A Phase 3 Randomized, Open-label Clinical Study to Evaluate the Pharmacokinetics and Safety of Subcutaneous Pembrolizumab Coformulated With Hyaluronidase (MK-3475A) Versus Intravenous Pembrolizumab, Administered With Chemotherapy, in the First-line Treatment of Participants With Metastatic Non-small Cell Lung Cancer
Phase: PHASE3
Conditions: Metastatic Non-small Cell Lung Cancer
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase 3 Randomized, Open-label Clinical Study to 
Evaluate the Pharmacokinetics and Safety of 
Subcutaneous Pembrolizumab Coformulated With 
Hyaluronidase (MK-3475A) Versus Intravenous 
Pembrolizumab, Administered With Chemotherapy, in the 
First-line Treatment of Participants With Metastatic Non-
small Cell Lung Cancer
NCT06212752
06-FEB-2024

PRODUCT: MK-3475A
1
PROTOCOL/AMENDMENT NO.: D77-03
MK-3475A-D77-03 FINAL PROTOCOL
06-FEB-2024
TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3 Randomized, Open-label Clinical Study to Evaluate the 
Pharmacokinetics and Safety of Subcutaneous Pembrolizumab Coformulated With 
Hyaluronidase (MK-3475A) Versus Intravenous Pembrolizumab, Administered With 
Chemotherapy, in the First-line Treatment of Participants With Metastatic Non-small Cell 
Lung Cancer
Protocol Number: D77-03
Compound Number: MK-3475A
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
05722015
EU CT
2022-501506-36
EudraCT
Not Applicable
jRCT
2031230049
WHO
Not Applicable
UTN
Not Applicable
IND
Approval Date: 06 February 2024
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 3
06-FEB-2024
To add G-CSF as primary prophylaxis during the 
first 4 platinum-doublet infusions in both arms.
Amendment 2
19-OCT-2023
To update the assumptions and timing of the 
analyses in the SAP.
Amendment 1
10-Apr-2023
To incorporate revisions based on health 
authority feedback.
Original Protocol
20-OCT-2022
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendment:
To add G-CSF as primary prophylaxis during the first 4 platinum-doublet infusions in both 
arms.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 4.1, 
Overall Design
Text was added that G-CSF will be received as 
primary prophylaxis during the first 4 platinum-
doublet infusions in both arms.
Section Number and 
Name
Description of Change
Brief Rationale
Additional Changes
Section 1.1, Synopsis
Number of participants was updated.
The faster screening rate and lower than 
anticipated screen failure rates resulted in over 
enrollment of participants. 
Section 1.1, Synopsis
Intervention Groups and Duration Table was 
updated to include G-CSF administration.
Refer to Section 4.1 rationale.
Section 1.2, Schema
Sample size was updated.
Refer to Section 1.1 rationale.
Section 1.3.1, SoA-
Screening to Cycle 2
A row was added to Table 1 to require that 
G-CSF will be administered in both arms. 
Also, a note was added to refer to 
Section 6.5.1.2.1 for G-CSF related 
information.
Refer to Section 4.1 rationale
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Section Number and 
Name
Description of Change
Brief Rationale
Section 1.3.3, SoA-PK 
and ADA Sample 
Collection
PK and ADA sample collection tables were 
updated
update the timepoints for the 
MK-5180 PK.
Changes were made to characterize 
PK and MK-5180 PK 
Section 2.2.6, 
Information on Other 
Study-related Therapy
Text was added to refer to Section 6.5.1.2.1 
for G-CSF related information.
Refer to Section 4.1 rationale.
Section 6.1., Study 
Interventions 
Administered
Filgrastim and pegylated filgrastim (G-CSF) 
were added to the study interventions table.
Refer to Section 4.1 rationale.
Section 6.5.1.2.1, 
Colony Stimulating 
Factors
Text was added to clarify the timing and 
considerations for G-CSF administration
Refer to Section 4.1 rationale.
Section 8.1.8.4, 
Chemotherapy 
Administration
Text was added to refer to Section 6.5.1.2.1 
for G-CSF related information.
Refer to Section 4.1 rationale.
Section 9.1, Statistical 
Analysis Plan 
Summary
Sample size and power for PK endpoints 
were updated.
Refer to Section 1.1 rationale.
The prevalences of histology and PDL1 status 
assumed in the ORR noninferiority test are 
different in the current study compared to the 
historical data.
Section 9.7.1, 
Pharmacokinetics 
Interim Analysis 
Evaluable participants for PK endpoints were 
updated.
Refer to Section 1.1 rationale.
Section 9.8.1, Cycle 1 
AUC0-6wks
Boundaries and characteristics of analyses for 
Cycle 1 AUC0-6wks were updated.
Refer to Section 1.1 rationale.
Section 9.8.2, Cycle 3 
Ctrough
Boundaries and characteristics of analyses for 
Cycle 3 Ctrough were updated.
Refer to Section 1.1 rationale.
Section 9.9, Sample 
Size and Power 
Calculations
To update the sample size and the 
assumptions in ORR noninferiority test 
Refer to Section 9.1 rationale. 
Section 10.8, 
Appendix 8: Synthesis 
Method for ORR 
Noninferiority
The assumptions in ORR noninferiority test 
were updated.
Refer to Section 9.1 rationale.
Throughout the 
document
Minor administrative, formatting, 
grammatical, and/or typographical changes 
were made throughout the document.
To ensure clarity and accurate interpretation 
of the intent of the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................20
1.3
Schedule of Activities...........................................................................................20
1.3.1
Screening to Cycle 2 ....................................................................................21
1.3.2
Cycle 3 to Posttreatment..............................................................................32
1.3.3
PK and ADA Sample Collection .................................................................36
1.3.4
Second Course Retreatment.........................................................................40
2
INTRODUCTION..........................................................................................................43
2.1
Study Rationale....................................................................................................43
2.2
Background ..........................................................................................................43
2.2.1
Subcutaneous Formulation...........................................................................43
2.2.2
Non-small Cell Lung Cancer .......................................................................45
2.2.3
Pharmaceutical and Therapeutic Background .............................................45
2.2.4
Preclinical and Clinical Studies ...................................................................46
2.2.5
Ongoing Clinical Studies.............................................................................47
2.2.6
Information on Other Study-related Therapy ..............................................47
2.3
Benefit/Risk Assessment......................................................................................47
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................48
4
STUDY DESIGN............................................................................................................50
4.1
Overall Design......................................................................................................50
4.2
Scientific Rationale for Study Design.................................................................51
4.2.1
Rationale for Endpoints ...............................................................................52
4.2.1.1
Pharmacokinetic Endpoints ...............................................................52
4.2.1.2
Antidrug Antibodies...........................................................................53
4.2.1.3
Efficacy Endpoints.............................................................................53
4.2.1.3.1
RECIST 1.1..............................................................................53
4.2.1.4
Safety Endpoints................................................................................53
4.2.1.5
Patient-reported Outcomes.................................................................53
4.2.1.5.1
EORTC QLQ-C30 ...................................................................53
4.2.1.5.2
EQ-5D-5L ................................................................................54
4.2.1.6
...................................54
4.2.1.7
Future Biomedical Research..............................................................55
4.2.2
Rationale for the Use of Comparator...........................................................56
4.3
Justification for Dose...........................................................................................56
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4.3.1
MK-3475A Subcutaneous Dose ..................................................................56
4.3.2
Pembrolizumab Intravenous Dose...............................................................58
4.3.3
Chemotherapy Dose.....................................................................................59
4.4
Beginning and End-of-Study Definition ............................................................59
4.4.1
Clinical Criteria for Early Study Termination .............................................60
5
STUDY POPULATION ................................................................................................61
5.1
Inclusion Criteria.................................................................................................61
5.2
Exclusion Criteria................................................................................................65
5.3
Lifestyle Considerations......................................................................................67
5.3.1
Meals and Dietary Restrictions....................................................................67
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................67
5.3.3
Activity Restrictions ....................................................................................67
5.4
Screen Failures.....................................................................................................68
5.5
Participant Replacement Strategy......................................................................68
6
STUDY INTERVENTION............................................................................................69
6.1
Study Intervention(s) Administered...................................................................69
6.1.1
Treatment .....................................................................................................73
6.1.2
Second Course .............................................................................................73
6.2
Preparation/Handling/Storage/Accountability .................................................74
6.2.1
Dose Preparation..........................................................................................74
6.2.2
Handling, Storage, and Accountability........................................................74
6.3
Measures to Minimize Bias: Randomization and Blinding..............................74
6.3.1
Intervention Assignment..............................................................................74
6.3.2
Stratification.................................................................................................75
6.3.3
Blinding........................................................................................................75
6.4
Study Intervention Compliance..........................................................................75
6.5
Concomitant Therapy..........................................................................................76
6.5.1
Rescue Medications and Supportive Care ...................................................77
6.5.1.1
Pembrolizumab ..................................................................................77
6.5.1.2
Chemotherapy....................................................................................77
6.5.1.2.1
Colony Stimulating Factors .....................................................78
6.6
Dose Modification (Escalation/Titration/Other)...............................................78
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................78
6.6.2
Chemotherapy Dose Modifications .............................................................88
6.7
Intervention After the End of the Study............................................................94
6.8
Clinical Supplies Disclosure................................................................................94
6.9
Standard Policies..................................................................................................94
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DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................95
7.1
Discontinuation of Study Intervention...............................................................95
7.2
Participant Withdrawal From the Study...........................................................96
7.3
Lost to Follow-up .................................................................................................96
8
STUDY ASSESSMENTS AND PROCEDURES........................................................97
8.1
Administrative and General Procedures ...........................................................97
8.1.1
Informed Consent.........................................................................................97
8.1.1.1
General Informed Consent.................................................................98
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................98
8.1.2
Inclusion/Exclusion Criteria ........................................................................98
8.1.3
Participant Identification Card.....................................................................98
8.1.4
Medical History ...........................................................................................99
8.1.4.1
Tobacco Use Assessment...................................................................99
8.1.4.2
Non-small Cell Lung Cancer History ................................................99
8.1.5
Prior and Concomitant Medications Review...............................................99
8.1.5.1
Prior Medications...............................................................................99
8.1.5.2
Concomitant Medications................................................................100
8.1.5.3
Subsequent Antineoplastic Therapy ................................................100
8.1.6
Assignment of Screening Number.............................................................100
8.1.7
Assignment of Treatment/Randomization Number...................................100
8.1.8
Study Intervention Administration ............................................................100
8.1.8.1
Timing of Dose Administration.......................................................100
8.1.8.2
MK-3475A Administration..............................................................101
8.1.8.3
Pembrolizumab Administration.......................................................101
8.1.8.4
Chemotherapy Administration.........................................................101
8.1.8.4.1
Pemetrexed (Nonsquamous)..................................................101
8.1.8.4.2
Cisplatin (Nonsquamous).......................................................102
8.1.8.4.3
Carboplatin (Nonsquamous and Squamous)..........................102
8.1.8.4.4
Paclitaxel or Nab-paclitaxel (Squamous)...............................103
8.1.9
Discontinuation and Withdrawal ...............................................................103
8.1.9.1
Withdrawal From Future Biomedical Research ..............................104
8.1.10
Participant Blinding/Unblinding................................................................104
8.1.11
Calibration of Equipment...........................................................................104
8.1.12
Tumor Tissue for Biomarker Status...........................................................104
8.2
Efficacy/ Assessments ........................................................................................105
8.2.1
Tumor Imaging and Assessment of Disease..............................................105
8.2.1.1
Initial Tumor Scans..........................................................................106
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8.2.1.2
Tumor Scans During the Study........................................................106
8.2.1.3
End-of-treatment and Follow-up Tumor Scans ...............................107
8.2.1.4
Second Course (Retreatment) Tumor Scans....................................108
8.2.1.5
RECIST 1.1 Assessment of Disease................................................108
8.2.2
Patient-reported Outcomes.........................................................................110
8.3
Safety Assessments.............................................................................................110
8.3.1
Physical Examinations...............................................................................111
8.3.1.1
Full Physical Examination...............................................................111
8.3.1.2
Directed Physical Examination........................................................111
8.3.1.3
Directed Injection-site Physical Examination..................................112
8.3.2
Vital Signs..................................................................................................113
8.3.3
Electrocardiograms ....................................................................................113
8.3.4
Clinical Safety Laboratory Assessments ...................................................113
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)........................................................................................114
8.3.5
Pregnancy Testing......................................................................................114
8.3.6
Performance Assessments..........................................................................114
8.3.6.1
Eastern Cooperative Oncology Group Performance Status.............114
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................115
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................115
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....118
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.118
8.4.4
Regulatory Reporting Requirements for SAE ...........................................118
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................119
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................119
8.4.7
Events of Clinical Interest..........................................................................119
8.5
Treatment of Overdose......................................................................................120
8.6
Pharmacokinetics...............................................................................................120
8.6.1
Blood Collection for Pembrolizumab and MK-5180 Pharmacokinetics ...120
8.6.2
Blood Collection for Antidrug Antibodies ................................................121
8.7
Pharmacodynamics............................................................................................121
8.8
Biomarkers .........................................................................................................121
8.8.1
Planned Genetic Analysis Sample Collection............................................122
8.9
Future Biomedical Research Sample Collection.............................................122
8.10
Medical Resource Utilization and Health Economics.....................................122
8.11
Pharmacoeconomics ..........................................................................................122
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8.12
Visit Requirements.............................................................................................123
8.12.1
Screening....................................................................................................123
8.12.2
Treatment Period........................................................................................123
8.12.2.1
Optional Home Health Visits for PK Sampling...............................123
8.12.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ..............................................................................124
8.12.4
Posttreatment Visit.....................................................................................124
8.12.4.1
Safety Follow-up Visit.....................................................................124
8.12.4.2
Efficacy Follow-up Visits................................................................124
8.12.4.3
Survival Follow-up Contacts ...........................................................124
8.12.5
Vital Status.................................................................................................125
9
KEY STATISTICAL CONSIDERATIONS .............................................................126
9.1
Statistical Analysis Plan Summary...................................................................126
9.2
Responsibility for Analyses/In-house Blinding ...............................................128
9.3
Hypotheses/Estimation ......................................................................................128
9.4
Analysis Endpoints.............................................................................................128
9.4.1
Pharmacokinetics Endpoints......................................................................129
9.4.2
Safety Endpoints........................................................................................130
9.4.3
Efficacy Endpoints.....................................................................................130
9.4.4
Immunogenicity Endpoint .........................................................................130
9.4.5
PRO Endpoints...........................................................................................131
9.5
Analysis Populations..........................................................................................131
9.5.1
Pharmacokinetics Analysis Populations ....................................................131
9.5.2
Safety Analysis Populations ......................................................................133
9.5.3
Efficacy Analysis Populations...................................................................133
9.5.4
PRO Analysis Populations.........................................................................134
9.6
Statistical Methods.............................................................................................134
9.6.1
Statistical Methods for Pharmacokinetics Analyses..................................134
9.6.2
Statistical Methods for Safety Analyses ....................................................134
9.6.2.1
Overall Safety Assessment ..............................................................135
9.6.2.2
Assessment of Safety Topics of Special Interest .............................136
9.6.3
Statistical Methods for Efficacy Analyses.................................................137
9.6.3.1
Objective Response Rate .................................................................137
9.6.3.2
Progression-free Survival.................................................................137
9.6.3.3
Overall Survival...............................................................................138
9.6.3.4
Duration of Response.......................................................................139
9.6.3.5
Analysis Strategy for Key Efficacy Variables.................................139
9.6.4
Statistical Methods for Patient-Reported Outcome Analyses....................140
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9.6.5
Demographic and Baseline Characteristics ...............................................140
9.7
Interim Analyses ................................................................................................141
9.7.1
Pharmacokinetics Interim Analysis ...........................................................141
9.7.2
Safety Interim Analysis..............................................................................142
9.8
Multiplicity .........................................................................................................142
9.8.1
Cycle 1 AUC0-6 wks .....................................................................................142
9.8.2
Cycle 3 Ctrough.............................................................................................143
9.8.3
Safety Analyses..........................................................................................144
9.9
Sample Size and Power Calculations ...............................................................144
9.10
Subgroup Analyses.............................................................................................146
9.11
Compliance (Medication Adherence)...............................................................146
9.12
Extent of Exposure.............................................................................................147
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................148
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......148
10.1.1
Code of Conduct for Interventional Clinical Trials ...................................148
10.1.2
Financial Disclosure...................................................................................151
10.1.3
Data Protection...........................................................................................152
10.1.3.1
Confidentiality of Data ....................................................................152
10.1.3.2
Confidentiality of Participant Records.............................................152
10.1.3.3
Confidentiality of IRB/IEC Information..........................................153
10.1.4
Committees Structure.................................................................................153
10.1.4.1
External Data Monitoring Committee .............................................153
10.1.4.2
Executive Oversight Committee......................................................153
10.1.5
Publication Policy......................................................................................153
10.1.6
Compliance with Study Registration and Results Posting Requirements .154
10.1.7
Compliance with Law, Audit, and Debarment ..........................................154
10.1.8
Data Quality Assurance .............................................................................155
10.1.9
Source Documents .....................................................................................156
10.1.10
Study and Site Closure...............................................................................156
10.2
Appendix 2: Clinical Laboratory Tests............................................................157
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................160
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................160
10.3.2
Definition of AE ........................................................................................160
10.3.3
Definition of SAE ......................................................................................161
10.3.4
Additional Events Reported.......................................................................162
10.3.5
Recording AE and SAE .............................................................................163
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10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................166
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................168
10.5
Appendix 5: Contraceptive Guidance..............................................................169
10.5.1
Definitions..................................................................................................169
10.5.2
Contraceptive Requirements......................................................................170
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................171
10.7
Appendix 7: Country-specific Requirements..................................................175
10.7.1
Argentina....................................................................................................175
10.7.2
China..........................................................................................................175
10.7.3
Czech Republic..........................................................................................176
10.7.4
France.........................................................................................................176
10.7.5
Italy ............................................................................................................176
10.7.6
Japan ..........................................................................................................177
10.7.7
Romania.....................................................................................................177
10.7.8
South Africa...............................................................................................177
10.7.9
United Kingdom.........................................................................................177
10.8
.................179
10.9
Appendix 9: Abbreviations ...............................................................................182
11
REFERENCES.............................................................................................................189
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LIST OF TABLES
Table 1
Screening to Cycle 2 ....................................................................................21
Table 2
Cycle 3 to Posttreatment..............................................................................32
Table 3
........36
Table 4
.........................................37
Table 5
................38
Table 6
3 to 18
......................................................................................................................39
Table 7
Second Course Retreatment.........................................................................40
Table 8
Adequate Organ Function Laboratory Values .............................................65
Table 9
Study Interventions......................................................................................70
Table 10
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...........................................................................80
Table 11
Pembrolizumab Monotherapy, Coformulations or IO Combinations 
Infusion/Injection Reaction Dose Modification and Treatment Guidelines................85
Table 12
Dose Level Modifications for Chemotherapeutic Agents ...........................91
Table 13
Recommended Chemotherapy Dose Modifications for Hematological 
Toxicity ......................................................................................................................92
Table 14
Recommended Chemotherapy Dose Modifications for 
Nonhematological Toxicity .........................................................................................93
Table 15
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................................117
Table 16
Analysis Strategy for Safety Endpoints.....................................................136
Table 17
Censoring Rules for Primary and Sensitivity Analysis of PFS..................138
Table 18
Censoring Rules for DOR..........................................................................139
Table 19
Analysis Strategy for Key Efficacy Variables...........................................140
Table 20
Summary of Analysis Strategy ..................................................................141
Table 21
Boundaries and Properties for Cycle 1 AUC NI Analysis.........................143
Table 22
Boundaries and Properties for Cycle 3 Ctrough NI Analysis .......................144
Table 23
Protocol-required Safety Laboratory Assessments....................................158
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LIST OF FIGURES
Figure 1
MK-3475A-D77 Study Design....................................................................20
Figure 2
Distribution of Ctrough at Cycle 1 and Steady State Using PK Model-
based Simulations at a Dose of 790 mg Q6W SC and 400 mg Q6W IV of 
Pembrolizumab ............................................................................................................57
Figure 3
Distribution of AUC0-6wks at Cycle 1 and Steady State Using PK Model-
based Simulations at a Dose of 790 mg Q6W SC and 400 mg Q6W IV of 
Pembrolizumab ............................................................................................................57
Figure 4
Distribution of Cmax at Steady State Using PK Model-based Simulations 
at a Dose of 790 mg Q6W SC and 400 mg Q6W IV of Pembrolizumab ....................58
Figure 5
Mean Cycle 1 PK Profile From Model-based Simulations at a Dose of 
790 mg Q6W SC (Blue Line) and 400 mg Q6W IV (Red Line) of Pembrolizumab ..58
Figure 6
Study Intervention Decision-Making Process When Progression per 
RECIST 1.1 is Observed by Investigator...................................................................110
Figure 7
Multiplicity Strategy..................................................................................142
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PRODUCT: MK-3475A
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PROTOCOL/AMENDMENT NO.: D77-03
MK-3475A-D77-03 FINAL PROTOCOL
06-FEB-2024
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Randomized, Open-label Clinical Study to Evaluate the 
Pharmacokinetics and Safety of Subcutaneous Pembrolizumab Coformulated With 
Hyaluronidase (MK-3475A) Versus Intravenous Pembrolizumab, Administered With 
Chemotherapy, in the First-line Treatment of Participants With Metastatic Non-small Cell 
Lung Cancer
Short Title: MK-3475A SC vs pembrolizumab IV, administered with chemotherapy, in 
treatment-naïve metastatic NSCLC
Acronym: Not Applicable
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In participants with treatment-naïve metastatic NSCLC.
Primary Objectives
Primary Endpoints
-Objective: To compare MK-3475A SC to 
pembrolizumab IV with respect to Cycle 1 
AUC
- Hypothesis (H1): MK-3475A SC is 
noninferior to pembrolizumab IV with 
respect to the geometric mean Cycle 1 AUC 
of pembrolizumab
- Cycle 1 AUC0-6wks
- Objective: To compare MK-3475A SC to 
pembrolizumab IV with respect to steady-
state (Cycle 3) Ctrough
- Hypothesis (H2): MK-3475A SC is 
noninferior to pembrolizumab IV with 
respect to the geometric mean steady-state 
(Cycle 3) Ctrough of pembrolizumab
- Steady-state (Cycle 3) Ctrough
The primary analysis will be performed 
on the model-based values of Ctrough
Secondary Objectives
Secondary Endpoints
- To evaluate pembrolizumab exposure for 
MK-3475A SC relative to pembrolizumab 
IV Q6W
- Cycle 1: Cmax and Ctrough
- Steady state (Cycle 3): AUC0-6wks and Cmax
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06-FEB-2024
- To evaluate the development of circulating 
anti-pembrolizumab antibodies for 
MK-3475A SC and pembrolizumab IV
- Anti-pembrolizumab antibodies
- To evaluate pembrolizumab Ctrough for 
MK-3475A SC relative to pembrolizumab 
IV Q3W
- Cycle 1: Model-based Ctrough
- Steady state: Model-based Ctrough
- To evaluate MK-3475A SC and 
pembrolizumab IV with respect to ORR per 
RECIST 1.1 as assessed by BICR
- Objective response: CR or PR
- To evaluate MK-3475A SC and 
pembrolizumab IV with respect PFS per 
RECIST 1.1 as assessed by BICR
- PFS: The time from randomization to the 
first documented disease progression or 
death due to any cause, whichever occurs 
first
- To evaluate MK-3475A SC and 
pembrolizumab IV with respect to OS
- OS: The time from randomization to death 
due to any cause
- To evaluate MK-3475A SC and 
pembrolizumab IV with respect DOR per 
RECIST 1.1 as assessed by BICR
- DOR: The time from the first documented 
evidence of CR or PR until disease 
progression or death due to any cause, 
whichever occurs first
- To evaluate the safety and tolerability of 
MK-3475A SC and pembrolizumab IV
- AE
- Discontinuation of study intervention due 
to AEs
- To evaluate the change from baseline in 
global health status/QoL for MK-3475A SC 
and pembrolizumab IV
- Change in score from baseline at a 
predefined timepoint evaluated by EORTC 
QLQ-C30 in the following items:
-
- Global health status/QoL (Items 29 
and 30)
-
- Physical functioning (Items 1 to 5)
- Role functioning (Items 6 and 7)
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PRODUCT: MK-3475A
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PROTOCOL/AMENDMENT NO.: D77-03
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06-FEB-2024
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
First line treatment of participants with metastatic Non-
small cell lung cancer
Population
Adult participants with treatment-naïve metastatic non-
small cell lung cancer
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Active Control Without Placebo
Study Blinding
Unblinded open-label
Blinding Roles
No blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 5 years from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent until the last participant’s 
last study-related contact.
Extension Study in Japan: The Sponsor estimates that the 
study will require approximately 1 additional year 
(beyond the global study’s last participant last study 
related contact) from the time the first participant (or 
their legally acceptable representative) provides 
documented informed consent until the last participant’s 
last study related contact.
Number of Participants:
Approximately 378 participants will be randomized.
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Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Arm 1 
(nonsquamous and 
squamous 
NSCLC)
MK-3475A
165 mg/mL
790 mg
SC
Day 1 of each 
cycle (Q6W) 
for 18 cycles; 
participants 
may be eligible 
for Second 
Course (9 
additional 
cycles)
Test 
Product
Arm 1 
(nonsquamous 
NSCLC)
Pemetrexed
Per Approved 
Product Label
500 mg/m²
IV Infusion
Days 1 and 22 
of each cycle 
(Q3W)
Background 
Treatment
Arm 1 
(nonsquamous 
NSCLC)
Cisplatin
Per Approved 
Product Label
75 mg/m²
IV Infusion
Days 1 and 22 
of Cycles 1 and 
2 (Q3W)
Background 
Treatment
Arm 1 
(nonsquamous and 
squamous 
NSCLC)
Carboplatin
Per Approved 
Product Label
AUC 5 for 
nonsquamous; 
AUC 6 for 
squamous
IV Infusion
Days 1 and 22 
of Cycles 1 and 
2 (Q3W)
Background 
Treatment
Arm 1 (squamous 
NSCLC)
Paclitaxel
Per Approved 
Product Label
200 mg/m²
IV Infusion
Days 1 and 22 
of Cycles 1 and 
2 (Q3W)
Background 
Treatment
Arm 1 (squamous 
NSCLC)
Nab-paclitaxel
Per Approved 
Product Label
100 mg/m²
IV Infusion
Days 1, 8, 15, 
22, 29, and 36 
of Cycles 1 and 
2
Background 
Treatment
Arm 2 
(nonsquamous and 
squamous 
NSCLC)
Pembrolizumab 25 mg/mL
400 mg
IV Infusion
Day 1 of each 
cycle (Q6W) 
for 18 cycles; 
participants 
may be eligible 
for Second 
Course (9 
additional 
cycles)
Comparator
Arm 2 
(nonsquamous 
NSCLC)
Pemetrexed
Per Approved 
Product Label
500 mg/m²
IV Infusion
Days 1 and 22 
of each cycle 
(Q3W)
Background 
Treatment
Arm 2 
(nonsquamous 
NSCLC)
Cisplatin
Per Approved 
Product Label
75 mg/m²
IV Infusion
Days 1 and 22 
of Cycles 1 and 
2 (Q3W)
Background 
Treatment
Arm 2 
(nonsquamous and 
squamous 
NSCLC)
Carboplatin
Per Approved 
Product Label
AUC 5 for 
nonsquamous; 
AUC 6 for 
squamous
IV Infusion
Days 1 and 22 
of Cycles 1 and 
2 (Q3W)
Background 
Treatment
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Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Arm 2 (squamous 
NSCLC)
Paclitaxel
Per Approved 
Product Label
200 mg/m²
IV Infusion
Days 1 and 22 
of Cycles 1 and 
2 (Q3W)
Background 
Treatment
Arm 2 (squamous 
NSCLC)
Nab-paclitaxel
Per Approved 
Product Label
100 mg/m²
IV Infusion
Days 1, 8, 15, 
22, 29, and 36 
of Cycles 1 and 
2
Background 
Treatment
Arm 1 and Arm 2 
(nonsquamous and 
squamous 
NSCLC)
Filgastrim
Per Approved 
Product Label
Per Approved 
Product Label
IV Infusion
Days 2 and 
D23 of cycles 1 
and 2.
Background 
Treatment
Arm 1 and Arm 2 
(nonsquamous and 
squamous 
NSCLC)
Pegylated 
Filgastrim
Per Approved 
Product Label
Per Approved 
Product Label
IV Infusion
Days 2 and 
D23 of cycles 1 
and 2 (not to be 
used with Nab-
Paclitaxel),
Background 
Treatment
AUC=area under the curve; IV=intravenous; Q3W=every 3 weeks; Q6W=every 6 weeks; SC=subcutaneous. 
For commercially available supplies, the unit dose strength or formulation may vary, depending on market availability.
Different formulations are still permitted as indicated.
Other current or former name(s) or alias(es) for study intervention(s) are as follows:
pembrolizumab (KEYTRUDA®, MK-3475 or SCH 900475).
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PROTOCOL/AMENDMENT NO.: D77-03
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06-FEB-2024
Total Number of Intervention 
Groups/Arms
2
Duration of Participation
Each participant will participate in the study for 
approximately 5 years from the time the participant 
provides documented informed consent through the 
final protocol-specified contact.
After a screening period of up to 28 days, each 
participant will be receiving assigned study 
intervention until one of the conditions for study 
discontinuation is met. After the end of treatment each 
participant will be followed for 4 years.
Participants who complete study intervention after 
receiving 18 administrations of MK-3475A (Arm 1) or 
pembrolizumab (Arm 2) and may be eligible for up to 9 
additional administrations of MK-3475A or 
pembrolizumab (approximately 1 year) upon 
experiencing disease progression. 
Participants are only eligible to receive additional 
administrations of the study intervention to which they 
were originally assigned.
Participants who discontinue for reasons other than 
radiographic disease progression will have 
posttreatment follow-up imaging for disease status until 
any of the conditions for discontinuation of imaging are 
met.
After the end of treatment, each participant will be 
followed for the occurrence of adverse events and 
spontaneously reported pregnancy. All participants will 
be followed for overall survival until death, withdrawal 
of consent, or the end of the study.
Study Governance Committees:
Executive Oversight Committee
Yes
External Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
STUDY ACCEPTS HEALTHY PARTICIPANTS: 
No
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A list of abbreviations is in Appendix 9.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
MK-3475A-D77 Study Design
ALK=anaplastic lymphoma kinase; ECOG=Eastern Cooperative Oncology Group; EGFR=epidermal growth factor 
receptor; IV=intravenous; NSCLC=non-small cell lung cancer; PD-L1=programmed cell death ligand 1; PS=performance 
status; Q3W=every 3 weeks; Q6W=every 6 weeks; ROS1=c-ros oncogene 1; SC=subcutaneous; TPS=tumor proportion 
score; vs=versus.
1.3
Schedule of Activities
The SoA is organized as follows:
•
Screening to posttreatment (Table 1 and Table 2)
•
PK and ADA sample collection (Table 3, Table 4, Table 5 and Table 6)
•
Second course retreatment (Table 7)
Details of each procedure outlined in the SoA are provided in Section 8. Unless otherwise 
indicated, procedures should be performed before study intervention administration. Refer to 
Appendix 7 for country-specific requirements.
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06-FEB-2024
1.3.1
Screening to Cycle 2
Table 1
Screening to Cycle 2
Study Period:
Screening
Intervention
(6-Week Cycles)
Notes
Cycle:
Screening
1
2
Cycle Day:
-28 to -1
1
2
4
8
15
22
23
26
29
36
1
2
4
8
15
22
23
26
29
36
Schedule Window:
±1
±1
±1
±1
±3
±1
±1
±1
±1
±1
±1
±1
±3
±1
±1
Administrative Procedures
Informed Consent
X
If the investigator 
plans to treat 
beyond disease 
progression, 
additional consent 
is required.
Informed Consent for 
FBR
X
This is optional 
for the 
participant.
Inclusion/Exclusion 
Criteria
X
Participant 
Identification Card
X
X
Add the 
randomization 
number at the 
time of 
randomization.
Demographics and 
Medical History
X
Tobacco Use 
Assessment
X
See 
Section 8.1.4.1 
for definitions of 
cigarette use.
NSCLC History
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
C1D2 is for 
participants in 
Arm 1 only.
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06-FEB-2024
Study Period:
Screening
Intervention
(6-Week Cycles)
Notes
Cycle:
Screening
1
2
Cycle Day:
-28 to -1
1
2
4
8
15
22
23
26
29
36
1
2
4
8
15
22
23
26
29
36
Schedule Window:
±1
±1
±1
±1
±3
±1
±1
±1
±1
±1
±1
±1
±3
±1
±1
Prior/Concomitant 
Medication Review
(Nab-paclitaxel)
X
X
X
X
X
X
X
X
Additional 
procedures only 
for participants 
receiving nab-
paclitaxel.
Enrollment Support 
Consultation Form
X
Form must be 
reviewed by 
Sponsor prior to 
randomization.
Intervention 
Randomization 
X
Randomization 
can occur up to 3 
days before C1D1 
(start of study 
intervention)
Vital Status
Participants may 
be contacted for 
vital status at any 
time during the 
study.
Study Intervention Administration
MK-3475A SC 
(Arm 1) OR
Pembrolizumab IV 
(Arm 2)
X
X
Pemetrexed 
(Nonsquamous)
X
X
X
X
Cisplatin OR
Carboplatin 
(Nonsquamous)
X
X
X
X
Carboplatin 
(Squamous)
X
X
X
X
Paclitaxel (Squamous) 
OR
X
X
X
X
If receiving 
paclitaxel
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PRODUCT: MK-3475A
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06-FEB-2024
Study Period:
Screening
Intervention
(6-Week Cycles)
Notes
Cycle:
Screening
1
2
Cycle Day:
-28 to -1
1
2
4
8
15
22
23
26
29
36
1
2
4
8
15
22
23
26
29
36
Schedule Window:
±1
±1
±1
±1
±3
±1
±1
±1
±1
±1
±1
±1
±3
±1
±1
Nab-paclitaxel 
(Squamous)
X
X
X
X
X
X
X
X
X
X
X
X
If receiving nab-
paclitaxel
G-CSF
X
X
X
X
Refer to 
Section 6.5.1.2.1 
for details.
Efficacy Assessments
Scans should 
follow calendar 
days from 
randomization 
and should not be 
adjusted for 
delays in cycle 
starts.
Tumor Scan (Chest, 
Abdomen, and Pelvis)
X
X
See note
Postbaseline 
scans should be 
performed at 
Week 6 (+7 
days), Week 12 
(±7 days), Week 
18 (±7 days), 
Q9W (±7 days) 
until Week 45, 
and then Q12W 
(±7 days) 
thereafter until 
one of the 
conditions for 
stopping tumor 
scans is met.
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PRODUCT: MK-3475A
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PROTOCOL/AMENDMENT NO.: D77-03
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06-FEB-2024
Study Period:
Screening
Intervention
(6-Week Cycles)
Notes
Cycle:
Screening
1
2
Cycle Day:
-28 to -1
1
2
4
8
15
22
23
26
29
36
1
2
4
8
15
22
23
26
29
36
Schedule Window:
±1
±1
±1
±1
±3
±1
±1
±1
±1
±1
±1
±1
±3
±1
±1
Brain Scan
X
All participants 
are required to 
have brain scans 
at screening. 
For participants 
with treated brain 
metastases at 
baseline, on-study 
brain scans will 
be acquired at 
Week 6 (+7 days) 
and then if 
clinically 
indicated and to 
confirm a CR. 
For participants 
without brain 
metastases at 
baseline, on-study 
brain scans 
should be 
acquired if 
clinically 
indicated. 
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PRODUCT: MK-3475A
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PROTOCOL/AMENDMENT NO.: D77-03
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06-FEB-2024
Study Period:
Screening
Intervention
(6-Week Cycles)
Notes
Cycle:
Screening
1
2
Cycle Day:
-28 to -1
1
2
4
8
15
22
23
26
29
36
1
2
4
8
15
22
23
26
29
36
Schedule Window:
±1
±1
±1
±1
±3
±1
±1
±1
±1
±1
±1
±1
±3
±1
±1
Bone Scan
X
Bone scans are 
required at 
screening for 
participants with 
a history of bone 
metastases or 
signs/symptoms 
suggestive of 
bone metastases. 
On-study bone 
scans should be 
performed if 
clinically 
indicated or to 
confirm CR when 
bone metastases 
existed at 
baseline.
Patient -reported Outcomes
EORTC QLQ-C30
X
X
X
X
Administer in the 
following order: 
EORTC QLQ-
C30 first, then 
EQ-5D-5L.
EQ-5D-5L
X
X
X
X
Safety Assessments 
Full Physical 
Examination
X
Height
X
Weight
X
X
X
X
X
Directed Physical 
Examination
X
X
X
X
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PRODUCT: MK-3475A
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PROTOCOL/AMENDMENT NO.: D77-03
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06-FEB-2024
Study Period:
Screening
Intervention
(6-Week Cycles)
Notes
Cycle:
Screening
1
2
Cycle Day:
-28 to -1
1
2
4
8
15
22
23
26
29
36
1
2
4
8
15
22
23
26
29
36
Schedule Window:
±1
±1
±1
±1
±3
±1
±1
±1
±1
±1
±1
±1
±3
±1
±1
Directed Injection-site 
Physical Examination 
(Arm 1)
X
In addition to the 
directed injection-
site physical 
examination, 
participants 
should report any 
injection-site AE 
that occurs at any 
time during the 
study. Any 
potential 
injection-site AE 
should be 
investigated 
further by the site.
Vital Signs
X
X
X
X
X
X
Temperature, 
heart rate, 
respiratory rate, 
blood pressure.
C1D2 is for 
participants in 
Arm 1 only.
Vital Signs (Nab-
paclitaxel)
X
X
X
X
X
X
X
X
Additional 
procedures only 
for participants 
receiving nab-
paclitaxel.
ANC and Platelet 
Count (Nab-
paclitaxel)
X
X
X
X
X
X
X
X
12-lead ECG
X
HIV, Hepatitis B, 
Hepatitis C Testing
X
Only perform if 
required by the 
local health 
authority.
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PRODUCT: MK-3475A
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Study Period:
Screening
Intervention
(6-Week Cycles)
Notes
Cycle:
Screening
1
2
Cycle Day:
-28 to -1
1
2
4
8
15
22
23
26
29
36
1
2
4
8
15
22
23
26
29
36
Schedule Window:
±1
±1
±1
±1
±3
±1
±1
±1
±1
±1
±1
±1
±3
±1
±1
Hematology and 
Chemistry
X
X
X
X
X
Collect screening 
samples within 
10 days before 
the start of study 
intervention. 
Collect on-
treatment samples 
and review results 
within 72 hours 
before Day 1 and 
Day 22 of each 
cycle.  
If screening 
collection is done 
within 72 hours 
before C1D1, do 
not need to repeat 
for C1D1.
CrCl
X
X
X
X
X
CBC (Arms 1 and 2)
X
X
X
X
For Arm 1 Only: 
For D4 of each 
cycle, CBCs may 
be collected 
between Days 4 
to 7.
Urinalysis
X
Collect screening 
samples within 
10 days before 
the start of study 
intervention.  
PT or INR and 
aPTT/PTT
X
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Study Period:
Screening
Intervention
(6-Week Cycles)
Notes
Cycle:
Screening
1
2
Cycle Day:
-28 to -1
1
2
4
8
15
22
23
26
29
36
1
2
4
8
15
22
23
26
29
36
Schedule Window:
±1
±1
±1
±1
±3
±1
±1
±1
±1
±1
±1
±1
±3
±1
±1
Thyroid Function 
Tests (Total T3 or 
Free T3, T4 or FT4, 
TSH)
X
X
Tests must be 
completed and 
reviewed within 
10 days before 
start of study 
intervention.
C2D1: Collect
samples within 
72 hours before 
study intervention
administration; 
participants may 
be dosed while 
results are 
pending. Total T4 
and T3 preferred 
over FT4 and 
FT3.
Pregnancy Testing 
(Urine or Serum)
X
X
X
X
X
POCBP require a 
negative
pregnancy test 
before the start of 
study intervention
(within 24 hours 
for urine or 
within 72 hours 
for serum). If 
screening 
collection is done 
within 72 hours 
before C1D1, do 
not need to repeat 
for C1D1.
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Study Period:
Screening
Intervention
(6-Week Cycles)
Notes
Cycle:
Screening
1
2
Cycle Day:
-28 to -1
1
2
4
8
15
22
23
26
29
36
1
2
4
8
15
22
23
26
29
36
Schedule Window:
±1
±1
±1
±1
±3
±1
±1
±1
±1
±1
±1
±1
±3
±1
±1
ECOG Performance 
Status
X
X
X
X
X
Evaluate within 
7 days before 
randomization.  
AE/SAE Review
Report AEs 
occurring within 
30 days after last 
dose of study 
intervention. 
Report SAEs 
within 90 days 
after the last dose 
of study 
intervention, or 
30 days after last 
dose of study 
intervention if the 
participant 
initiates new 
anticancer 
therapy, 
whichever occurs 
first.
Pharmacokinetics
Anti-pembrolizumab 
Antibody (ADA/Nab)
See Table 3, Table 4, Table 5 and Table 6 for details
Pembrolizumab PK
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PROTOCOL/AMENDMENT NO.: D77-03
MK-3475A-D77-03 FINAL PROTOCOL
06-FEB-2024
Study Period:
Screening
Intervention
(6-Week Cycles)
Notes
Cycle:
Screening
1
2
Cycle Day:
-28 to -1
1
2
4
8
15
22
23
26
29
36
1
2
4
8
15
22
23
26
29
36
Schedule Window:
±1
±1
±1
±1
±3
±1
±1
±1
±1
±1
±1
±1
±3
±1
±1
Biomarkers
Archival or Newly 
Obtained Tissue 
Collection
X
Tissue must be 
submitted to the 
central laboratory 
for determination 
of PD-L1 status 
before 
randomization.
Tissue will also 
be used for 
EGFR, ALK, and 
ROS1 testing 
before 
randomization if 
this testing was 
not already 
completed locally 
(not required for 
predominantly 
squamous 
histology).
Blood for Genetic 
Analysis
X
Collect predose
samples from 
randomized 
participants only. 
See Section 8.8.1.
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Study Period:
Screening
Intervention
(6-Week Cycles)
Notes
Cycle:
Screening
1
2
Cycle Day:
-28 to -1
1
2
4
8
15
22
23
26
29
36
1
2
4
8
15
22
23
26
29
36
Schedule Window:
±1
±1
±1
±1
±3
±1
±1
±1
±1
±1
±1
±1
±3
±1
±1
Blood for ctDNA 
Analysis
X
X
Collect predose 
samples on C1D1 
and C2D1.
ADA=antidrug antibodies; AE=adverse event; ALK=anaplastic lymphoma kinase; ANC=Absolute neutrophil count; aPTT=activated partial thromboplastin time; C=cycle; 
CBC=complete blood count; CR=complete response; CrCl=creatinine clearance; ctDNA=circulating tumor deoxyribonucleic acid; D=day; DC/Discon=discontinuation; 
DNA=deoxyribonucleic acid; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EGFR=epidermal growth factor receptor; EORTC QLQ-C30=European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Cancer 30; EQ-5D-5L=EuroQol 5-dimension, 5-level Questionnaire; FBR=future biomedical 
research; FT4=free thyroxine; HIV=human immunodeficiency virus; IEC=Independent Ethics Committee; INR=international normalized ratio; IRB=Institutional Review 
Board; IV=intravenous; NAB=neutralizing antibody; NSCLC=non-small cell lung cancer; PD L1=programmed cell death ligand 1; PK=pharmacokinetics; 
POCBP=participant/participants of childbearing potential; PT=prothrombin time; PTT=partial thromboplastin time; QXW=every X weeks; ROS=c-ros oncogene 1; 
SAE=serious adverse event; SC=subcutaneous; T3=triiodothyronine; TSH= thyroid-stimulating hormone.
08W594

