A Randomized, Phase 3, Open-label Study to Investigate the Pharmacokinetics and Safety of Subcutaneous Pembrolizumab Versus Intravenous Pembrolizumab, Administered With Platinum Doublet Chemotherapy, in the First-Line Treatment of Participants With Metastatic Squamous or Nonsquamous Non-Small-Cell Lung Cancer
Phase: PHASE3
Conditions: Non-Small Cell Lung Cancer
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Randomized, Phase 3, Open-label Study to Investigate the
Pharmacokinetics and Safety of Subcutaneous Pembrolizumab 
versus Intravenous Pembrolizumab, Administered with 
Platinum Doublet Chemotherapy, in the First-Line Treatment of 
Participants with Metastatic Squamous or Nonsquamous Non-
Small-Cell Lung Cancer
NCT04956692
12-JULY-2023
12- July-2023

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Title Page
THIS PROTOCOL AMENDMENT 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 Randomized, Phase 3, Open-label Study to Investigate the 
Pharmacokinetics and Safety of Subcutaneous Pembrolizumab versus Intravenous 
Pembrolizumab, Administered with Platinum Doublet Chemotherapy, in the First-Line 
Treatment of Participants with Metastatic Squamous or Nonsquamous Non-Small-Cell Lung 
Cancer
Protocol Number: A86-07
Compound Number: MK-3475
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
147059
EudraCT
2020-002729-27
Approval Date: 12 July 2023
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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 07
12-JUL-2023
To remove Tertiary/Exploratory objective that includes pharmacoeconomic substudy 
(Time and Motion study) and the corresponding endpoint as it is no longer needed and 
to add an option of IV pembrolizumab in the Second Course of the study available to 
participants randomized to the SC treatment arm.
Amendment 05
21-JUL-2022
Amendment 04
31-MAR-2022
To correct a typographical error in the inclusion criterion for adequate renal function.
Amendment 03
03-MAR-2022
Update the 
 Ctrough primary endpoint from an observed endpoint to a model-
based endpoint and to further clarify the PP population definitions and requirements.
Amendment 02 
(Country-specific for 
Japan)
15-JUL-2021
Updates made to Section 10.7.5 (Japan-specific appendix) inclusion criteria to clarify 
breastfeeding eligibility and clarify ICF requirement for participants under 20 years of 
age.
Amendment 01 
26-MAY-2021
Changes made in response to FDA feedback to update Section 6.6.2.2 Table 4, Dose 
Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab, to add guidance for injection reactions related to SC pembrolizumab. 
Given that this study is looking at both SC and IV pembrolizumab, safety information 
about administration reactions in this table is required for both the IV infusion and SC 
injection.
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Document
Date of Issue
Overall Rationale
Original Protocol
26-MAR-2021
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 07
Overall Rationale for the Amendments:
To remove Tertiary/Exploratory objective that includes pharmacoeconomic substudy (Time and Motion study) and the corresponding 
endpoint as it is no longer needed and to add an option of IV pembrolizumab in the Second Course of the study available to 
participants randomized to the SC treatment arm.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
3 Hypotheses, Objectives, 
and Endpoints
4.2.1.5 Pharmacoeconomic 
Endpoints
Tertiary/Exploratory objective that 
includes pharmacoeconomic substudy
(Time and Motion study) and the 
corresponding endpoint and 
Section 4.2.1.5 have been removed.
It is no longer needed.
1.3.4 Second Course 
Retreatment Phase
4.1 Overall Design
6.6.3 Second Course
Text added to allow IV pembrolizumab 
option for SC treatment arm patients 
during the Second Course.
To provide an option of IV pembrolizumab in the 
Second Course to participants randomized to the SC 
treatment arm.
Throughout 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...............................................5
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................20
1.3
Schedule of Activities...........................................................................................21
1.3.1
Screening and Intervention Phase................................................................21
.......................................29
.......................................30
.......................................34
2
INTRODUCTION..........................................................................................................39
2.1
Study Rationale....................................................................................................39
2.2
Background ..........................................................................................................39
2.2.1
Key Benefits of Subcutaneous Versus Intravenous Formulation ................39
2.2.2
Pembrolizumab ............................................................................................39
2.2.3
Non-Small-Cell Lung Cancer ......................................................................40
2.2.4
Subcutaneous Formulation...........................................................................42
2.2.5
Pharmaceutical and Therapeutic Background .............................................43
2.2.6
Preclinical and Clinical Studies ...................................................................44
2.2.7
Ongoing Clinical Studies.............................................................................44
2.2.8
Information on Other Study-related Therapy ..............................................44
2.3
Benefit/Risk Assessment......................................................................................44
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................45
4
STUDY DESIGN............................................................................................................47
4.1
Overall Design......................................................................................................47
4.2
Scientific Rationale for Study Design.................................................................49
4.2.1
Rationale for Endpoints ...............................................................................50
4.2.1.1
Pharmacokinetic Endpoints ...............................................................50
4.2.1.2
Safety Endpoints................................................................................51
4.2.1.3
Efficacy Endpoints.............................................................................51
4.2.1.3.1
RECIST 1.1..............................................................................51
4.2.1.4
Patient-reported Outcomes.................................................................52
4.2.1.4.1
EORTC QLQ-C30 ...................................................................52
4.2.1.4.2
EQ-5D-5L ................................................................................52
4.2.1.5
Antidrug Antibodies...........................................................................52
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....................................52
....................................54
4.2.2
Rationale for the Use of Comparator...........................................................54
4.3
Justification for Dose...........................................................................................55
4.3.1
Justification of Pembrolizumab IV Dose.....................................................55
4.3.2
Justification of Pembrolizumab SC Dose ....................................................56
4.3.3
Justification of Chemotherapy Dose............................................................57
4.4
Beginning and End-of-Study Definition ............................................................57
4.4.1
Clinical Criteria for Early Study Termination .............................................57
5
STUDY POPULATION ................................................................................................58
5.1
Inclusion Criteria.................................................................................................58
5.2
Exclusion Criteria................................................................................................61
5.3
Lifestyle Considerations......................................................................................64
5.3.1
Meals and Dietary Restrictions....................................................................64
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................64
5.3.3
Activity Restrictions ....................................................................................64
5.4
Screen Failures.....................................................................................................64
5.5
Participant Replacement Strategy......................................................................64
6
STUDY INTERVENTION............................................................................................65
6.1
Study Intervention(s) Administered...................................................................65
6.1.1
Medical Devices...........................................................................................68
6.2
Preparation/Handling/Storage/Accountability .................................................68
6.2.1
Dose Preparation..........................................................................................68
6.2.2
Handling, Storage, and Accountability........................................................68
6.3
Measures to Minimize Bias: Randomization and Blinding..............................69
6.3.1
Intervention Assignment..............................................................................69
...................................................................................69
...................................................................................69
6.4
Study Intervention Compliance..........................................................................69
6.5
Concomitant Therapy..........................................................................................69
6.5.1
Rescue Medications and Supportive Care ...................................................71
6.5.1.1
Pembrolizumab ..................................................................................71
6.5.1.2
Chemotherapy....................................................................................71
6.6
Pembrolizumab Courses, Immune-Related Events and Dose Modification ..72
6.6.1
Intervention Phase or First Course...............................................................72
6.6.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................72
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6.6.2.1
Dose Modification and Toxicity Management for Immune-related 
AEs Associated with Pembrolizumab................................................72
6.6.2.2
Dose Modification and Toxicity Management of 
Infusion/Injection Reactions Related to Pembrolizumab ..................77
6.6.2.3
Other Allowed Dose Interruption for Pembrolizumab ......................78
6.6.3
Second Course .............................................................................................78
6.6.4
Dose Modifications for Chemotherapy........................................................79
6.7
Intervention After the End of the Study............................................................86
6.8
Clinical Supplies Disclosure................................................................................86
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................86
7.1
Discontinuation of Study Intervention...............................................................86
7.2
Participant Withdrawal From the Study...........................................................87
7.3
Lost to Follow-up .................................................................................................88
7.4
Potential Early Discontinuation of Study Due to Futility ................................88
8
STUDY ASSESSMENTS AND PROCEDURES........................................................88
8.1
Administrative and General Procedures ...........................................................89
8.1.1
Informed Consent.........................................................................................89
8.1.1.1
General Informed Consent.................................................................89
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................90
8.1.2
Inclusion/Exclusion Criteria ........................................................................90
8.1.3
Participant Identification Card.....................................................................90
8.1.4
Medical History ...........................................................................................90
8.1.4.1
Non-small Cell Lung Cancer History ................................................91
8.1.5
Prior and Concomitant Medications Review...............................................91
8.1.5.1
Prior Medications...............................................................................91
8.1.5.2
Concomitant Medications..................................................................91
8.1.5.3
Subsequent Antineoplastic Therapy ..................................................91
8.1.6
Assignment of Screening Number...............................................................91
8.1.7
Assignment of Treatment/Randomization Number.....................................91
8.1.8
Study Intervention Administration ..............................................................92
8.1.8.1
Timing of Dose Administration.........................................................92
8.1.8.1.1
Pembrolizumab IV and SC ......................................................92
8.1.8.1.2
Chemotherapy..........................................................................93
8.1.8.1.2.1
Carboplatin (AUC 6 [Squamous] or AUC 5 
[Nonsquamous]).............................................................93
8.1.8.1.2.2
Paclitaxel or Nab-paclitaxel (Squamous).......................94
8.1.8.1.2.3
Pemetrexed (Nonsquamous)..........................................94
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8.1.8.1.2.4
Cisplatin (Nonsquamous)...............................................94
8.1.8.1.3
Antiemetic Therapy .................................................................95
8.1.9
Discontinuation and Withdrawal .................................................................95
8.1.9.1
Withdrawal From Future Biomedical Research ................................95
8.1.10
Participant Blinding/Unblinding..................................................................95
8.1.11
Domiciling ...................................................................................................95
8.1.12
Calibration of Equipment.............................................................................96
8.1.13
Tumor Tissue for Biomarker Status.............................................................96
8.2
Efficacy Assessments ...........................................................................................96
8.2.1
Tumor Imaging and Assessment of Disease................................................96
8.2.1.1
Initial Tumor Imaging........................................................................97
8.2.1.2
Tumor Imaging During the Study......................................................97
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging............................98
8.2.1.4
Second Course (Retreatment) Tumor Imaging..................................99
8.2.1.5
RECIST 1.1 Assessment of Disease..................................................99
8.2.2
Patient-reported Outcomes.........................................................................101
8.3
Safety Assessments.............................................................................................101
8.3.1
Physical Examinations...............................................................................102
8.3.1.1
Complete Physical Examination......................................................102
8.3.1.2
Directed Physical Examination........................................................102
8.3.2
Vital Signs..................................................................................................103
8.3.3
Electrocardiograms ....................................................................................103
8.3.4
Eastern Cooperative Oncology Group Performance Status.......................103
8.3.5
Clinical Safety Laboratory Assessments ...................................................104
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)........................................................................................104
8.3.6
Pregnancy Testing......................................................................................104
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................105
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................105
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....108
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.108
8.4.4
Regulatory Reporting Requirements for SAE ...........................................108
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................108
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................109
8.4.7
Events of Clinical Interest..........................................................................109
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8.4.8
Medical Device and Drug-device Combination Products/Combination 
Medicinal Product - PQCs/Malfunctions...................................................110
8.5
Treatment of Overdose......................................................................................110
8.6
Pharmacokinetics...............................................................................................110
8.6.1
Blood Collection for PK ............................................................................110
8.6.2
Blood Collection for Antidrug Antibodies ................................................110
8.7
Pharmacodynamics............................................................................................111
8.8
Biomarkers .........................................................................................................111
8.8.1
Planned Genetic Analysis Sample Collection............................................111
8.9
Future Biomedical Research Sample Collection.............................................111
8.10
.....................................111
8.11
Visit Requirements.............................................................................................112
8.11.1
Screening....................................................................................................112
8.11.2
Treatment Period (Intervention Phase)......................................................112
8.11.2.1
Optional Home Health Visits for PK Sampling...............................113
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ..............................................................................113
8.11.4
Post-Treatment (Post-Intervention) Visit...................................................113
8.11.4.1
Safety Follow-up Visits ...................................................................113
8.11.4.2
Efficacy Follow-up Visits................................................................114
8.11.4.3
Survival Follow-up Assessments.....................................................114
8.11.5
Vital Status.................................................................................................114
9
STATISTICAL ANALYSIS PLAN ...........................................................................115
9.1
Statistical Analysis Plan Summary...................................................................115
9.2
Responsibility for Analyses/In-house Blinding ...............................................117
9.3
Hypotheses/Estimation ......................................................................................117
9.4
Analysis Endpoints.............................................................................................117
9.4.1
Pharmacokinetics Endpoints......................................................................117
9.4.2
Safety Endpoints........................................................................................118
9.4.3
Efficacy Endpoints.....................................................................................118
9.4.4
Immunogenicity Endpoint .........................................................................119
9.4.5
PRO Endpoints...........................................................................................119
9.5
Analysis Populations..........................................................................................119
9.5.1
Pharmacokinetics Analysis Populations ....................................................119
9.5.2
Safety Analysis Populations ......................................................................120
9.5.3
Efficacy Analysis Populations...................................................................121
9.5.4
PRO Analysis Populations.........................................................................121
9.6
Statistical Methods.............................................................................................121
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9.6.1
Statistical Methods for Pharmacokinetics Analyses..................................121
9.6.2
Statistical Methods for Safety Analyses ....................................................122
9.6.3
Statistical Methods for Efficacy Analyses.................................................123
9.6.3.1
Objective Response Rate .................................................................124
9.6.3.2
Progression-free Survival.................................................................124
9.6.3.3
Overall Survival...............................................................................125
9.6.3.4
Duration of Response.......................................................................126
9.6.3.5
Analysis Strategy for Key Efficacy Variables.................................126
9.6.4
Statistical Methods for Patient-Reported Outcome Analyses....................127
9.6.5
Demographic and Baseline Characteristics ...............................................127
9.7
Interim Analysis.................................................................................................128
9.7.1
Pharmacokinetics Interim Analysis ...........................................................128
9.7.2
Safety Interim Analysis..............................................................................129
.........................................................................................................129
.130
.131
9.9
Sample Size and Power Calculations ...............................................................132
9.10
Subgroup Analyses.............................................................................................134
9.11
Compliance (Medication Adherence)...............................................................134
9.12
Extent of Exposure.............................................................................................134
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................135
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......135
10.1.1
Code of Conduct for Clinical Trials...........................................................135
10.1.2
Financial Disclosure...................................................................................137
10.1.3
Data Protection...........................................................................................137
10.1.3.1
Confidentiality of Data ....................................................................138
10.1.3.2
Confidentiality of Participant Records.............................................138
10.1.3.3
Confidentiality of IRB/IEC Information..........................................138
10.1.4
Committees Structure.................................................................................139
10.1.4.1
External Data Monitoring Committee .............................................139
10.1.4.2
Executive Oversight Committee......................................................139
10.1.5
Publication Policy......................................................................................139
10.1.6
Compliance with Study Registration and Results Posting Requirements .139
10.1.7
Compliance with Law, Audit, and Debarment ..........................................140
10.1.8
Data Quality Assurance .............................................................................141
10.1.9
Source Documents .....................................................................................141
10.1.10
Study and Site Closure...............................................................................142
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10.2
Appendix 2: Clinical Laboratory Tests............................................................143
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................145
10.3.1
Definition of AE ........................................................................................145
10.3.2
Definition of SAE ......................................................................................146
10.3.3
Additional Events Reported in the Same Manner as SAE.........................147
10.3.4
Recording AE and SAE .............................................................................148
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................151
10.4
Appendix 4: Medical Device, Drug-Device Combination 
Product/Combination Medicinal Product: Definitions, Collection, and 
Documentation ...................................................................................................153
10.5
Appendix 5: Contraceptive Guidance..............................................................156
10.5.1
Definitions..................................................................................................156
10.5.2
Contraception Requirements......................................................................157
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................158
10.7
Appendix 7: Country-specific Requirements..................................................162
10.7.1
Brazil..........................................................................................................162
10.7.2
Colombia....................................................................................................162
10.7.3
France.........................................................................................................162
10.7.4
Guatemala ..................................................................................................163
10.7.5
Japan ..........................................................................................................164
10.7.6
Peru ............................................................................................................165
10.7.7
Romania.....................................................................................................166
10.7.8
South Africa...............................................................................................166
10.7.9
Spain ..........................................................................................................167
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................169
10.9
Appendix 9: Other Medical Device: Complaints Including Product 
Quality Complaints/Malfunction, Serious Injury, Death, Fetal 
Distress/Fetal Death and Congenital Anomaly: Definitions and Reporting 170
10.10 Appendix 10: Eastern Cooperative Oncology Group.....................................171
10.11 Appendix 11: Abbreviations .............................................................................172
............................175
11
REFERENCES.............................................................................................................178
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values .................................................61
Table 2
Study Interventions..........................................................................................66
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...............................................................73
Table 4
Pembrolizumab Infusion/Injection Reaction Dose Modification and 
Treatment Guidelines.......................................................................................77
Table 5
Dose-level Modifications for Chemotherapeutic Agents ................................83
Table 6
Recommended Chemotherapy Dose Modifications for Hematological 
Toxicity............................................................................................................84
Table 7
Recommended Chemotherapy Dose Modifications for Nonhematological 
Toxicity............................................................................................................85
Table 8
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events...............................................................................107
Table 9
Analysis Strategy for Safety Parameters........................................................123
Table 10
......................125
Table 11
..............................................................................126
Table 12
Analysis Strategy for Key Efficacy Variables...............................................127
Table 13
.........................................129
Table 14
.............................130
Table 15
Boundaries and Properties for Ctrough Analyses .............................................131
Table 16
Protocol-required Safety Laboratory Assessments........................................143
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LIST OF FIGURES
Figure 1
....20
Figure 2
....43
Figure 3
Study Intervention Decision Making Process When Progression per 
RECIST 1.1 is Observed by Investigator.......................................................101
Figure 4
......................................................................................130
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Randomized, Phase 3, Open-label Study to Investigate the 
Pharmacokinetics and Safety of Subcutaneous Pembrolizumab versus Intravenous 
Pembrolizumab, Administered with Platinum Doublet Chemotherapy, in the First-Line 
Treatment of Participants with Metastatic Squamous or Nonsquamous Non-Small-Cell Lung 
Cancer
Short Title: Phase 3 study of pembrolizumab SC versus pembrolizumab IV, administered 
with platinum doublet chemotherapy, in 1L metastatic squamous or nonsquamous NSCLC 
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
In males and females with treatment-naïve metastatic squamous or nonsquamous non-small-
cell lung cancer who will be receiving chemotherapy:
Primary Objectives
Primary Endpoints
•
Objective: To compare AUC between 
pembrolizumab SC vs pembrolizumab 
IV.
•
Hypothesis: Pembrolizumab SC is non-
inferior to pembrolizumab IV for 
 
