 
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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – 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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SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
NCT03950674
16-Nov-2017
Document Date: 
A Randomized, Double-Blind, Phase III Study of Platinum+ 
Pemetrexed Chemotherapy with or without Pembrolizumab 
(MK-3475) in First Line Metastatic Non-squamous Non-small Cell 
Lung Cancer Subjects (KEYNOTE-189)


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Supplemental SAP
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Supplemental Statistical Analysis Plan (sSAP)
TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................ 1
1.0
Introduction......................................................................................................................... 3
2.0
Summary of Changes.......................................................................................................... 3
3.0
Analytical and methodological details for global study ..................................................... 3
Statistical Analysis Plan Summary .................................................................................. 3
Responsibility for Analyses/In-House Blinding .............................................................. 5
Hypotheses/Estimation..................................................................................................... 5
Analysis Endpoints........................................................................................................... 5
Efficacy Endpoints.................................................................................................... 5
Safety Endpoints....................................................................................................... 6
Analysis Population.......................................................................................................... 6
Efficacy Analysis Population.................................................................................... 6
Safety Analysis Populations ..................................................................................... 7
Statistical Methods........................................................................................................... 7
Statistical Methods for Efficacy Analyses................................................................ 7
3.6.1.1
Progression-Free Survival (PFS)....................................................................... 7
3.6.1.2
Overall Survival (OS)........................................................................................ 9
3.6.1.3
Objective response rate (ORR) and Duration of Response (DOR)................... 9
3.6.1.4
Exploratory Analyses of Efficacy.................................................................... 10
Statistical considerations for patient-reported outcomes (PRO)............................. 10
3.6.2.1
Analysis Populations ....................................................................................... 13
3.6.2.2
Analysis Approaches ....................................................................................... 14
3.6.2.3
Treatment effect on PRO................................................................................. 14
3.6.2.4
Effect of disease progression on PRO............................................................. 15
3.6.2.5
Analysis of the Proportions of Deterioration/Stable/Improvement................. 15
3.6.2.6
Analysis of the Time to Deterioration ............................................................. 16
3.6.2.7
Compliance Summary ..................................................................................... 16
Statistical Methods for Safety Analyses ................................................................. 16
Summaries of Demographics, Baseline Characteristics and Other Analyses ................ 18
Interim Analyses ............................................................................................................ 18
Multiplicity..................................................................................................................... 19
Sample Size and Power Calculation........................................................................... 21


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Subgroup Analyses and Effect of Baseline Factors.................................................... 21
Extent of Exposure ..................................................................................................... 22
4.0
References......................................................................................................................... 23


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Supplemental SAP
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1.0 INTRODUCTION
This supplemental statistical analysis plan (sSAP) is a companion document to the protocol. In 
addition to the information presented in the protocol SAP which provides the principal 
features of analyses for this trial, this sSAP provides additional statistical analysis details/data 
derivations and documents modifications or additions to the analysis plan that are not 
‘principal’ in nature and result from information that was not available at the time of protocol 
finalization. Compared to the protocol SAP, this sSAP contains more details on PRO analyses 
for inclusion in the clinical study report of the protocol.
2.0 SUMMARY OF CHANGES
This sSAP aligns with the protocol amendment v07 for the global study with regard to statistical 
analysis plan.
3.0 ANALYTICAL AND METHODOLOGICAL DETAILS FOR GLOBAL STUDY
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is 
Sections 3.2-3.12.
Study Design
Overview
A Phase 3 Study of Platinum+Pemetrexed Chemotherapy with or without 
Pembrolizumab (MK-3475) in First Line Metastatic Nonsquamous Non-small 
Cell Lung Cancer Subjects (KEYNOTE-189)
Treatment
Assignment
Approximately 570 subjects will be randomized in a 2:1 ratio to receive 
pembrolizumab or saline placebo in combination with pemetrexed/platinum. 
Stratification factors are in Section 5.4 of the protocol. This is a randomized 
double-blinded study. 
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary
Endpoints/Hypotheses

Progression-free Survival (PFS) per RECIST 1.1 assessed by BICR

Overall Survival (OS)
Statistical Methods for
Key Efficacy Analyses
The primary hypotheses for PFS and OS will be evaluated by comparing
pembrolizumab to saline placebo in combination with pemetrexed/platinum 
using a stratified Log-rank test. The HR will be estimated using a stratified
Cox regression model. Event rates over time will be estimated within each 
treatment group using the Kaplan-Meier method.
Statistical Methods for
Key Safety Analyses
The analysis of safety results will follow a tiered approach. There are no Tier 
1 safety parameters in this trial. All safety parameters are considered either 
Tier 2 or Tier 3.  Tier 2 parameters will be assessed via point estimates with 
95% confidence intervals provided for between-group comparisons; only 
point estimates by treatment group are provided for Tier 3 safety parameters. 
The between-treatment difference will be analyzed using the Miettinen and 
Nurminen method.
In the primary safety comparison, subjects who crossover to pembrolizumab 
are censored at time of crossover (ie, 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.
Interim Analyses
Two interim analyses are planned in this study. Results will be reviewed by
an external data monitoring committee. Details are provided in Section 3.8.


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Interim analysis 1 (IA1)
o
Timing: To be performed after target number of PFS events 
(~370) are observed
o
Purpose: To demonstrate superiority of pembrolizumab in 
combination with pemetrexed/platinum in PFS and OS. ORR 
will be tested after superiority of pembrolizumab
in 
combination with pemetrexed/platinum is demonstrated in 
PFS and OS.