PRODUCT: MK-3475A
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1.3.2
Cycle 3 to Posttreatment
Table 2
Cycle 3 to Posttreatment
Study Period:
Intervention
(6-Week Cycles)
End-of-
Treatment
Posttreatment
Notes
Cycle:
3
4 to 18
19+
Discon
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Cycle Day:
1
2
22
1
22
1
22
At time of 
discon
30 days 
after last 
dose
(+7 days)
Per imaging 
schedule
Every 
12 weeks 
(±7 days)
If DC visit occurs ≥30 days from the 
last dose of study intervention, a 
Safety Follow-up is not required.
Schedule Window:
±1
±1
±1
±3
±3
±3
±3
Administrative Procedures
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
C3D2 is for participants in Arm 1 
only.
Subsequent Antineoplastic 
Therapy Status
X
X
X
X
Vital Status
X
Participants may be contacted for 
vital status at any time during the 
study.
Study Intervention Administration
MK-3475A SC (Arm 1) OR
Pembrolizumab IV (Arm 2)
X
X
Pemetrexed (Nonsquamous)
X
X
X
X
X
X
Pemetrexed maintenance continues 
until one of the conditions for 
discontinuation of study intervention 
is met.
Efficacy Assessments
Scans should follow calendar days 
from randomization and should not be 
adjusted for delays in cycle starts.
Tumor Scan (Chest, 
Abdomen, and Pelvis)
X
See note
X
X
Postbaseline scans should be 
performed at Week 6 (+7 days),
Week 12 (±7 days), Week 18 
(±7 days), Q9W (±7 days) until
Week 45, and then Q12W (±7 days) 
thereafter until one of the conditions 
for stopping tumor scans is met.
If a scan was obtained within 4 weeks 
before treatment DC, a scan at DC is 
not required.
08W594

PRODUCT: MK-3475A
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06-FEB-2024
Study Period:
Intervention
(6-Week Cycles)
End-of-
Treatment
Posttreatment
Notes
Cycle:
3
4 to 18
19+
Discon
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Cycle Day:
1
2
22
1
22
1
22
At time of 
discon
30 days 
after last 
dose
(+7 days)
Per imaging 
schedule
Every 
12 weeks 
(±7 days)
If DC visit occurs ≥30 days from the 
last dose of study intervention, a 
Safety Follow-up is not required.
Schedule Window:
±1
±1
±1
±3
±3
±3
±3
Brain Scan
For participants with brain metastases 
at baseline, on-study brain scans will 
be acquired at Week 6 (+7 days) and 
then if clinically indicated and to 
confirm a CR. 
For participants without brain 
metastases at baseline, on-study brain 
scans should be acquired if clinically 
indicated.
Bone Scan
On-study bone scans should be 
performed if clinically indicated or to 
confirm CR when bone metastases 
existed at baseline.
Patient-reported Outcomes
EORTC QLQ-C30
X
X
X
See note
X
X
Administer on D1 and D22 of cycles 
3 and 4, and D1 of Cycles 5 to 9. In 
Years 2 and 3, administer PROs every 
2 cycles (C10D1, C12D1, etc.) until 
discontinuation. From Cycle 27 (after 
Year 3), PROs will not be collected 
for participants receiving study 
intervention until the discontinuation 
visit.
Administer in the following order: 
EORTC QLQ-C30 first, then EQ-5D-
5L.
EQ-5D-5L
X
X
X
See note
X
X
Safety Assessments
Full Physical Examination
X
Weight
X
X
X
X
X
X
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
08W594

PRODUCT: MK-3475A
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06-FEB-2024
Study Period:
Intervention
(6-Week Cycles)
End-of-
Treatment
Posttreatment
Notes
Cycle:
3
4 to 18
19+
Discon
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Cycle Day:
1
2
22
1
22
1
22
At time of 
discon
30 days 
after last 
dose
(+7 days)
Per imaging 
schedule
Every 
12 weeks 
(±7 days)
If DC visit occurs ≥30 days from the 
last dose of study intervention, a 
Safety Follow-up is not required.
Schedule Window:
±1
±1
±1
±3
±3
±3
±3
Directed Injection-site 
Physical Examination (Arm 
1)
X
X
On C3D1, examination of the 
injection site should be performed as 
part of the directed physical 
examination.
In addition to the directed injection-
site physical examination, participants 
should report any injection-site AE 
that occurs at any time during the 
study. Any potential injection-site AE 
should be investigated further by the 
site. 
Vital Signs
X
X
X
X
X
X
X
X
X
Temperature, heart rate, respiratory 
rate, blood pressure.
C3D2 is for participants in Arm 1 
only.
Hematology and Chemistry
X
X
X
X
X
X
X
X
Collect on-treatment samples and 
review results within 72 hours before 
Day 1 and Day 22 of each cycle.
CrCl
X
X
X
X
X
X
X
X
Urinalysis
X
Thyroid Function Tests (Total 
T3 or Free T3, T4 or FT4, 
TSH)
X
X
X
X
Collect samples within 72 hours 
before study intervention
administration; participants may be 
dosed while results are pending. Total 
T4 and T3 preferred over FT4 and 
FT3.
Pregnancy Testing (Urine or 
Serum)
X
X
X
X
X
X
X
X
Pregnancy testing should be 
conducted at the end of relevant 
systemic exposure (see Section 8.3.5).
ECOG Performance Status
X
X
X
X
X
X
X
X
X
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PRODUCT: MK-3475A
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06-FEB-2024
Study Period:
Intervention
(6-Week Cycles)
End-of-
Treatment
Posttreatment
Notes
Cycle:
3
4 to 18
19+
Discon
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Cycle Day:
1
2
22
1
22
1
22
At time of 
discon
30 days 
after last 
dose
(+7 days)
Per imaging 
schedule
Every 
12 weeks 
(±7 days)
If DC visit occurs ≥30 days from the 
last dose of study intervention, a 
Safety Follow-up is not required.
Schedule Window:
±1
±1
±1
±3
±3
±3
±3
AE/SAE Review
X
X
Report AEs occurring within 30 days 
after last dose of study intervention. 
Report SAEs within 90 days after the 
last dose of study intervention, or 30 
days after last dose of study 
intervention if the participant initiates 
new anticancer therapy, whichever 
occurs first.
Pharmacokinetics
Anti-pembrolizumab 
Antibody (ADA/Nab)
See Table 3, Table 4, Table 5 and Table 6 for details
Pembrolizumab PK
Biomarkers
Blood for ctDNA Analysis
X
See note
X
Collect predose samples on C4D1,
C7D1, and EOT.
ADA=antidrug antibodies; AE=adverse event; C=cycle; CR=complete response; CrCl=creatinine clearance; ctDNA=circulating tumor deoxyribonucleic acid; D=day; 
DC/Discon=discontinuation; ECOG=Eastern Cooperative Oncology Group; EORTC QLQ-C30=European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-Cancer 30; EQ-5D-5L=EuroQol 5-dimension, 5-level Questionnaire; FBR=future biomedical research; FT4=free thyroxine; IV=intravenous; NAB=neutralizing 
antibody; PK=pharmacokinetics; QXW=every X weeks; SAE=serious adverse event; SC=subcutaneous; T3=triiodothyronine; T4=thyroxine; TSH= thyroid-stimulating 
hormone. 
08W594

PRODUCT: MK-3475A
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06-FEB-2024
1.3.3
PK and ADA Sample Collection
Study Period
Intervention
(6-week cycles)
Notes
Pred
ose
End 
of 
infusi
on
Postdose
Cycle
1
Cycle Day
1
1
1
2
3
4
5
6
7
10
15
29
42
Schedule 
Window
±1
±2
±3
±1
Serum for 
Anti-
pembrolizum
ab Antibody 
(ADA/Nab)
X
X
Arm 1 (SC): 
Serum for 
Pembrolizum
ab PK
X
X
X
X
X
X
X
X
X
X
X
Arm 2 (IV): 
Serum for 
Pembrolizum
ab PK
X
X
X
X
X
X
Arm 1 (SC): 
Serum for 
Anti-
MK-5180 
Antibody 
(ADA)
X
X
Arm 1 (SC): 
Plasma for 
MK-5180 PK
X
X
X
X
ADA=antidrug antibodies; C=cycle; D=day; IV=intravenous; Nab=neutralizing antibody; PK=pharmacokinetics; QXW=every X weeks; SC=subcutaneous.
CCI
CCI
CCI
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PRODUCT: MK-3475A
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06-FEB-2024
CCI
CCI
08W594

PRODUCT: MK-3475A
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MK-3475A-D77-03 FINAL PROTOCOL
06-FEB-2024
CCI
CCI
08W594

PRODUCT: MK-3475A
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06-FEB-2024
Study 
Intervention
Intervention
(6-week Cycles)
Notes
Cycle
3
6 to 18
Cycle Day:
Predose
End of 
Infusion
Postdose
Predose
Postdose
1
1
1
2
4
10
42
1
1
2
Schedule 
Window
±2
±2
±1
±3
Serum for 
Anti-
pembrolizumab 
Antibody 
(ADA/Nab)
X
X
X
Arm 1 (SC): 
Serum for 
Pembrolizumab 
PK
X
X
X
X
X
Arm 2 (IV): 
Serum for 
Pembrolizumab 
PK
X
X
X
X
X
Arm 1 (SC): 
Serum for 
Anti-MK-5180 
Antibody 
(ADA)
X
Arm 1 (SC): 
Plasma for 
MK-5180 PK
X
X
X
X
X
X
ADA=antidrug antibodies; C=cycle; D=day; IV=intravenous; Nab= neutralizing antibodies; PK=pharmacokinetics; QXW=every X weeks; SC=subcutaneous
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
08W594