.
•
•
Objective: To compare Ctrough between 
pembrolizumab SC vs pembrolizumab 
IV.
•
Hypothesis: Pembrolizumab SC is non-
inferior to pembrolizumab IV for 
•
Secondary Objectives
Secondary Endpoints
•
Objective: To evaluate pembrolizumab 
SC and pembrolizumab IV with respect 
to ORR per RECIST 1.1 as assessed by 
blinded independent central review 
(BICR).
•
OR: CR or PR
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Secondary Objectives
Secondary Endpoints
•
Objective: To evaluate exposure of 
pembrolizumab SC compared to 
pembrolizumab IV.
•
•
•
Objective: To evaluate the safety and 
tolerability of pembrolizumab SC 
compared to pembrolizumab IV.
•
AE
•
Study intervention discontinuation due 
to AEs
•
Objective: To evaluate pembrolizumab 
SC and pembrolizumab IV with respect 
to 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
•
Objective: To evaluate pembrolizumab 
SC and pembrolizumab IV with respect 
to OS.
•
OS: the time from randomization to 
death due to any cause
•
Objective: To evaluate pembrolizumab 
SC and pembrolizumab IV with respect 
to DOR per RECIST 1.1 as assessed by 
BICR.
•
DOR: the time from first response (CR 
or PR) to subsequent disease 
progression or death from any cause, 
whichever occurs first
•
Objective: To evaluate the development 
of ADAs following administration of 
pembrolizumab SC compared to 
pembrolizumab IV.
•
Anti-pembrolizumab antibody levels
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
First-line treatment of metastatic squamous or 
nonsquamous NSCLC with pembrolizumab SC 
administered with platinum doublet chemotherapy
Population
Adult patients with treatment-naïve metastatic squamous 
or nonsquamous NSCLC 
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active control
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.
Number of Participants:
Approximately 512 participants will be randomized.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Regimen/ 
Treatment 
Period/ 
Vaccination 
Regimen
Use
Arm A
Pembro-
lizumab SC
SC
Test Product
Arm B
Pembro-
lizumab IV
Arms A and B
(Squamous 
Histology)
Paclitaxel
200 mg/m2
IV
Background 
Treatment
Arms A and B
(Squamous 
Histology)
Nab-
paclitaxel
100 mg/m2
IV
Background 
Treatment
Arms A and B 
(Squamous and
Non-squamous 
Histology)
Carboplatin
Squamous:
AUC 
6 mg/mL/min
Non-
squamous: 
AUC 
5 mg/mL/min
IV
Background 
Treatment
Arms A and B
(Non-squamous 
Histology)
Cisplatin
75 mg/m2
IV
Background 
Treatment
Arms A and B
(Non-squamous 
Histology)
Pemetrexed
500 mg/m2
IV
Until 
progression, 
intolerable AE, 
participant or 
physician 
decision
Background 
Treatment
Abbreviations: AUC = area under curve; IV=intravenous; 
 SC=subcutaneous.
Total 
Number of 
Intervention 
Groups/
Arms
2
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Duration of 
Participation
Each participant will participate in the study for approximately 4 years 
from the time the participant provides documented informed consent 
through the final contact. 
After a screening phase of up to 28 days, each participant will be assigned 
to receive study intervention until one of the conditions for discontinuation 
of study intervention is met.
Participants who complete study intervention after receiving
 