Interim analysis 2 (IA2)
o
Timing: To be performed after ~468 PFS events are observed
o
Purpose: To demonstrate superiority of pembrolizumab in 
combination with pemetrexed/platinum in PFS and OS.
Final Analysis

Final analysis (FA)
o
Timing: To be performed after target number of deaths 
(~416) are observed
o
Purpose: To demonstrate superiority of pembrolizumab in 
combination with pemetrexed/platinum in OS.
Multiplicity
The overall Type I error rate for each endpoint in the group sequential tests is 
strictly controlled at 2.5% (one-sided); for both PFS and OS, this is based on 
the Lan-DeMets O'Brien-Fleming spending function (see Section 3.9). 
Between the endpoints, the type I error is controlled by the following rollover 
rule. The total type I error allocated to PFS (0.0095) is subject to rollover to 
OS if the PFS test is positive. The type I error allocated to OS (0.0155) is 
subject to rollover to PFS if the OS test is positive. Furthermore, the total 
type I error (0.025) is subject to rollover to ORR at IA1 if the PFS and OS 
tests are both positive. 
Sample Size and
Power
Enrollment of 570 subjects is assumed to occur over 12 months at 2:1 ratio 
between the experimental and control groups. The actual enrollment is 
616 subjects within 13 months. 
With 370 PFS events at IA1, the study has ~72% power for detecting a PFS 
HR of 0.7 at 0.0095 (one-sided) and ~84% power for detecting a HR of 0.7 at 
0.025 (one-sided). With 468 PFS events at IA2, the study has ~90% power 
for detecting a HR of 0.7 at 0.0095 (one-sided) and ~96% power for detecting 
a HR of 0.7 at 0.025 (one-sided). The duration of PFS in the control group is 
assumed to follow an exponential distribution with a median of 6.5 months 
based on historical data. The assumed follow-up time after last patient 
enrolled is 13 months for IA2. An exponential dropout rate of 0.35% per 
month is assumed.
With 242 deaths at IA1, the study has ~37% power for detecting an OS HR of 
0.7 at 0.0155 (one-sided) and ~47% power for detecting a HR of 0.7 at 0.025 
(one-sided) when the PFS test is significant. With 332 deaths at IA2, the 
study has ~73% power for detecting a HR of 0.7 at 0.0155 (one-sided) and 
~80% power for detecting a HR of 0.7 at 0.025 (one-sided) when the PFS test 
is significant. With 416 deaths at FA, the study has ~90% power for detecting 
a HR of 0.7 at 0.0155 (one-sided) and ~93% power for detecting a HR of 0.7 
at 0.025 (one-sided) when the PFS test is significant. The duration of OS in 
the control group is assumed to follow an exponential distribution with a 
median of 13 months based on historical data. The exponential dropout rate 
assumed for OS is 0.1% per month.


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Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
The SPONSOR will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IVRS.
This trial is double blinded with a crossover phase. At the time of documented progression, 
subjects will have treatment assignment unblinded and be able to continue therapy in the 
Crossover Phase, please refer to the protocol Section 2.1 Trial Design for details. In addition, 
independent central radiologist(s) will perform the central imaging review without knowledge of 
treatment assignment.
The study team at the Sponsor consisting of clinical, statistical, statistical programming and data 
management personnel, will be blinded to subject-level PD-L1 biomarker results. An unblinded 
data management personnel, unblinded Sponsor statistician and unblinded Sponsor statistical 
programmer will have access to the subject-level PD-L1 results for the purpose of data review 
and will have no other responsibilities associated with the study. A summary of PD-L1 
biomarker prevalence may be provided to the study team at the Sponsor by the IVRS vendor or 
the unblinded Sponsor statistician. 
An external data monitoring committee (eDMC) will be convened to review accumulating safety 
to provide an opportunity to terminate the study early if there are concerns regarding safety. The 
eDMC will also review the unblinded efficacy results at the planned interim analysis. The eDMC 
responsibilities and review schedules will be outlined in the eDMC charter. The recommendation 
of the eDMC will be communicated to an executive oversight committee of the Sponsor and, in 
the event of a recommendation to halt the trial early due to safety concerns, to the appropriate 
regulatory agencies. If the eDMC recommends modifications to the design of the protocol or 
discontinuation of the study, this executive oversight committee may be unblinded to results at 
the treatment level in order to act on these recommendations.
Limited numbers of additional SPONSOR personnel may be unblinded, if required, in order to 
act on the recommendations of the eDMC. The extent to which individuals are unblinded with 
respect to the results will be documented. Additional logistical details, revisions to the above 
plan and data monitoring guidance will be provided in the eDMC Charter.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0 of the protocol.
Analysis Endpoints
Efficacy Endpoints
Primary 
Progression-free survival - RECIST 1.1 assessed by blinded independent central imaging 
vendor (BICR)


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Progression-free-survival (PFS) is defined as the time from randomization to the first 
documented disease progression per RECIST 1.1 based on blinded central imaging vendor 
review or death due to any cause, whichever occurs first. See Section 3.6.1 for definition of 
censoring.
Overall Survival
Overall Survival (OS) is defined as the time from randomization to death due to any cause.  
Subjects without documented death at the time of analysis will be censored at the date of last 
known contact.
Secondary
Objective response rate (ORR) – RECIST 1.1 assessed by BICR
Overall Response Rate (ORR) is defined as the proportion of subjects who have a complete 
response (CR) or a partial response (PR). Responses are based on confirmed assessments by 
BICR review per RECIST 1.1.
Response Duration (DOR) – RECIST 1.1 assessed by BICR
For subjects who demonstrated confirmed CR or PR, DOR is defined as the time from first 
documented evidence of CR or PR until disease progression or death. Response duration for 
subjects who have not progressed or died at the time of analysis will be censored at the date of 
their last tumor assessment.
Exploratory 
PFS – RECIST 1.1 assessed by BICR, OS and ORR – RECIST 1.1 assessed by BICR in subjects 
with different PD-L1 expression levels.
PFS, ORR and DOR assessed by the investigator using RECISIT 1.1.
PFS, ORR and DOR per investigator assessed irRECIST response criteria.
Patient-reported outcomes (PROs) while on treatment and post-discontinuation will be 
examined.
The PRO endpoints include EORTC QLQ-C30, EORTC QLQ-LC13 and 
EuroQoL(EQ)-5D.
PFS and OS following crossover to pembrolizumab in subjects initially treated with saline 
placebo in combination with chemotherapy.
Safety Endpoints
Safety measurements are described in Section 4.2.3.3 of the protocol.
Analysis Population
Efficacy Analysis Population
The Intention-to-Treat (ITT) population will serve as the population for primary efficacy 
analysis. All randomized subjects will be included in this population. Subjects will be included in 
the treatment group to which they are randomized.