PRODUCT: MK-3475A
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PROTOCOL/AMENDMENT NO.: D77-03
MK-3475A-D77-03 FINAL PROTOCOL
06-FEB-2024
1.3.4
Second Course Retreatment
Table 7
Second Course Retreatment
Study Period:
Intervention
(6-Week Cycles)
End-of-
Treatment
Posttreatment
Notes
Cycle:
1
2
3 to 9
Discon
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Cycle Day:
1
1
1
At time of 
discon
30 days 
after last 
dose
(+7 days)
Per imaging 
schedule
Every 
12 weeks 
(±7 days)
If DC visit occurs ≥30 days from the last dose of study 
intervention, a Safety Follow-up is not required.
Schedule Window:
±3
±3
±3
Administrative Procedures
Eligibility Criteria
X
Concomitant Medication 
Review
X
X
X
X
X
Subsequent Antineoplastic 
Therapy Status
X
X
X
X
Vital Status
X
Participants may be contacted for vital status at any 
time during the study.
Study Intervention Administration
MK-3475A SC (Arm 1) OR
Pembrolizumab IV (Arm 2)
X
X
X
Participants are to receive MK-3475A SC or 
pembrolizumab IV based on the Arm to which they 
were initially randomized.
Efficacy Assessments
Scans should follow calendar days and should not be 
adjusted for delays in cycle starts.
Tumor Scan (Chest, 
Abdomen, and Pelvis)
X
See note
X
X
Second Course baseline images are to be captured 
within 28 days before Second Course C1D1. Scans 
should be performed Q12W (±7 days) from Second 
Course C1D1 (Weeks 12, 24, 36, and 48). 
If a scan was obtained within 4 weeks before treatment 
DC, a scan at DC is not required.
Brain Scan
X
For participants with brain metastases at baseline or 
before entering Second Course, perform baseline brain 
scans within 28 days before Second Course C1.
Brain scans during Second Course to be performed as 
clinically indicated.
Safety Assessments
Full Physical Examination
X
X
Weight
X
X
X
X
X
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PRODUCT: MK-3475A
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Study Period:
Intervention
(6-Week Cycles)
End-of-
Treatment
Posttreatment
Notes
Cycle:
1
2
3 to 9
Discon
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Cycle Day:
1
1
1
At time of 
discon
30 days 
after last 
dose
(+7 days)
Per imaging 
schedule
Every 
12 weeks 
(±7 days)
If DC visit occurs ≥30 days from the last dose of study 
intervention, a Safety Follow-up is not required.
Schedule Window:
±3
±3
±3
Directed Physical 
Examination
X
X
X
Participants in Arm 1 should report any injection-site 
AE that occurs at any time during the study. Any 
potential injection-site AE should be investigated 
further by the site.
Vital Signs
X
X
X
X
X
Temperature, heart rate, respiratory rate, blood 
pressure.
12-lead ECG
X
Hematology and Chemistry
X
X
X
X
X
Collect baseline samples within 10 days before Second 
Course C1.
After Second Course C1, samples to be collected and 
results reviewed within 72 hours before administration 
of study intervention in each cycle.
CrCl
X
X
X
X
X
Urinalysis
X
X
Collect baseline samples within 10 days before Second 
Course C1.
PT or INR and aPTT/PTT
X
Thyroid Function Tests (Total 
T3 or Free T3, FT4, TSH)
X
X
X
X
X
Tests must be completed and reviewed within 10 days 
before Second Course C1.
For Second Course C2 and on, collect samples within 
72 hours before study intervention administration; 
participants may be dosed while results are pending.
Pregnancy Testing (Urine or 
Serum)
X
X
X
X
X
POCBP require a negative pregnancy test before the 
start of study intervention (within 24 hours for urine or 
within 72 hours for serum) before Second Course C1.
At home pregnancy testing should be conducted 
midcycle (Day 22 ±3 days of each treatment cycle) 
during the intervention period.
Pregnancy testing should be conducted at the end of 
relevant systemic exposure (see Section 8.3.5).
08W594