 
After the end of treatment, each participant will be followed for the 
occurrence of adverse events and spontaneously reported pregnancy as 
described under Section 8.4.
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.
All participants will be followed for overall survival until death, withdrawal 
of consent, or the end of the study.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 11.
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1.2
Schema
The study design is depicted in Figure 1.
Abbreviations: AE = adverse event; ALK = Anaplastic lymphoma kinase; ECOG = Eastern Cooperative 
Oncology Group; EGFR = epidermal growth factor receptor; IV = intravenous; NSCLC = non-small cell lung 
cancer; PD-L1 TPS = programmed cell death ligand 1 tumor proportion score; 
 
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1.3
Schedule of Activities
1.3.1
Screening and Intervention Phase
Study Period
Screening 
Phase
Intervention Phase 
Notes
Schedule 
Window
± 1 day for Cycles 1-7; ±3 days for Cycle 8 onward
Administrative Procedures
Informed 
Consent
X
If the investigator plans to treat beyond 
the initial radiologic disease progression 
per RECIST 1.1, additional consent will 
be required prior to post-progression 
intervention (see Section General 
Informed Consent).
Informed 
Consent for 
FBR
X
This is optional for the participant. 
Participants can still participate in the 
study if they decline to provide the FBR 
ICF.
Inclusion/
Exclusion 
Criteria
X
Participant 
Identification 
Card
X
X
The Participant Identification Card 
should be updated with the randomization 
number at the time of randomization. 
Demographics 
and Medical 
History
X
Prior/ 
Concomitant 
Medication
Prior medications: Record medications 
taken within 28 days prior to first dose 
and medications regularly administered at 
intervals greater than 28 days prior to 
first dose. Concomitant medications: 
Record new medications started during 
the study through the postintervention 
follow-up, as well as any changes to 
dose, frequency, and route that occur.  
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Study Period
Screening 
Phase
Intervention Phase 
Notes
Schedule 
Window
± 1 day for Cycles 1-7; ±3 days for Cycle 8 onward
NSCLC 
Disease Details 
and Prior 
Treatment
X
Randomization
X
Randomization can occur up to 3 days 
prior to C1D1 (study drug 
administration).
Vital Status
See Section Vital Status for full details.
Upon Sponsor request, participants may 
be contacted for vital status at any time 
during the study.
Clinical Procedures/Assessments
AE/SAE 
Review
AEs: Report all AEs occurring from the 
start of study intervention through 30 
days after the last dose of study 
intervention. SAEs: Report all SAEs from 
the start of study intervention through 90 
days after the last dose of study 
intervention, or 30 days following the last 
dose of study intervention if the 
participant initiates new anticancer 
therapy, whichever occurs first.
Complete 
Physical 
Examination, 
Height
X
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Study Period
Screening 
Phase
Intervention Phase 
Notes
Window
± 1 day for Cycles 1-7; ±3 days for Cycle 8 onward
Weight
Taken prior to intervention 
administration.
Vital Signs 
To be measured at screening and prior to 
dosing study intervention.
12-lead ECG
X
Additional ECGs performed as clinically 
indicated.
ECOG 
Performance 
Status
ECOG performance status will be 
evaluated within 7 days prior to 
randomization, as well as before 
administration of study intervention in 
each cycle.
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Study Period
Screening 
Phase
Intervention Phase 
Notes
Schedule 
Window
± 1 day for Cycles 1-7; ±3 days for Cycle 8 onward
Laboratory Procedures/Assessments: Analysis Performed by Local Laboratory
Pregnancy 
Testing
X
X
A WOCBP must have a negative highly 
sensitive pregnancy test (as required by 
local regulations) within 24 hours for 
urine or within 72 hours for serum before 
the first dose of study intervention.
Serum test is required if urine test is 
positive or not evaluable.
Pregnancy testing (urine or serum as 
required by local regulations or as 
clinically indicated) should be conducted 
at every cycle during intervention.
PT or INR and 
aPTT/PTT
X
PT or INR and aPTT/PTT should be 
monitored more closely in participants 
receiving anticoagulant therapy during 
intervention and safety Follow-up Phase.
HBV, HCV, 
and HIV 
Testing
X
Testing at Screening only required if 
mandated by local health authority or 
institutional guidelines. Refer to 
Appendix 7, for country-specific 
requirements.
Urinalysis
X
Screening samples to be collected within 
10 days prior to the first dose of study 
intervention. 
Hematology 
and Chemistry
X
X
X*
X*
X
X*
X*
X
X*
X*
X
X*
X*
X
X
Screening samples to be collected within 
10 days prior to the first dose of study 
intervention. On treatment samples to be 
collected and reviewed prior to 
administration of study intervention, 
which can be conducted within 72 hours 
prior to the first dose of study 
intervention in each cycle.
*Predose ANC and platelet count are 
required on Days 8 and 15 of Cycles 1-4 
only for participants receiving nab-
paclitaxel.
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Study Period
Screening 
Phase
Intervention Phase 
Notes
Schedule 
Window
± 1 day for Cycles 1-7; ±3 days for Cycle 8 onward
Tumor Tissue Collection
Archival or 
Newly 
Obtained 
Tissue 
Collection for 
PD-L1 IHC 
and Other 
Biomarkers
X
A new incisional or core biopsy will be 
required if archival tissue is not available. 
PD-L1 IHC will be mandatory to stratify 
participants prior to randomization. 
The biopsy will also be utilized for 
EGFR, ALK, and ROS1 testing prior to 
randomization if this testing was not 
already completed locally.
Efficacy Measurements
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Study Period
Screening 
Phase
Intervention Phase 
Notes
Schedule 
Window
± 1 day for Cycles 1-7; ±3 days for Cycle 8 onward
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Study Period
Screening 
Phase
Intervention Phase 
Notes
Schedule 
Window
± 1 day for Cycles 1-7; ±3 days for Cycle 8 onward
Patient-reported Outcomes (PRO)
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Study Period
End of 
Intervention
Post-Intervention Visits
Notes
Visit Title
Discontin-
uation
Safety FU
Efficacy FU 
Survival FU
Schedule Window
At Tx DC
30 Days After 
Last Dose (If DC
visit occurs ≥30 
days from last dose 
of Tx, a Safety FU
visit is not 
required)
Follow-up 
imaging to 
maintain same 
schedule as 
while on 
treatment
Q12W 30 Days Post 
Discon (±14 days)
Patient-reported Outcomes (PRO)
EORTC QLQ-C30
X
X
PROs are completed at the intervention discontinuation 
visit and 30-day safety follow-up visit. 
Perform ePROs in the following order listed: EORTC 
QLQ-C30 followed by EQ-5D-5L.
EQ-5D-5L
X
X
AE=adverse event; ADA=Antidrug Antibodies; BICR=Blinded independent central review; CrCl=creatinine clearance; CT=computed tomography; ctDNA=circulating tumor deoxyribonucleic acid; 
DC/Discon=discontinuation; DNA=deoxyribonucleic acid; ECOG=Eastern Cooperative Oncology Group; EORTC QLQ-C30=European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire-Cancer 30; ePRO=electronic patient-reported outcome; EQ-5D-5L=EuroQol 5-dimension, 5-level Questionnaire; FT4= free thyroxine; FU=follow-up; IV=intravenous; 
MRI=magnetic resonance imaging; NSCLC=non-small cell lung cancer; PD=progressive disease; PD-L1=programmed cell death ligand 1; PK=pharmacokinetics; PRO=patient-reported outcome; 
QXW=every X weeks; SAE=serious adverse event; SC=subcutaneous; T3/FT3= free or total triiodothyronine; TSH= thyroid-stimulating hormone; Tx=treatment. 
Note: See Appendix 7 for country-specific requirements.
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2
INTRODUCTION
This clinical study will evaluate pembrolizumab SC as first-line therapy in the treatment of 
metastatic squamous and nonsquamous NSCLC by assessing the PK, safety, and efficacy of 
pembrolizumab when administered as an SC injection 
 in combination with standard-of-
care chemotherapy.
2.1
Study Rationale
Pembrolizumab is currently indicated for a number of tumor types including both squamous 
and nonsquamous NSCLC as monotherapy and in combination with chemotherapy. Adult 
patients are currently to be treated with pembrolizumab at an IV dose of 200 mg every 3 
weeks (Q3W). However, there is high demand for SC formulations, with over 80% of 
patients preferring SC to IV administration [Rummel, M., et al 2017] [Pivot, X., et al 2013]. 
A SC formulation of pembrolizumab has been developed for use as an alternative to the IV 
formulation of pembrolizumab.
 