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If an unexpectedly large number of randomized subjects are not treated, analyses may be 
performed using the Full Analysis Set (FAS), including all randomized subjects who received at 
least 1 dose of study treatment and did not have a major protocol violation.
Details on the approach to handling missing data are provided in Section 3.6 Statistical Methods.
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in this 
study.  The ASaT population consists of all randomized subjects who received at least one dose 
of study treatment. Subjects will be included in the treatment group corresponding to the study 
treatment they actually received for the analysis of safety data using the ASaT population.  For 
most subjects this will be the treatment group to which they are randomized.  Subjects who take 
incorrect study treatment for the entire treatment period will be included in the treatment group 
corresponding to the study treatment actually received. Any subject who receives the incorrect 
study medication for one cycle but receives the correct treatment for all other cycles will be 
analyzed according to the correct treatment group and a narrative will be provided for any events 
that occur during the cycle for which the subject is incorrectly dosed. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 3.6
Statistical Methods.
Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary objectives.
Methods for biomarker exploratory objectives 4) and 8) and pharmacokinetic objective 7) will be 
documented in separate SAPs.
Efficacy results that will be deemed to be statistically significant after consideration of the Type 
I error control strategy are described in Section 3.9, Multiplicity. Nominal p-values will be 
computed for other efficacy analyses, but should be interpreted with caution due to potential 
issues of multiplicity.
All statistical tests, unless otherwise specified, will be stratified for treatment and stratification 
factors.  
3.6.1.1
Progression-Free Survival (PFS)
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 
(based on the stratification factors defined in Section 5.4 of the protocol). A stratified Cox 
proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (i.e., hazard ratio) between the treatment arms. The hazard 
ratio and its 95% confidence interval from the stratified Cox model with Efron's method of tie 


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handling and with a single treatment covariate will be reported. The stratification factors used for 
randomization (See Section 5.4 of the protocol) 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 by central imaging vendor, 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 per RECIST 1.1 by central imaging 
vendor, we will perform two sensitivity analyses with a different set of censoring rules. The first 
sensitivity analysis 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. The second sensitivity analysis is the same as the primary analysis except that it 
considers discontinuation of treatment or initiation of an anticancer treatment subsequent to 
discontinuation of study-specified treatments, whichever occurs later, to be a PD event for 
subjects without documented PD or death. The censoring rules for primary and sensitivity 
analyses are summarized in Table 1. In case there is an imbalance between the treatment groups 
on disease assessment schedules or censoring patterns, we will perform an additional PFS 
sensitivity analysis using time from randomization to scheduled tumor assessment time instead 
of actual tumor assessment.
Table 1  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
No PD and no death; 
≥ 2 consecutive 
missed disease 
assessments
Censored at last 
disease assessment
Censored at last 
disease assessment 
prior to ≥2 
consecutive missed 
visits
Censored at last 
disease assessment
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


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PD or death 
documented at any 
time after ≥ 2 
consecutive missed 
disease assessments
Progressed at date of 
documented PD or 
death
Censored at last 
disease assessment 
prior to the ≥ 2 
consecutive missed 
disease assessment
Progressed at date of 
documented PD or 
death
In case the proportional hazards assumption is not valid, Restricted Mean Survival Time (RMST) 
method may be conducted for PFS to account for the possible non-proportional hazards effect.
In case of potential gross imbalance in baseline prognostic factors in the ITT population with 
TPS≥50% (due to lack of stratification according to TPS≥50% vs. TPS<50%), a sensitivity PFS 
analysis may be performed using the multivariate Cox regression to adjust for those imbalanced 
baseline prognostic factors.
3.6.1.2
Overall Survival (OS)
The non-parametric 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 (based on the 
stratification factor defined in section 5.4 of the protocol). A stratified Cox proportional hazard 
model with Efron's method of tie handling will be used to assess the magnitude of the treatment 
difference (i.e., the hazard ratio). The hazard ratio and its 95% confidence interval from the 
stratified Cox model with a single treatment covariate will be reported. The stratification factors
used for randomization (See Section 5.4 of the protocol) will be applied to both the stratified log-
rank test and the stratified Cox model. 
Since subjects in the control arm are allowed to switch to the pembrolizumab treatment after 
progressive disease, adjustment for the effect of crossover on OS may be performed based on 
recognized methods, e.g., a two-stage method or the Rank Preserving Structural Failure Time 
(RPSFT) model proposed by Robins and Tsiatis , based on an examination of the appropriateness 
of the data to the assumptions required by the methods.
In case of potential gross imbalance in baseline prognostic factors in the ITT population with 
TPS≥50% (due to lack of stratification according to TPS≥50% vs. TPS<50%), a sensitivity OS 
analysis may be performed using the multivariate Cox regression to adjust for those imbalanced 
baseline prognostic factors.
3.6.1.3
Objective response rate (ORR) and Duration of Response (DOR)
Stratified Miettinen and Nurminen’s method will be used for comparison of the ORR between 
two treatment groups. The difference in ORR and its 95% confidence interval from the stratified 
Miettinen and Nurminen’s method with strata weighting by sample size with a single treatment 
covariate will be reported. The stratification factors used for randomization (See Section 5.4 of 
the protocol) will be applied to the analysis.
If sample size permits, duration of response duration will be summarized descriptively using 
Kaplan-Meier medians and quartiles. Only the subset of patients who show a complete response 
or partial response will be included in this analysis.
For each DOR analysis, a corresponding summary of the reasons responding subjects are 
censored will also be provided.  Responding subjects who are alive, have not progressed, have 
not initiated new anti-cancer treatment, have not been determined to be lost to follow-up, and 