PRODUCT: MK-3475A
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06-FEB-2024
Study Period:
Intervention
(6-Week Cycles)
End-of-
Treatment
Posttreatment
Notes
Cycle:
1
2
3 to 9
Discon
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
Cycle Day:
1
1
1
At time of 
discon
30 days 
after last 
dose
(+7 days)
Per imaging 
schedule
Every 
12 weeks 
(±7 days)
If DC visit occurs ≥30 days from the last dose of study 
intervention, a Safety Follow-up is not required.
Schedule Window:
±3
±3
±3
ECOG Performance Status
X
X
X
X
X
X
Perform within 7 days before Second Course C1.
To be assessed before dosing at each cycle.
AE/SAE Review
X
X
Report AEs occurring within 30 days after last dose of 
study intervention. Report SAEs within 90 days after 
the last dose of study intervention, or 30 days after last 
dose of study intervention if the participant initiates 
new anticancer therapy, whichever occurs first.
AE=adverse event; aPTT=activated partial thromboplastin time; C=cycle; DC/Discon=discontinuation; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
FT4=free thyroxine; IV=intravenous; POCBP=participant/participants of childbearing potential; PT=prothrombin time; PTT=partial thromboplastin time; QXW=every X 
weeks; SAE=serious adverse event; SC=subcutaneous; T3=triiodothyronine; TSH= thyroid-stimulating hormone.
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2
INTRODUCTION
This is a Phase 3 study evaluating the noninferiority of PK exposure between MK-3475A SC 
and pembrolizumab IV, both administered in combination with platinum doublet 
chemotherapy, in participants with treatment-naïve metastatic NSCLC.
2.1
Study Rationale
KEYTRUDA® (MK-3475, pembrolizumab) is approved globally for the treatment of patients 
across multiple indications. The recommended dose of pembrolizumab in adults is either 
200 mg Q3W or 400 mg Q6W administered by IV infusion. SC formulations of 
pembrolizumab are being developed to provide an alternative route of administration with the 
potential for increased accessibility. Benefits of SC administration include time savings for 
patients and providers, convenience, reduced administration costs, ease of administration, 
and reduced health care resource burden. SC administration will also reduce patient chair 
time, making it feasible for infusion centers to treat more patients.
MK-3475A is a coformulation of pembrolizumab with MK-5180, a novel hyaluronidase that 
increases the volume of SC pembrolizumab delivery and enhances its dispersion. This study 
will evaluate the noninferiority of PK exposure between MK-3475A SC and pembrolizumab 
IV, both administered Q6W. MK-3475A or pembrolizumab will be administered in 
combination with platinum doublet chemotherapy in participants with treatment-naïve 
metastatic NSCLC.
2.2
Background
2.2.1
Subcutaneous Formulation
There is a strong patient preference for therapeutics to be administered by SC injection over 
IV infusion. In an open-label, randomized study of the preference for SC or IV 
administration of trastuzumab, 91.5% of participants preferred SC administration (95% CI: 
87.2 to 94.7; p<0.0001) [Pivot, X., et al 2013]. The 2 most common reasons for this 
preference were because SC administration saved time and resulted in less pain or 
discomfort. Healthcare professionals also preferred SC administration of trastuzumab; of 
103 healthcare professionals, 73.8% preferred SC, 1.9% preferred IV, and 24.3% had no 
preference [Pivot, X., et al 2013]. Similar results were reported from a study evaluating the 
preference for SC or IV administration of rituximab [Rummel, M., et al 2017]. 
An SC formulation of pembrolizumab has been developed to provide an alternative route of 
administration with the potential for increased accessibility. Clinical data from Cohort A of 
Study KEYNOTE-555
which is 
consistent with the bioavailability reported for other SC administered mAbs (range: 50% to 
85%). Clearance was the same for SC and IV formulations and no positive ADA were 
observed. Preliminary safety data from the first 3 cycles of treatment revealed no new safety 
signals. Injection-site data gathered from participant questionnaires as well as reported drug-
CCI
CCI
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PRODUCT: MK-3475A
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related skin and SC tissue disorder AEs indicate a low frequency of primarily mild pruritus, 
rash, or redness. 
Phase 3 study KEYNOTE-A86 is evaluating noninferiority of PK exposure between 
pembrolizumab SC and IV administration. Participants with treatment-naïve metastatic 
NSCLC are randomly assigned in a 2:1 ratio to study intervention Arm A (pembrolizumab 
SC Q3W with chemotherapy) or Arm B (pembrolizumab IV Q3W with chemotherapy). The 
dual primary endpoints of Cycle 1 AUC0-3wks and Cycle 6 Ctrough enable characterization of 
pembrolizumab exposure.
Both KEYNOTE-555 and KEYNOTE-A86 are evaluating SC pembrolizumab as a single 
entity for Q3W dosing. One constraint of SC administration without a hyaluronidase is the 
skin’s resistance to bulk fluid flow that limits drug delivery and dispersion and makes Q6W 
dosing infeasible for SC pembrolizumab as a single entity. MK-3475A, a coformulation of 
pembrolizumab with a novel hyaluronidase (MK-5180), is being developed to increase the 
volume of SC pembrolizumab delivery and enhance its dispersion. Hyaluronidase products 
have been used clinically for more than 70 years to facilitate the distribution of 
coadministered drugs by temporarily breaking down local connective tissue [Wohlrab, J., et 
al 2014]. The Q6W dosing regimen of MK-3475A SC is being evaluated in Phase 1 study 
MK-3475A-C18 and this Phase 3 study, MK-3475A-D77.
MK-3475A-C18 is a FIH, Phase 1 study to evaluate the PK, safety, and tolerability of 
MK-3475A administered by SC injection to participants with unresectable, advanced 
melanoma, metastatic NSCLC, or advanced or metastatic RCC. A primary objective of 
MK-3475A-C18 is to establish the bioavailability of pembrolizumab when administered 
subcutaneously at a solution strength of 165 mg/mL or 130 mg/mL, coformulated with 
MK-5180, as MK-3475A. The 2 solution strengths of MK-3475A have different viscosities, 
so pembrolizumab bioavailability will be assessed at each solution strength in 2 study arms. 
These data inform a PK model used to conduct simulations and select an optimal SC Q6W 
dose of pembrolizumab in MK-3475A. The selected pembrolizumab SC dose will have 
exposures comparable to the approved 400 mg Q6W dose of pembrolizumab IV (see 
Section 4.3.1).
Pembrolizumab serum concentration data available from 81 participants collected during 
Cycle 1 (ie, Weeks 1 to 6; MK-3475A SC administration) and Cycle 2 (ie, Weeks 7 to 12; 
pembrolizumab IV administration) across both study arms of MK-3475A-C18, along with 
extensive historical pembrolizumab IV PK data, were used to characterize the PK of SC 
pembrolizumab given as MK-3475A using population PK modeling. The analysis showed 
that pembrolizumab combined with hyaluronidase when administered SC as MK-3475A had 
an estimated bioavailability of 57% (range: 38% to 75%). Median time to achieve maximum 
pembrolizumab serum concentration was estimated to be 4 days (range: 2 to 35 days). The 
2 SC solution strengths of pembrolizumab (165 mg/mL and 130 mg/mL) had similar 
absorption PK when administered as MK-3475A. As of 22-JUN-2022, ADA were observed 
in 1 of 83 participants (<2%). A preliminary review of systemic safety data from 
MK-3475A-C18 revealed no new safety signals. All local injection-site reactions were 
nonserious, mostly mild (Grade 1), and effectively managed.
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2.2.2
Non-small Cell Lung Cancer
The global incidence of lung cancer was 2.2 million cases in 2020, resulting in an estimated 
1.8 million deaths, representing the second most frequently diagnosed cancer and the leading 
cause of cancer death in 2020 [Sung, H., et al 2021]. NSCLC represents approximately 85% 
of all lung cancers [National Cancer Institute 2020]. Of patients with NSCLC, tumor 
histology is approximately 46% adenocarcinoma, 16% squamous, and most of the remainder 
“not otherwise specified” [Sulpher, J. A., et al 2013], though histology varies somewhat by 
geographic region. At the time of diagnosis, approximately 80% of patients in the US with 
lung cancer have locally advanced or metastatic disease that is not amenable to surgical 
resection, and the 5-year relative survival for patients with metastatic lung cancer is only 
approximately 7% [National Cancer Institute 2022].
The therapeutic landscape in metastatic NSCLC was dramatically changed with approvals of 
immunotherapy agents, particularly immune checkpoint inhibitors targeting the PD-1/PD-L1 
pathway (pembrolizumab, nivolumab, and atezolizumab) for both treatment-naïve and 
previously treated disease, irrespective of histology. KEYNOTE-024 and KEYNOTE-042 
established pembrolizumab monotherapy as first-line therapy for participants with metastatic 
NSCLC whose tumors express PD-L1 with a TPS ≥50% (EU) or TPS ≥1% (in US and other 
countries), respectively, with no EGFR or ALK genomic tumor aberrations [Reck, M., et al 
2021] [Mok, T. S. K., et al 2019]. 
Following this, the positive results from KEYNOTE-189 and KEYNOTE-407 led to the 
approval of pembrolizumab in combination with pemetrexed and platinum chemotherapy for 
first-line treatment of patients with metastatic nonsquamous NSCLC whose tumors have no 
EGFR or ALK genomic tumor aberrations, and pembrolizumab in combination with 
carboplatin and paclitaxel/nab-paclitaxel for first-line treatment of patients with metastatic 
squamous NSCLC, regardless of PD-L1 status [Rodriguez-Abreu, D., et al 2021] [Gandhi, 
L., et al 2018] [Paz-Ares, L., et al 2018]. Other options for treatment in first-line NSCLC for 
patients without actionable genomic alteration include other immune checkpoint inhibitor 
regimens such as nivolumab and ipilimumab ± chemotherapy and atezolizumab ± 
chemotherapy (with or without bevacizumab).
2.2.3
Pharmaceutical and Therapeutic Background
MK-3475A is a SC drug product of pembrolizumab and 2000 U/mL MK-5180 (recombinant 
human hyaluronidase) being developed to enhance the permeation of SC pembrolizumab. 
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV or SC immunotherapy for multiple malignancies. 
Hyaluronan (also known as hyaluronic acid) is key to creating the skin resistance that limits 
SC dispersion and absorption of drugs [Frost, G. I. 2007]. Hyaluronidases increase tissue 
permeability by degrading glycosaminoglycan hyaluronan [Wohlrab, J., et al 2014]. When 
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administered SC, hyaluronidase results in a temporary breakdown of local connective tissue, 
increasing the dispersion and absorption of drugs and fluids. After injection, hyaluronic acid 
is regenerated and the barrier is restored within 48 hours. 
There are ovine, bovine, and human recombinant hyaluronidase drug products that have 
received regulatory approval as adjuvants or permeation enhancers to increase the dispersion 
and absorption of drugs injected SC. Several IV administered oncology products have 
introduced hyaluronidase into formulations with mAbs to allow SC injection. Products such 
as trastuzumab (Genentech), rituximab (Roche), daratumumab (Janssen), and 
pertuzumab/trastuzumab (Genentech) have been approved in the EU and US as formulations 
with hyaluronidase. These products, trastuzumab and hyaluronidase (Genentech), rituximab 
and hyaluronidase (Genentech), daratumumab and hyaluronidase (Janssen), and pertuzumab, 
trastuzumab, and hyaluronidase (Genentech), use from 10,000 U to 30,000 U of 
hyaluronidase injected SC over 2 to 8 minutes. The SC images of these drug products have 
been approved for some of the same indications as their respective IV images.
Refer to the respective IBs for additional background information about MK-3475A and 
pembrolizumab.
2.2.4
Preclinical and Clinical Studies
The nonclinical development program for MK-3475A relies on previously conducted studies 
in support of pembrolizumab, supplemented with studies related to MK-5180 or the SC drug 
product, MK-3475A. 
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2.2.5
Ongoing Clinical Studies
Refer to the respective IBs for a summary of ongoing clinical studies for MK-3475A and 
pembrolizumab.
2.2.6
Information on Other Study-related Therapy
Pemetrexed, carboplatin, cisplatin, paclitaxel and/or nab-paclitaxel are standard of care 
therapies for the treatment of patients with NSCLC. Refer to the product labels for additional 
information.
Refer to Section 6.5.1.2.1 or information on G-CSF.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
MK-3475A may provide important benefits such as improved patient convenience and 
compliance with therapy. This product may also provide an alternative SC dosage form of 
pembrolizumab that could facilitate the delivery of a larger volume of drug and result in less 
discomfort to the patient and increased tolerability of the injection. It is expected that 
pembrolizumab delivered by SC administration will maintain a favorable benefit-risk profile 
comparable to that of IV administration. 
In NSCLC, the safety profile of pembrolizumab in combination with chemotherapy is 
generally consistent with the known safety profile of pembrolizumab monotherapy and the 
combination regimens administered. Further, the combination of pembrolizumab and 
platinum doublet chemotherapy is approved for the first-line treatment of patients with 
metastatic NSCLC [Rodriguez-Abreu, D., et al 2021] [Gandhi, L., et al 2018] [Paz-Ares, L., 
et al 2018].
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In participants with treatment-naïve metastatic NSCLC.
Primary Objectives
Primary Endpoints
-Objective: To compare MK-3475A SC to 
pembrolizumab IV with respect to Cycle 1 
AUC
- Hypothesis (H1): MK-3475A SC is 
noninferior to pembrolizumab IV with 
respect to the geometric mean Cycle 1 AUC 
of pembrolizumab
- Cycle 1 AUC0-6wks
- Objective: To compare MK-3475A SC to 
pembrolizumab IV with respect to steady-
state (Cycle 3) Ctrough
- Hypothesis (H2): MK-3475A SC is 
noninferior to pembrolizumab IV with 
respect to the geometric mean steady-state 
(Cycle 3) Ctrough of pembrolizumab
- Steady-state (Cycle 3) Ctrough
The primary analysis will be performed 
on the model-based values of Ctrough
Secondary Objectives
Secondary Endpoints
- To evaluate pembrolizumab exposure for 
MK-3475A SC relative to pembrolizumab 
IV Q6W
- Cycle 1: Cmax and Ctrough
- Steady state (Cycle 3): AUC0-6wks and Cmax
- To evaluate the development of circulating 
anti-pembrolizumab antibodies for 
MK-3475A SC and pembrolizumab IV
- Anti-pembrolizumab antibodies
- To evaluate pembrolizumab Ctrough for 
MK-3475A SC relative to pembrolizumab 
IV Q3W
- Cycle 1: Model-based Ctrough
- Steady state: Model-based Ctrough
- To evaluate MK-3475A SC and 
pembrolizumab IV with respect to ORR per 
RECIST 1.1 as assessed by BICR
- Objective response: CR or PR
- To evaluate MK-3475A SC and 
pembrolizumab IV with respect PFS per 
RECIST 1.1 as assessed by BICR
- PFS: The time from randomization to the 
first documented disease progression or 
death due to any cause, whichever occurs 
first
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- To evaluate MK-3475A SC and 
pembrolizumab IV with respect to OS
- OS: The time from randomization to death 
due to any cause
- To evaluate MK-3475A SC and 
pembrolizumab IV with respect DOR per 
RECIST 1.1 as assessed by BICR
- DOR: The time from the first documented 
evidence of CR or PR until disease 
progression or death due to any cause, 
whichever occurs first
- To evaluate the safety and tolerability of 
MK-3475A SC and pembrolizumab IV
- AE
- Discontinuation of study intervention due 
to AEs
- To evaluate the change from baseline in 
global health status/QoL for MK-3475A SC 
and pembrolizumab IV
- Change in score from baseline at a 
predefined timepoint evaluated by EORTC 
QLQ-C30 in the following items:
-
- Global health status/QoL (Items 29 
and 30)
-
- Physical functioning (Items 1 to 5)
- Role functioning (Items 6 and 7)
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
This study will have met its success criterion if MK-3475A SC is noninferior to 
pembrolizumab IV at Q6W dosing regimens with respect to Cycle 1 AUC or steady-state 
(Cycle 3) Ctrough.
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, randomized, active-controlled, parallel-group, multisite, open-label study 
of MK-3475A SC and platinum doublet chemotherapy versus pembrolizumab IV and 
platinum doublet chemotherapy in participants with treatment-naïve metastatic NSCLC.
Participants must have newly diagnosed, untreated Stage IV NSCLC, and ECOG PS of 0 to 
1. 
After a screening period of up to 28 days, participants will be randomly assigned in a 2:1 
ratio to Arm 1 or Arm 2. One cycle is 6 weeks.
•
Arm 1: MK-3475A SC Q6W for up to 18 cycles in combination with platinum doublet 
chemotherapy.
•
Arm 2: Pembrolizumab IV Q6W for up to 18 cycles in combination with platinum 
doublet chemotherapy.
•
Platinum doublet chemotherapy.
-
Nonsquamous NSCLC: Up to 4 infusions of pemetrexed Q3W with investigator’s 
choice of a platinum chemotherapy (cisplatin Q3W or carboplatin Q3W), followed by 
pemetrexed maintenance until one of the conditions for discontinuation of study 
intervention is met.
-
Squamous NSCLC: Up to 4 infusions of carboplatin Q3W with investigator’s choice 
of a taxane (paclitaxel Q3W or nab-paclitaxel [Days 1, 8, 15, 22, 29, and 36 of Cycles 
1 and 2]).
Randomization will be stratified by ECOG performance status, histology, PD-L1 TPS, and
region. Each participant will receive study intervention until one of the conditions for 
discontinuation of study intervention is met (Section 7.1). 
The dual primary objectives of the study are to compare Cycle 1 AUC0-6wks and steady-state 
(Cycle 3) Ctrough for MK-3475A SC vs pembrolizumab IV at Q6W dosing regimens. 
Noninferiority will be evaluated with the noninferiority margin of 0.8. Tumor response will 
be evaluated per an adjustment to RECIST 1.1 (Section 8.2.1). Safety assessments are 
detailed in Section 8. AEs will be monitored throughout the study and graded in severity 
according to the guidelines outlined in NCI CTCAE Version 5.0. 
Participants are not permitted to crossover to the other study intervention arm. 
Participants who complete study intervention after receiving 18 cycles of MK-3475A or 
pembrolizumab may be eligible for up to 9 additional cycles of MK-3475A (if on Arm 1) or 
pembrolizumab (if on Arm 2) (approximately 1 year) upon experiencing BICR-verified 
disease progression (Section 6.1.2).
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After the end-of-treatment, each participant will be followed for the occurrence of AEs and 
spontaneously reported pregnancy. Participants who discontinue for reasons other than 
centrally-verified radiographic disease progression will have posttreatment follow-up 
imaging for disease status until any of the conditions for discontinuation of imaging are met 
(Section 8.2.1.3). All participants will be followed for OS until death, withdrawal of consent, 
or the end of the study. 
After enrollment of the global study has completed, participants in Japan will continue to be 
enrolled and randomized in a 2:1 ratio in Arms 1 and 2 until the sample size for the Japanese 
participants reaches approximately 39. The extension study will be identical to the global 
study (eg, open-label, with identical inclusion and exclusion criteria, and study procedures), 
with the exception of an additional sSAP for participants enrolled in Japan. Details of the 
analysis will be provided in the separate Japan-specific sSAP document.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
Pembrolizumab IV in combination with platinum doublet chemotherapy is indicated for the 
first-line treatment of patients with metastatic NSCLC. MK-3475A SC is a coformulation of 
pembrolizumab with MK-5180 that is being developed to provide an alternative route of 
administration with potential benefits for patients. This study will primarily compare 
pembrolizumab exposures between MK-3475A SC (Arm 1) and pembrolizumab IV (Arm 2) 
over Q6W dosing regimens, both in combination with chemotherapy, in participants with 
treatment-naïve metastatic NSCLC. 
Additional descriptive comparisons of pembrolizumab Ctrough between MK-3475A and 
pembrolizumab 200 mg IV Q3W will also be made using model-based exposures. Note that 
there is no arm in the study with the pembrolizumab 200 mg IV Q3W regimen; the Ctrough
exposure outcomes for this dosing regimen will be only based on a PK model. 
Randomization will be stratified by the following 4 factors, which all have the potential to 
influence efficacy outcomes, to ensure an approximately equal allocation of participants 
across the 2 arms.  
1. ECOG performance status (0 vs 1): ECOG performance status affects survival and is a 
known prognostic factor in NSCLC [Dall'Olio, F. G., et al 2020]. 
2. Histology (squamous vs nonsquamous):
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3. PD-L1 TPS (<50% vs ≥50%): Tumor expression of PD-L1 is associated with clinical 
benefit from pembrolizumab in participants with NSCLC. Exploratory analyses from 
KEYNOTE-042, KEYNOTE-189, and KEYNOTE-407 show trends in improved efficacy 
outcomes with increased PD-L1 TPS expression (PD-L1 TPS ≥50%) [Mok, T. S. K., et al 
2019a] [Gandhi, L., et al 2018] [Paz-Ares, L., et al 2018a].
4. Stratification by geographic region (East Asia vs North America/Western 
Europe/Australia/New Zealand vs Rest of the World) is to ensure an approximately equal 
allocation of participants from these regions across the treatment arms.
4.2.1
Rationale for Endpoints
4.2.1.1
Pharmacokinetic Endpoints
The dual primary endpoints of Cycle 1 AUC0-6wks and steady-state (Cycle 3) Ctrough will be 
used to compare pembrolizumab exposures between MK-3475A SC and pembrolizumab IV 
Q6W.
Cycle 1 AUC0-6wks is the most conservative PK value to ensure noninferiority of SC exposure 
relative to IV. Any differences in exposure between SC and IV administrations of 
pembrolizumab should reduce after multiple dosing due to accumulation. Therefore, 
demonstrating noninferiority of SC AUC exposure at Cycle 1 will imply noninferiority at 
steady-state as well. The higher AUC exposure at steady-state following SC dosing is not 
expected to exceed the established clinical safety margin for pembrolizumab (ie, exposure at 
10 mg/kg Q2W IV).
Steady-state (Cycle 3) Ctrough is the concentration at the end of the 6-week dosing interval 
after the third dose, which is steady state for pembrolizumab. Because the pharmacological 
activity of mAbs is mediated through direct interaction with a specific target, target 
saturation can be used as a surrogate for maximal pharmacologic and therapeutic activity. 
Pembrolizumab exposures at the approved IV doses are expected to maintain PD-1 target 
saturation throughout the dosing interval and thereby efficacy. Therefore, Ctrough for the 
approved IV dose of 400 mg Q6W can be considered a threshold above which target 
saturation and efficacy will be maintained. Demonstration of noninferiority of 
pembrolizumab steady-state (Cycle 3) Ctrough for MK-3475A SC would enable the inference 
that efficacy similar to pembrolizumab IV dosing will be maintained.
The secondary PK endpoints will enable further characterization of pembrolizumab 
exposure: 
•
For comparison with pembrolizumab IV Q6W: 
-
Cycle 1: Cmax and Ctrough
-
Steady state (Cycle 3): AUC0-6wks and Cmax
•
For comparison with pembrolizumab IV Q3W: 
-
Model-based Ctrough at Cycle 1 and steady state
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4.2.1.2
Antidrug Antibodies
Formation of ADA can potentially confound drug exposures at therapeutic doses and prime 
for subsequent toxicities. The emergence of pembrolizumab ADA will be evaluated as a 
secondary endpoint to assess pembrolizumab immunogenicity after SC administration of 
MK-3475A. 
4.2.1.3
Efficacy Endpoints
Secondary efficacy endpoints include OS and ORR, PFS, and DOR based on RECIST 1.1 
criteria as assessed by BICR. These are commonly accepted endpoints by both regulatory 
authorities and the oncology community.
4.2.1.3.1
RECIST 1.1 
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures. 
Although original RECIST 1.1 publication recommends a maximum of 5 target lesions in 
total and 2 per organ, this protocol has implemented an adjustment to RECIST 1.1 to allow a 
maximum of 10 target lesions in total and 5 per organ, if a larger number of target lesions is 
needed to adequately represent the tumor burden. Refer to Section 8.2.1.5 for additional 
detail.
4.2.1.4
Safety Endpoints
Safety parameters frequently used for evaluating investigational-systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs, and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version [5.0].
4.2.1.5
Patient-reported Outcomes
Symptomatic improvement is considered a clinical benefit and accepted by health authorities
as additional evidence of the risk-benefit profile of any new study intervention. In this study, 
HRQoL and disease-related symptoms will be investigated via the following assessment 
tools: EORTC QLQ-C30 and EQ-5D-5L questionnaires. Health utilities will be evaluated 
using the EQ-5D-5L PRO instrument. These measures are not pure efficacy or safety 
endpoints because they are affected by both disease progression and treatment tolerability.
4.2.1.5.1
EORTC QLQ-C30
EORTC QLQ-C30 is a psychometrically and clinically validated instrument appropriate for 
assessing HRQoL in oncology studies [Aaronson, N. K., et al 1993]. The EORTC QLQ-C30 
is the most widely used cancer-specific HRQoL instrument, which contains 30 items and 
measures 5 functional dimensions (physical, role, emotional, cognitive and social), 3 
symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, sleep 
disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health 
and QoL scale [Aaronson, N. K., et al 1993]. For the global health status or QoL and function 
scales, a higher value indicates a better level of function; for symptom scales and items, a 
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higher value indicates increased severity of symptoms. TTD and mean change from baseline 
in global health status or QoL scale of the EORTC QLQ-C30, will be evaluated as secondary
objectives.
4.2.1.5.2
EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. and de 
Charro, F. 2001]. The 5 health state dimensions in the EQ-5D-5L include the following: 
Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each 
dimension is rated on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems). 
The EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the 
participant rates his or her general state of health at the time of the assessment. This 
instrument has been used extensively in cancer studies and published results from these 
studies support its validity and reliability [Pickard, A. S., et al 2007].
4.2.1.6
Germline genetic analyses (eg, SNP analyses, whole exome sequencing, whole genome 
sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy, the data might inform optimal use of therapies in the patient population. 
Furthermore, it is important to evaluate germline DNA variation across the genome to 
interpret tumor-specific DNA mutations.
Genetic (DNA) tumor analyses 
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify important tumor-specific DNA changes (eg, mutations, 
methylation status, microsatellite instability, etc). Key molecular changes of interest to 
oncology drug development may also include the mutational burden of tumors and the 
clonality of T-cells in the tumor microenvironment. Microsatellite instability may also be 
evaluated as this is an important biomarker for some cancers (eg, colorectal cancer). 
Genome-wide approaches may be used for this effort. Note that to understand tumor-specific 
mutations, it is necessary to compare the tumor genome with the germline genome. 
Circulating tumor DNA may also be evaluated from biospecimens (eg, blood, urine, etc).
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Tumor and/or blood RNA analyses
Both genome-wide and targeted mRNA expression profiling and sequencing in tumor tissue 
and/or in blood may be performed to define gene signatures that might correlate to clinical 
response to treatment with antitumor therapies. Specific gene sets (eg, those capturing 
interferon-gamma transcriptional pathways) may be evaluated and new signatures may be 
identified. Expression of individual genes may also be evaluated. MicroRNA profiling may 
also be pursued as well as exosomal profiling. Circulating tumor RNA may also be evaluated 
from biospecimens (eg, blood, urine, etc).
Immunohistochemical (IHC) and/or proteomic analyses using tumor
Tumor samples from this study may undergo histopathological (eg, PD-L1 IHC), proteomic, 
and/or immunological analyses. These approaches could identify novel protein biomarkers 
that could aid in patient selection for antitumor therapy.
Other biomarkers
In addition to expression on the tumor tissue, tumor-derived proteins can be shed from tumor 
and released into the blood. Assays such as ELISA may be used to measure such proteins in 
serum and/or plasma. Correlation of expression with response to therapy may identify new 
approaches for predictive biomarkers in blood, representing a major advance from today’s 
reliance on assessing tumor biomarkers.
Other molecular changes of interest may include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated. Furthermore, when applicable, cell populations may be also separated by either 
flow cytometry or mass cytometry-based sorting. These approaches may be used to quantify 
cell- and/or tissue-based analytes to further elucidate mechanism of action and/or assess 
disease-related parameters.
4.2.1.7
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in
Appendix 6.
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4.2.2
Rationale for the Use of Comparator
All participants will receive pembrolizumab administered with platinum doublet 
chemotherapy based on histology.
The use of pembrolizumab IV as an active comparator ensures that participants receive the 
current approved formulation in the control arm. The PK exposures of MK-3475A SC will be 
compared to pembrolizumab IV.
To reduce participant and site burden, the different routes of administration will not be 
masked; therefore, this is an unblinded, open-label study. 
4.3
Justification for Dose
4.3.1
MK-3475A Subcutaneous Dose
Available PK data from the FIH, Phase 1 study of MK-3475A, Study MK-3475A-C18, was 
used to estimate the bioavailability of pembrolizumab when administered SC as MK-3475A 
to enable Phase 3 dose selection and further clinical development. 
PK model-based simulations indicate that a pembrolizumab SC dose of 790 mg Q6W leads 
to comparable exposures as the approved pembrolizumab IV dose of 400 mg Q6W. The 
mean PK profiles comparing 790 mg Q6W SC and 400 mg Q6W IV doses are presented in 
Figure 5. In principle, similar PK exposures lead to similar efficacy and safety of 
pembrolizumab, given that the exposure-response relationships for both efficacy and safety 
are well established for pembrolizumab.
Efficacy is expected to be retained with SC pembrolizumab at the dose of 790 mg Q6W 
based on the following: 
•
Ctrough at a 790 mg Q6W SC dose is expected to be approximately 30% higher than 
400 mg Q6W IV throughout the treatment duration. Moreover, the distributions of Ctrough
overlap between SC and IV at both Cycle 1 and steady state (Figure 2). 
•
AUC0-6wks exposure at a 790 mg Q6W SC dose is expected to be approximately 10% 
higher than 400 mg Q6W IV throughout the treatment duration. Moreover, the 
distributions of AUC0-6wks overlap between SC and IV at both Cycle 1 and steady state 
(Figure 3). 
Safety is expected to be maintained with SC pembrolizumab at the dose of 790 mg Q6W 
based on the following: 
•
Cmax is expected to be lower (by approximately 35% at Cycle 1 and approximately 22% 
at steady state) than the Cmax achieved at 400 mg Q6W IV (Figure 4). Therefore, there is 
no increase in Cmax expected throughout the duration of treatment relative to the approved 
dose of 400 mg Q3W IV. 
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•
All SC exposures (Cmax, Cavg, Ctrough) over the dosing interval of 6 weeks and throughout 
the duration of treatment are expected to remain below the Cmax and initial concentrations 
of 400 mg Q6W IV and well below the highest dose and exposures established for 
clinical safety (ie, 10 mg/kg Q2W).
Figure 2
Distribution of Ctrough at Cycle 1 and Steady State Using PK Model-based 
Simulations at a Dose of 790 mg Q6W SC and 400 mg Q6W IV of Pembrolizumab
Ctrough=trough concentration; IV=intravenous
Figure 3
Distribution of AUC0-6wks at Cycle 1 and Steady State Using PK Model-based 
Simulations at a Dose of 790 mg Q6W SC and 400 mg Q6W IV of Pembrolizumab
AUC=area under the curve; IV=intravenous
Cycle 1
Steady State
Cycle 1
Steady State
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Figure 4
Distribution of Cmax at Steady State Using PK Model-based Simulations at a 
Dose of 790 mg Q6W SC and 400 mg Q6W IV of Pembrolizumab
Cmax=maximum concentration; IV=intravenous
Figure 5
Mean Cycle 1 PK Profile From Model-based Simulations at a Dose of 790 mg 
Q6W SC (Blue Line) and 400 mg Q6W IV (Red Line) of Pembrolizumab
MK-3475A also includes MK-5180 at a 2000 U/mL concentration to maintain consistency 
with marketed mAbs formulated with hyaluronidase. Rituximab and hyaluronidase 
(Genentech), trastuzumab and hyaluronidase (Genentech), and daratumumab and 
hyaluronidase (Janssen) all contain 2000 U/mL of hyaluronidase. The enzyme activity of 
MK-5180 in the dose concentration is comparable to the marketed rHuPH20 from Halozyme 
Therapeutics present in these other products. Limited existing clinical data also indicate no 
specific benefit on bioavailability by increasing the concentration of hyaluronidase. Study 
MK-3475A-C18 will provide data on the safety of MK-5180 being used as part of 
MK-3475A.
4.3.2
Pembrolizumab Intravenous Dose
The planned dose of pembrolizumab for this study is 400 mg Q6W.
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The current approved dosing regimens of pembrolizumab for IV administration are 200 mg 
Q3W and 400 mg Q6W for adults.
A 400 mg Q6W dosing regimen of pembrolizumab is expected to have a similar benefit-risk 
profile as 200 mg Q3W, in all treatment settings in which 200 mg Q3W pembrolizumab is 
currently appropriate [Lala, M., et al 2020]. Specifically, the dosing regimen of 400 mg Q6W 
for pembrolizumab is considered adequate based on M&S analyses, given the following 
rationale:
PK simulations demonstrating that in terms of pembrolizumab exposures:
•
Cavg (or AUC) at 400 mg Q6W is similar to the approved 200 mg Q3W dose, thus 
bridging efficacy between dosing regimens.
•
Trough concentrations (Cmin) at 400 mg Q6W are generally within the range of those 
achieved with 2 mg/kg or 200 mg Q3W in the majority (>99%) of patients.
•
Peak concentrations (Cmax) at 400 mg Q6W are well below the Cmax for the highest 
clinically tested dose of 10 mg/kg Q2W, supporting that the safety profile for 400 mg 
Q6W should be comparable to the established safety profile of pembrolizumab.
•
E-R for pembrolizumab has been shown to be flat across indications, and OS predictions 
in melanoma and NSCLC show that efficacy at 400 mg Q6W is expected to be similar to 
200 mg or 2 mg/kg Q3W, given the similar exposures; thus, 400 mg Q6W is expected to 
be efficacious across indications.
Efficacy, safety, and PK data from KEYNOTE-555 Cohort B continue to support the 
consistency of the benefit-risk profile for pembrolizumab 400 mg Q6W to the 200 mg Q3W 
dosing, and further support the conclusion that the 400 mg Q6W dosing regimen provides 
comparable efficacy and safety to the Q3W regimen in all approved adult indications. 
4.3.3
Chemotherapy Dose
The platinum doublet chemotherapy treatments used in this study are established regimens 
for metastatic NSCLC (pemetrexed and carboplatin or cisplatin [nonsquamous] or 
carboplatin with paclitaxel or nab-paclitaxel [squamous]). 
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
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If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
The Sponsor estimates that the study will require approximately 5 years from the time the 
first participant (or their legally acceptable representative) provides documented informed 
consent until the last participant’s last study-related contact, which is the LPLV for the final 
assessment of the study (eg, to evaluate safety and/or long-term efficacy). Therefore, the 
maximum follow-up will be approximately 5 years from the time the first participant 
provides documented informed consent (approximately 3 years after study intervention has 
been completed). The last participant that provides documented informed consent will be 
followed for approximately 4 years (or approximately 2 years after study intervention has 
been completed).
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects is such that the risk/benefit ratio to the study population as a whole is 
unacceptable. In addition, further recruitment in the study or at (a) particular study site(s) 
may be stopped as described in Appendix 1.10.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Refer to Appendix 7 for country-specific requirements.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Histologically or cytologically confirmed diagnosis of squamous or nonsquamous
NSCLC (Stage IV: M1a, M1b, M1c, AJCC Staging Manual, version 8).
Note: Mixed tumors will be characterized by the predominant cell type (squamous or 
nonsquamous); however, small cell elements are not permitted.
2. Confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as primary 
therapy (documentation of absence of tumor-activating EGFR mutations [eg, DEL19 or 
L858R] AND absence of ALK and ROS1 gene rearrangements).
Note: If participant’s tumor has a predominantly squamous histology, molecular testing
for EGFR mutation and ALK and ROS1 translocations is not required.
Note: The presence of a KRAS mutation in a participant’s tumor is permitted. 
Note: Due to insufficient sensitivity, negative ctDNA results for EGFR, ALK, and ROS1
cannot be used to satisfy this inclusion criterion.
3. Measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. 
Lesions situated in a previously irradiated area are considered measurable (eligible for 
selection as target lesions) if progression has been shown in such lesions.
Demographics
4. An individual who is at least 18 years of age at the time of providing informed consent.
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Assigned Male Sex at Birth
5. If capable of producing sperm, the participant agrees to the following during the 
intervention period and for at least the time needed to eliminate each study intervention 
after the last dose of study intervention. The length of time required to continue 
contraception for each study intervention is as follows:
-
Chemotherapy: 90 days
-
MK-3475A and pembrolizumab: No contraception required for participants capable 
of producing sperm
•
Refrains from donating sperm
PLUS either:
•
Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on 
a long-term and persistent basis) and agrees to remain abstinent
OR
•
Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to 
medical cause, documented from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview) as detailed below:
-
Uses a penile/external condom when having penile-vaginal intercourse with a 
nonparticipant of childbearing potential who is not currently pregnant PLUS partner 
use of an additional contraceptive method, as a condom may break or leak. 
Note: Participants capable of producing ejaculate whose partner is pregnant or 
breastfeeding must agree to use a penile/external condom during each episode of sexual 
activity in which the partner is at risk of drug exposure via ejaculate.
-