 
Benefits of SC administration include time savings for patients and providers, convenience, 
reduced administration costs, ease of administration, and reduced health care resource 
burden. Additionally, a SC dosing option will reduce patient chair time, thus making it 
feasible for infusion centers to treat more patients.
2.2
Background
2.2.1
Key Benefits of Subcutaneous Versus Intravenous Formulation
Confirmed benefits of SC administration include improved patient convenience and reduced 
use of hospital resources and health care professionals. In a 2013 Lancet manuscript 
describing an open-label randomized study of the preference for SC or IV administration of 
trastuzumab in patients with HER2-positive early breast cancer, 216 of 236 participants 
preferred SC administration to IV administration [Pivot, X., et al 2013]. The 2 main reasons 
participants gave for preferring SC administration were time savings (195 of
216 participants) and less pain and discomfort (88 of 216 participants). Most of participants 
reported their overall preference for SC administration as “very strong” (67.4%; 95% CI: 
61.0% to 73.3% SC versus 3.4%; 95% CI: 1.5% to 6.6% IV). Health care professionals were 
also more satisfied with SC administration (73.8%; 76 of 103 SC versus 1.9%; 2 of 103 IV); 
the remaining 25 (24.3%) health care professionals expressed no preference for route of 
administration. Similar results were reported in a 2017 manuscript describing the preference 
for SC or IV administration of rituximab among patients with CD20+ diffuse large B-cell 
lymphoma or follicular lymphoma [Rummel, M., et al 2017].
2.2.2
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. 
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Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. KEYTRUDA® (pembrolizumab) is 
indicated for the treatment of patients across a number of indications. For more details on 
specific indications refer to the IB.
2.2.3
Non-Small-Cell Lung Cancer
Lung cancer is the most common malignancy in the world, with an estimated incidence in 
2018 of 2.1 million and an associated 1.8 million deaths [Bray, F., et al 2018]. Among males, 
the estimated incidence rates of new diagnoses are highest in Central and Eastern Europe 
(49.3 per 100,000/year) and Eastern Asia (47.2), while the incidence rates among females are 
highest in Northern America (30.7), Northern Europe (26.9), Western Europe (25.7), and 
Micronesia/Polynesia (24.3) [Bray, F., et al 2018]. Mortality from lung cancer is the leading 
cause of cancer death in men and the second leading cause in women [Bray, F., et al 2018]. 
In the US in 2020, there were an estimated 229,000 new cases and 136,000 deaths from lung 
cancer [National Cancer Institute 2020].
Non-small-cell lung cancer represents approximately 80% to 85% of all lung cancers 
[American Cancer Society 2019] and consists of 2 major types: nonsquamous carcinoma 
(~65% to 70% of cases) and squamous carcinoma (~30% to 35% of cases) [Mok, T. S. K., et 
al 2019] [Reck, M., et al 2020] [Hellmann, M. D., et al 2018]. At the time of diagnosis, 79% 
of patients with lung cancer have locally advanced or metastatic disease that is not amenable 
to surgical resection [National Cancer Institute 2019]. Of those patients diagnosed with early-
stage NSCLC and treated with surgery, a significant percentage subsequently develop distant 
recurrence [Pisters, K. M. W. and Le Chevalier, T. 2005]. These factors contribute to the 
dismal 5 year relative survival rates of 23% in patients diagnosed with NSCLC, and a mere 
6% in those with advanced/metastatic disease [American Cancer Society 2019].
Importantly, in nonsquamous NSCLC, molecular profiling and availability of targeted 
therapy have helped change the treatment approach for a subset of patients. The EGFR 
tyrosine kinase inhibitors gefitinib, erlotinib, and afatinib have showed marked superiority 
over chemotherapy in patients with activating EGFR mutations; and osimertinib in front line 
has shown improved outcomes over earlier generations of EGFR tyrosine kinase inhibitors. 
Similarly, multiple ALK inhibitors, including crizotinib, ceritinib, alectinib, and brigantinib 
have shown significant activity in ALK-rearranged NSCLC and have received regulatory 
approval for use. Interestingly, the ALK inhibitors are also active in a rare subgroup of ROS-
1-rearranged NSCLC patients; and crizotinib and entrectinib have received regulatory 
approval in ROS-1-rearranged lung cancers. Data have shown poorer outcomes in patients 
with tumors harboring a targetable mutation that are not treated with a tyrosine kinase 
inhibitor [Kris, M. G., et al 2014]. In contrast, no targeted therapy has been approved for 
maintenance therapy in squamous cell NSCLC. While squamous cell lung cancers harbor 
putative oncogenic drivers, these have little clinical relevance and cannot be targeted.
Immunotherapy, in particular pembrolizumab as monotherapy or in combination with 
chemotherapy, has changed the treatment paradigm for those patients with NSCLC. In the 
Phase 3 study, KEYNOTE-024, pembrolizumab showed statistically significant increases in 
OS and PFS compared with platinum-based chemotherapy for treatment-naïve participants 
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with metastatic NSCLC whose tumors expressed high levels of PD-L1 (TPS ≥50%) with no 
EGFR or ALK genomic tumor aberrations, leading to regulatory approval for this indication 
in the US and other countries around the world. Approximately 23% to 28% of patients with 
newly diagnosed, advanced NSCLC highly express PD-L1 to a TPS ≥50% [Reck, M., et al 
2016]. With the findings from KEYNOTE-042, the TPS cutoff has been lowered, as 
pembrolizumab monotherapy significantly improved OS for participants with NSCLC who 
had TPS ≥1% (16.7 months vs 12.1 months; HR: 0.81), compared with chemotherapy alone, 
while continuing to show an OS benefit in those with TPS ≥50% (20.0 months versus 12.2 
months; HR: 0.69). Thus, both KEYNOTE-024 and KEYNOTE-042 showed that 
pembrolizumab monotherapy is effective in participants with PD-L1 positive metastatic 
NSCLC. 
To further expand on the efficacy of pembrolizumab, KEYNOTE-407, KEYNOTE-021 
Cohort G, and KEYNOTE-189 were designed to combine the agent with chemotherapy in 
participants with metastatic NSCLC, as chemotherapy has been shown to augment the 
antitumor immune response. 
•
KEYNOTE-407 is a Phase 3 study that randomized 559 participants with newly 
diagnosed metastatic squamous NSCLC to pembrolizumab with carboplatin and a taxane 
(paclitaxel or nab-paclitaxel) versus carboplatin and a taxane (paclitaxel or nab-
paclitaxel) [Paz-Ares, L., et al 2018]. The study showed a clinically meaningful and 
statistically significant improvement in OS for participants in the pembrolizumab 
combination arm (median OS of 15.9 months versus 11.3 months; HR: 0.64 [95% CI: 
0.49-0.85, p=0.008]), compared with chemotherapy alone. Similarly, there was 
significant PFS benefit for participants in the pembrolizumab combination arm (median 
PFS of 6.4 months versus 4.8 months; HR: 0.56 [95% CI: 0.45-0.70, p<0.0001]), 
compared with chemotherapy alone. ORR also was significantly improved in the 
pembrolizumab combination arm (58.4%) compared with chemotherapy alone (35%), p = 
0.0004. Importantly all subgroups benefited from pembrolizumab in combination with 
carboplatin and taxane-based chemotherapy, including participants whose tumors did not 
express PD-L1; therefore, extending the benefit of pembrolizumab to those with PD-L1 
negative tumors.
•
KEYNOTE-021 (Cohort G) is a Phase 2 study that randomized 123 participants to 
pembrolizumab with pemetrexed and carboplatin versus pemetrexed with carboplatin in 
participants with metastatic nonsquamous NSCLC in whom there were no EGFR or ALK 
genomic tumor aberrations who had not previously received systemic therapy for their 
advanced disease. The study met its primary endpoint of improvement in ORR, as well as 
the key secondary endpoint of PFS [Borghaei, H., et al 2017], leading to FDA accelerated 
approval of pembrolizumab in combination with pemetrexed/carboplatin. In an updated 
analysis, the following were noted: improvement in ORR was 24.8% (95% CI: 7.2 to 
40.9) with 56.7% for the pembrolizumab with chemotherapy arm and 31.7% for the 
control; PFS HR 0.54 (95% CI: 0.33 to 0.88) with median PFS 19.0 versus 8.9 months, 
for the pembrolizumab with chemotherapy arm compared with the control, respectively; 
and OS HR 0.59 (95% CI: 0.34 to 1.05) with median OS not reached in the 
pembrolizumab combination arm and 20.9 months in the control [Borghaei, H., et al 
2017].
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•
KEYNOTE-189 is a global, multicenter, placebo-controlled trial that randomized 
616 participants with untreated Stage IV nonsquamous NSCLC in a 2:1 fashion to 
receive pemetrexed and investigator’s choice of either carboplatin or cisplatin in 
combination with pembrolizumab or saline placebo for 4 cycles, followed by 
pembrolizumab or saline for a total of 35 cycles, plus pemetrexed maintenance therapy. 
Participants in the saline placebo arm had the option to cross over to pembrolizumab 
monotherapy if progressive disease had been verified by BICR and other safety criteria 
were met. The study showed a clinically meaningful and statistically significant 
improvement in OS with an HR of 0.56 (95% CI: 0.45 to 0.70) and a median OS of 22.0 
months in the pembrolizumab combination arm compared with 10.7 months in the 
chemotherapy alone arm [Gadgeel, S., et al 2020]. Similarly, there was significant PFS 
benefit with an HR of 0.48 (95% CI: 0.40 to 0.58) with a median PFS of 9.0 months and 
4.9 months in the pembrolizumab combination arm vs. chemotherapy alone arm, 
respectively. ORR also was significantly improved in the pembrolizumab combination 
arm (48.0%) compared with chemotherapy alone (19.4%). Importantly, all subgroups 
benefited from pembrolizumab in combination with pemetrexed and carboplatin or
cisplatin, including participants whose tumors did not express PD-L1; therefore, 
extending the benefit of pembrolizumab to those with PD-L1 negative tumors.
2.2.4
Subcutaneous Formulation
KEYNOTE-555 was designed to estimate the relative bioavailability of an SC versus an IV 
dose of pembrolizumab, and to characterize the PK profile of pembrolizumab administered 
SC. Participants in the study were limited to those with a diagnosis of advanced melanoma, 
and the crossover design was chosen to eliminate effects of interindividual variability 
inherent in a parallel-group design. The relative bioavailability of 2 different SC formulations 
of pembrolizumab 
was estimated in this study 
using the SC dose 
 of pembrolizumab 
compared with the IV dose of pembrolizumab (200 mg).
 