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have had a disease assessment within ~5 months of the data cutoff date are considered ongoing 
responders at the time of analysis. If a subject meets multiple criteria for censoring, the censoring 
criterion that occurs earliest will be applied.
Table 2 Censoring Rules for DOR
Situation
Date 
of 
Progression 
or 
Censoring
Outcome
No progression nor death, no 
new 
anti-cancer 
therapy 
initiated
Last 
adequate 
disease 
assessment
Censor
(non-event)
No progression nor death, new 
anti-cancer therapy initiated
Last 
adequate 
disease 
assessment before new anti-
cancer therapy initiated
Censor
(non-event)
Death or progression after ≥ 2 
consecutive missed disease 
assessments 
Last 
adequate 
disease 
assessment prior to ≥ 2 missed 
adequate disease assessments
Censor
(non-event)
Death or progression after ≤ 1 
missed disease assessments
PD or death
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered 
inadequate for evaluation of response.  
3.6.1.4
Exploratory Analyses of Efficacy
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, 
may be carried out. Subjects alive and for whom a PFS event has not been observed should be 
censored at the last time the subject was known alive and without disease progression.
Statistical considerations for patient-reported outcomes (PRO)
The patient-reported outcomes are exploratory objectives in KEYNOTE 189, and thus no formal 
hypotheses were formulated. This sSAP will focus on PRO endpoints as measured by the 
EORTC QLQ-C30, EORTC QLQ-LC13 and EuroQol-5D Visual Analogue Scale (EQ-5D VAS). 
The global health status/quality of life scale from EORTC QLQ-C30 and the composite endpoint 
of cough (LC13-Q1), chest pain (LC13-Q10) and dyspnea (QC30 Q8) will be key PRO 
endpoints. The time to deterioration (TTD) of this composite endpoint has been used as the key 
PRO endpoint in advanced NSCLC clinical trials [2, 3, 4]. The time to true deterioration of the 
composite endpoint is defined in as the time to first onset of 10 or more decrease from baseline 
with confirmation under right-censoring rule. The time to true deterioration will be used in the 
analysis.
Supportive analyses will include all QLQ-C30 and QLQ-LC13 sub-scales/items, and the EQ-5D 
VAS. The QLQ-C30 includes five functional dimensions (physical, role, emotional, cognitive, 


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and social), three symptom scales (fatigue, nausea/vomiting, and pain), and six single item 
measures (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial 
difficulties). The QLQ-LC13 comprises 13 questions consisting of one multi-item scale 
(dyspnea) and nine single items that assess the specific symptoms (dyspnea, cough, hemoptysis, 
and site specific pain), side effects (sore mouth, dysphagia, neuropathy, and alopecia), and pain 
medication use of lung cancer patients. Supportive analysis will also include alternative 
approaches to TTD in addition to estimating the effect of disease progression on HRQoL.
Combined with EORTC QLQ-C30, the EORTC QLQ-LC13 measures lung cancer associated 
symptoms (cough, hemoptysis, dyspnea, and site specific pain), and treatment related symptoms 
(sore mouth, dysphagia, peripheral neuropathy, and alopecia). 
EQ-5D is another set of endpoints as a measure of health outcome. The analyses in this SAP 
focus on the EQ-5D VAS within the EQ-5D.
Results for the EORTC QLQC30 and EORTC QLQ-LC13.will be reported for the overall study 
population and the biomarker positive strata (>=1%) as described in the exploratory PRO 
objective in the study protocol.
Key PRO Endpoints:
1. The mean score changes from baseline to weeks 12 and 21 as measured by the EORTC QLQ-
C30 global health status/quality of life scale. 
2. Time to True Deterioration in the composite endpoint of cough (LC13-Q1), chest pain (LC13-
Q10) and dyspnea (LC30-Q8).
Supportive PRO Endpoints: 
The mean score changes, and the number and proportions of deterioration/stable/improvement 
from baseline to weeks 12 and 21.  Specifically:
–
EORTC QLQ-C30 global health status/quality of life scale (the number and proportions 
of deterioration/stable/improvement only).
–
Each EORTC QLQ-C30 functional subscale: physical functioning, role functioning, 
emotional functioning, cognitive functioning, social functioning.
–
Each EORTC QLQ-C30 symptom subscale score: Fatigue, Nausea and vomiting, Pain, 
Dyspnoea, Insomnia, Appetite loss, Constipation, Diarrhea.
–
Each EORTCQLQ-LC13 item: pain, coughing, sore mouth, dysphagia, peripheral 
neuropathy, alopecia, and haemoptysis (mean score changes from baseline only).
–
The EORTC QLQ-LC13 dyspnea multi-item sub-scale (mean score changes from 
baseline only). 