Contraceptive use by participants capable of producing sperm should be consistent 
with local regulations regarding the methods of contraception for those participating 
in clinical studies. If the contraception requirements in the local label for any of the 
study interventions are more stringent than the requirements above, the local label 
requirements are to be followed.
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Assigned Female Sex at Birth
6. A participant assigned female sex at birth is eligible to participate if not pregnant or 
breastfeeding, and at least one of the following conditions applies:
•
Is not a POCBP
OR
•
Is a POCBP and:
-
Uses a contraceptive method that is highly effective (with a failure rate of <1% per 
year), with low user dependency, or is abstinent from penile-vaginal intercourse as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as 
described in Appendix 5 during the intervention period and for at least the time 
needed to eliminate each study intervention after the last dose of study intervention. 
The participant agrees not to donate eggs (ova, oocytes) to others or freeze/store 
during this period for the purpose of reproduction. The length of time required to 
continue contraception for each study intervention is as follows:
◦
Chemotherapy: 180 days
◦
MK-3475A: 120 days
◦
Pembrolizumab: 120 days
The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention. Contraceptive use by POCBPs should be consistent with local 
regulations regarding the methods of contraception for those participating in clinical 
studies. If the contraception requirements in the local label for any of the study 
interventions are more stringent than the requirements above, the local label 
requirements are to be followed.
-
Has a negative highly sensitive pregnancy test (as required by local regulations) 
within 24 hours (for urine test) or within 72 hours (for serum test) before the first 
dose of study intervention. If a urine test cannot be confirmed as negative (eg, an 
ambiguous result), a serum pregnancy test is required. In such cases, the participant 
must be excluded from participation if the serum pregnancy result is positive. 
Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.5.
-
Abstains from breastfeeding during the study intervention period and for at least 120
days after study intervention.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a POCBP with an early 
undetected pregnancy.
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Informed Consent
7. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide consent for FBR. However, the 
participant may participate in the study without participating in FBR.
Additional Categories
8. Archival tumor tissue sample or newly obtained core, incisional, or excisional biopsy of a 
tumor lesion not previously irradiated has been provided. Details pertaining to tumor 
tissue submission can be found in the Laboratory Manual.
Note: Tumor tissue will be used to determine PD-L1 status by central testing before 
randomization. Tumor tissue from after diagnosis of metastatic disease is preferred.
9. An ECOG performance status of 0 to 1 assessed 7 days before randomization.
10. A life expectancy of at least 3 months.
11. Participants who have AEs due to previous anticancer therapies must have recovered to 
≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated 
with hormone replacement or participants who have ≤Grade 2 neuropathy are eligible.
12. Adequate organ function as defined in the following table (Table 8). Specimens must be 
collected within 10 days before the start of study intervention.
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Table 8
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Measured or calculatedb creatinine clearance
≥60 mL/min 
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of 
normal.
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within 
last 2 weeks.
b Estimated creatinine clearance using Cockcroft-Gault:
(140-age [years] × weight (kg)     (×F)*
Serum creatinine (mg/dL) × 72
*where F = 0.85 for females and F = 1 for males
5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. Diagnosis of small cell lung cancer or, for mixed tumors, presence of small cell elements.
Prior/Concomitant Therapy
2. Received prior systemic anticancer therapy for their metastatic NSCLC.
Note: Prior treatment with chemotherapy and/or radiation as a part of neoadjuvant or 
adjuvant therapy or chemoradiation therapy for nonmetastatic NSCLC is allowed as long 
as therapy was completed at least 12 months before diagnosis of metastatic NSCLC.
3. Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-
40, CD137).
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4. Received prior systemic anticancer therapy including investigational agents within 
4 weeks before randomization.
5. Received prior radiotherapy within 2 weeks of start of study intervention or has radiation-
related toxicity requiring corticosteroids.
Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease, with a 1-week 
washout, is permitted.
6. Received radiation therapy to the lung that is >30 Gray within 6 months of start of study 
intervention.
7. Received a live or live-attenuated vaccine within 30 days before the first dose of study 
intervention. Administration of killed vaccines are allowed.
Refer to Section 6.5 for information on COVID-19 vaccines.
Prior/Concurrent Clinical Study Experience
8. Has received an investigational agent or has used an investigational device within 
4 weeks prior to study intervention administration.
Diagnostic Assessments
9. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study intervention.
10. Known additional malignancy that is progressing or has required active treatment within 
the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have 
undergone potentially curative therapy are not excluded. Participants with low-risk early-
stage prostate cancer (T1-T2a, Gleason score ≤6, and PSA <10 ng/mL) either treated with 
definitive intent or untreated in active surveillance with stable disease are not excluded.
11. Known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, (ie, without evidence of progression) for at least 4 weeks as confirmed by repeat 
imaging performed during study screening, are clinically stable and have not required
steroid treatment for at least 14 days before the first dose of study intervention.
12. Severe hypersensitivity (≥Grade 3) to study intervention and/or any of its excipients.
13. Active autoimmune disease that has required systemic treatment in past 2 years. 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed.
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14. History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or 
has current pneumonitis/interstitial lung disease.
Note: Participants with lymphangitic spread of their NSCLC are not excluded.
15. Active infection requiring systemic therapy.
16. History of HIV infection. HIV testing is not required unless mandated by local health 
authority.
17. History of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus 
(defined as detectable HCV RNA [qualitative]) infection.
Note: Testing for Hepatitis B or C is not required unless mandated by local health 
authority.
18. History or current evidence of any condition, therapy, laboratory abnormality, or other 
circumstance that might confound the results of the study or interfere with the 
participant's participation for the full duration of the study, such that it is not in the best 
interest of the participant to participate, in the opinion of the treating investigator.
19. Known psychiatric or substance abuse disorder that would interfere with the participant’s 
ability to cooperate with the requirements of the study.
Other Exclusions
20. Participants who have not adequately recovered from major surgery or have ongoing 
surgical complications.
21. History of allogenic tissue/solid organ transplant.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
There are no restrictions on caffeine, alcohol, or tobacco.
5.3.3
Activity Restrictions
There are no restrictions on activity.
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5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
Participants who fail screening may be rescreened for eligibility after consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study interventions provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 9.
Refer to Appendix 7 for country-specific requirements.
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Table 9
Study Interventions
Arm Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulatio
n
Unit Dose 
Strength(s
)
Dosage 
Level(s)
Route of 
Administratio
n
Regimen/
Treatment 
Period/
Vaccinatio
n Regimen
Use
IMP or 
NIMP/
AxMP
Sourcin
g
Arm 1 
(nonsquamou
s and 
squamous 
NSCLC)
Experimenta
l
MK-3475A
Biological/Vaccin
e
Solution
165 mg/m
L
790 mg
SC
Day 1 of 
each cycle 
(Q6W) for 
18 cycles; 
participants 
may be 
eligible for 
Second 
Course (9 
additional 
cycles)
Test 
Product
IMP
Central
Arm 1 
(nonsquamou
s NSCLC)
Experimenta
l
Pemetrexed
Drug
Injection, 
Powder, 
Lyophilized, 
For Solution
Per 
Approved 
Product 
Label
500 mg/m²
IV Infusion
Days 1 and 
22 of each 
cycle 
(Q3W)
Backgroun
d 
Treatment
NIMP/AxM
P
Local or 
central
Arm 1 
(nonsquamou
s NSCLC)
Experimenta
l
Cisplatin
Drug
Solution
Per 
Approved 
Product 
Label
75 mg/m²
IV Infusion
Days 1 
and 22 of 
Cycles 1 
and 2 
(Q3W)
Backgroun
d 
Treatment
NIMP/AxM
P
Local or 
central
Arm 1 
(nonsquamou
s and 
squamous 
NSCLC)
Experimenta
l
Carboplatin
Drug
Solution
Per 
Approved 
Product 
Label
AUC 5 for 
nonsquamous
; AUC 6 for 
squamous
IV Infusion
Days 1 
and 22 of 
Cycles 1 
and 2 
(Q3W)
Backgroun
d 
Treatment
NIMP/AxM
P
Local or 
central
Arm 1 
(squamous 
NSCLC)
Experimenta
l
Paclitaxel
Drug
Solution
Per 
Approved 
Product 
Label
200 mg/m²
IV Infusion
Days 1 and 
22 of 
Cycles 1 
and 2 
(Q3W)
Backgroun
d 
Treatment
NIMP/AxM
P
Local or 
central
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Arm Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulatio
n
Unit Dose 
Strength(s
)
Dosage 
Level(s)
Route of 
Administratio
n
Regimen/
Treatment 
Period/
Vaccinatio
n Regimen
Use
IMP or 
NIMP/
AxMP
Sourcin
g
Arm 1 
(squamous 
NSCLC)
Experimenta
l
Nab-paclitaxel
Drug
Solution
Per 
Approved 
Product 
Label
100 mg/m²
IV Infusion
Days 1, 8, 
15, 22, 29, 
and 36 of 
Cycles 1 
and 2
Backgroun
d 
Treatment
NIMP/AxM
P
Local or 
central
Arm 2 
(nonsquamou
s and 
squamous 
NSCLC)
Active 
Comparator
Pembrolizuma
b
Biological/Vaccin
e
Solution
25 mg/mL
400 mg
IV Infusion
Day 1 of 
each cycle 
(Q6W) for 
18 cycles; 
participants 
may be 
eligible for 
Second 
Course (9 
additional 
cycles)
Comparato
r
IMP
Central
Arm 2 
(nonsquamou
s NSCLC)
Active 
Comparator
Pemetrexed
Drug
Injection, 
Powder, 
Lyophilized, 
For Solution
Per 
Approved 
Product 
Label
500 mg/m²
IV Infusion
Days 1 and 
22 of each 
cycle 
(Q3W)
Backgroun
d 
Treatment
NIMP/AxM
P
Local or 
central
Arm 2 
(nonsquamou
s NSCLC)
Active 
Comparator
Cisplatin
Drug
Solution
Per 
Approved 
Product 
Label
75 mg/m²
IV Infusion
Days 1 and 
22 of 
Cycles 1 
and 2 
(Q3W)
Backgroun
d 
Treatment
NIMP/AxM
P
Local or 
central
Arm 2 
(nonsquamou
s and 
squamous 
NSCLC)
Active 
Comparator
Carboplatin
Drug
Solution
Per 
Approved 
Product 
Label
AUC 5 for 
nonsquamous
; AUC 6 for 
squamous
IV Infusion
Days 1 and 
22 of 
Cycles 1 
and 2 
(Q3W)
Backgroun
d 
Treatment
NIMP/AxM
P
Local or 
central
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Arm Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulatio
n
Unit Dose 
Strength(s
)
Dosage 
Level(s)
Route of 
Administratio
n
Regimen/
Treatment 
Period/
Vaccinatio
n Regimen
Use
IMP or 
NIMP/
AxMP
Sourcin
g
Arm 2 
(squamous 
NSCLC)
Active 
Comparator
Paclitaxel
Drug
Solution
Per 
Approved 
Product 
Label
200 mg/m²
IV Infusion
Days 1 and 
22 of 
Cycles 1 
and 2 
(Q3W)
Backgroun
d 
Treatment
NIMP/AxM
P
Local or 
central
Arm 2 
(squamous 
NSCLC)
Other
Nab-paclitaxel
Other
Solution
Per 
Approved 
Product 
Label
100 mg/m²
IV Infusion
Days 1, 8, 
15, 22, 29, 
and 36 of 
Cycles 1 
and 2
Backgroun
d 
Treatment
NIMP/AxM
P
Local 
or 
central
Arm 1 and 
Arm 2 
(nonsquamou
s and 
squamous 
NSCLC)
Other
Filgastrim
Other
Solution
Per 
Approved 
Product 
Label
Per 
Approved 
Product 
Label
IV Infusion
Days 2 and 
D23 of 
cycles 1 
and 2.
Backgroun
d 
Treatment
NIMP/AxM
P
Local
Arm 1 and 
Arm 2 
(nonsquamou
s and 
squamous 
NSCLC)
Other
Pegylated 
Filgastrim
Other
Solution
Per 
Approved 
Product 
Label
Per 
Approved 
Product 
Label
IV Infusion
Days 2 and 
D23 of 
cycles 1 
and 2 (not 
to be used 
with Nab-
Paclitaxel),
Backgroun
d 
Treatment
NIMP/AxM
P
Local
AUC=area under the concentration-time curve; EEA=European Economic Area; IMP=investigational medicinal product; IV=intravenous; NIMP/AxMP=noninvestigational medicinal product/auxiliary 
medicinal product; NSCLC=non-small cell lung cancer; Q3W=every 3 weeks; Q6W=every 6 weeks; SC=subcutaneous.
For commercially available supplies, the unit dose strength or formulation may vary, depending on market availability. Different formulations are still permitted as indicated. 
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with respect to the 
definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 9 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary, or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Treatment
The initial treatment or first course of MK-3475A (Arm 1) or pembrolizumab (Arm 2) 
consists of 18 treatments. Note: The number of treatments is calculated starting with the first 
dose.
Participants are not permitted to crossover to the other study intervention arm.
These participants may be eligible for Second Course described in Section 6.1.2.
6.1.2
Second Course
All participants who have completed the first course (achieved SD, PR, or CR) may be 
eligible for up to an additional 9 cycles of MK-3475A (if on Arm 1) or pembrolizumab (if on 
Arm 2) if there is BICR-verified progressive disease by RECIST 1.1 after initial treatment. 
This retreatment is the Second Course of this study.
Participants may enter the Second Course if all of the following criteria are met:
1. The participant received MK-3475A or pembrolizumab, determined on unblinding if 
applicable.
2. No new anticancer treatment was administered after the last dose of study intervention
3. The participant meets all of the inclusion criteria and none of the exclusion criteria
4. The study is ongoing
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6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of MK-3475A and pembrolizumab are provided in 
the Pharmacy Manual. Chemotherapeutic agents will be prepared and administered as per 
local and institutional guidelines according to the approved product labels.
The rationale for selection of doses to be used in this study is in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study 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.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 2 study 
intervention arms. Participants will be assigned randomly in a 2:1 ratio to Arm 1 (MK-3475A 
SC) and Arm 2 (pembrolizumab IV), respectively.
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All participants will be evaluated prior to randomization, during which an enrollment support 
consultation form will be completed by the Investigator and reviewed by the Sponsor.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. ECOG performance status (0 vs 1)
2. Histology (squamous vs nonsquamous)
3. PD-L1 TPS (<50% vs ≥50%; PD-L1 nonevaluable participants will be included with the 
TPS <50% group)
4. Region (East Asia vs North America/Western Europe/Australia/New Zealand vs Rest of 
the World)
A rationale for the selected stratification factors is provided in Section 4.2.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption or infusion/injection cessation of study 
intervention will be documented in the participant’s medical record.
Refer to Section 6.6.1 for Dose Modification and Toxicity Management Guidelines for irAEs
associated with pembrolizumab monotherapy, coformulations, or IO combinations and for 
other allowed dose interruptions.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study-site staff other than the person administering the 
study intervention. 
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6.5
Concomitant Therapy
If there is a clinical indication for any medications or vaccinations prohibited, the 
investigator must discuss any questions regarding this with the Sponsor’s Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator and the Sponsor.
•
Live or live-attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study.
•
Systemic glucocorticoids except when used for the following purposes:
-
To modulate symptoms of an AE that is suspected to have an immunologic etiology
-
For the prevention of emesis
-
To premedicate for IV contrast allergies
-
To treat asthma or COPD exacerbations (only short-term oral or IV use in doses 
>10 mg/day prednisone equivalent)
-
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent
•
Other glucocorticoid use except when used for the following purposes:
-
For topical use or ocular use
-
Intraarticular joint use
-
For inhalation in the management of asthma or chronic obstructive pulmonary disease
-
For use as premedication for chemotherapeutic agents
•
Phenytoin during therapy with cisplatin/carboplatin
•
For each chemotherapy agent used in the study, any medication prohibited in the 
approved product label 
If the investigator determines that a participant requires any of the following prohibited 
medications and vaccinations for any reason during the study, study intervention, all study 
interventions must be discontinued:
•
Systemic antineoplastic chemotherapy, immunotherapy, or biological therapy not 
specified in this protocol
•
Investigational agents other than those specified in this protocol
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•
Radiation therapy
Note: Palliative radiation therapy to a symptomatic nontarget solitary lesion or to the 
brain may be allowed at the investigator’s discretion and on discussion with the Sponsor.
•
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated 
just as any other concomitant therapy.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medications will be recorded on the eCRF including all 
prescriptions, OTC products, herbal supplements, and IV medications, and fluids. If changes 
occur during the study period, documentation of drug dosage, frequency, route, and date 
should also be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.4.
Refer to Appendix 7 for country-specific requirements.
6.5.1
Rescue Medications and Supportive Care
6.5.1.1
Pembrolizumab
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
Suggested supportive care measures for the management of AEs with potential immunologic
etiology are outlined along with the dose modification guidelines in Section 6.6.
6.5.1.2
Chemotherapy
For supportive care measures for the management of AEs that may result from treatment with 
chemotherapy, refer to the approved product labels for these agents. 
For all agents and all administration, antiemetic therapy should follow MASCC guidelines 
[Roila, F., et al 2016]and should include a 5-HT3 receptor antagonist, dexamethasone (or 
equivalent) and/or aprepitant as per the MASCC guidelines. 
Prior to pemetrexed infusion, all participants should receive the appropriate supplementation 
of vitamin B12, folic acid, and dexamethasone. See Section 8.1.8.4.1.
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Prior to paclitaxel infusion, all participants should be premedicated with oral or IV 
corticosteroids, diphenhydramine, and H2 antagonists according to the approved product 
label and/or standard practice. See Section 8.1.8.4.4.
In addition, all participants should receive the appropriate corticosteroid premedications as 
per the local approved label.
Additional predications and pre- and post-cisplatin hydration should be administered as per 
standard practice.
6.5.1.2.1
Colony Stimulating Factors
The use of CSFs is highly recommended as primary prophylaxis to reduce the risk of febrile 
neutropenia in this patient population, especially as many subjects have multiple co-
morbidities and advanced disease. 
•
For all participants, G-CSF primary prophylaxis is required during the first 4 platinum-
doublet infusions in both arms, starting on Days 2 and 23 of Cycles 1 and 2.
•
Filgrastim will be administered for 7 days for platinum/pemetrexed or 
platinum/paclitaxel, and 5 days for platinum/nab-paclitaxel. 
•
Pegylated filgrastim will be administered once for platinum/pemetrexed or 
platinum/paclitaxel. It cannot be used for platinum/nab-paclitaxel.
Please note that G-CSF should not be used within 14 days before randomization and within 
at least 24 hours (7 days for pegylated G-CSF) before the last dose of study intervention 
unless absolutely necessary.
The American Society of Clinical Oncology guidelines for use of CSFs should be followed 
for this study [Smith, T. J., et al 2015].
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
AEs associated with pembrolizumab monotherapy, coformulation, or IO combination 
exposure may represent an immune-related response. These irAEs may occur shortly after 
the first dose or several months after the last dose of pembrolizumab monotherapy, 
coformulation, or IO combination treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab monotherapy, coformulation, or IO 
combination administration of corticosteroids and/or other supportive care. For suspected 
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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.
Attribution of Toxicity:
When study interventions are administered in combination, attribution of an adverse event to 
a single component is likely to be difficult. Therefore, while the investigator may attribute a 
toxicity event to pembrolizumab monotherapy, coformulations, or IO combinations, 
pembrolizumab monotherapy, coformulations, or IO combinations must be held according to 
the criteria in the Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events.
Holding Study Interventions:
When study interventions are administered in combination and if the AE is considered 
immune-related, pembrolizumab monotherapy, coformulations, or IO combinations should 
be held according to recommended Dose Modification criteria.
If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from pembrolizumab monotherapy, coformulations, or IO 
combinations.
Restarting Study Interventions:
Participants may restart pembrolizumab monotherapy, coformulations, or IO combinations as 
described below:
If the toxicities do resolve and conditions are aligned with what is defined in the Dose 
Modification and Toxicity Management Guidelines for irAEs, pembrolizumab monotherapy, 
coformulations, or IO combinations may be restarted at the discretion of the investigator.
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 10.
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Table 10
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment.
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1 to 
2 mg/kg prednisone or 
equivalent) followed by 
taper
Add prophylactic 
antibiotics for 
opportunistic infections
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
Recurrent Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and Follow-up
Diarrhea/Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1 to 
2 mg/kg prednisone or 
equivalent) followed by 
taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus)
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
AST or ALT Elevation 
or Increased Bilirubin
Grade 2 a
Withhold
Administer corticosteroids 
(initial dose of 0.5 to 
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 b or 4 c
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1 to 
2 mg/kg prednisone or 
equivalent) followed by 
taper
T1DM or 
Hyperglycemia
New onset T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold d
Initiate insulin 
replacement therapy for 
participants with T1DM
Administer 
antihyperglycemic in 
participants with 
hyperglycemia
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and Follow-up
Hypophysitis
Grade 2
Withhold
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hyperthyroidism
Grade 2
Continue
Treat with nonselective 
beta-blockers (eg, 
propranolol) or 
thionamides as 
appropriate
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hypothyroidism
Grade 2
Continue
Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyronine) per standard 
of care
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold until 
clinically stable or 
permanently 
discontinue d
Nephritis:
grading according to 
increased creatinine or 
acute kidney injury
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1 to 2 mg/kg 
or equivalent) followed by 
taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Neurological 
Toxicities
Grade 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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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and Follow-up
Myocarditis
Asymptomatic 
cardiac enzyme 
elevation with 
clinical suspicion of 
myocarditis (which 
was previously 
myocarditis Grade 1 
using CTCAE v4.0)
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
or exclude other causes
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and Follow-up
All Other irAEs
PersistentGrade2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
or exclude other causes
Grade 3
Withhold or 
discontinue based on 
the event e
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x 
baseline if baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion/Injection Reactions Related to 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
Pembrolizumab monotherapy, coformulations or IO combinations may cause severe or life-
threatening infusion/injection reactions including severe hypersensitivity or anaphylaxis. 
Signs and symptoms usually develop during or shortly after drug infusion/injection and 
generally resolve completely within 24 hours of completion of infusion/injection. Dose 
modification and toxicity management guidelines on pembrolizumab monotherapy,
coformulations or IO combinations associated infusion/injection reactions are provided in
Table 11.
Table 11
Pembrolizumab Monotherapy, Coformulations or IO Combinations 
Infusion/Injection Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction, IV infusion/ 
SC administration 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator
None
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 2
Requires therapy or IV 
infusion/ SC 
administration interruption 
but responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 h
Stop IV infusion/SC injection (if not 
already fully administered)
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 participant 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 (eg, from 100 mL/h to 
50 mL/h). Similarly, if symptoms resolve 
within 1 hour of stopping the SC 
injection, the injection may be continued. 
Otherwise dosing will be held until 
symptoms resolve and the participant 
should be premedicated for the next 
scheduled dose.
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
study intervention.
Participant may be 
premedicated 1.5 h (±30 
min) prior to 
infusion/injection of 
study intervention with:
Diphenhydramine 50 mg 
PO (or equivalent dose 
of antihistamine).
Acetaminophen 500 to 
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 (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of IV infusion 
or SC administration); 
recurrence of symptoms 
after initial improvement; 
hospitalization indicated 
for other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
Stop IV infusion/SC injection (if not 
already fully administered).
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 participant is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine 
should be used immediately.
Participant is permanently discontinued 
from further study intervention.
No subsequent dosing
h=hour; IV=intravenous; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute; 
NSAIDs=nonsteroidal anti-inflammatory drugs; PO=oral; SC=subcutaneous.
Note:  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 CTCAE v5.0 at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab Monotherapy, Coformulations, 
or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations may be interrupted for 
situations other than treatment-related AEs such as medical or surgical events and/or 
unforeseen circumstances not related to study intervention. However, study intervention is to 
be restarted within 6 weeks or 42 days of the originally scheduled dose and within 84 days of 
the previously administered dose, unless otherwise discussed with the Sponsor. The reason 
for study intervention interruption is to be documented in the participant's study record.
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6.6.2
Chemotherapy Dose Modifications
If a participant experiences a >10% weight change from baseline, the doses of paclitaxel/nab-
paclitaxel, pemetrexed, and cisplatin/carboplatin should be recalculated.
Dose modifications due to AEs will depend on the investigator’s assessment of causality. If 
appropriate, the investigator may attribute each toxicity event to paclitaxel/nab-paclitaxel, 
pemetrexed, and cisplatin/carboplatin, or pembrolizumab alone, or to the combination, and 
use a stepwise dose modification (Table 12 through Table 14).
If a dose reduction for toxicity occurs with any agent, the dose may not be re-escalated. 
Participants 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 participant 
experiences several toxicities and there are conflicting recommendations, the most 
conservative recommended dose adjustment should be followed (ie, the dose reduction 
appropriate to the most severe toxicity). Participants who require a third dose modification to 
any particular component will have that intervention discontinued. Once the dose has been 
decreased, it should remain reduced for all subsequent administrations or be further reduced, 
if necessary. There will be no dose escalations in this study.
Reduction of 1 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 
agents should be reduced according to recommended dose modifications. If the toxicity is 
related to the combination of 3 agents, all 3 agents should be reduced (if applicable), 
interrupted, or discontinued according to the recommended dose modifications. If all 3 agents 
are discontinued due to a toxicity, the participant must be discontinued from the study.
Study intervention-related toxicities must be resolved to baseline or Grade ≤1 (with the 
exception of alopecia, Grade 2 fatigue, Grade 2 peripheral neuropathy, Grade 2 anemia, 
endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement and creatinine 
clearance, for which the guidelines provided below may be followed) prior to administering 
the subsequent cycle. Participants must not receive the next cycle of chemotherapy if any of 
the following apply:
•
ANC <1500/mm3
•
Platelet count <100,000/mm3
•
Hemoglobin level <8 g/dL
•
Total bilirubin level >1.5 × ULN
•
AST and ALT levels ≥2.5 × ULN, or ≥5 × ULN if liver metastases are present
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•
CrCl will be based on the Cockcroft-Gault formula or another acceptable standard 
formula. Alternatively, CrCl can be determined from a 24-hour urine collection.
-
For participants receiving cisplatin, the scheduled dose of cisplatin may only be 
administered if the calculated CrCl is ≥50 mL/min.
If CrCl falls to <50 mL/min, delay the start of that cycle for ≤21 days. In the interim, monitor 
renal function weekly and consider IV hydration. When CrCl improves to ≥50 mL/min, 
decrease cisplatin to DL -1 (Table 12). Alternatively, if in the investigator’s judgment it is in 
the best interest of the participant, cisplatin can be switched to carboplatin if the calculated 
CrCl is appropriate, and in consultation with the Sponsor.
•
At the second occurrence of CrCl <50 mL/min, decrease cisplatin to DL -2 upon 
improvement of CrCl to ≥50 mL/min. Alternatively, if in the investigator’s judgment it is 
in the best interest of the participant, cisplatin can be switched to carboplatin if the 
calculated CrCl is appropriate, and in consultation with the Sponsor. 
•
At the third occurrence of CrCl <50 mL/min, cisplatin should be discontinued. If in the 
investigator’s judgment it is in the best interest of the participant, cisplatin can be 
switched to carboplatin if the calculated CrCl is appropriate, at the discretion of the 
investigator and in consultation with the Sponsor.
-
For participants receiving carboplatin, the scheduled dose of carboplatin may only be 
administered if the calculated CrCl is ≥40 mL/min.
If CrCl falls to <40 mL/min, delay the start of that cycle for ≤21 days. In the interim, monitor 
renal function weekly and consider IV hydration. When CrCl improves to ≥40 mL/min, 
decrease carboplatin to DL-1 (Table 12).
At the second occurrence of CrCl <40 mL/min, decrease carboplatin to DL -2 (Table 12) 
upon improvement of CrCl to ≥40 mL/min.
•
At the third occurrence of CrCl <40 mL/min, carboplatin should be discontinued.
During concurrent chemotherapy treatment:
•
If paclitaxel/nab-paclitaxel or pemetrexed dosing is delayed or interrupted on Day 1, the 
platinum agent and MK-3475A/pembrolizumab should also be delayed/interrupted. If 
platinum-based chemotherapy doublet is delayed or interrupted during Cycles 1 through 
2, participants should be seen weekly until toxicity resolves.
•
If platinum dosing is delayed or interrupted on Day 1, MK-3475A/pembrolizumab and 
pemetrexed/paclitaxel/nab-paclitaxel should also be delayed/interrupted. If platinum-
based chemotherapy doublet is delayed or interrupted during Cycles 1 through 2, 
participants should be seen weekly until toxicity resolves.
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•
If MK-3475A/pembrolizumab dosing is delayed or interrupted, platinum-based 
chemotherapy can continue as scheduled. MK-3475A/pembrolizumab administration 
should be attempted at the next cycle of therapy.
•
Each chemotherapy cycle may not be delayed by more than 3 weeks (>21 days) despite 
supportive treatment. If only one of the agents is thought to be causing the specified 
toxicity leading to a 21-day delay of administration of the next cycle, that 
chemotherapeutic agent can be withheld and treatment can continue with 
MK-3475A/pembrolizumab and the remaining chemotherapy drug. 
MK-3475A/pembrolizumab dosing can continue with 1 agent or as monotherapy.
The reason for the dose interruption or reduction should be captured on the appropriate 
eCRF.
A participant is allowed to switch from cisplatin to carboplatin if the participant develops 
unexpected toxicities with the use of cisplatin (including hearing loss), becomes ineligible for 
further cisplatin therapy, and/or the investigator considers switching to carboplatin to be in 
the best interest of the participant. This switch from cisplatin to carboplatin requires 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision.
A participant may be allowed to switch from paclitaxel to nab-paclitaxel if the participant 
experiences an infusion reaction to paclitaxel and the investigator considers switching to be 
in the best interest of the participant. This switch from paclitaxel to nab-paclitaxel requires 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision.
CTCAE v5.0 must be used to grade the severity of AEs. All dose modifications should be 
based on the AE requiring the greatest dose modification. Dose modifications are detailed in 
Table 12 through Table 14. These serve as a guide and do not replace investigator judgment 
and applicable local label recommendations, if more stringent.
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Table 12
Dose Level Modifications for Chemotherapeutic Agents
Nonsquamous: Pemetrexed Plus Platinum-
based Chemotherapy
Squamous: Carboplatin Plus Taxane 
(Paclitaxel or Nab-paclitaxel)
Pemetrexed
Carboplatin
Cisplatin
Carboplatin
Paclitaxel
Nab-
paclitaxel
Dose Level 
0 (starting 
dose)
500 mg/m2
AUC 
5 mg/mL/min
75 mg/m2
AUC 
6 mg/mL/mi
n
200 mg/m2
100 mg/m2
Dose Level 
-1
375 mg/m2
AUC 
3.75 mg/mL/
min
56 mg/m2
AUC 
4.5 mg/mL/
min
150 mg/m2
75 mg/m2
Dose Level 
-2
250 mg/m2
AUC 
2.5 mg/mL/m
in
38 mg/m2
AUC 
3 mg/mL/mi
n
100 mg/m2
50 mg/m2
Dose Level 
-3
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
AUC=area under the curve
Recommended dose modifications for key chemotherapy toxicities are outlined in Table 13
and Table 14. These serve as a guide and do not replace investigator judgment and applicable 
local label recommendations, if more stringent. These data are based on Day 1 cell counts.
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Table 13
Recommended Chemotherapy Dose Modifications for Hematological Toxicity
Drug-related Toxicitya
Cisplatin Carboplatin Paclitaxel
Nab-paclitaxel
Pemetrexed
Dose Level (DL) from Table 12
Neutrophils (ANC) <500/mm3
without fever
DL -1
DL -1
DL-1
DL-1
DL-1
Febrile neutropenia (fever ≥38.5C 
and ANC <1,000/mm3)
DL -1
DL -1
DL-1
DL-1
DL-1
Platelets <50,000/mm3 without 
significant bleeding or requiring 
blood transfusion
DL -1
DL -1
DL-1
DL-1
DL-1
Platelets <50,000/mm3 with 
Grade ≥2 hemorrhage or requiring 
blood transfusion
DL -2
DL -2
DL-2
DL-2
DL-2
Grade 4 hemoglobin
DL -1
DL -1
DL-1
DL-1
DL-1
ANC = absolute neutrophil count; DL = dose level
Note: If toxicity can clearly be attributed to one of the drugs, the investigator may choose to only reduce the dose of one of 
the chemotherapy agents. Investigators may decide to use supportive measures/treatment and/or secondary prophylaxis as 
per institutional standards (eg, filgrastim, pegfilgrastim, transfusions) instead of dose reductions for the next dose, if 
considered in the best interest of the participant.
a
Should the hematologic toxicity recur; the dose of the agent could be reduced further. However, not more than 2 dose 
reductions per chemotherapy agent are permitted.
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Table 14
Recommended Chemotherapy Dose Modifications for Nonhematological 
Toxicity
Drug-Related 
Toxicitya
CTCAE 
Grade
Cisplatin
Carboplatin
Paclitaxel
Nab-
paclitaxel
Pemetrexed
Dose Level (DL) from Table 12
Nausea/vomiting
Grade ≥3b
DL -1
DL -1
DL-1
DL-1
No 
modification
Mucositis
Grade ≥3b
DL -1
DL -1
DL-1
DL-1
DL-2
Diarrhea
Grade ≥3b
DL -1
DL -1
DL-1
DL-1
DL-1
Peripheral 
neuropathy
Grade 2
DL -1c
No 
modification
DL-1
DL-1
No 
modification
Grade 3
Discontinued
DL -1
Discontinue
Discontinue
DL-1
Grade 4
Discontinue
DL -1
Discontinue
Discontinue
DL-1
Total bilirubin
Grade 2
No 
modification
No 
modification
DL-2
DL-2
No 
modification
Grade 3
No 
modification
No 
modification
Discontinue
Discontinue
No 
modification
Grade 4
No 
modification
No 
modification
Discontinue
Discontinue
No 
modification
AST or ALT 
Elevation
Grade 3
DL -1
DL -1
Discontinue
Discontinue
DL-1
Grade 4
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
Other 
nonhematologic 
toxicity (except 
fatigue and 
transient arthralgia 
and myalgia)
Grade ≥3
DL -1
DL -1
DL-1
DL-1
DL-1
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = common terminology criteria for adverse 
events; DL = dose level.
Note: If considered in the best interest of the participant, and consistent with local practice, investigators may decide to use 
supportive measures/treatment, and/or secondary prophylaxis instead of dose reductions for the next dose. Also, if toxicity 
can clearly be attributed to one of the drugs, the investigator may choose to only reduce the dose of one of the 
chemotherapy agents.
a
Should the toxicity recur; the dose of the agent could be reduced further. However, not more than 2 dose reductions per 
chemotherapy agent are permitted.
b
The first occurrence of Grade ≥3 nausea/vomiting, mucositis, and diarrhea should be managed symptomatically with 
optimal medical therapy and improve to Grade ≤1 prior to proceeding with additional therapy. Should these events 
recur despite aggressive management, a dose modification can be employed once the AE improves to Grade ≤1.