 
 Participants then 
received an IV infusion of 200 mg pembrolizumab 
 
Additionally,
 
 
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2.2.5
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
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The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an IgV–type domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 
and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70, 
which are involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, 
J. M., et al 2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which 
PD-1 down-modulates T-cell responses is similar to, but distinct from, that of CTLA-4, 
because both molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 
2005] [Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an 
attractive target for therapeutic intervention in metastatic squamous NSCLC and 
nonsquamous NSCLC.
2.2.6
Preclinical and Clinical Studies
For a summary of preclinical and clinical study data for pembrolizumab, refer to the IB.
2.2.7
Ongoing Clinical Studies
For a summary of ongoing clinical study data for pembrolizumab, refer to the IB.
2.2.8
Information on Other Study-related Therapy
As described above, pembrolizumab in combination with carboplatin and paclitaxel or nab-
paclitaxel has become the standard of care in patients with metastatic squamous NSCLC due 
to the positive results of the randomized Phase 3 study, KEYNOTE-407. Similarly, with the 
results of KEYNOTE-189, the standard of care 1L therapy for patients with treatment naïve 
metastatic nonsquamous NSCLC is pembrolizumab in combination with pemetrexed and 
cisplatin or carboplatin.
Based on safety and efficacy data from these combination studies with pembrolizumab, the 
current study will use pembrolizumab in combination with carboplatin plus paclitaxel or nab-
paclitaxel OR pembrolizumab in combination with platinum (cisplatin/carboplatin) plus 
pemetrexed at approved doses.
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.
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
In males and females with treatment-naïve metastatic squamous or nonsquamous non-small-
cell lung cancer who will be receiving chemotherapy:
Objectives
Endpoints
Primary
•
Objective: To compare AUC between 
pembrolizumab SC vs pembrolizumab 
IV.
•
Hypothesis: Pembrolizumab SC is non-
inferior to pembrolizumab IV for 
 
.
•
•
Objective: To compare Ctrough between 
pembrolizumab SC vs pembrolizumab 
IV.
•
Hypothesis: Pembrolizumab SC is non-
inferior to pembrolizumab IV for 
•
Secondary
•
Objective: To evaluate pembrolizumab 
SC and pembrolizumab IV with respect 
to ORR per RECIST 1.1 as assessed by 
blinded independent central review 
(BICR).
•
OR: CR or PR
•
Objective: To evaluate exposure of 
pembrolizumab SC compared to 
pembrolizumab IV.
•
•
•
Objective: To evaluate the safety and 
tolerability of pembrolizumab SC 
compared to pembrolizumab IV.
•
AE
•
Study intervention discontinuation due 
to AEs
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Objectives
Endpoints
•
Objective: To evaluate pembrolizumab 
SC and pembrolizumab IV with respect 
to 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
•
Objective: To evaluate pembrolizumab 
SC and pembrolizumab IV with respect 
to OS.
•
OS: the time from randomization to 
death due to any cause
•
Objective: To evaluate pembrolizumab 
SC and pembrolizumab IV with respect 
to DOR per RECIST 1.1 as assessed by 
BICR.
•
DOR: the time from first response (CR 
or PR) to subsequent disease 
progression or death from any cause, 
whichever occurs first
•
Objective: To evaluate the development 
of ADAs following administration of 
pembrolizumab SC compared to 
pembrolizumab IV.
•
Anti-pembrolizumab antibody levels
Tertiary/Exploratory
•
Objective: To evaluate the change from 
baseline in HRQoL following treatment 
with pembrolizumab SC or 
pembrolizumab IV.
•
Score change from baseline at 
predefined time point evaluated by 
EORTC QLQ-C30 in the following 
items:
- Global health status/QoL 
(C30/Items 29 and 30)
- Physical functioning 
(C30/Items 1 through 5)
- role functioning (C30/Items 6 and 7)
•
Objective: To evaluate health status 
using the EQ-5D-5L.
•
Change from baseline per predefined 
time point of EQ-5D-5L VAS score
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Objectives
Endpoints
•
•
4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, randomized, active-controlled, parallel-group, multisite, open-label study 
of pembrolizumab SC administered with platinum doublet chemotherapy (Arm A) versus 
pembrolizumab IV administered with platinum doublet chemotherapy (Arm B) in 
512 participants with metastatic squamous or nonsquamous NSCLC. Participants must have 
newly diagnosed, untreated Stage IV NSCLC, an ECOG PS of 0 to 1, and no current 
pneumonitis or interstitial lung disease at enrollment.
After providing the informed consent, candidate participants will be screened against all of 
the eligibility criteria. Eligible participants will be randomly assigned to study intervention 
arm in a 
 (Arm A to Arm B). 
•
Arm A – Participants will receive up to 
 of 
 pembrolizumab SC 
 
administered with platinum doublet chemotherapy
•
Arm B – Participants will receive up to 35 cycles of 200 mg pembrolizumab IV Q3W 
administered with platinum doublet chemotherapy 
•
Platinum Doublet Chemotherapy:
-
Participants with squamous NSCLC will receive 4 cycles of carboplatin in 
combination with a taxane, investigator’s choice (paclitaxel/nab-paclitaxel). 
-
Participants with nonsquamous NSCLC will receive 4 cycles of pemetrexed with a 
platinum, investigator’s choice (cisplatin/carboplatin), followed by pemetrexed 
maintenance until progression, an intolerable AE, or discontinuation by participant or 
physician decision.
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Randomization will be performed to avoid bias in the assignment of participants to study 
intervention, to increase the likelihood that known and unknown participant attributes are 
balanced across intervention arms, and to ensure the validity of statistical comparisons 
between intervention arms. 
 
 
 
One interim analysis and one final analysis are planned for this study. Details regarding the 
interim analysis are provided in Section 9.7. An external DMC will serve as the primary 
reviewer of the treatment-level results and will make recommendations for discontinuation of 
the study or modification to the study to an EOC of the Sponsor (Section 10.1.4). The eDMC 
responsibilities and review schedules will be outlined in the eDMC charter.
A decision to stop the trial early due to futility will be based on the eDMC recommendations 
with review by the Sponsor EOC after IA 1. If a decision is made to stop the trial, all 
participants that have already been randomized and are receiving pembrolizumab treatment, 
SC or IV, will be given the option to continue on IV pembrolizumab. Enrollment will 
continue during the period of the futility analysis.
The primary objectives of the study are to compare 
 
 pembrolizumab SC versus pembrolizumab IV, administered with platinum 
doublet chemotherapy. Non-inferiority will be evaluated with the non-inferiority margin of 
0.8. 
Efficacy will be evaluated by ORR, DOR, and PFS per RECIST 1.1 as determined by BICR, 
and OS. On-study imaging assessments will be performed as described in Section 1.3. 
RECIST 1.1 (Section 4.2.1.3.1) will be used by the site for therapy decisions for both arms 
until verification of the initial site-assessed PD by BICR. Participants may not crossover to 
the other intervention arm.
Adverse event monitoring will be ongoing throughout the study and graded in severity 
according to the guidelines outlined in the NCI CTCAE v5.0 (Section 8.4). Adverse events 
will be reported by the investigator or delegate from the start of study intervention through 
30 days after cessation of study intervention. Serious AEs will be reported by the investigator 
or delegate from the start of intervention through either 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.
Health related quality of life and patient health utilities will be estimated using EORTC-
QLQ-C30 and EQ-5D-5L questionnaires. 
In addition, blood/tissue for identification of molecular biomarkers (genomic, metabolic, 
and/or proteomic) that may be indicative of clinical response/resistance, safety, and/or the 
mechanism of action of pembrolizumab will be collected at regular intervals (see 
Section 4.2.1.7).
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Tumor imaging showing site-assessed PD will be submitted for verification by BICR. 
Treatment beyond centrally verified PD per RECIST 1.1 may be permitted at the discretion 
of the investigator after consulting the Sponsor and receiving documented informed consent 
addendum from the participant.
Participants who discontinue treatment for reasons other than centrally verified progressive 
disease will have Efficacy Follow-up for disease status (including imaging) until progressive 
disease, initiating a new anticancer therapy, withdrawing consent for study participation, or 
becoming lost to follow up. After documented progressive disease, each participant will be 
contacted by telephone approximately every 12 weeks (84 ±14 days) for survival until 
withdrawal of consent to participate in the study, becoming lost to follow-up, death, or end of 
the study, whichever occurs first.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
In multiple countries, pembrolizumab in combination with standard chemotherapy is 
indicated for the 1L treatment of patients with metastatic squamous or nonsquamous 
NSCLC. Further improvements can be made for patients to receive intervention by SC 
injection as an alternative to IV infusion. The results of this study will determine the 
similarity in exposure of pembrolizumab administered SC compared with pembrolizumab 
administered IV, as well as determine the safety of pembrolizumab SC in participants with 
advanced NSCLC. 
There are several known potential factors that may influence outcomes in Study 
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Scagliotti, G. V., et al 2008] 
[Paz-Ares, L., et al 2018] [Gandhi, L., et al 2018]. Tumor expression of PD-L1 has been 
identified as a biomarker associated with clinical benefit for participants with NSCLC treated 
with pembrolizumab. 
 