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Although no formal hypothesis was formulated, the p-value from the constrained longitudinal 
data Analysis (cLDA) model and Cox regression model will be provided for treatment 
comparisons of pembrolizumab in combination with chemotherapy vs. saline placebo with 
chemotherapy for key PRO endpoints 1 and 2, respectively. No multiplicity adjustment will be 
performed.
The mean score change for multi-item subscale(s) and single item scores from baseline to week 
12 and 21 and the proportions of deterioration/stable/improvement QLQ-LC13 and QLQ-C30 
will have a nominal p-values using the CMH test for general association to compare 
pembrolizumab in combination with chemotherapy vs. saline placebo with chemotherapy. For 
multi-item scale(s), the analysis will focus on the subscale score rather than each single item.
Scoring Algorithm:
QLQ-C30 Scoring: For each scale or item, a linear transformation will be applied to standardize 
the score as between 0 and 100, according to the corresponding scoring standard. For functioning 
and global health status/quality-of-life scales, a higher value indicates a better level of function; 
for symptom scales and items, a higher value indicates increased severity of symptoms. 
According to the QLQ-C30 Manuals, if items I1, I2,…,In are included in a scale, the linear 
transformation procedure is as follows:
1. Compute the raw score:
2. Linear transformation to obtain the score S:
Function scales: 
Symptom scales/items: 
Global health status/QoL: 
100
1 

Range
RS
S
Range is the difference between the maximum possible value of RS and the minimum possible 
value. If more than half of the items within one scale are missing, then the scale is considered 
missing, otherwise, the score will be calculated as the average score of those available items [5].
QLQ-LC13 scoring: The lung cancer questionnaire module comprises both multi-item and 
single-item measures of lung cancer-associated symptoms (i.e. coughing, haemoptysis, dyspnoea 
and pain) and treatment related symptom scores: sore mouth, dysphagia, peripheral neuropathy, 
and alopecia. A linear transformation will be applied to standardize the scores between 0 (worst) 
and 100 (best) as described above for the EORTC QLQ-C30 Scoring.
n
I
I
I
RS
n /)
...
(
2
1




100
1
1










Range
RS
S
100
1 

Range
RS
S


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EQ-5D scoring: EQ-5D utility score will be calculated based on the European algorithm [6]. The 
five health state dimensions in this instrument include the following: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression (5). 
The schedule for PRO data collection: 
Table 3 provides the schedule for PRO data collection.
Table 3 PRO Data Collection Schedule
Original Phase Treatment Week
DC1
Safety 
Follow-
up1
Observation 
Phase
0
3
6
9
12
21
30
39
48
60 and 
Q12W 
beyond
EuroQol (EQ)-5D
EORTC QLQ-C30
EORTC QLQ-LC13
C1
C2
C3
C4
C5
C8
C11
C14
C17
C21 
and 
every 4 
cycles 
beyond
X
X
Every 12 
weeks until 
PD
C: Cycle. 
DC: Discontinuation
1 If the 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.
The general rule of mapping relative day to analysis visit is provided in Table 4 (due to space 
limit, only up to Week 48 is displayed).
Table 4 Mapping Relative Day to Analysis Visit
Treatment 
Week
Week
0
3
6
9
12
21
30
39
48
Day
1
21
42
63
84
147
210
273
336
Range
-59 to 1
2 to 31
32 to 52
53 to73
74 to 
115
116 to 178
179 to 241
242 to 304
305 to 378
At each scheduled visit, three instruments, EQ5D, EORTC QLQ-C30, and EORTC QLQ-LC13, 
will be collected. If a patient does not complete the PRO instruments, the site staff will record 
the reason for the missing from the pre-defined choices. If there are multiple PRO collections 
within any of the stated time windows, we use the closest collection to the target day. 
3.6.2.1
Analysis Populations
The primary analysis approach for the pre-specified exploratory PRO endpoints will be based on 
a quality of life related full analysis set (FAS) population following the intention-to-treat (ITT) 


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principle and ICH E9 guidelines. This population consists of all randomized patients who have 
received at least one dose of study medication, and have completed at least one PRO assessment.    
3.6.2.2
Analysis Approaches
This section describes the planned analyses for the PRO endpoints. Table 5 gives an overview of 
the analyses planned for all PRO endpoints. Compliance will be summarized by treatment group 
and visit. 
Table 5 Planned Statistical Analysis
Endpoint
Analysis
Primary 
Statistical 
Method
Report
Score change from baseline
Treatment effect 
estimation/comparison
Mixed effect 
model based on 
the missing at 
random (MAR) 
assumption
least-square mean score (95% 
C.I.) by treatment group and visit,  
least-square mean score change 
(95% C.I.) from baseline by 
treatment group and visit, 
pairwise between-group 
difference in score change from 
baseline (95% C.I., p-value).
Disease progression 
effect estimation
Mixed effect 
model based on 
the MAR 
assumption
P-value of the interaction effect 
between progression and 
treatment discontinuation, by 
treatment group.
Time to deterioration
Treatment effect 
estimation/comparison
Kaplan-Meier 
plot, stratified 
log rank test and 
Cox proportional 
hazards model
Hazard Ratio (95% C.I.)
Proportion of 
deterioration/stable/improvement
Treatment effect 
estimation/comparison
Summary with 
multiple 
imputation based 
on the MAR 
assumption
Proportion by treatment group 
and visit
3.6.2.3
Treatment effect on PRO
To assess the treatment effects of treatment on the PRO, for each continuous endpoint defined, a 
constrained longitudinal data analysis (cLDA) model will be used as the primary analysis 
method, with the PRO score as the response variable, and treatment by study visit interaction, 
and stratification factors (Section 5.4 of the protocol) as covariates. 
The cLDA model is specified as follows:
,...
3,2,1,0
    