c
If Grade 2 neurotoxicity recurs after DL -1, drug will be given at DL -2 or switch can be made to the appropriate dose 
of carboplatin at the discretion of the investigator in consultation with the Sponsor. If Grade 2 neurotoxicity persists 
after 2 dose level reductions and 21-day hold, switch can be made to the appropriate dose of carboplatin at the 
discretion of the investigator in consultation with the Sponsor.
d
If Grade 3 neurotoxicity occurs, cisplatin will be discontinued, and, upon improvement, a switch can be made to the 
appropriate dose of carboplatin at the discretion of the investigator in consultation with the Sponsor.
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6.7
Intervention After the End of the Study
Upon study completion, participants are to be discontinued and may be enrolled in an 
extension study using pembrolizumab, if available.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
6.9
Standard Policies
This section is not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period will still continue to be monitored in this study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.12.3 unless the participant has 
withdrawn from the study Section 7.2.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
Interruption of chemotherapy for more than 6 weeks. Participants may continue on study 
following Sponsor consultation. 
•
Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Section 6.6.1, require 
Sponsor consultation prior to restarting treatment. If treatment will not be restarted, the 
participant will continue to be monitored in the study and the reason for discontinuation 
of study intervention will be recorded in the medical record.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Radiographic disease progression outlined in Section 8.2.1.5 (after obtaining informed 
consent addendum and Sponsor communication, the investigator may elect to continue 
treatment beyond disease progression).
•
Any progression or recurrence of malignancy, or any occurrence of another malignancy 
that requires active treatment.
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•
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 6.6.
For participants who are discontinued from study intervention, but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued 
from study intervention, they shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before providing documented informed consent may be used for 
screening or baseline purposes provided the procedures meet the protocol-specified 
criteria and were performed within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent, be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
The maximum amount of blood collected from each participant over the duration of the 
study is outlined in the Laboratory Manual.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. 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 participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of their 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
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the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout, or run-in treatment including placebo run-in).
8.1.4.1
Tobacco Use Assessment
Definitions for cigarette use are as follows [Land, S. R., et al 2016]:
•
Current smokers: persons who report smoking ≥100 cigarettes during their lifetime and 
who, at the time of screening, reported smoking every day or some days within the last 
year.
•
Former smokers: persons who report smoking ≥100 cigarettes during their lifetime and 
who, at the time of screening, had stopped smoking 1 year prior.
•
Never smokers: persons who report smoking <100 cigarettes during their lifetime.
8.1.4.2
Non-small Cell Lung Cancer History
The investigator or qualified designee will obtain prior and current details regarding the 
participant’s NSCLC.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the study. Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.
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8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit. In addition, new medications started 
during the Second Course through the Second Course Safety Follow-up Visit should be 
recorded.
8.1.5.3
Subsequent Antineoplastic Therapy
Details of subsequent therapies for cancer and/or details of radiation therapy and surgery for 
the treatment of the cancer, after discontinuation of study intervention, will be collected. 
Reasons for starting subsequent antineoplastic therapies, including access to other 
PD-1/PD-L1 inhibitors or investigational drugs will be collected.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.12.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
randomization. Once a randomization number is assigned to a participant, it can never be 
reassigned to another participant. 
A single participant cannot be assigned more than 1 randomization number. 
8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or appropriately qualified 
designee according to the specifications within the Pharmacy Manual. All study interventions 
will be administered on an outpatient basis.
Study intervention should begin within 3 days of randomization. The investigator will select 
the chemotherapy regimen before randomization.
8.1.8.1
Timing of Dose Administration
Study interventions should be administered after all procedures and assessments have been 
completed. On applicable visits, MK-3475A or pembrolizumab will be administered before 
chemotherapy. 
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8.1.8.2
MK-3475A Administration
MK-3475A (790 mg Q6W) will be administered by SC injection in the participant’s 
abdomen or thigh.
The Pharmacy Manual contains specific instructions on the preparation and administration of 
MK-3475A.
8.1.8.3
Pembrolizumab Administration
Pembrolizumab (400 mg Q6W) will be administered by IV infusion over approximately 
30 minutes.
The Pharmacy Manual contains specific instructions on the preparation and administration of 
pembrolizumab.
8.1.8.4
Chemotherapy Administration
Unless there is a change in weight >10%, the same dose of chemotherapy can be used 
throughout the intervention period (provided there are no additional toxicities).
For all agents and all administration, antiemetic therapy should follow MASCC guidelines 
[Roila, F., et al 2016] and should include a 5-HT3 receptor antagonist, dexamethasone (or 
equivalent) and/or aprepitant as per the MASCC guidelines. For details regarding G-CSF 
primary prophylaxis, please refer to Section 6.5.1.2.1.
8.1.8.4.1
Pemetrexed (Nonsquamous)
Pemetrexed (500 mg/m2 Q3W) will be administered as an IV infusion over approximately 
10 minutes as per local and institutional guidelines according to the approved product labels. 
Pemetrexed administration is to be completed at least 30 minutes before the initiation of 
carboplatin or cisplatin. All participants should receive the appropriate supplementation of 
vitamin B12, folic acid, and corticosteroid prophylaxis as listed below (or as per local label):
•
Folic acid 350 to 1000 μg po: 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 pemetrexed infusions thereafter. Subsequent vitamin B12 injections 
may be given the same day as pemetrexed administration.
•
Dexamethasone prophylaxis 4 mg po bid (or equivalent). Taken the day before, day of, 
and day after pemetrexed administration. Higher or additional doses are permitted for 
antiemetic prophylaxis during the first 4 pemetrexed infusions but not to exceed doses in 
MASCC guidelines [Roila, F., et al 2016].
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8.1.8.4.2
Cisplatin (Nonsquamous)
Cisplatin (75 mg/m2 Q3W) will be administered as an IV infusion over 30 to 180 minutes on 
Day 1 and Day 22 for two 42-day cycles as per local and institutional guidelines according to 
the approved product labels. 
Participants are allowed to switch from cisplatin to carboplatin if the participant becomes 
ineligible for further cisplatin therapy according to local guidelines and the investigator 
considers switching to carboplatin to be in the best interest of the participant. 
8.1.8.4.3
Carboplatin (Nonsquamous and Squamous)
Carboplatin (AUC 6 [mg/mL/min] squamous; AUC 5 [mg/mL/min] nonsquamous) will be 
administered as an IV infusion over approximately 60 minutes Q3W on Day 1 and Day 22 
for two 42-day cycles as per local and institutional guidelines according to the approved 
product labels. The carboplatin dose should be calculated using the Calvert Formula (see 
below) and should not exceed 900 mg (squamous) or 750 mg (nonsquamous).
Calvert Formula (Squamous dose):
•
Total dose (mg) = (target AUC) × (CrCl + 25)
•
The estimated CrCl in the Calvert Formula should not exceed 125 mL/min
•
Maximum carboplatin dose (mg) = target AUC 6 × (125 + 25)
= 6 × 150
= 900 mg
Calvert Formula (Nonsquamous dose):
•
Total dose (mg) = (target AUC) × (CrCl + 25)
•
The estimated CrCl in the Calvert Formula should not exceed 125 mL/min
•
Maximum carboplatin dose (mg) = target AUC 5 × (125 + 25)
= 5 × 150
= 750 mg
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CrCl must be calculated using the Cockcroft-Gault formula for estimating CrCl in mL/min 
based on serum creatinine:
•
Male: [(140 - age (y)) × weight (kg)]/[72 × serum creatinine (mg/dL)]
•
Female: [(140 - age (y)) × weight (kg)] × 0.85/[72 × serum creatinine (mg/dL)]
Alternatively, CrCl can be determined from a 24-hour urine collection.
Note: Dose may be rounded to the nearest 50 mg at the discretion of the investigator, and 
according to institutional standards.
Additional premedications should be administered as per standard practice.
8.1.8.4.4
Paclitaxel or Nab-paclitaxel (Squamous)
Paclitaxel or nab-paclitaxel will be administered immediately after MK-3475A or 
pembrolizumab and should be completely administered prior to initiating the carboplatin 
dose.
•
Paclitaxel (200 mg/m2 Q3W) will be administered as an IV infusion over 3 hours on 
Day 1 and Day 22 for two 42-day cycles as per local and institutional guidelines 
according to the approved product labels. All participants should be premedicated with 
oral or IV steroid and antihistamines according to the approved product label and/or 
standard practice. Additional premedications should be administered as per standard 
practice. 
•
Nab-paclitaxel (100 mg/m2) will be administered as an IV infusion over 30 minutes on 
Day 1, 8, 15, 22, 29, and 36 for two 42-day cycles as per local and institutional guidelines 
according to the approved product labels.
Participants are allowed to switch from paclitaxel to nab-paclitaxel if the participant 
experiences an infusion reaction to paclitaxel and the investigator considers switching to be 
in the best interest of the participant. 
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.12.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4 and 8.12.3.
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8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study
intervention in emergency situations where the investigator is not available.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.12
Tumor Tissue for Biomarker Status
During the screening period, a tumor sample for each participant is required and is to be:
•
A newly obtained core, incisional, or excisional biopsy of a tumor lesion, which was not 
previously irradiated
Or
•
An archival tumor tissue sample if a new biopsy is unavailable (depending on protocol 
requirements)
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FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived 
tissue.
Details pertaining to tumor tissue submission can be found in the Laboratory Manual.
The central laboratory will use the tissue sample to ascertain PD-L1 status using the PD-L1 
IHC 22C3 pharmDx (Investigational Use Only) diagnostic kit. The diagnostic test is identical 
to the US FDA-approved PD-L1 IHC 22C3 pharmDx diagnostic kit except it is labeled IUO. 
The PD-L1 IHC 22C3 pharmDx assay kit is currently approved to assess PD-L1 status in 
participants with NSCLC for treatment with pembrolizumab.
The PD-L1 result will be masked to the site.
8.2
Efficacy/ Assessments
8.2.1
Tumor Imaging and Assessment of Disease
Throughout this section, the term ‘scan’ refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, or other methods as specified in this protocol.
In addition to survival, efficacy will be assessed based on evaluation of scan changes in 
tumor burden over time, until the participant is discontinued from the study or goes into 
survival follow-up. The process for scan collection and transmission to the iCRO can be 
found in the SIM. Tumor scans by CT are strongly preferred. For the abdomen and pelvis, 
contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or 
when mandated by local practice. The same scan technique should be used in a participant 
throughout the study to optimize the reproducibility of the assessment of existing and new 
tumor burden and improve the accuracy of the response assessment based on scans.
Note: For the purposes of assessing tumor scans, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer at the site or at an offsite facility. 
If brain scans are performed, magnetic resonance imaging is preferred; however, CT imaging 
will be acceptable, if MRI is medically contraindicated.
Bone scans may be performed to evaluate bone metastases. Any supplemental scans 
performed to support a positive or negative bone scan, such as plain x-rays acquired for 
correlation, should also be submitted to the iCRO.
Other imaging modalities that may be collected, submitted to the iCRO, and included in the 
response assessment include PET or PET-CT. Other types of medical imaging (such as 
ultrasound) should not be submitted to the iCRO and will not be included in response 
assessment.
At Screening, participant eligibility will require radiographic documentation of at least 1 
lesion that meets the requirements for selection as a target lesion, as defined by RECIST 1.1 
and as assessed by the local site investigator/radiology, prior to participant randomization.  
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All scheduled scans for participants will be submitted to the iCRO. In addition, a scan that is 
obtained at an unscheduled time point, for any reason (including suspicion of progression or 
other clinical reason), should also be submitted to the iCRO if it shows disease progression, 
or if it is used to support a response assessment. All scans acquired within the protocol-
specified window of time around a scheduled scan visit are to be classified as pertaining to 
that visit.
8.2.1.1
Initial Tumor Scans
Initial tumor scans at Screening must be performed within 28 days prior to the date of 
randomization. Any scans obtained after Cycle 1 Day 1 cannot be included in the screening 
assessment. The site must review screening scans to confirm the participant has measurable 
disease per RECIST 1.1.
The screening scans must be submitted to the iCRO for retrospective review.
Tumor scans performed as part of routine clinical management are acceptable for screening if 
they are of acceptable diagnostic quality and performed within 28 days of randomization and 
can be assessed by the iCRO.
If brain scans are required to document the stability of existing metastases, the brain scan 
should be acquired during screening. The specific methods permitted for this study are 
described in the SIM.
Bone scans are required at screening for participants with a history of bone metastases and/or 
for those participants with indicative clinical signs/symptoms such as bone pain or elevated 
alkaline phosphatase levels.
Bone scan refers to imaging methods used to assess bone metastasis. The specific methods 
permitted for this study are described in the SIM.
8.2.1.2
Tumor Scans During the Study
The first on-study scan should be performed at 6 weeks (42 days +7 days) and at 12 weeks 
(84 days ±7 days) and 18 weeks (126 days ±7 days) from the date of randomization. 
Subsequent tumor scans should be performed every 9 weeks (63 days ±7 days) or more 
frequently if clinically indicated. After 45 weeks (315 days ±7 days), participants who 
remain on treatment will have scans performed every 12 weeks (84 days ±7 days). Scan 
timing should follow calendar days and should not be adjusted for delays in cycle starts.
Scans are to be performed until disease progression is identified by the investigator and 
verified by the BICR, or until any of these conditions are met:
•
the start of new anticancer treatment
•
pregnancy 
•
death
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•
withdrawal of consent
•
the end of study
Objective response should be confirmed by a repeat scan performed at least 4 weeks after the 
first indication of a response is observed. Participants will then return to the regular scan 
schedule, starting with the next scheduled time point. Participants who receive additional 
scans for confirmation do not need to undergo the next scheduled scan if it is fewer than 4 
weeks later; scans may resume at the subsequent scheduled time point.
On-study brain or bone scans should be performed if clinically indicated or to confirm CR (if 
other lesions indicate CR and brain or bone lesions existed at baseline).
For participants with treated brain metastases at baseline, on-study brain scans will be 
acquired at Week 6 (+7 days) and then if clinically indicated and to confirm a CR. For 
participants without brain metastases at baseline, on-study brain scans should be acquired if 
clinically indicated.
8.2.1.3
End-of-treatment and Follow-up Tumor Scans
If participants discontinue study intervention, tumor scans should be performed at the time of 
discontinuation (±4-week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to documented disease 
progression, this is the final required tumor scan.
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans using the same 
schedule calculated from the date of randomization, refer to Section 8.2.1.2.
Scans are to be continued until one of the following conditions are met:
•
disease progression as defined by RECIST 1.1 verified by BICR
•
the start of a new anticancer treatment
•
pregnancy
•
death
•
withdrawal of consent
•
the end of the study
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8.2.1.4
Second Course (Retreatment) Tumor Scans
Tumor scans must be performed within 28 days before restarting study intervention with 
MK-3475A or pembrolizumab.
If disease progression has been verified by BICR for the First Course, the Second Course 
may be initiated. The disease progression scan may be used as the Second Course baseline 
scan if performed within 4 weeks prior to dosing and meets scan standards.
The first scan should be performed at 12 weeks (84 days ±7 days) after restarting study
intervention. Subsequent tumor scans are to be performed every 12 weeks (84 days ±7 days) 
or more frequently, if clinically indicated.
Scans are to be performed until: 
•
disease progression
•
the start of new anticancer treatment
•
pregnancy
•
withdrawal of consent
•
death
•
completion of Second Course
•
or notification by the Sponsor, whichever occurs first.
Response assessments and progressive disease are determined by investigator assessment. 
The only Second Course scan to be provided to the iCRO is the baseline scan if it is the final 
scan for the Initial Treatment or First Course.
8.2.1.5
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used 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 (eg, 
discontinuation of study intervention). Although RECIST 1.1 references a maximum of 5 
target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions in 
total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
Upon investigator-assessed disease progression, the indicative scan(s) is/are to be submitted 
immediately to iCRO for BICR verification of progression. After submission of scan(s), the 
iCRO will email the assessment to the site and Sponsor.
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If disease progression is not verified, the process continues as follows:
•
If participant is clinically stable, continue study intervention per protocol
-
continue scans per protocol schedule (the next scheduled scan should be ≥4 weeks 
from most recent scan acquired)
-
send scans to iCRO
-
continue local assessment
-
do not change investigator assessment of progression
-
if subsequent scan(s) indicate progression, request verification from iCRO
•
If the participant is not clinically stable, best medical practice is to be applied
Before stopping study intervention or imaging or starting new anticancer therapy in a 
participant who is clinically stable, communication with the Sponsor is required.
If disease progression is verified, the process continues as follows:
•
investigator judgment will determine action
•
if the participant is clinically stable and study intervention is to continue, communication 
with the Sponsor is required and a reconsent addendum must be signed
•
obtain scans locally per original protocol schedule
•
do not send scans to iCRO
Figure 6 illustrates the study intervention decision process involving verification of disease 
progression for participants.
•
For the purpose of this decision process, lack of clinical stability is defined as:
-
unacceptable toxicity
-
clinical signs or symptoms indicating clinically significant disease progression
-
decline in performance status
-
rapid disease progression or threat to vital organs or critical anatomical sites (eg, CNS 
metastasis, respiratory failure due to tumor compression, spinal cord compression) 
requiring urgent alternative medical intervention
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Figure 6
Study Intervention Decision-Making Process When Progression per RECIST 
1.1 is Observed by Investigator
8.2.2
Patient-reported Outcomes
The EORTC QLQ-C30 and EQ-5D-5L questionnaires will be administered by trained site 
personnel and completed electronically by participants in the following order: EORTC QLQ-
C30 first, then EQ-5D-5L. The questionnaires should be administered Day 1 and Day 22 of 
Cycles 1 to 4, and Day 1 for Cycles 5 to 9. In Years 2 and 3, administer questionnaires every 
2 cycles (Cycle 10 Day 1, Cycle 12 Day 1, etc.) until discontinuation. From Cycle 27 (after 
Year 3), PROs will not be collected for participants receiving study intervention until the 
discontinuation visit.
If the Treatment Discontinuation Visit occurs 30 days from the last dose of study 
intervention, at the time of the mandatory Safety Follow-up Visit, the ePROs do not need to 
be repeated.
It is best practice and strongly recommended that ePROs are administered to randomized 
participants before drug administration, AE evaluation, and disease status notification. If the 
participant does not complete the ePROs at a scheduled time point, the MISS_MODE form 
must be completed to capture the reason the assessment was not performed.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Laboratory 
Manual.
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Planned time points for all safety assessments are provided in the SoA.
Refer to Appendix 7 for country-specific requirements.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. Height and weight 
will also be measured and recorded.
A brief directed physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard. Participants 
randomized to receive MK-3475A SC (Arm 1) will also receive a directed physical 
examination of the injection site.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 1.3. After the first 
dose of study intervention, new clinically significant abnormal findings should be recorded 
as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated prior to study intervention administration. New clinically significant abnormal 
findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
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8.3.1.3
Directed Injection-site Physical Examination
Participants randomized to receive MK-3475A SC (Arm 1) must receive a directed physical 
examination at the injection site at the timepoints detailed in Section 1.3. Any injection-site 
AE should be reported using standard AE/SAE reporting methods. Injection-site reaction and 
pain may include, but are not limited to, the following:
•
Injection-site redness/erythema
•
Injection-site swelling/edema 
•
Injection-site tenderness/pain/discomfort/irritation 
•
Injection-site bruising
•
Injection-site infection
•
Injection-site hard lump (mass, nodule)/induration 
•
Injection-site inflammation 
•
Injection-site rash 
•
Injection-site hematoma/hemorrhage 
•
Injection-site extravasation 
•
Injection-site dermatitis 
•
Injection-site discoloration/pallor 
•
Injection-site vesicles/ulcers 
Participants in Arm 1 will be informed about the potential injection-site reactions listed 
above. In addition to a directed injection-site physical examination, any injection-site AE 
should be reported by participants at any time during the study. Any potential injection-site 
AE should be investigated further by the site. At all scheduled visits, including at PK sample 
collections, any injection-site AEs should be recorded in the AE eCRF.
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8.3.2
Vital Signs
The investigator or qualified designee will measure vital signs and weight at Screening, prior 
to the administration of each dose of study intervention, end-of-treatment, and during the 30-
day Safety Follow-up as specified in the SoA.
•
Vital signs include temperature, heart rate, respiratory rate, and blood pressure.
•
Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available.
•
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions.
•
Vital signs will be measured in a semisupine position after 5 minutes rest.
8.3.3
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures. The timing of 
ECG is specified in Section 1.3. Clinically significant abnormal findings should be recorded 
as medical history. Additional ECGs may be performed as clinically necessary.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the Laboratory Manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
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8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.5
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine and/or serum) should be conducted at every protocol cycle
as per SoA.
-
Pregnancy testing should be conducted midcycle (Day 22 of each treatment cycle), as 
per SoA, during intervention.
-
Pregnancy testing (urine and/or serum) should be conducted for the time required to 
eliminate systemic exposure after the last dose of each study intervention and should 
correspond with the time frame for participant's contraception, as noted in
Section 5.1. The length of time required to continue pregnancy testing for each study 
intervention is:
◦
Chemotherapy: 180 days
◦
MK-3475A: 120 days
◦
Pembrolizumab: 120 days
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
8.3.6
Performance Assessments
8.3.6.1
Eastern Cooperative Oncology Group Performance Status
The ECOG Performance Status is standardized criteria to measure how cancer impacts level 
of functioning (performance status) in terms of ability to care for oneself, daily activity, and 
physical ability (walking, working, etc) with Grades 0 to 5.
The investigator or qualified designee will assess ECOG status at Screening, before the 
administration of each dose of study intervention and during the follow-up period as 
specified in the SoA (Section 1.3).
The ECOG performance status closest to randomization will be used to stratify participants.
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8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
Adverse events will not be collected for participants during the prescreening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention. If the participant requires a blood draw, fresh 
tumor biopsy, etc, the participant is first required to provide consent to the main study, and 
AEs will be captured according to guidelines for standard AE reporting.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention randomization, must be reported by 
the investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event cause the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
•
All AEs from the time of intervention randomization through 30 days after cessation of 
study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation/randomization 
through 90 days after cessation of study intervention or 30 days after cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator.
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•
All pregnancies and exposure during breastfeeding, from the time of intervention 
randomization through the time required to eliminate systemic exposure after cessation of 
study intervention as described in Sections 5.1 and 8.3.5, or 30 days after cessation of 
study intervention if the participant initiates new anticancer therapy must be reported by 
the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside the 
time specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 15.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 15
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE including 
Cancer and 
Overdose
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation Exposure
Report if:
- participant has 
been exposed to 
any protocol-
specified 
intervention (eg, 
procedure, 
washout or run-in 
treatment 
including placebo 
run-in)
Exception: A 
positive 
pregnancy test at 
the time of initial 
screening is not a 
reportable event.
Report all
Previously reported –
Follow to completion/
termination; report 
outcome
Within 24 hours 
of learning of 
event
ECI (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- potential DILI
- require 
regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
ECI (do not require 
regulatory reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
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An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), or a pregnancy that occurs during the study in a 
nonparticipant whose sexual partner is a participant capable of producing ejaculate is 
reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing that the fetus will be 
born with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
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Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3X the ULN and an elevated total bilirubin laboratory value that is 
greater than or equal to 2X the ULN and, at the same time, an alkaline phosphatase 
laboratory value that is less than 2X the ULN, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.*
*Note: These criteria are based on 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 study-site guidance for assessment 
and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
8.5
Treatment of Overdose
An overdose of MK-3475-A will be defined as ≥ 5 times the recommended dose.
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater.
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
Refer to the approved label for guidance on an overdose of any chemotherapy agents.
8.6
Pharmacokinetics
Refer to Appendix 7 for country-specific requirements.
8.6.1
Blood Collection for Pembrolizumab and MK-5180 Pharmacokinetics
Sample collection, storage, and shipment instructions for serum and plasma samples will be 
provided in the Laboratory Manual. PK samples should be drawn according to the PK 
collection schedule for all participants (Section 1.3.3); however
•
Arm 1 (SC) participants
-
Cycle 1 Days 2 to 7:
•
Arm 2 (IV) participants
-
Cycle 1:
-
Cycle 1 Days 15 and 29:
CCI
CCI
CCI
CCI
CCI
CCI
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•
•
MK-5180 PK (plasma) collection for Arm 1 (SC) participants
-
If ongoing PK sample collection for MK-5180 is deemed to be unnecessary by the Sponsor 
based on available data, sample collection for MK-5180 may be reduced or discontinued.
Blood samples collected may be stored and further analysis may be performed, if required.
8.6.2
Blood Collection for Antidrug Antibodies
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the Laboratory Manual. ADA samples should be drawn according to the ADA collection 
schedule for all participants (Section 1.3.3). Every effort should be taken to collect samples 
at 30 days after end of study intervention for anti-pembrolizumab antibody. Simultaneous PK 
sampling is required for interpretation of ADA analysis.
If ongoing ADA sample collection for MK-5180 is deemed to be unnecessary by the Sponsor 
based on available data, sample collection for MK-5180 may be reduced or discontinued.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
CCI
CCI
CCI
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8.8.1
Planned Genetic Analysis Sample Collection
8.9
Future Biomedical Research Sample Collection
8.10
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics data associated with medical encounters, 
will be collected in the CRF by the investigator and study-site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to conduct exploratory economic analyses and will include:
•
All-cause hospitalizations and emergency room visits must be reported in the eCRF, from 
the time of treatment allocation/randomization through 90 days after cessation of study 
intervention, or 30 days after cessation of study intervention, if the participant initiates 
new anticancer therapy, whichever is earlier.
8.11
Pharmacoeconomics
Time and resource savings have been established for SC administration of oncology drugs 
compared with IV administration [De Cock, E., et al 2016]. A Time & Motion observational 
pharmacoeconomic study will be conducted in parallel and will assess healthcare utilization 
parameters by collecting data on time and resource use at a selected subset of sites 
participating in the MK-3475A-D77 study. Details of this observational study will be 
described and reported in a separate protocol.
CCI
CCI
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8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Documented informed consent must be provided before performing any protocol-specific 
procedure. Results of a test performed before the participant 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 before the first dose of study 
intervention.or sooner as indicated in the SoA.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
All participants will be evaluated prior to randomization. Investigators will review 
inclusion/exclusion criteria to ensure eligibility. An enrollment support consultation form
will be completed by the Investigator and reviewed by Sponsor.
8.12.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
8.12.2.1
Optional Home Health Visits for PK Sampling
A global home health vendor is available to be used for participants in both Arm 1 and Arm 2 
who must have additional PK samples taken during Cycle 1 and Cycle 3. The home health 
visiting nurse service may be used if approved by local health authorities for PK sampling at 
the following PK visits: Cycle 1 Days 3, 4, 5, 6, 7, 10, 15, 29, 42 and Cycle 3 Days 4, 10, 42.
If the visiting nurse service is used for any of the visits listed above, the nurse will be 
instructed to immediately contact the site if the participant reports any potential AE to the 
nurse. In addition to this, the investigator should contact the participant by phone on the same 
day as the nurse visit, or as soon as possible (if the home health visit occurred on a weekend 
or holiday) to perform an investigator AE assessment. Refer to the nursing manual for 
additional details.
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8.12.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Randomized participants who discontinue study intervention for reasons other than 
progressive disease will move into the Follow-up Phase (Section 8.12.4).
8.12.4
Posttreatment Visit
8.12.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer treatment, whichever 
comes first.
If a participant has a discontinuation visit ≥30 days after the last dose of study intervention, 
the Safety Follow-up Visit is not required.
Participants who are eligible for Second Course retreatment with MK-3475A or 
pembrolizumab may have up to 2 safety follow-up visits: 1 after the Initial Treatment or First 
Course and 1 after the Second Course.
8.12.4.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than BICR-verified disease progression will 
begin Efficacy Follow-up and should be assessed as detailed in the SoA (Section 1.3) to 
monitor disease status. Every effort should be made to collect information regarding disease 
status until the start of new anticancer therapy, disease progression, death, end of study.
Information regarding poststudy anticancer treatment will be collected if new treatment is 
initiated. Participants who completed all efficacy assessments and/or will not have further 
efficacy assessments must enter Survival Follow-up.
Participants who are eligible to receive retreatment with MK-3475A or pembrolizumab 
according to the criteria in Section 6.1.2 will move from Efficacy Follow-up to Second 
Course when they experience BICR-verified disease progression. Details are provided in the 
SoA (Section 1.3) for retreatment with MK-3475A or pembrolizumab.
8.12.4.3
Survival Follow-up Contacts
Participant survival follow-up status will be assessed approximately every 12 weeks to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
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The first survival follow-up assessment should be scheduled as described below:
•
For participants who discontinue treatment intervention and who will not enter Efficacy 
Follow-up, the first survival follow-up contact will be scheduled 12 weeks after the 
Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).
•
For participants who completed assessments in Efficacy Follow-up, the first survival 
follow-up contact will be scheduled 12 weeks after the last efficacy assessment follow-up 
visit has been performed.
8.12.5
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an eDMC review, 
interim and/or final analysis. Upon Sponsor notification, all participants who do not/will not 
have a scheduled study visit or study contact during the Sponsor-defined period will be 
contacted for their vital status.
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9
KEY STATISTICAL CONSIDERATIONS
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding/final database lock, changes are made to 
primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses, then the protocol will be amended (consistent with ICH Guideline E9). Changes 
to exploratory or other nonconfirmatory analyses made after the protocol has been finalized, 
but prior to the conduct of any analysis, will be documented in a sSAP and referenced in the 
CSR for the study. Post hoc exploratory analyses will be clearly identified in the CSR. Other 
planned analyses (ie, those specific to the analysis of future biomedical research) will be 
documented in separate analysis plans.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12. See Appendix 7 for country-specific information.
Study Design 
Overview
A Phase 3 Randomized, Open-label Clinical Study to Evaluate the Pharmacokinetics 
and Safety of Subcutaneous Pembrolizumab Coformulated With Hyaluronidase (MK-
3475A) Versus Intravenous Pembrolizumab, Administered With Chemotherapy, in the 
First-line Treatment of Participants With Metastatic Non-small Cell Lung Cancer
Treatment
Assignment
Approximately 378 participants will be randomized in a 2:1 ratio between 2 treatment 
groups: (1) MK-3475A SC Q6W in combination with platinum doublet chemotherapy
and (2) pembrolizumab IV Q6W in combination with platinum doublet chemotherapy.
Randomization stratification factors are: 1) ECOG (0 versus 1), 2) Histology (squamous 
versus nonsquamous), 3) PD-L1 TPS (<50% versus ≥50%; PD-L1 nonevaluable 
participants will be included with the TPS <50% group), and 4) Region (East Asia 
versus North America/Western Europe/Australia/New Zealand versus Rest of the 
World). This is an open-label study.
Analysis 
Populations