 
 
 
 
4.2.1
Rationale for Endpoints
4.2.1.1
Pharmacokinetic Endpoints
Dual primary endpoints: 
•
•
Secondary endpoints:
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4.2.1.2
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs; and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version 5.0.
4.2.1.3
Efficacy Endpoints
Secondary endpoints will include ORR, DOR, and PFS per RECIST 1.1 as assessed by BICR 
and OS. These endpoints 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 and by 
the local site when determining eligibility (see Section 8.2.1.5). Although traditional 
RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, this protocol 
has implemented a modification to RECIST 1.1 to allow a maximum of 10 target lesions in 
total and 5 per organ. 
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4.2.1.4
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. As part of the 
analyses for this study, HRQoL and disease-related symptoms will be investigated among all 
participants 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.
4.2.1.4.1
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 
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 tertiary
objectives.
4.2.1.4.2
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, selfcare, 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].
4.2.1.5
Antidrug Antibodies
Formation of pembrolizumab ADA can potentially confound drug exposures at therapeutic 
doses and prime for subsequent toxicities. The presence of ADAs will be determined for 
participants at time points outlined in the SoA in Section 1.3 to understand drug exposure and 
immunogenicity. Incidence of ADAs and neutralizing ADAs will be evaluated over time.
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Proteomics and IHC using blood or tumor
4.2.2
Rationale for the Use of Comparator
All participants will be receiving pembrolizumab, administered with platinum doublet 
chemotherapy based on histology. 
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The use of the active comparator pembrolizumab IV ensures that participants receive the 
current approved formulation in the control arm. In this study, the PK of pembrolizumab SC 
will be compared versus pembrolizumab IV.
In order to reduce patient and site burden, the different routes of administration, SC versus 
IV, will not be masked and therefore the study will be unblinded open-label.
4.3
Justification for Dose
4.3.1
Justification of Pembrolizumab IV Dose
The planned dose of pembrolizumab for this study is 200 mg Q3W. 
Based on the totality of data generated in the Keytruda development program, 200 mg Q3W 
is an appropriate dose of pembrolizumab for adults across all indications. As outlined below, 
this dose is justified by:
•
Clinical data from 8 randomized studies in melanoma and NSCLC indications
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg Q2W representing an approximate 5- to 7.5-fold exposure range (refer to IB, 
Section 5.2.2)
•
Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W 
•
Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications
•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W
 
 Among the 8 randomized dose-comparison studies, a total of 
2262 participants were enrolled with melanoma and NSCLC, covering different disease 
settings (treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different 
treatment settings (monotherapy and in combination with chemotherapy). Five studies 
compared 2 mg/kg Q3W versus 10 mg/kg Q3W (KN001 Cohort B2, KN001 Cohort D, 
KN002, KN010, and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg 
Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of these studies demonstrated 
flat dose- and exposure-response relationships across the doses studied representing an 
approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W 
provided similar responses to the highest doses studied. Subsequently, flat dose-exposure-
response relationships were also observed in other tumor types including head and neck 
cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg 
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Q3W as the appropriate dose independent of the tumor type. These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune 
cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating TMDD conclusively demonstrated saturation of PD-1 in systemic 
circulation at doses much lower than 200 mg Q3W. Second, a PBPK analysis was conducted 
to predict tumor PD-1 saturation over a wide range of tumor penetration and PD-1 
expression. This evaluation concluded that pembrolizumab at 200 mg Q3W achieves full PD-
1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
4.3.2
Justification of Pembrolizumab SC Dose
The planned dose of pembrolizumab SC for this study is 
. Based on data from 
KEYNOTE-555 Cohort A, the bioavailability of pembrolizumab SC is estimated at 
 
To ensure robust SC dose selection, both mean level and stochastic simulations (considering 
variability) were performed using PK parameter estimates from the combined SC and IV PK 
model, which was 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 from 
KEYNOTE-555 Cohort A. Pembrolizumab PK was simulated for SC doses ranging from 
 
 using estimates of typical values of PK parameters, covariate 
effects, between-participant variability and residual error. 
 
 
 
 
 
 
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4.3.3
Justification of Chemotherapy Dose
The chemotherapy treatments used in this study are well-established regimens for squamous 
(carboplatin with paclitaxel or nab-paclitaxel) or nonsquamous (pemetrexed and carboplatin 
or cisplatin) NSCLC, as described above. See Section 6.1 for information on the order in 
which study interventions should be administered.
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 (ie, the 
participant is unable to be contacted by the investigator).
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
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/clinical endpoints 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 due to insufficient compliance with the protocol, GCP, and/or 
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other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Male and female participants with metastatic squamous or nonsquamous NSCLC will be 
enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible for the study only if all of the following criteria are met:
Type of Participant and Disease Characteristics
1. Has pathologically (histologically or cytologically) confirmed diagnosis of squamous or 
nonsquamous NSCLC.
2. Has Stage IV (T any, N any, M1a, M1b, or M1c - American Joint Committee on Cancer 
8th Edition) squamous or nonsquamous NSCLC.
3. Has confirmation that EGFR, ALK, or ROS1-directed therapy is not indicated 
(documentation of absence of tumor-activating EGFR mutations AND absence of ALK 
and ROS1 gene rearrangements, OR presence of a KRAS mutation) in nonsquamous 
NSCLC as well as mixed nonsquamous/squamous NSCLC. Participants with purely 
squamous NSCLC do not require testing.
4. Has not received prior systemic treatment for their metastatic NSCLC. Participants who 
received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy 
was completed at least 12 months prior to the development of metastatic disease.
Demographics
5. Participants are at least 18 years of age at the time of providing informed consent.
6. Has an ECOG PS of 0 or 1 (as assessed within 7 days prior to randomization, see 
Appendix 10).
Male Participants
Contraceptive use by men 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 is more stringent than the requirements 
above, the local label requirements are to be followed. 
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7. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 95 days from the last dose of chemotherapy:
•
Refrain from donating sperm
PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent
OR
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
Female Participants
Contraceptive use by women 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 is more stringent than the 
requirements above, the local label requirements are to be followed.
See Section 10.7.5 for Japan-specific requirements.
8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Is not a WOCBP
OR
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, or be abstinent from heterosexual 
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 180 days 
after the last dose of chemotherapy or 120 days after the last dose of pembrolizumab, 
whichever occurs last, and agrees not to donate eggs (ova, oocytes) to others or 
freeze/store for her own use for the purpose of reproduction during this same time period
after the last dose of study intervention. The investigator should evaluate the potential for 
contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the 
first dose of study intervention. 
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•
A WOCBP must have a negative highly sensitive pregnancy test (as required by local 
regulations) within 24 hours for urine or within 72 hours for serum before the first dose 
of study intervention. If a urine test is positive or not evaluable, a serum test will be 
required.
•
Abstains from breastfeeding during the study intervention period and for at least 120 days 
after the last dose of study intervention.
•
Additional requirements for pregnancy testing during and after study intervention are in
Section 8.3.6.
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Refer to Appendix 7 for country-specific requirements.
Informed Consent
9. The participant (or legally acceptable representative) provides documented informed 
consent/assent for the study. The participant may also provide consent/assent for future 
biomedical research. However, the participant may participate in the main study without 
participating in future biomedical research.
Additional Categories
10. Has measurable disease per RECIST 1.1 as assessed by the local site 
investigator/radiology. Lesions situated in a previously irradiated area are considered 
measurable if progression has been shown in such lesions.
11. Submit an archival tumor tissue sample or newly obtained core or incisional biopsy of a 
tumor lesion not previously irradiated for PD-L1 status determination prior to 
randomization. FFPE tissue blocks are preferred to slides. Biopsies obtained prior to 
receipt of adjuvant/neoadjuvant chemotherapy will be permitted if recent biopsy is not 
feasible. Details pertaining to tumor tissue submission can be found in the
 