,2
,1
    
,
)
0
(
)
(
0






t
j
X
t
I
Y
E
i
it
jt
ijt



, where Yijt is the PRO score for subject 
i, with treatment assignment j, at visit t, 
0
is the baseline mean for all treatment groups,
jt

is 


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the mean change from baseline for treatment group j at time t, 
i
X is the stratification factor 
vector for this patient, and 
it
is the coefficient vector for stratification factor at time t.
Treatment effect on PRO score change from baseline will be evaluated at 12 weeks and 
potentially at 21 weeks, if the completion rate in the control arm is larger than 50%. Between-
group comparison will be performed and the differences in the lsmean change from baseline will 
be reported, together with 95% C.I. and nominal p-value at the primary analysis time points. In 
addition, model-based lsmean score with 95% C.I. will be provided by treatment group and study 
visit. 
Most of the patients without disease progression are expected to have complete data up to 12 and 
21 weeks. Patients with disease progression confirmed or feeling worse due to drug-related AE 
may have missing PRO assessments. The missing data must be handled accordingly to obtain 
valid statistical inference. The cLDA model implicitly treats missing data as missing at random 
(MAR). Sensitivity analyses may be conducted in case the robustness of MAR assumption is 
questionable.
3.6.2.4
Effect of disease progression on PRO
A supportive analysis will be performed to assess the effects of disease progression and 
treatment on global health status/quality of life. A constrained longitudinal data analysis (cLDA) 
model will be applied, with the PRO score as the response variable, and treatment by study visit 
interaction, stratification, and progression status (time-varying) as covariates. 
The cLDA model is specified as follows:
,..
3,2,1,0
    
,2
,1
    
,
)
0
(
)
(
0







t
j
Z
X
t
I
Y
E
t
j
i
jt
ijt




, where Yijt is the PRO score for 
subject i, with treatment assignment j, at visit t, 
0
is the baseline mean for all treatment groups,
jt

is the mean change from baseline for treatment group j at time t, 
i
X is the stratification 
factor vector for this patient, is the coefficient vector for stratification factors, 
j
is the 
disease progression effect for treatment j, and 
tZ is the progression status at visit t.
The point estimate of the effect of disease progression on the lsmean PRO score change from 
baseline will be reported, together with 95% C.I., overall and by treatment groups.
3.6.2.5
Analysis of the Proportions of Deterioration/Stable/Improvement 
Patients’ post-baseline PRO score will be classified as “improved” “stable” or “deteriorated” 
according to a 10 points or greater change for each of the instrument/scale, as this magnitude of 
change is perceived by patients as being clinically significant [7]. The number and proportion of 
patients who “improved”, “stable”, or “deteriorated”, from baseline will be summarized by 
treatment group and at week 12 and 21. 
Since missing data cannot be ignored at week 12 and week 21, additional summaries of 
deterioration/stable/improvement will be provided based on multiply-imputed data sets to handle 
the issue of missing data at week 12 and potentially at 21 weeks. Specifically, proportions will be 
calculated based on the multiply imputed data sets in the PRO score analysis, and then 


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synthesized based on Rubin’s rule. Proportions based on MAR imputation will be the primary 
result for proportions of deterioration/stable/improvement.
3.6.2.6
Analysis of the Time to Deterioration 
The true time-to-deterioration is defined in as the time to first onset of 10 or more decrease from 
baseline with confirmation under right-censoring rule. The non-parametric Kaplan-Meier method 
will be used to estimate the deterioration curve in each group. The treatment difference in time-
to-deterioration will be assessed by the stratified log-rank test. A stratified Cox proportional 
hazard model with Efron’s method of tie handling will be used to assess the magnitude of the 
treatment difference (hazard ratio) between treatment arms. The traditional time-to-deterioration, 
defined in as the time to first onset of 10 or more decrease from baseline without confirmation 
under right-censoring rule, may also be summarized.
3.6.2.7
Compliance Summary
Completion and compliance of QLQ-C30, QLQ-LC13 and EQ-5D by visit and by treatment will 
be described based on the ITT population and the PRO FAS population, respectively. Numbers 
and percentages of complete and missing data at each visit will be summarized for each of the 
treatment groups. 
Completion rate in the ITT population is defined as the percentage of the number of subjects who 
complete at least one item over the number of randomized subjects at each time points.
Completion rate in the FAS population is defined as the percentage of number of subjects who 
complete at least one item over the number of subjects in the FAS population at each time points.
The completion rate is expected to shrink in the later visit during study period due to the subjects 
who discontinued early. Therefore, another measurement, Compliance rate, defined as the 
percentage of observed visit over number of eligible subjects who are expected to complete the 
PRO assessment (not including the subjects missing by design (such as death, discontinuation, 
translation not available) will be employed as the support for completion rate).
The reasons of non-completion and non-compliance will also be provided. An instrument is 
considered complete if at least one valid score available according to the missing item rules 
outlined in the EORTC QLQ-C30 Manual for each functional and symptoms scale.
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, etc.
Adverse Events
Adverse events (AEs) will be coded using the standard MedDRA and grouped system organ 
class. Adverse events (AEs) will be graded by the investigator according to the Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.0.
Tiered Approach
The analysis of safety results will follow a tiered approach (Table 6).  The tiers differ with 
respect to the analyses that will be performed. “Tier 1” safety endpoints that will be subject to 


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inferential testing for statistical significance with p -values and 95% confidence intervals 
provided for between-group comparisons. For this protocol, there are no Tier 1 events. Other 
safety parameters will be considered Tier 2 or Tier 3. Tier 2 parameters will be assessed via point 
estimates with 95% confidence  intervals provided for between-group comparisons; only point 
estimates by treatment group are provided for Tier 3 safety parameters. 
Adverse experiences (specific terms as well as system organ class terms) 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 event s 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% confidence interval 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% confidence intervals may be provided 
without adjustment for multiplicity, the confidence intervals should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences in adverse experiences and predefined limits of 
change.
Continuous measures such as changes from baseline in laboratory, vital signs, 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, the broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, any drug related AE, any Grade 3-5 AE, any serious AE, any AE which is 
both drug-related and Grade 3-5, any AE which is both serious and drug-related, dose 
modification due to AE, and who discontinued due to an AE, and death will be considered Tier 2 
endpoints. 95% confidence intervals (Tier 2) will be provided for between- treatment differences 
in the percentage of subjects with events; these analyses will be performed using the Miettinen 
and Nurminen method (1985), an unconditional, asymptotic method.