PK (primary): Per-protocol Set

Efficacy: ITT

Safety: APaT

PRO: PRO FAS
Primary 
Endpoint(s)

Cycle 1 AUC0-6 wks 

Steady-state (Cycle 3) Ctrough (the primary analysis will be performed on the 
model-based values of Ctrough)
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Secondary 
Endpoints

For descriptive comparison to pembrolizumab IV Q6W:
o
Cycle 1: Cmax, Ctrough
o
Cycle 3: AUC0-6 wks, Cmax

For descriptive comparison to pembrolizumab IV Q3W:
o
Model-based Ctrough at Cycle 1 and steady state

ADA

ORR

PFS

OS

DOR

Safety and tolerability 

PROs
Statistical 
Methods for Key 
Immunogenicity/ 
Pharmacokinetic 
Analyses
For both primary hypotheses of noninferiority of MK-3475A SC versus pembrolizumab 
IV with respect to Cycle 1 AUC0-6 wks and Cycle 3 Ctrough, the noninferiority margin with 
respect to the AUC and Ctrough GMR of MK-3475A SC versus pembrolizumab IV is 
specified to be 0.8. Computation of the CIs of GMR will be calculated using Welch’s t-
test statistics (which does not rely on the assumption of equal variances for SC and IV) 
with the log-transformed AUC and Ctrough.
Statistical 
Methods for Key 
Safety Analyses
For analyses in which 95% CIs will be provided for between-treatment differences in 
the percentage of participants with events, these analyses will be performed using the 
Miettinen and Nurminen’s method [Miettinen, O. and Nurminen, M. 1985].
Interim Analyses
Pharmacokinetics
There are no planned IAs for pharmacokinetics analysis in this study. One final analysis 
(FA) is planned to be performed when a minimum of 27 weeks follow-up after last 
participant randomized. This is expected about 16.2 months after first participant 
randomized. The purpose of FA is for noninferiority of Cycle 1 AUC0-6wks and Cycle 3 
Ctrough.
Safety
The study plans 1 interim safety analysis, which will be performed approximately 7 
months after first participant is randomized. Details will be specified in the DMC 
charter.
Multiplicity
The overall Type I error over the primary endpoints is strongly controlled at 0.05 (1-
sided), with 0.02 initially allocated to Cycle 1 AUC0-6 wks and 0.03 to Cycle 3 Ctrough. 
By using the graphical approach of Maurer and Bretz [Maurer, W., et al 2011], if 1
hypothesis is rejected, the alpha will be shifted to the other hypothesis.
Sample Size and 
Power 
The planned sample size is approximately 378 participants.
For the primary endpoint of Cycle 1 AUC0-6 wks, based on 318 participants with 
evaluable Cycle 1 AUC0-6 wks, the study has approximately >99.9% power to reject the 
null hypothesis (AUC GMR ≤0.8) under a true AUC GMR = 1.07 at the initially 
assigned 0.02 (1-sided) significance level.
For the primary endpoint of Cycle 3 Ctrough, based on 240 participants with evaluable
Cycle 3 Ctrough data, the study has approximately 99.8% power to reject the null 
hypothesis (Ctrough GMR ≤0.8) under a true Cycle 3 Ctrough GMR = 1.29 at the initially 
assigned 0.03 (1-sided) significance level.
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Japan Extension 
Study
Japan participants randomized during the global study phase will be included in all 
global study analyses (PK, efficacy and safety). Japan participants randomized during 
the Japan extension phase will be excluded from all global study analyses. Japan 
participants randomized during global and extension phases will both be included in the 
Japan-specific analyses. Details of the analysis regarding to the endpoints, population, 
analysis timing, etc will be provided in the separate Japan-specific sSAP document.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a randomized, open-label study, ie, participants, 
investigators, and Sponsor personnel will be aware of participant treatment assignments after 
each participant is enrolled and treatment is assigned.
The Sponsor will generate the randomized allocation schedule(s) for study intervention
assignment, and the randomization will be implemented in an interactive voice response 
system by a study vendor.
Although the study is open-label, analyses or summaries generated by randomized 
intervention assignment, or actual intervention received will be limited and documented.
Extension Study In Japan
For all participants in Japan, including participants randomized in the global study and the 
extension study, analyses or summaries generated by randomized intervention assignment, or 
actual intervention received will be limited and documented to the 
statistician(s)/programmer(s) responsible for the analysis of the Extension Study in Japan. 
The extent to which individuals are unblinded to the results will be limited, and blinded and 
unblinded members will be clearly documented.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3. For the primary hypotheses of 
noninferiority of MK-3475A SC to pembrolizumab IV based on assessment of Cycle 1 
AUC0-6 wks and Cycle 3 Ctrough, the noninferiority margin for the GMR of MK-3475A SC 
versus pembrolizumab IV is set to be 0.8. The rationale for the 0.8 noninferiority margin is 
based on the standard lower bound recommended in regulatory guidance documents for 
demonstration of bioequivalence for PK bridging [Food and Drug Administration 2014]. An 
upper bound for the bioequivalence interval was not applied due to the established wide 
therapeutic window of pembrolizumab.
9.4
Analysis Endpoints
Pharmacokinetics, safety, and efficacy endpoints that will be evaluated for within- and/or 
between-treatment differences are listed below.
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9.4.1
Pharmacokinetics Endpoints
The methodological details for assessment of model-based PK exposures (AUC0-6 wks and 
Ctrough) will be summarized in a separate MAP.
Primary
•
Cycle 1 AUC0-6 wks
Cycle 1 AUC0-6 wks is defined as the model-based area under curve exposure over a 6-week 
dosing interval in Cycle 1.
•
Cycle 3 Ctrough
Cycle 3 Ctrough is defined as the trough concentration at the end of the dosing interval in 
Cycle 3, representing steady-state.
Two assessments of this endpoint will be made: model-based Ctrough, which is the value 
predicted by the PK model, and observed Ctrough, which is the measured value. The primary 
analysis for Cycle 3 Ctrough will be based on the model-based value. A sensitivity analysis of 
this endpoint will be performed on the observed value.
Secondary
For descriptive comparison with pembrolizumab IV Q6W:
•
Cycle 1 Ctrough
Cycle 1 Ctrough is defined as the trough concentration at the end of the dosing interval in 
Cycle 1. Two assessments of this endpoint will be made: observed Ctrough, which is the 
measured value, and model-based Ctrough, which is the value predicted by the PK model. 
•
Cycle 3 AUC0-6 wks
Cycle 3 AUC0-6 wks is defined as the model-based area under curve exposure over a 6-week 
dosing interval in Cycle 3, representing steady-state.
•
Cycle 1 Cmax
Cycle 1 Cmax is defined as the peak concentration over the dosing interval in Cycle 1. Two 
assessments of this endpoint will be made: observed Cmax, which is the measured value, and 
model-based Cmax, which is the value predicted by the PK model.
•
Cycle 3 Cmax
Cycle 3 Cmax is defined as the peak concentration over the dosing interval in Cycle 3, 
representing steady-state. Two assessments of this endpoint will be made: observed Cmax, 
which is the measured value, and model-based Cmax, which is the value predicted by the PK 
model.
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For descriptive comparison with pembrolizumab IV Q3W:
•
Model-based Cycle 1 Ctrough
Model-based Cycle 1 Ctrough is defined as the value of trough concentration at the end of the 
dosing interval in Cycle 1, as predicted by the PK model.
•
Model-based steady-state Ctrough
Model-based steady-state Ctrough is defined as the value of trough concentration at the end of 
the dosing interval at steady-state, as predicted by the PK model. This corresponds to the 
model-predicted Ctrough value at Cycle 3 for MK-3475A Q6W and at Cycle 6 for 
pembrolizumab 200 mg IV Q3W.
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory values, and vital signs.
9.4.3
Efficacy Endpoints
Secondary
•
Objective Response Rate (ORR)
The ORR is defined as the percentage of participants who achieve a confirmed CR or PR per 
RECIST 1.1 as assessed by BICR.
•
Progression-free survival (PFS) 
PFS is defined as the time from randomization to the first documented disease progression 
per RECIST 1.1 by BICR or death due to any cause, whichever occurs first.
•
Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause.
•
Duration of Response (DOR)
For participants who show confirmed CR or PR, DOR is defined as the time from the first 
documented evidence of CR or PR until disease progression or death due to any cause, 
whichever occurs first.
9.4.4
Immunogenicity Endpoint
Immunogenicity (ADA incidence) will be assessed by analyzing the development of ADAs 
following administration of MK-3475A SC and pembrolizumab IV.
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9.4.5
PRO Endpoints
Change from baseline in EORTC QLQ-C30 global health/QoL scale (Items 29 and 30) and 
physical functioning domain score (Items 1 through 5) and role functioning domain scores
(Items 6 and 7).
Exploratory PRO endpoints as described in Section 4.2.1.5 will be evaluated. Details will be 
provided in the sSAP.
9.5
Analysis Populations
9.5.1
Pharmacokinetics Analysis Populations
The PP population will be used for the analysis of PK data in this study. 
PP Populations for Primary PK Endpoints
•
Cycle 1 AUC0-6 wks
The PP population for the primary PK endpoint of Cycle 1 AUC0-6 wks consists of the subset 
of participants in the global study who received the Cycle 1 dose, with at least 1 valid 
postdose PK sample in Cycle 1 and for whom a model-based assessment of AUC0-6 wks can be 
made. 
•
Cycle 3 Ctrough
The primary analysis for the primary PK endpoint of Cycle 3 Ctrough will be performed on the 
model-based Cycle 3 Ctrough. An additional sensitivity analysis of this endpoint will be 
performed using observed Cycle 3 Ctrough.
-
The PP population for model-based Cycle 3 Ctrough consists of the subset of 
participants in the global study who received the Cycle 1 dose, with at least 1 valid 
postdose sample and for whom a model-based assessment of Cycle 3 Ctrough can be 
made.
-
The PP population for the observed Cycle 3 Ctrough consists of the subset of 
participants in the global study who received all 3 doses from Cycle 1 to 3 within the 
permissible dosing window as per the SoA and have a valid PK sample on Cycle 3 
Day 42 with no documented assay or bioanalytical error and within permissible 
window as per the PK SoA (ie, within Days 41 to 43 of the dosing day in Cycle 3).
Any participants or data values excluded from the primary analyses for the primary PK 
endpoints will be identified, along with the reasons for exclusion, in the CSR. 
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PP Populations for Secondary PK Endpoints
For descriptive comparison with pembrolizumab IV Q6W
•
Cycle 1 Ctrough
The PP population for observed Cycle 1 Ctrough consists of the subset of participants in the 
global study who received the Cycle 1 dose and have a valid PK sample on Cycle 1 Day 42 
with no documented assay or bioanalytical error and within permissible window as per the 
PK SoA (ie, within Days 41 to 43 of the dosing day in Cycle 1).
The PP population for model-based Cycle 1 Ctrough consists of the subset of participants in the 
global study who received the Cycle 1 dose, with at least 1 valid postdose sample in Cycle 1 
and for whom a model-based assessment of Ctrough can be made. 
•
Cycle 3 AUC0-6 wks
The PP population for Cycle 3 AUC0-6 wks consists of the subset of participants in the global 
study who received the Cycle 1 dose, with at least 1 valid postdose sample and for whom a 
model-based assessment of Cycle 3 AUC0-6 wks can be made.
•
Cycle 1 Cmax and Cycle 3 Cmax
The PP population for the observed Cycle 1 Cmax consists of the subset of participants in the 
global study who received the Cycle 1 dose within the permissible dosing window as per the 
SoA, and have a valid PK sample on Cycle 1 Day 1 end-of-infusion for the IV arm or at least 
1 valid PK sample on Cycle 1 Days 5 to 10 for the SC arm with no documented assay or 
bioanalytical error and within permissible window as per the PK SoA.
The PP population for the observed Cycle 3 Cmax consists of the subset of participants in the 
global study who received all 3 doses from Cycle 1 to 3 within the permissible dosing 
window as per the SoA, and have a valid PK sample on Cycle 3 Day 1 end-of-infusion for 
the IV arm or at least 1 valid PK sample on Cycle 3 Days 5 to 10 for the SC arm with no 
documented assay or bioanalytical error and within permissible window as per the PK SoA.
The PP population for model-based Cycle 1 Cmax and model-based Cycle 3 Cmax consists of 
the subset of participants in the global study who received the Cycle 1 dose, with at least 1 
valid postdose sample in Cycle 1 and for whom a model-based assessment of Cycle 1 Cmax
and Cycle 3 Cmax, respectively, can be made.
For descriptive comparison with pembrolizumab IV Q3W
•
Model-based Cycle 1 Ctrough and Steady-state Ctrough
The PP population for model-based Cycle 1 Ctrough and model-based steady-state Ctrough
consists of the subset of participants in the global study who received the Cycle 1 dose, with 
at least 1 valid postdose sample in Cycle 1 and for whom a model-based assessment of 
Cycle 1 and steady-state Ctrough, respectively, can be made. 
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Extension Study in Japan
After enrollment of the global study is completed, the study will continue to randomize 
participants in Japan until the sample size for participants in Japan reaches approximately 39. 
The participants in Japan randomized and treated in the extension study after completion of 
the global enrollment will not be included in the PP population for the global study. The 
Japan PP population for PK endpoint of Cycle 1 AUC0-6 wks consists of the subset of 
participants in the global study and extension study who received the Cycle 1 dose, with at 
least 1 valid postdose PK sample in Cycle 1 and for whom a model-based assessment of 
AUC0-6 wks can be made. The Japan PP population for PK endpoint of Cycle 3 Ctrough consists 
of participants in the global study and extension study who received the Cycle 1 dose, with at 
least 1 valid postdose sample and for whom a model-based assessment of Cycle 3 Ctrough can 
be made.
9.5.2
Safety Analysis Populations
Safety Analyses will be conducted in the APaT population, which consists of all randomized 
participants in the global study who received at least 1 dose of study treatment. Participants 
will be included in the treatment group corresponding to the study treatment they actually 
received for the analysis of safety data using the APaT population. This will be the treatment 
group to which they are randomized except for participants who take incorrect study 
treatment for the entire treatment period; such participants will be included in the treatment 
group corresponding to the study treatment actually received.
At least 1 laboratory, vital sign, or ECG measurement obtained subsequent to at least 1 dose 
of study treatment is required for inclusion in the analysis of the respective safety parameter. 
To assess change from baseline, a baseline measurement is also required.
Extension Study in Japan
The participants in Japan randomized and treated in the Japan extension study after 
completion of the global enrollment will not be included in the safety analysis population for 
the global study. The Japan APaT population, including all participants in Japan randomized 
in the global study and the extension study who received at least 1 dose of study treatment, 
will be analyzed separately.
9.5.3
Efficacy Analysis Populations
The ITT population will serve as the population for efficacy analysis. All randomized 
participants in the global study will be included in this population. Participants will be 
included in the treatment group to which they are randomized. 
Extension Study in Japan
The participants in Japan randomized in the extension study after completion of the global 
enrollment will not be included in the efficacy analysis population for the global study. The 
Japan ITT population, including all participants in Japan randomized in the global study and 
the extension study, will be analyzed separately.
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9.5.4
PRO Analysis Populations
The PRO analyses are based on the PRO FAS population, defined as all randomized 
participants in the global study who have at least 1 PRO assessment available for the specific 
endpoint and have received at least 1 dose of the study intervention. Participants will be 
analyzed in the treatment group to which they are randomized.
9.6
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 9.6.2. 
Pharmacokinetics results that will be deemed to be statistically significant after consideration 
of the Type I error control strategy are described in Section 9.8. Nominal p-values may be
computed for efficacy analyses and other pharmacokinetics analyses, but should be 
interpreted with caution due to potential issues of multiplicity, sample size, etc. 
9.6.1
Statistical Methods for Pharmacokinetics Analyses
The primary objectives are to compare GMR between MK-3475A SC and pembrolizumab IV 
based on Cycle 1 AUC0-6 wks and Cycle 3 Ctrough. These objectives will be assessed via the 
following noninferiority hypothesis:
The hypothesis testing for noninferiority and the CIs for GMR will be based on Welch’s t-
test statistics (which does not rely on the assumption of equal variances for SC and IV) with 
the log-transformed AUC and Ctrough. For Cycle 3 Ctrough, the primary analysis will be based 
on Cycle 3 model-based Ctrough. A sensitivity analysis will be performed for Cycle 3 observed 
Ctrough.
For each PK exposure (Ctrough, AUC0-6 wks and Cmax, for Cycles 1 and 3) by treatment, the 
following descriptive statistics will be provided: N (number of participants with nonmissing 
data), median, minimum, maximum, GM, and geometric percent CV (calculated as 100 x 
sqrt(exp(s2) – 1), where s2 is the observed variance on the natural log-scale). 
Based on PK data obtained in this study as well as historical PK data, an integrated 
population PK analysis will be performed to characterize the PK profile of pembrolizumab 
following SC and IV administrations and provide individual model-based PK exposure 
measures. Details are provided in the MAP.
9.6.2
Statistical Methods for Safety Analyses
The primary safety analyses will include only events that occur prior to Second Course 
treatment.
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9.6.2.1
Overall Safety Assessment 
The overall safety evaluation will include a summary by treatment group of the number and 
percentage of participants with at least 1 AE, drug-related AE, serious AE, serious drug-
related AE, Grade 3 to 5 AE, a discontinuation from study treatment due to an AE, an AE 
that led to treatment interruption, and an AE resulting in death. Only point estimates by 
treatment group are provided. The number and percentage for injection-site reactions will be 
provided for the MK-3475A SC arm.
Point estimate and 95% CIs for the difference between treatment groups in the percentage of 
participants with specific AEs will be provided if at least 10% of participants in any 
treatment group exhibit the event. The threshold of at least 10% of participants was chosen 
because the population enrolled in this study is in critical condition and usually experiences 
various AEs of similar types regardless of treatment; events reported less frequently than 
10% of participants would obscure the assessment of the overall safety profile and add little 
to the interpretation of potentially meaningful treatment differences. In addition, difference in 
the percentage of participants with specific Grade 3 to 5 AEs (≥5% of participants in 1 of the 
treatment groups) and SAEs (≥2% of participants in 1 of the treatment groups) will also be 
summarized by point estimate and 95% CIs.
CIs for between treatment group differences will be provided using the Miettinen and 
Nurminen’s method [Miettinen, O. and Nurminen, M. 1985]. Because many 95% CIs may be 
provided without adjustment for multiplicity, the CIs should be regarded as a helpful 
descriptive measure to be used in safety review, not as a formal method for assessing the 
statistical significance of the between-group differences.
Table 16 summarizes the analysis strategy for safety endpoints in this study.
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Table 16
Analysis Strategy for Safety Endpoints
Analysis Part
Safety Endpoint
Descriptive 
Statistics
95% between-
group CI 
Overall Safety 
Assessment
Specific AEs (incidence ≥10% of participants in 
1 of the treatment groups)
X
X
Specific Grade 3-5 AE (incidence ≥5% of 
participants in 1 of the treatment groups)
X
X
Specific serious AE (incidence ≥2% of 
participants in 1 of the treatment groups)
X
X
Any AE
X
Any Grade 3-5 AE
X
Any Serious AE 
X
Any Drug-related AE
X
Any Serious and Drug-related AE
X
Any Grade 3-5 and Drug-related AE
X
  Discontinuation from Study Treatment due to 
AE
X
AE that Resulted in Death
X
AE that Led to Treatment Interruption
X
Injection-site Reaction
X
Specific AEs, SOCs (incidence >0% of 
participants in any treatment group)
X
Change from Baseline Results (lab toxicity 
shift)
X
Assessment of 
safety topics of 
special interest
Pembrolizumab AEOSI
X
AE=adverse event; AEOSI=adverse event of special interest; CI=confidence interval; SOC=system organ class
9.6.2.2
Assessment of Safety Topics of Special Interest
AEs that are immune-mediated or potentially immune-mediated will be evaluated separately.
These events have been characterized consistently throughout the pembrolizumab clinical 
development program. Point estimates and 95% CIs for between-group difference is not 
expected to add value to the safety evaluation, and hence only number and percentage of 
participants with such pembrolizumab AEOSI will be provided, as well as the number and 
percentage of participants with corticosteroids administration to treat an AEOSI. Summary 
statistics will be provided for the analysis of time from first dose to the onset of an AEOSI.
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9.6.3
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the efficacy objectives (which are 
secondary objectives in the study). For this study, efficacy analyses are descriptive only. No 
Type I error control is applied to efficacy analyses, so p-values, if provided, are nominal only 
and provided for descriptive purposes.
The stratification factors used for randomization (see Section 6.3.2) will be applied to all 
stratified analyses, in particular, stratified Miettinen and Nurminen method [Miettinen, O. 
and Nurminen, M. 1985], stratified Cochran-Mantel-Haenszel method, and stratified Cox 
model. In the event that there are small strata, for the purpose of analysis, strata will be 
combined to ensure sufficient number of participants, responses and events in each stratum. 
Details regarding the pooling strategy will be prespecified in the sSAP prior to the database 
lock for the first analysis when each applicable endpoint will be analyzed, and decisions 
regarding the pooling will be based on a blinded review of response and event counts by 
stratum.
The efficacy analyses for ORR, DOR and PFS will include responses and documented 
progression events that occur prior to Second Course treatment.
9.6.3.1
Objective Response Rate
The 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% CI from the stratified 
Miettinen and Nurminen’s method with strata weighting by sample size will be reported. 
Furthermore, the stratified Cochran-Mantel-Haenszel method for ORR ratio will also be used 
for comparison of the ORR between 2 treatment groups. The stratification factors used for 
randomization (see Section 6.3.2) will be applied to the stratified analysis specified above. 
The ratio of ORR and its 95% CI on the logarithmic scale based on the normal approximation 
will be reported as applicable.
9.6.3.2
Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. 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, HR) between 
the treatment arms. The HR and its 95% CI from the stratified Cox model with Efron's 
method of tie handling and with a single treatment covariate will be reported. The 
stratification factors used for randomization (see Section 6.3.2) will be applied to 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. The true date of disease progression will be approximated by the earlier of the 
date of the first assessment at which PD is objectively documented per RECIST 1.1 by BICR 
and the date of death.
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For the primary analysis, any participant who experiences an event (PD or death) 
immediately after 2 or more missed disease assessments will be censored at the last disease 
assessment prior to the missed visits. In addition, any participant who initiates new 
anticancer therapy will be censored at the last disease assessment prior to the initiation of 
new anticancer therapy. Participants who do not start new anticancer therapy and who do not 
experience an event will be censored at the last disease assessment. If a participant meets 
multiple criteria for censoring, the censoring criterion that occurs earliest will be applied. 
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 BICR, an 
additional sensitivity analysis with different sets of censoring rules will be performed. The 
sensitivity analysis follows the intention-to-treat principle. That is, PDs/deaths are counted as 
events regardless of missed study visits or initiation of new anticancer therapy. If a 
participant meets multiple criteria for censoring, the censoring criterion that occurs earliest 
will be applied. The censoring rules for the primary and sensitivity analysis are summarized 
in Table 17.
Table 17
Censoring Rules for Primary and Sensitivity Analysis of PFS
Situation
Primary Analysis
Sensitivity Analysis
PD or death documented after ≤1 
missed disease assessment, and 
before new anticancer therapy, if any
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
Death or progression immediately 
after ≥2 consecutive missed disease 
assessments, or after new anticancer 
therapy
Censored at last disease 
assessment prior to the earlier 
date of ≥2 consecutive 
missed disease assessment 
and new anticancer therapy, 
if any
Progressed at date of 
documented PD or death
No PD and no death; and new 
anticancer treatment is not initiated
Censored at last disease 
assessment 
Censored at last disease 
assessment 
No PD and no death; new anticancer 
treatment is initiated
Censored at last disease 
assessment before new 
anticancer treatment 
Censored at last disease 
assessment
PD=progressive disease; PFS=progression-free survival
9.6.3.3
Overall Survival
The nonparametric Kaplan-Meier method will be used to estimate the survival curves. 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 HR). The HR and its 95% CI from 
the stratified Cox model with a single treatment covariate will be reported. The stratification 
factors used for randomization (see Section 6.3.2) will be applied to the stratified Cox model. 
Participants without documented death at the time of analysis will be censored at the date the 
participant was last known to be alive. 
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9.6.3.4
Duration of Response
If sample size permits, DOR will be summarized descriptively using Kaplan-Meier medians 
and quartiles. Only the subset of participants who show a confirmed complete response or 
partial response will be included in this analysis. Censoring rules for DOR are summarized in 
Table 18. 
For each DOR analysis, a corresponding summary of the reasons responding participants are 
censored will also be provided. Responding participants who are alive, have not progressed, 
have not initiated new anticancer treatment, have not been determined to be lost to follow-up, 
and have had a disease assessment within ~ 5 months of the data cutoff date are considered 
ongoing responders at the time of analysis. If a participant meets multiple criteria for 
censoring, the censoring criterion that occurs earliest will be applied.
Table 18
Censoring Rules for DOR
Situation
Date of Progression or 
Censoring
Outcome
No progression nor death, no 
new anticancer therapy initiated
Last adequate disease 
assessment
Censor
(nonevent)
No progression nor death, new 
anticancer therapy initiated
Last adequate disease 
assessment before new 
anticancer therapy initiated
Censor
(nonevent)
Death or progression 
immediately after ≥2 
consecutive missed disease 
assessments or after new 
anticancer therapy, if any
Earlier date of last adequate 
disease assessment prior to ≥2 
missed adequate disease 
assessments and new anticancer 
therapy, if any
Censor
(nonevent)
Death or progression after ≤1 
missed disease assessments and 
before new anticancer therapy, 
if any
PD or death
End of response
(event)
DOR=duration of response; PD=progressive disease
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
9.6.3.5
Analysis Strategy for Key Efficacy Variables 
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 19.
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Table 19
Analysis Strategy for Key Efficacy Variables 
Endpoint/
Variable
Statistical Method
Analysis 
Population
Missing Data Approach
ORR per 
RECIST 1.1 
by BICR
Estimation: stratified Miettinen 
and Nurminen method, stratified 
CMH method
ITT
Participants with missing data 
are considered nonresponders
PFS per 
RECIST 1.1 
by BICR
Estimation: stratified Cox model 
with Efron’s tie handling method 
ITT
Censored according to rules in 
Table 17
OS
Estimation: stratified Cox model 
with Efron’s tie handling method
ITT
Censored at participant’s last 
known alive date
BICR=blinded independent central review; CMH=Cochran-Mantel-Haenszel; ITT=intent-to-treat; ORR=objective 
response rate; OS=overall survival; PFS=progression-free survival; RECIST 1.1=Response Evaluation Criteria in Solid 
Tumors.
9.6.4
Statistical Methods for Patient-Reported Outcome Analyses 
This section describes the planned analyses for the PRO endpoints.
Change from Baseline
The time point for the change from baseline will be determined based on data review prior to 
the database lock for any PRO analysis and documented in the sSAP. 
To assess the treatment effects on the PRO score change from baseline in the global health 
status/QoL, physical functioning, role functioning, dyspnea, chest pain, and cough, a 
constrained longitudinal data analysis model proposed by Liang and Zeger [Liang, K-Y. and 
Zeger, S. L. 2000]will be applied, with the PRO score as the response variable, and 
treatment, time, the treatment by time interaction, and stratification factors used for 
randomization (see Section 6.3.2) as covariates. The treatment difference in terms of LS 
mean change from baseline will be estimated from this model together with 95% CI. Model-
based LS mean with 95% CI will be provided by treatment group for PRO scores at baseline 
and postbaseline time point. 
9.6.5
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
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 participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables, baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables.
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9.7
Interim Analyses
There are no planned IAs for pharmacokinetics and efficacy endpoints for this study. The 
study plans 1 interim safety analysis.
An eDMC will serve as the primary reviewer of the results of the interim safety analysis of 
the study and will make recommendations for discontinuation of the study or protocol 
modifications to an executive committee of the Sponsor. If the eDMC recommends 
modifications to the design of the protocol or discontinuation of the study, this executive 
committee (and potentially other limited Sponsor personnel) may be unblinded to results at 
the treatment level in order to act on these recommendations. The extent to which individuals 
are unblinded with respect to results will be documented by the unblinded statistician. 
Additional logistical details will be provided in the eDMC Charter. 