12. Has adequate organ function as detailed in Table 1. Specimens must be collected within 
10 days prior to the start of study intervention.
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Table 1
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
(GFR can also be used in place of CrCl)
≥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 Creatinine clearance (CrCl) should be calculated per the Cockcroft-Gault formula. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a 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.
2. Has known central nervous system (ie, brain and/or spinal cord) metastases and/or
carcinomatous meningitis. Participants with treated brain metastases (eg, whole brain 
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radiation treatment [WBRT], stereotactic radiosurgery, or equivalent) may participate 
only if they satisfy all of the following:
•
Have no evidence of new or enlarging brain metastases confirmed by post-treatment 
repeat brain imaging (using the same modality) performed at least 4 weeks after pre-
treatment brain imaging, and
•
Are neurologically stable without the need for steroids for at least 14 days before first 
dose of trial treatment as per local site assessment.
3. Has severe hypersensitivity (≥Grade 3) to study intervention and/or any of its excipients 
(refer to the IB and/or approved product label(s) for a list of excipients). 
4. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed.
5. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease. Lymphangitic spread of the 
NSCLC is not exclusionary.
6. Has an active infection, requiring systemic therapy.
7. Has a known history of HIV infection. No HIV testing is required unless mandated by 
local health authority.
8. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active 
Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority.
9. Has a history or current evidence of any condition, therapy, or laboratory abnormality, or 
other circumstance that might confound the results of the study, 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. 
10. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
11. Has symptomatic ascites or pleural effusion. A participant who is clinically stable after 
treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
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12. Before the first dose of study intervention:
•
Has received prior systemic cytotoxic chemotherapy for metastatic NSCLC.
•
Has received antineoplastic biological therapy (eg, erlotinib, crizotinib, cetuximab) 
for metastatic NSCLC.
•
Has had major surgery (<3 weeks prior to first dose).
•
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or 
with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, 
CTLA-4, OX 40, CD137).
13. Received radiation therapy to the lung that is >30 Gray within 6 months of the first dose 
of study intervention.
14. Is expected to require any other form of antineoplastic therapy while on study.
Pemetrexed-Specific Concomitant Therapy 
15. Is unable to interrupt aspirin or other NSAIDs, other than an aspirin dose ≤1.3 g/day, for 
a 5-day period (8-day period for long-acting agents, such as piroxicam).
16. Is unable or unwilling to take folic acid or vitamin B12 supplementation.
Prior/Concomitant Therapy
17. Has received prior radiotherapy within 2 weeks of start of study intervention or have had 
a history of radiation pneumonitis.
Note: Participants must have recovered from all radiation-related toxicities and not 
require corticosteroids. A 1-week washout is permitted for palliative radiation (≤2 weeks 
of radiotherapy) to non-CNS disease.
18. Has received a live or live attenuated vaccine within 30 days prior to the first dose of 
study intervention. Note: Killed vaccines are allowed.
Refer to Section 6.5 for information on COVID-19 vaccines.
Prior/Concurrent Clinical Study Experience
19. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
intervention.
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Note: Participants who have entered the Follow-up Phase of an investigational study may 
participate if the last dose of the previous investigational agent was at least 4 weeks prior 
to the first dose of study intervention.
Diagnostic Assessments
20. Has a 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.
Other Exclusions
21. Has had an allogenic tissue/solid organ transplant.
Refer to Appendix 7 for country-specific requirements.
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.
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 one time for eligibility.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws consent 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 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 2.
When concurrently administered, pembrolizumab should be given prior to chemotherapy; 
chemotherapy should be given as per local SOC.
All products indicated in Table 2 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.
Refer to Appendix 7 for country-specific requirements.
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Table 2
Study Interventions
Arm Name
Arm Type
Interven-
tion Name
Inter-
vention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage Level(s)
Route of 
Adminis-
tration
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm A
Experimental
Pembro-
lizumab SC
Drug
SC
Test Product
IMP
Central
Arm B
Active 
comparator
Pembro-
lizumab IV
Drug
Solution for 
Infusion
IV
Test Product
IMP
Central
Arms A and 
B
(squamous)
Other
Paclitaxel
Drug
Solution for 
infusion
6 mg/mL
200 mg/m2
IV
Background 
Treatment
NIMP/
AxMP
Local or 
central
Arms A and 
B 
(squamous)
Other
Nab-
paclitaxel
Drug
Lyophilized 
Powder for 
IV infusion
5 mg/mL
100 mg/m2
IV
Background 
Treatment
NIMP/
AxMP
Local or 
central
Arms A and 
B (squamous 
and non-
squamous)
Other
Carboplatin
Drug
Solution for 
infusion
10 mg/mLb
Squamous: AUC 
6 mg/mL/min
Nonsquamous: 
AUC
5 mg/mL/min
IV
Background 
Treatment
NIMP/
AxMP
Local or 
central
Arms A and 
B
(non-
squamous)
Other
Cisplatin
Drug
Solution for 
infusion
1 mg/mL
75 mg/m2
IV
Background 
Treatment
NIMP/
AxMP
Local or 
central
Arms A and 
B (non-
squamous)
Other
Pemetrexedc
Drug
Lyophilized 
Powder for 
IV infusion
500 mgb
500 mg/m2
IV
Background 
Treatment
NIMP/
AxMP
Local or 
central
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Arm Name
Arm Type
Interven-
tion Name
Inter-
vention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP or 
NIMP/
AxMP
Sourcing
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6.1.1
Medical Devices
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab SC and pembrolizumab IV are 
provided separately in the 
Carboplatin, cisplatin, pemetrexed, paclitaxel, and nab-paclitaxel should be prepared per 
local and institutional guidelines according to the approved product labels.
The rationale for selection of doses to be used in this study is provided 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.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Treatment randomization will occur centrally using an IRT system. There are 2 study 
intervention arms (Arm A and Arm B). After Screening, eligible participants will be 
randomly assigned in a 
 into the 2 arms and receive corresponding study intervention 
as described in Section 4.1.
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 6.6.2 for Dose Modification and Toxicity Management Guidelines for irAEs 
associated with pembrolizumab monotherapy, coformulations, or IO combinations and for 
other allowed dose interruptions.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during Screening and while on study. If there is a clinical indication for any medications or 
vaccinations specifically prohibited, discontinuation from study intervention may be 
required. The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director. The final decision on any supportive therapy 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, the Sponsor, and the 
participant.
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The following medications or vaccinations are prohibited during the study (exceptions noted; 
also see Appendix 7 for country-specific information):
1. Antineoplastic systemic chemotherapy, immunotherapy, or biological therapy not 
specified in this protocol
2. Investigational agents other than pembrolizumab
3. Surgery or radiotherapy for tumor control not specified in the protocol

Note: Participants are allowed to receive palliative radiotherapy for painful bone 
lesions. Targeted external beam irradiation should not be used in the primary lung 
field where assessment for tumor is indicated. Radiation therapy to the brain may be 
allowed after Sponsor consultation.
4. Live or live attenuated vaccines within 30 days prior to the first dose of study 
intervention and while participating in the study. See Appendix 7 for country-specific 
requirements. Note: Killed vaccines are 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, adenoviral 
vaccines, or inactivated vaccines. These vaccines will be treated just as any other 
concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not
allowed.
5. Anticancer hormonal therapy (eg, androgen deprivation, androgen receptor blockade, 
antiestrogens).

Note: Hormonal replacement therapy (eg, thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency) is allowed.
6. 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 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
•
For use as premedication for chemotherapeutic agents specified in Section 6.5.1
Other glucocorticoid use except when used for the following purposes:
•
For topical use or ocular use
•
Intraarticular joint use
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•
For inhalation in the management of asthma or COPD
7. Phenytoin during therapy with cisplatin/carboplatin.
In addition to the medications listed here, site staff should refer to the approval product labels 
for prohibited medications, as well as drug-drug interactions for each chemotherapy agent 
used in this study.
If the investigator determines that a participant requires any of the aforementioned treatments 
for any reason, all study intervention must be discontinued.
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 medication will be recorded on the eCRF including all 
prescription, 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. 
Concomitant medications administered 30 days after the last dose of study intervention 
should be recorded for SAEs and ECIs as defined in Section 8.4.7.
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 
(http://www.mascc.org/antiemetic - 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 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 8.1.8.1.2.2.
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Prior to pemetrexed infusion, all participants should receive the appropriate supplementation 
of vitamin B12, folic acid, and dexamethasone; see Section 8.1.8.1.2.3.
In addition, all participants should receive the appropriate corticosteroid premedications as 
per the local approved label.
Additional premedications and pre- and post-cisplatin hydration should be administered as 
per standard practice.
6.6
Pembrolizumab Courses, Immune-Related Events and Dose Modification
Dose modification and toxicity management will be the same for both formulations of 
pembrolizumab (SC and IV), therefore, SC and IV formulations are not specified in this 
section.
Toxicity events may be attributed to pembrolizumab, individual chemotherapy agents, or to 
the combination of any of these treatments.
6.6.1
Intervention Phase or First Course
 
6.6.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
temporarily suspended as described below or discontinued due to toxicity. Pembrolizumab 
treatment suspensions greater than those specified below will result in discontinuation.
6.6.2.1
Dose Modification and Toxicity Management for Immune-related AEs 
Associated with Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation.
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 3.
Refer to Appendix 7 for country-specific requirements.
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Table 3
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
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
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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
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 β-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
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, 3 or 4
Continue

Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
·
Monitor for signs and symptoms of thyroid 
disorders
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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
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
Myocarditis
Asymptomatic 
cardiac enzyme 
elevation with 
clinical suspicion 
of myocarditis 
(previously 
CTCAE v4.0 
Grade 1)
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
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
Persistent 
Grade 2
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology or exclude other causes
Grade 3
Withhold or 
discontinue 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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6.6.2.2
Dose Modification and Toxicity Management of Infusion/Injection
Reactions Related to Pembrolizumab
Pembrolizumab 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 associated infusion/injection reaction are provided in Table 4.
Table 4
Pembrolizumab Infusion/Injection Reaction Dose Modification and Treatment 
Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; IV 
infusion 
interruption/holding 
the second SC 
injection 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
Grade 2
Requires therapy or IV 
infusion 
interruption/holding 
the second SC 
injection but responds 
promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop IV infusion/hold the second SC injection (if 
not already given).
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/hr to 50 mL/hr). Similarly, if symptoms 
resolve within 1 hour of holding the second SC 
injection, the second injection may be given. 
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 drug intervention.
Participant may be 
premedicated 1.5 h (±30 
minutes) prior to 
infusion/injection of study 
intervention with:
Diphenhydramine 50 mg PO 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
PO (or equivalent dose of 
analgesic).
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
IV infusion/second SC 
injection hold); 
recurrence of 
symptoms following
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/hold the second SC injection (if 
not already given).
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 drug intervention.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov
6.6.2.3
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab 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. 
 
 
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6.6.4
Dose Modifications for Chemotherapy
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 5 through Table 7).
Dose modifications and toxicity management guidelines for immune-related AEs associated 
with pembrolizumab are outlined in Section 6.6.2 and Table 3.
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.
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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.
Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
delayed/interrupted for a maximum of 12 weeks for an adverse event [Section 6.4]. 
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
•
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 intravenous (IV) hydration. When CrCl improves to 
≥50 mL/min, decrease cisplatin to dose level (DL) -1 (Table 5). 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.
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-
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 5).
At the second occurrence of CrCl <40 mL/min, decrease carboplatin to DL -2 (Table 5) 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 pembrolizumab should also be delayed/interrupted. If platinum-based 
chemotherapy doublet is delayed or interrupted during Cycles 1 through 4, participants 
should be seen weekly until toxicity resolves.
•
If platinum dosing is delayed or interrupted on Day 1, pembrolizumab and 
pemetrexed/paclitaxel/nab-paclitaxel should also be delayed/interrupted. If platinum-
based chemotherapy doublet is delayed or interrupted during Cycles 1 through 4, 
participants should be seen weekly until toxicity resolves.
•
If pembrolizumab dosing is delayed or interrupted, platinum-based chemotherapy can 
continue as scheduled. 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 pembrolizumab 
and the remaining chemotherapy drug. 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.
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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.
The CTCAE 5.0 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 5 through Table 7. These serve as a guide and do not replace investigator judgment and 
applicable local label recommendations, if more stringent.
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Table 5
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/min
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/min
38 mg/m2
AUC 
3 mg/mL/min
100 mg/m2
50 mg/m2
Dose Level -3
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
AUC=area under the curve.
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Recommended dose modifications for key chemotherapy toxicities are outlined in Table 6
and Table 7. These serve as a guide and do not replace investigator judgment and applicable 
local label recommendations, if more stringent. These data are based on Day 1 cell counts.
Table 6
Recommended Chemotherapy Dose Modifications for Hematological Toxicity
Drug-related Toxicitya
Cisplatin
Carboplatin
Paclitaxel
Nab-paclitaxel
Pemetrexed
Dose Level (DL) from Table 5
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 7
Recommended Chemotherapy Dose Modifications for Nonhematological Toxicity
Drug-Related 
Toxicitya
CTCAE 
Grade
Cisplatin
Carboplatin
Paclitaxel
Nab-
paclitaxel
Pemetrexed
Dose Level (DL) from Table 5
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
There is no study-specified intervention following the end of the study.
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. 
 or 
pembrolizumab IV [25 mg/mL]) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
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 prior to completion of the protocol-specified treatment 
regimen will still continue to participate in the study as specified in Section 1.3 and Section 
8.11.4 unless the participant has withdrawn from the study (Section 7.2).
Participants may discontinue study intervention at any time for any reason or be dropped 
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. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
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 (carboplatin and/or taxane [paclitaxel/nab-paclitaxel] for 
squamous NSCLC; pemetrexed and/or carboplatin/cisplatin for nonsquamous NSCLC)
for more than 6 weeks. Participants may continue on study upon consultation with 
Sponsor.
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 
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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 8.2.1.2; however, after obtaining 
informed consent addendum and Sponsor communication, the investigator may elect to 
continue treatment beyond disease progression.
•
Progression or recurrence of any malignancy, or any occurrence of another malignancy 
that requires active treatment.
•
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.
Note: The number of treatments is calculated starting with the first dose.
 