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Table 6 Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Serious AE 
X
X
Any Grade 3-5 AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade 3-5 and Drug-Related AE
X
X 
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
Specific AEs, SOCs, or PDLCs (incidence ≥4 of subjects 
in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs (incidence <4 of subjects 
in all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, Vital Signs)
X
Summaries of Demographics, Baseline Characteristics 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 reasons for 
discontinuation will be displayed.  Demographic variables (e.g., age, gender) and baseline 
characteristics will be summarized by treatment either by descriptive statistics or categorical 
tables. 
Interim Analyses
Two interim efficacy analyses are planned in addition to the final analysis.

The first interim analysis (IA1) will evaluate PFS and OS. It will be performed after 
enrollment is complete and approximately 370 PFS events have been observed, 
approximately 19 months after first patient enrolled. It is estimated that approximately 
242 deaths will be observed. ORR will be tested at this interim analysis if both the PFS 
and OS test results are significant.

The second interim analysis (IA2) is the final analysis for PFS and will be performed 
after approximately 468 PFS events have been observed, approximately 26 months after 
first patient enrolled. An interim analysis of OS will be performed; it is estimated that 
approximately 332 deaths will be observed. 

The final analysis (FA) will evaluate OS only and will be performed after approximately 
416 deaths have been observed. It is estimated that this will occur approximately 35 
months after enrollment begins.
The analyses planned, endpoints evaluated and drivers of the timing are summarized in Table 7.


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Table 7 Analyses Planned, Endpoints Evaluated, and Drivers of Timing
Analysis
Endpoint(s)
Timing
IA1
PFS; OS; ORR if both PFS 
and OS are positive
~370 PFS events (~242 OS 
events expected at this time)
IA2
PFS; OS
~468 PFS events (~332 OS 
events expected at this time)
FA
OS
~416 OS events
Decisions to stop the trial early will be based on DMC recommendations with review by the 
Executive Oversight Committee.
Type I error control for the efficacy analyses as well as efficacy bounds are described in the next 
section.
Multiplicity
The trial uses the graphical method of Maurer and Bretz to provide strong multiplicity control 
for multiple hypotheses as well as interim analyses. 
Figure 1 shows the initial one-sided α-allocation for each hypothesis in the ellipse representing 
the hypothesis. The weights for reallocation from each hypothesis to the others are represented in 
the boxes on the lines connecting hypotheses. This is further explained below.
See Figure 1 for the type I error reallocation strategy for endpoints PFS, OS, and ORR.
Figure 1 Type I Error Reallocation Strategy
PFS
PFS hypothesis will be tested at α=0.0095. When OS test is significant, the PFS hypothesis may 
be tested at α=0.025 (re-allocated α). The Lan-DeMets O'Brien-Fleming spending function was 
used to control the type I error in the interim analysis. Table 8 below demonstrates the bounds 
and boundary properties for PFS hypothesis testing. The table will be updated using the actual 
number of PFS events at the interim and final PFS analyses.


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Table 8  Boundary properties for planned analyses of PFS based on potential alpha-levels to be 
used for testing
Analysis
Value
α=0.0095
α=0.025
IA 1: 79%
Z
2.6946
2.2676 
N: 616
p (1-sided)
0.0035
0.0117 
Events: 370
HR at bound
0.7427
0.7790 
Month: 19.2
P(Cross) if HR=1
0.0035
0.0117 
P(Cross) if HR=0.7
0.7160
0.8439 
IA2*
Z
2.3895
2.0222 
N: 616
p (1-sided)
0.0084
0.0216 
Events: 468
HR at bound
0.7910
0.8204 
Month: 26
P(Cross) if HR=1
0.0095
0.0250 
P(Cross) if HR=0.7
0.9040
0.9550 
*The final analysis of PFS will be performed at IA2.
If the OS superiority null hypotheses are rejected at an interim or final analysis, each PFS interim 
analysis test may be compared to its updated rejection boundary for formal testing.
OS
The OS hypothesis will be tested at α=0.0155. When PFS test is significant, the OS hypothesis 
may be tested at α=0.025 (re-allocated α). Table 9 demonstrates the bounds and boundary 
properties for OS hypothesis testing. The HR of OS between the experimental group and control 
group is assumed to be 0.7. The table will be updated using the actual number of OS events at 
the interim and final OS analyses. The Lan-DeMets O'Brien-Fleming spending function was 
used to derive the design in α columns.
Table 9 Boundary properties for planned analyses of OS
Analysis
Value
α=0.0155
α=0.025
IA 1: 58% 
Z 
2.9715 
2.7215 
N: 616
p (1-sided) 
0.0015 
0.0032 
Events: 242
HR at bound 
0.6662 
0.6893 
Month: 19.3 
P(Cross) if HR=1 
0.0015 
0.0032 
P(Cross) if HR=0.7 
0.3711 
0.4695 
IA 2: 80% 
Z 
2.4926 
2.2831 
N: 616
p (1-sided) 
0.0063 
0.0112 
Events: 332
HR at bound 
0.7482 
0.7666 
Month: 26.2 
P(Cross) if HR=1 
0.0068 
0.0122 
P(Cross) if HR=0.7 
0.7332 
0.7991 
Final 
Z 
2.2155 
2.0300 
N: 616 
p (1-sided) 
0.0134 
0.0212 
Events: 416 
HR at bound 
0.7940 
0.8095 
Month: 35 
P(Cross) if HR=1 
0.0155 
0.0250 
P(Cross) if HR=0.7 
0.9000 
0.9300 
Unplanned OS analysis might be requested by DMC for assessment of risk and benefit during 
the trial. These analyses are not to declare a positive efficacy finding. If requested by regulators, 