Treatment-level results from the interim safety analysis will be provided to the eDMC by the 
unblinded statistician. Prior to final study unblinding, the unblinded statistician will not be 
involved in any discussions regarding modifications to the protocol, statistical methods, 
identification of protocol deviations, or data validation efforts after the interim safety 
analysis.
Although the study is open label, analyses or summaries generated by randomized treatment 
assignment, or actual treatment received, will be limited and documented. In addition, the 
independent radiologist(s) will perform the central imaging review without knowledge of 
treatment group assignment.
9.7.1
Pharmacokinetics Interim Analysis
There is no planned IAs for pharmacokinetics analysis in this study. The analysis planned, 
endpoints evaluated, and driver of timing are summarized in Table 20. 
Table 20
Summary of Analysis Strategy
Key Endpoints 
Timing
Estimated 
Time after 
First 
Participant 
Randomized 
Primary Purpose of 
Analysis
Cycle 1 
AUC0-6 wks, Cycle 3 Ctrough
~A minimum of 27 weeks 
follow-up after last 
participant randomized 
~ 16.2 months
noninferiority of Cycle 
1 
AUC0-6 wks and Cycle 3
Ctrough
AUC0-6 wks=area under the curve from 0-6 weeks; Ctrough=trough concentration; 
By the timing of analysis, ~240 participants with evaluable Cycle 3 model-based Ctrough data are expected, and ~318
participants with evaluable Cycle 1 AUC0-6 wks data are expected. 
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9.7.2
Safety Interim Analysis
The eDMC will be responsible for periodic interim safety reviews as specified in the DMC 
charter. The study plans 1 interim safety analysis, which will be performed approximately 7 
months since first participant is randomized. Details will be specified in the DMC charter.
9.8
Multiplicity
The study uses the graphical method of Maurer and Bretz [Maurer, W., et al 2011] to provide 
strong multiplicity control for multiple hypotheses. According to this approach, study 
hypotheses may be tested more than once, and when a particular null hypothesis is rejected, 
the α allocated to that hypothesis can be reallocated to other hypothesis tests. Figure 7 shows 
the initial 1-sided α allocation for each hypothesis in the ellipse representing the hypothesis. 
The weights for reallocation from each hypothesis to the others are shown in the boxes on the 
lines connecting hypotheses. 
The Type I error rate for testing of the primary endpoints will be strongly controlled at an 
overall α level of 0.05 (1-sided). The initial α assigned to the hypothesis for Cycle 1 AUC0-
6 wks and the hypothesis for Cycle 3 Ctrough will be 0.02 (1-sided) and 0.03 (1-sided) 
respectively. If the hypothesis for Cycle 1 AUC0-6 wks is rejected, the corresponding alpha can 
be reallocated to Cycle 3 Ctrough. If the hypothesis for Cycle 3 Ctrough is rejected, the 
corresponding alpha can be reallocated to Cycle 1 AUC0-6 wks.
Figure 7
Multiplicity Strategy
AUC0-6 wks=area under the curve from 0-6 weeks; Ctrough=trough concentration.
9.8.1
Cycle 1 AUC0-6 wks
The study will test the Cycle 1 AUC0-6 wks noninferiority hypothesis only once. Following the 
multiplicity strategy as outlined in Figure 7, the hypothesis for Cycle 1 AUC0-6 wks may be 
tested at α=0.02 one-sided (initially allocated α) or at α=0.05 one-sided (if the hypothesis for 
Cycle 3 Ctrough is rejected). Table 21 shows the boundary properties for each of these α levels 
for the Cycle 1 AUC0-6 wks analysis. 
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Table 21
Boundaries and Properties for Cycle 1 AUC NI Analysis
Analysis
Value
=0.02
=0.05
n*: 318
Month: 16.2
p (1-sided)a
0.02
0.05
Approximate GMR at boundb
0.87
0.85
P(Cross) if GMR=0.8c
0.02
0.05
P(Cross) if GMR=0.9d
0.82
0.91
P(Cross) if GMR=1.07e
>0.999
>0.999
AUC=area under the curve; GMR=geometric mean ratio; NI=noninferiority; PP=per protocol
The number of participants with evaluable data and timings are estimated approximately.
*n is the number of participants with evaluable Cycle 1 AUC0-6 wks in the PP population.
ap (1-sided) is the nominal α.
bGMR at bound is the approximate GMR required to reach a noninferiority bound.
cP(Cross if GMR=0.8) is the probability of crossing a bound under the null hypothesis.
dP(Cross if GMR=0.9) is the probability of crossing a bound when the true GMR=0.9.
eP(Cross if GMR=1.07) is the probability of crossing a bound when the true GMR=1.07.
Additional assumptions used for the calculation are specified in Section 9.9.
9.8.2
Cycle 3 Ctrough
The study will test the hypothesis for Cycle 3 Ctrough noninferiority only once. Following the 
multiplicity strategy as outlined in Figure 7, the Cycle 3 Ctrough hypothesis may be tested at 
α=0.03 one-sided (initially allocated α) or at α=0.05 one-sided (if the hypothesis for Cycle 1 
AUC0-6 wks is rejected). Table 22 shows the boundary properties for each of these α levels for 
the Cycle 3 Ctrough analysis. 
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Table 22
Boundaries and Properties for Cycle 3 Ctrough NI Analysis
Analysis
Value
=0.03
=0.05
  n*: 240
Month: 16.2
p (1-sided)a
0.03
0.05
Approximate GMR at boundb
0.97
0.95
P(Cross) if GMR=0.8c
0.03
0.05
P(Cross) if GMR=1d
0.63
0.71
P(Cross) if GMR=1.29e
0.998
0.999
Ctrough=trough concentration; GMR=geometric mean ratio; NI=noninferiority; PP=per protocol.
The number of participants with evaluable data and timings are estimated approximately.
*n is the number of participants with evaluable Cycle 3 model-based Ctrough in the PP population.
ap (1-sided) is the nominal α.
bGMR at bound is the approximate GMR required to reach the noninferiority bound.
cP(Cross if GMR=0.8) is the probability of crossing a noninferiority bound under the null hypothesis.
dP(Cross if GMR=1) is the probability of crossing a noninferiority bound when the true GMR=1.
eP(Cross if GMR=1.29) is the probability of crossing a noninferiority bound when the true GMR=1.29.
Additional assumptions used for the calculation are specified in Section 9.9.
9.8.3
Safety Analyses
The DMC has responsibility for assessment of overall risk/benefit. When prompted by safety 
concerns, the DMC can request corresponding PK and/or efficacy data. DMC review of PK
data to assess the overall risk/benefit to study participants will not require a multiplicity 
adjustment. However, to account for any multiplicity concerns raised by the DMC review of 
unplanned PK data prompted by safety concerns, a sensitivity analysis for Cycle 1 AUC0-6 wks
and Cycle 3 Ctrough adopting a conservative multiplicity adjustment will be prespecified in the 
sSAP.
9.9
Sample Size and Power Calculations
The study will randomize approximately 378 participants in a 2:1 ratio into the MK-3475A 
SC and pembrolizumab IV arms. Cycle 1 AUC0-6 wks and Cycle 3 Ctrough are dual primary 
endpoints for the study, with ORR as a secondary endpoint. 
For the Cycle 1 AUC0-6 wks endpoint, based on a target number of 318 evaluable participants 
for Cycle 1 AUC0-6 wks, the study has approximately >99.9% power to reject the null 
hypothesis (Cycle 1 AUC0-6 wks GMR≤0.8) when the true GMR for Cycle 1 AUC0-6 wks is 1.07
at the initially allocated α=0.02 (1 sided).
For the Cycle 3 Ctrough endpoint, based on a target number of 240 evaluable participants for 
model-based Cycle 3 Ctrough, the study has approximately 99.8% power to reject the null 
hypothesis (Cycle 3 Ctrough GMR ≤0.8) when the true GMR for Cycle 3 Ctrough is 1.29 at the 
initially allocated α=0.03 (1 sided).
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The assumptions for the above sample size and power calculations are listed below. The 
assumptions come from PK modeling based on historical pembrolizumab IV data/reference 
PK model and MK-3475A-C18 data for SC (N=81). To ensure robust SC dose selection, 
both mean level and stochastic simulations were performed using PK parameter estimates 
from the combined SC and IV PK model informed by the reference pembrolizumab IV PK 
dataset (including 2993 participants with melanoma or NSCLC, pooled from KEYNOTE-
001, KEYNOTE-002, KEYNOTE-006, KEYNOTE-010, and KEYNOTE-024) and SC PK 
dataset including MK-3475A-C18 and KN-555 Cohort A data for SC. 
•
Log(AUC) and Log(Ctrough) follows a normal distribution for both MK-3475A SC and 
pembrolizumab IV arms, thus the GMR under natural log-scale follows a normal 
distribution.
•
Cycle 1 AUC0-6 wks GMR = 1.07 and Cycle 3 Ctrough GMR = 1.29 under the alternative 
hypothesis. 
•
The standard deviations for log(AUC0-6 wks) at Cycle 1 are 0.313 and 0.371 for IV and 
SC, respectively.
•
The standard deviations for log(Ctrough) at the end of Cycle 3 are 0.741 and 0.737 for IV 
and SC, respectively.
•
Approximately 84% participants among the ITT population will have evaluable Cycle 1 
AUC0-6 wks data. 
•
Approximately 64% participants among the ITT population will have evaluable model-
based Cycle 3 Ctrough data. 
•
The projected enrollment period is approximately 10 months.
ORR is a secondary endpoint for the study. Although ORR will not be formally tested for 
noninferiority, based on the overall sample size of 378 participants in the global study, the 
study can have approximately 89% power to reject the null hypothesis, ie, log(ORR ratio of 
Arm 1 versus Arm 2) ≤50% of -log(ORR ratio of pembrolizumab IV in combination with 
chemotherapy versus chemotherapy), under a true ORR of 51.1% for both arms at an overall 
α level of 0.025 (1 sided) using the synthesis method for noninferiority [U.S. Food and Drug 
Administration 2016]. Details are provided in Appendix 8. 
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Based on the historical data from KEYNOTE-189 and KEYNOTE-407, the power 
calculation for ORR assumes the following:
•
In the current study, the projected prevalence of PDL1 TPS ≥50% is 19% and PDL1 
TPS<50% is 81%.
•
•
•
•
ORR ratio=1 (MK-3475A SC vs pembrolizumab IV) under the alternative hypothesis.
•
The sample size and power calculations were performed using R.
Extension Study in Japan
After the enrollment for the global study has completed, the study will continue to randomize 
participants in a 2:1 ratio into the MK-3475A SC and pembrolizumab IV arms in Japan until 
the sample size for the Japanese participants reaches approximately 39. Participants in Japan 
randomized after completion of enrollment in the global study will not be included in the 
analysis of the global study.
9.10
Subgroup Analyses
Subgroup analysis will not be performed for AUC0-6 wks and Ctrough given that historical data 
from KEYTRUDA® development program has consistently shown that there is no clinically 
relevant impact of covariates on PK. Details about subgroup analyses for ORR will be 
provided in the Japan-specific sSAP.
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
CCI
CCI
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9.12
Extent of Exposure
Extent of exposure for a participant is defined as the number of cycles in which the 
participant receives the study intervention. Summary statistics will be provided on the extent 
of exposure for the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, conducting, analyzing, 
and reporting these trials in compliance with the highest ethical and scientific 
standards. Protection of participants in clinical trials is the overriding concern in the 
design and conduct of clinical trials. In all cases, MSD clinical trials will be 
conducted in compliance with MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP) E6 and 
ICH General Considerations for Clinical Studies E8, and in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD 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 that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
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 MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial and shall respect the data 
protection rights of all participants, trial site staff and, where applicable, third 
parties. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
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proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. All trial protocols are and will be assessed for the 
need and capability to enroll underrepresented groups. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. 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 such as multiplicity.
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MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). 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. MSD 
funding of a trial will be acknowledged in publications.
III.Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations and ICH Guidelines. Changes to the protocol that are required 
urgently to eliminate an immediate hazard and to protect participant safety may be 
enacted in anticipation of ethics committee approval. MSD will inform regulatory 
authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants 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.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. Participants may 
withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on medical record review and medical evaluation 
to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD 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.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the 
trial protocol, and in signing the protocol, agree to support these ethical and scientific 
standards.
10.1.2
Financial Disclosure
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 
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financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, 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 study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
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By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules,
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7) and 
recommend to the EOC whether the study 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 study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.4.2
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
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If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, https://euclinicaltrials.eu, or other local registries. MSD, as 
Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. MSD entries are not limited to FDAAA or the EMA clinical trials 
Regulation 536/2014 mandated trials. Information posted will allow participants to identify 
potentially appropriate studies for their disease conditions and pursue participation by calling 
a central contact number for further information on appropriate study locations and study-site 
contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials Regulation 536/2014, or other locally mandated registries 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
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Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study 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 or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
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completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 23 will be performed by the local laboratory.
•
All on-treatment samples will be collected before administration of study intervention.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
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Table 23
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCVa
MCHa
%Reticulocytesa
WBC count with 
Differentialb:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN or ureac
Potassium
AST/SGOT
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is above 
the ULN)
Albumin
Carbon dioxide 
(CO2 or 
bicarbonate)a
Chloride
Phosphorousa
Creatinined
Sodium
ALT/SGPT
Total Protein
Glucose 
(nonfasting)
Calcium
Alkaline phosphatase
Lactate 
dehydrogenase
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterasea by dipstick
•
Microscopic examinationa (if blood or protein is abnormal)
Pregnancy 
Testing
•
Highly sensitive serum or urine hCG pregnancy test (as needed for POCBP)
Other Screening 
Tests
•
FSH (as needed in PONCBP only)
•
Serology (HIV antibody, HBsAg, and hepatitis C virus antibody) as required by local 
health authority or institutional regulations
•
Coagulation factors (PT or INR, and aPTT/PTT). Additional testing to be conducted 
as clinically indicated for participants taking anticoagulation therapy.
•
Thyroid function tests (T3 (or Free T3), Total T4 (or FT4), TSH) Total T4 and T3 
preferred over FT4 and FT3.   
ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase;
BUN=blood urea nitrogen; FSH=follicle-stimulating hormone; FT4=free thyroxine; hCG=human chorionic 
gonadotropin; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; POCBP=participant of 
childbearing potential; PONCBP=participant of nonchildbearing potential; RBC=red blood cell; PT=prothrombin time; 
PTT=partial thromboplastin time; SGOT=serum glutamic oxaloacetic transaminase; SGPT=serum glutamic pyruvic 
transaminase; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; ULN=upper limit of normal.
Notes:
a
Performed only if considered the local standard of care.
b
Absolute or % acceptable per institutional standard.
c
BUN is preferred; if not available, urea may be tested.
d
Measured or calculated creatinine clearance. Creatinine clearance should be calculated per the Cockcroft-Gault 
formula.
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The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Refer to Appendix 7 for country-specific requirements.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not a reportable event. Refer to Section 8.4.6 for additional details.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing 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 preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study).
•
Is associated with an overdose.
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10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
- 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.
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Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE 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 product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
- Exposure: Is there evidence that the participant was actually exposed to the study 
intervention 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 study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with IMP)?
- 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.
- Dechallenge: Was the study intervention 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 study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention(s) 
is/are only used 1 time.)
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- Rechallenge: Was the participant re-exposed to the study intervention 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 study is a single-dose drug study; or (3) study 
intervention(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF RE-
EXPOSURE TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention 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 their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
- Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence 
of the AE onset relative to the administration of the study intervention is 
reasonable. The AE is more likely explained by the study intervention than by 
another cause.
- No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the 
AE onset relative to administration of the study intervention is not reasonable 
OR the AE is more likely explained by another cause than the study 
intervention. (Also entered for a participant with overdose without an associated 
AE.)
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•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, 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 AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
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•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Participants of Childbearing Potential (POCBP)
A participant assigned female sex at birth is considered fertile and capable of becoming 
pregnant following menarche and until becoming postmenopausal unless permanently sterile 
(see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, not considered POCBP:
•
Premenarchal
•
Premenopausal with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in participants assigned female sex at birth who are not 
using hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with two FSH measurements in the postmenopausal 
range is required.
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- Participants assigned female sex at birth who are on HRT and whose menopausal 
status is in doubt will be required to use one of the non-hormonal highly effective 
contraception methods if they wish to continue their HRT during the study. 
Otherwise, they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment.
10.5.2
Contraceptive Requirements
Contraceptives allowed during the study include:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implanta
•
IUSb
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
All sexual partner(s) of the POCBP must be azoospermic. The participant must provide verbal 
confirmation of partner azoospermia during Medical History. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from penile-vaginal
intercourse with partner(s) capable of producing sperm during the entire period of risk associated with the 
study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the duration of 
the study and the preferred and usual lifestyle of the participant.
a
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
b
IUS is a progestin releasing IUD.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is
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 study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
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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 Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the 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 study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study 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 Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
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9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants 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 Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
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 emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Argentina
Section 1.3 Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
10.7.2
China
Biomarker sample collection, testing, and analysis as described in the following sections will 
be dependent on approval by the Human Genetic Resources Administration of China for 
participants enrolled in China:
•
Section 1.3: Schedule of Activities
•
Section 4.2.1.6: Planned Exploratory Biomarker Research
•
Section 5: Inclusion Criteria, Exclusion Criteria
•
Section 8.8: Biomarkers
Future biomedical research will not be conducted in China.
Section 4.1 Overall Design 
After enrollment of the global study is complete, the study may remain open to enrollment in 
China until the target number of participants in China has been enrolled to meet local 
requirements. 
Section 6.1 Study Intervention(s) Administered
All study interventions will be administered on an outpatient basis. However, hospitalization 
is acceptable if it is standard procedure for the local site.
Section 8.6.1 Blood Collection for Pembrolizumab and MK-5180 Pharmacokinetics and
Section 8.6.2 Blood Collection for Antidrug Antibodies
PK and ADA sample collection for MK-5180 will not be reduced or discontinued.
Appendix 2 Clinical Laboratory Tests
Routine Urinalysis by dipstick: a urine leukocyte count by microscopy is acceptable when 
the leukocyte esterase by dipstick cannot be performed.
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10.7.3
Czech Republic
Section 1.3 Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
Section 6.5 Concomitant Therapy
In addition to all restrictions or concomitant medications listed in Section 6.5, specific 
concomitant therapies or vaccinations noted below are prohibited during the study:
•
Live vaccines must not be administered within 30 days prior to the first dose of study 
intervention, while participating in the study, and for 90 days after the last dose of study 
intervention. 
10.7.4
France
Section 1.3 Schedule of Activities
An audiogram will be performed at screening and at the beginning of each cycle.
Section 5.2 Exclusion Criteria
Participants with a hearing impairment.
Section 8.3 Safety Assessments
An audiogram will be performed at screening and at the beginning of each cycle. If any 
hearing issues arise, an additional audiogram will be performed.
10.7.5
Italy
Section 1.3 Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
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10.7.6
Japan
Section 1.3 Schedule of Activities
•
For the assistance to early diagnosis of pneumonitis/interstitial lung disease in study 
participants, the following items, such as SpO2, CRP, KL-6, and SP-D, will be measured 
in this study. These items should be measured as follows:
-
SpO2 at the timing of vital sign assessment.
-
CRP, KL-6, and SP-D at screening*, predose on Day 1 of every cycle, EOT, and the 
Safety Follow-up Visit (30 days after last dose).
*Should be measured at the timing of clinical laboratory tests (such as 
hematology/chemistry).
If pneumonitis/ILD occurs, regardless of causality with study intervention, an independent 
ILD evaluation committee will conduct adjudication of cases of the pneumonitis/ILD. For 
this purpose, relevant data, such as chest imaging (from the baseline to the recovery of 
pneumonitis/ILD) will be submitted to MSD K.K.
Section 9 Statistical Analysis Plan
A Japan sSAP will be prepared separately to address Japan-specific study objectives to meet 
the local regulatory requirements.
10.7.7
Romania
Section 1.3 Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
10.7.8
South Africa
Section 1.3 Schedule of Activities
HIV testing at screening is mandatory.
Testing for active tuberculosis is required at screening and every 6 months during treatment 
as mandated by local regulation.
10.7.9
United Kingdom
Section 5.1 Inclusion Criteria - Demographics 
Participants assigned male sex at birth are to be advised to seek counseling on sperm storage 
before starting treatment with pemetrexed and/or platinum-based therapy as per respective 
SmPCs.
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Section 6.5 Concomitant Therapy 
Listed below are specific concomitant therapies or vaccinations that are prohibited during the 
study (exceptions noted):
•
Live vaccines must not be administered for 90 days after the last dose of study 
intervention. Refer to Section 6.5 for information on COVID-19 vaccines.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated 
just as any other concomitant therapy.
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10.8
CCI
CCI
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CCI
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
ADA
antidrug antibodies
ADL
Activities of daily living
AE
adverse event 
AEOSI
adverse event of special interest
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
APaT
All-Participants-as-Treated
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-3wks
area under the curve from 0 to 3 weeks
AUC0-6wks
area under the curve from 0 to 6 weeks
BICR
blinded independent central review
bid
twice a day
C
Cycle
Cavg
average concentration
CBC
complete blood count
CFR
Code of Federal Regulations
CHO
Chinese hamster ovary
CI
confidence interval
CL
clearance
Cmax
maximum concentration
Cmin
minimum concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
COVID-19
Coronavirus disease caused by severe acute respiratory syndrome 
coronavirus 2
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Abbreviation
Expanded Term
CR
complete response 
CrCl
creatinine clearance
CRF
Case Report Form 
CRP
c-reactive protein
CSFs
Colony Stimulating Factors
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
ctDNA
circulating tumor deoxyribonucleic acid
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
Ctrough
trough concentration
CV
coefficient variation
DILI
drug-induced liver injury
DL
dose level
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
duration of response
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
EEA
European Economic Area
EGFR
epidermal growth factor receptor
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
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Abbreviation
Expanded Term
EOC
Executive Oversight Committee 
EORTC
European Organisation for Research and Treatment of Cancer
EORTC QLQ-
C30
European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire C30
EOT
End-of-Treatment
ePROs
electronic patient-reported outcomes
EQ-5D-5L
EuroQol 5-dimension, 5-level Questionnaire
E-R
exposure-response 
EU
European Union 
FA
final analysis
FAS
Full Analysis Set
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed, paraffin embedded
FIH
first in human
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice 
G-CSF
Granulocyte colony-stimulating factor
GM
geometric mean
GMR
geometric mean ratio
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HGRAC
Human Genetic Resources Administration of China
HIV
human immunodeficiency virus
HR
hazard ratio
HRQoL
health-related quality of life
HRT
hormone replacement therapy
IA(s)
interim analysis(ses)
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Abbreviation
Expanded Term
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
iCRO
imaging CRO
ICU
intensive care unit
IEC
Independent Ethics Committee
IgG4
immunoglobulin G4
IHC
immunohistochemistry
IL-10
Interleukin 10
ILD
interstitial lung disease
IM
intramuscular
IMP
investigational medicinal product
IND
Investigational New Drug 
INR
international normalized ratio
IO
immune-oncology
irAE
immune-related AE
IRB
Institutional Review Board
IRT
interactive response technology
ITT
Intent-to-Treat
IUD
intrauterine device
IUO
internal use only
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
KRAS
KRAS proto-oncogene
LAM
lactational amenorrhea method
LLN
lower limit of normal
LPLV
Last Patient, Last Visit
LS
least square
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Abbreviation
Expanded Term
mAb
monoclonal antibody
MAP
Modeling and Simulation Analysis Plan
MASCC
Multinational Association of Supportive Care in Cancer
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
NCI
National Cancer Institute
NI
noninferiority
NSCLC
Non-small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PD
progressive disease
PD-1
programmed cell death 1 protein
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic
po
oral
POCBP
participant/participants of childbearing potential
PONCBP
participant/participants of nonchildbearing potential
PP
per-protocol
PQC
product quality complaint
PR
partial response
PRO
patient-reported outcome
PT
prothrombin time
PTT
partial thromboplastin time
Q2W
every 2 weeks
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Abbreviation
Expanded Term
Q3W
every 3 weeks
Q6W
every 6 weeks
QoL
quality of life
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria In Solid Tumors
rHuPH20
recombinant human hyaluronidase
RNA
ribonucleic acid
ROS1
c-ros oncogene 1
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SC
subcutaneous(ly)
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SIM
Site Imaging Manual
SLAB
Supplemental laboratory test(s)
SNP
single nucleotide polymorphism
SoA
schedule of activities
SOP
Standard Operating Procedures
SP-D
surfactant protein D
SpO2
saturation of peripheral oxygen
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
t1/2
half life
T3
triiodothyronine
T4
thyroxine
TEA
Treatment Eligibility Assessment (form)
TPS
tumor proportion score
TSH
thyroid stimulating hormone
TTD
time to true deterioration
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Abbreviation
Expanded Term
ULN
upper limit of normal
US
United States
VAS
Visual Analog Scale
VS
vital signs
WBC
white blood cell
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11
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