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a sensitivity analysis of OS will be performed to count these DMC required OS analyses as 
interim analyses and adjust Type I error by the pre-specified alpha spending function in the 
protocol.
If the PFS superiority null hypotheses are rejected at any interim analyses, each OS interim and 
final analysis test may be compared to its updated rejection boundary for formal testing.
ORR
When both PFS and OS tests are significant, =0.025 will be allocated to the ORR test. If the OS 
test does not achieve statistical significance at IA1, the p value of the ORR test from IA1 will be 
compared to 2.5% if the null hypotheses for PFS and OS are rejected at a later time.
Sample Size and Power Calculation
This trial is well-powered for the primary and key secondary endpoints. Enrollment of 
570 subjects is assumed to occur over 12 months at 2:1 ratio between the experimental and 
control groups. The actual enrollment is 616 subjects within 13 months. With 370 PFS events at 
IA1, the study has ~72% power for detecting a HR of 0.7 at 0.0095 (one-sided) and ~84% power 
for detecting a HR of 0.7 at 0.025 (one-sided). With 468 PFS events at IA2, the study has ~90% 
power for detecting a HR of 0.7 at 0.0095 (one-sided) and ~96% power for detecting a HR of 0.7 
at 0.025 (one-sided). The duration of PFS in the control group is assumed to follow an 
exponential distribution with a median of 6.5 months based on historical data. The assumed 
follow-up time after last patient enrolled is 13 months for IA2. An exponential dropout rate of 
0.35% per month is assumed.
With 242 deaths at IA1, the study has ~37% power for detecting a HR of 0.7 at 0.0155 (one-
sided) and ~47% power for detecting a HR of 0.7 at 0.025 (one-sided) when the PFS test is 
significant. With 332 deaths at IA2, the study has ~73% power for detecting a HR of 0.7 at 
0.0155 (one-sided) and ~80% power for detecting a HR of 0.7 at 0.025 (one-sided) when the PFS 
test is significant. With 416 deaths at FA, the study has ~90% power for detecting a HR of 0.7 at 
0.0155 (one-sided) and ~93% power for detecting a HR of 0.7 at 0.025 (one-sided) when the PFS 
test is significant. The duration of OS in the control group is assumed to follow an exponential 
distribution with a median of 13 months based on historical data. The exponential dropout rate 
assumed for OS is 0.1% per month. 
The sample size of 616 yields 89% (α=0.025) power to detect an ORR difference from an 
underlying 45% response rate in the control group to 60% in the experimental group, when both 
PFS and OS tests are significant.  The approximate treatment difference required to reach the 
bound (Δ ORR) is 0.0575.
Power and interim analysis calculations were performed using EAST 5 and the gsDesign R 
package.
Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the between-
group treatment effect for PFS, OS and ORR (with a nominal 95% CI) will be estimated and 
plotted within each category of the following classification variables: 


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
Age category (≤65, >65 years)

ECOG Performance Scale (0, 1)

Sex (female, male)

Race (white, non-white)

Geographic region (US, Ex US)

Geographic region (EU, Ex EU)Smoking status (never, former/current)

Brain metastasis status at baseline (yes, no)

PD-L1 expression (unknown, TPS <1%, or TPS ≥1%) 

PD-L1 expression (unknown, TPS <50%, or TPS ≥50%)

PD-L1 expression (unknown, TPS <1%, 1%≤TPS≤49%, or TPS ≥50%)

Platinum chemotherapy (cisplatin, carboplatin) 
For PFS and OS, the stratified Cox model will be used. For ORR, the unstratified Miettinen and 
Nurminen method will be used. The consistency of the treatment effect will be assessed 
descriptively via summary statistics by category for the classification variables listed above. If 
any level of a subgroup variable has fewer than 10% of the ITT population, above analysis will 
not be performed for this level of the subgroup variable. If a subgroup variable has two levels 
and one level of the subgroup variable has fewer than 10% of the ITT population, then this 
subgroup will not be displayed in the forest plot. 
The EU region includes countries from both EU member states (2016) and EFTA members.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.


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4.0 REFERENCES
1. Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models. Commun Stat-Theor M 1991;20(8):2609-31.
2. Bezjak A, Tu D, Seymour L et al., Symptom Improvement in Lung Cancer Patients 
Treated With Erlotinib: Quality of Life Analysis of the National Cancer Institute of 
Canada Clinical Trials Group Study BR.21 J Clin Oncol 24:3831-3837.
3. Blackhall F, Kim DW, Besse B, et al.  Patient-reported outcomes and quality of life in 
PROFILE 1007: A randomized trial of crizotinib compared with chemotherapy in 
previously treated patients with ALK positive NSCLC.  J Thorac Oncol. 2014;9: 1625–
1633.
4. Yang JC, Hrish V, Schuler M, et al. Symptom Control and Quality of Life in LUX-
Lung 3: A Phase III Study of Afatinib or Cisplatin/Pemetrexed in Patients With 
Advanced Lung Adenocarcinoma With EGFR Mutations.  J Clin Oncol 31:3342-3350.
5. The EORTC QLQ-C30 Manuals, Reference Values and Bibliography.
6. EQ-5D-3L User Guide, Oct 2013.
7. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes 
in health-related quality-of-life scores. J Clin Oncol 1998; 16:139-44.
8. Maurer W, Bretz F. Multiple testing in group sequential trials using graphical 
approaches. Stat Biopharm Res 2013;5(4):311-20.


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Revision History
Date
Summary of Change
7MAY2016
Original Document
16NOV2017
Original document is updated to align with the protocol amendment v07 
for the global study with regard to statistical analysis plan.