 
 
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 future biomedical research, 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.
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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.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
7.4
Potential Early Discontinuation of Study Due to Futility
Decision to stop the trial early due to futility will be based on the eDMC recommendations 
with review by the Sponsor EOC. If a decision is made to stop the trial, all participants that 
have already been randomized and are receiving pembrolizumab treatment, SC or IV, will be 
given the option to continue on IV pembrolizumab. Enrollment will continue during the 
period of the futility analysis.
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.
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•
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 procedure met 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 
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 future biomedical 
research. 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.
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 trial protocol number, trial
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.
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•
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 his/her 
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 
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 identification 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.
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8.1.4.1
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 the first dose of study intervention.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record new medication, if any, taken by the 
participant during the study through the postintervention follow-up visits. In addition, new 
medications started during the Second Course Retreatment Phase 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 prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Any participant who is rescreened will retain the original screening number assigned at the 
initial Screening visit.
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8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the pharmacy manual.
Study intervention should begin within 3 days of randomization.
8.1.8.1
Timing of Dose Administration
Chemotherapy regimen is determined by histology. Participants with squamous NSCLC will 
receive 4 cycles of carboplatin in combination with a taxane, investigator’s choice of
paclitaxel or nab-paclitaxel, as the chemotherapy. Participants with nonsquamous NSCLC 
will receive 4 cycles of pemetrexed with a platinum, investigator’s choice of cisplatin or 
carboplatin, followed by pemetrexed maintenance until progression, an intolerable AE, or 
discontinuation by participant or physician decision.
8.1.8.1.1
Pembrolizumab IV and SC
Pembrolizumab IV will be administered as a 30-minute IV infusion Q3W, and it will be 
administered prior to chemotherapy. Sites should make every effort to target infusion timing 
to be as close to 30 minutes as possible. However, given the variability of infusion pumps 
from site to site, a window of -5 minutes and +10 minutes is permitted (ie, infusion time is 30 
minutes: -5 minutes/+10 minutes). The pharmacy manual contains specific instructions for 
pembrolizumab storage, reconstitution, preparation of the infusion fluid, and administration. 
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8.1.8.1.2
Chemotherapy
Unless there is a change in weight >10%, the same dose of chemotherapy can be used 
throughout the 4 cycles of the Intervention Phase (provided there are no additional toxicities).
8.1.8.1.2.1
Carboplatin (AUC 6 [Squamous] or AUC 5 [Nonsquamous])
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 for each of the 
4 cycles (Intervention Phase) and after pembrolizumab as per local practice and 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
Creatinine clearance must be calculated using either the Cockcroft-Gault formula or another 
acceptable standard 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.
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Additional premedications should be administered as per standard practice.
8.1.8.1.2.2
Paclitaxel or Nab-paclitaxel (Squamous)
Paclitaxel or nab-paclitaxel will be administered immediately after 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 for 4 
cycles as per local practice and 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 at as an IV infusion over 30 minutes for 
4 cycles as per local practice and labels. Participants will be dosed on Day 1, 8, and 15 of 
each 3-week cycle.
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.
8.1.8.1.2.3
Pemetrexed (Nonsquamous)
Pemetrexed (500 mg/m2 Q3W) will be administered as an IV infusion over 10 minutes. 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 cycles 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 Cycles 1-4 but not to exceed doses in MASCC guidelines
(Section 8.1.8.1.3).
8.1.8.1.2.4
Cisplatin (Nonsquamous)
Cisplatin (75 mg/m2 Q3W) will be administered as an IV infusion over 30 to 180 minutes on 
Day 1 for up to 4 cycles (Intervention Phase) and after pembrolizumab as per local practice 
and labels. 
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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. This switch 
from cisplatin to carboplatin requires consultation between the investigator and the Sponsor 
and written documentation of the collaborative decision.
8.1.8.1.3
Antiemetic Therapy
Antiemetic therapy should follow the MASCC guidelines. In each cycle of treatment during 
the Intervention Phase, antiemetic therapy should include a 5-HT3 receptor antagonist, 
dexamethasone (or equivalent), and/or aprepitant [Roila, F., et al 2016].
8.1.9
Discontinuation and Withdrawal
Section 7.2 provides a complete description of withdrawal of consent from the study.
Participants who withdraw consent from the study should be encouraged to complete all 
applicable activities scheduled for the final study visit at the time of withdrawal.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main 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 future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main 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.
8.1.11
Domiciling
Not applicable.
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8.1.12
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.
8.1.13
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 or incisional biopsy of a tumor lesion, which was not previously 
irradiated
or
•
An archival tumor tissue sample if a new biopsy is unavailable
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 
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 is identical to 
the US FDA-approved PD-L1 IHC 22C3 pharmDx 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
In addition to survival, efficacy will be assessed based on scans to evaluate changes in tumor 
burden over time, until the participant is discontinued from the study or enters the survival 
follow-up. The process for scan collection and transmission to the iCRO can be found in the 
Site Imaging Manual. CT scans are preferred over other tumor imaging methods. 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 type of scan 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. 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.
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Magnetic resonance scans are preferred for brain imaging; however, CT scans are acceptable, 
if MRI is medically contraindicated.
All scheduled scans for all study participants from the sites will be submitted to the central 
imaging vendor. In addition, scans (including via other modalities, such as PET-CT, X-ray) 
that are obtained at an unscheduled time point to determine disease progression, and scans 
obtained for other reasons, but captures radiologic progression based on investigator 
assessment, should also be submitted to the central imaging vendor.
8.2.1.1
Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 28 days prior to the date of 
randomization. Any imaging obtained after Cycle 1 Day 1 of treatment cannot be included in 
the screening assessment. The site study team must review screening images to confirm the 
participant has measurable disease per RECIST 1.1.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality and performed within 28 days prior to 
the date of randomization and can be assessed by the iCRO.
Brain imaging is required for all participants at screening. Participants with treated brain 
metastases (eg, whole brain radiation treatment [WBRT], stereotactic radiosurgery, or 
equivalent) may participate only if they satisfy all of the following: Have no evidence of new 
or enlarging brain metastases confirmed by post-treatment repeat brain imaging (using the 
same modality) performed at least 4 weeks after pre-treatment brain imaging, and are 
neurologically stable without the need for steroids for at least 14 days before first dose of 
trial treatment as per local site assessment. This exception does not include carcinomatous 
meningitis, as participants with carcinomatous meningitis are excluded regardless of clinical 
stability.
8.2.1.2
Tumor Imaging During the Study
Imaging should continue to be performed until disease progression is identified by the 
investigator and verified by BICR, or until any of these conditions are met:
•
the start of new anticancer treatment
•
pregnancy
•
withdrawal of consent
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•
death
•
or notification by the Sponsor
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting with
the next scheduled imaging time point. Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 4 
weeks later; tumor imaging may resume at the subsequent scheduled imaging time point. 
Note: Response will not be verified by BICR in real time and no notification will be sent to 
sites for this purpose.
On-study brain imaging should be performed if clinically indicated or to confirm CR (if other 
lesions indicate CR and brain metastases existed at baseline).
Treatment beyond centrally verified PD per RECIST 1.1 may be permitted at the discretion 
of the investigator after consulting with the Sponsor and receiving signed informed consent 
addendum from the participant (Figure 3). Participants who continue treatment beyond 
centrally verified PD must continue tumor imaging assessments as described in the SoA 
(Section 1.3). Investigator assessments are to be documented on the eCRF, but scans are not 
to be submitted to the iCRO. Further progression and discontinuation of study intervention 
are to be determined by the investigator.
In participants who do not have disease progression by central verification (investigator 
assessment of disease progression, however BICR assessment of disease progression per 
RECIST 1.1 = “No”), treatment can continue to be administered at investigator’s discretion 
for clinically stable participants and after a new informed consent addendum is signed. 
Imaging should continue to be performed as per imaging schedule and must be submitted to 
the iCRO along with a VOP request until central verification of progression is received.
All investigator evaluations of tumor response will utilize the RECIST 1.1 criteria and should 
be entered into the appropriate electronic case report forms by the sites.
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (±4-week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study intervention due to documented 
disease progression, this is the final required tumor imaging.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment calculated from the date of
randomization (see Section 8.2.1.2) until the start of a new anticancer treatment, disease 
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progression, pregnancy, death, withdrawal of consent, or the end of the study, whichever 
occurs first.
Note: new anticancer treatment is defined as a different treatment than the anticancer therapy 
provided in this study.
8.2.1.4
Second Course (Retreatment) Tumor Imaging
Tumor scans must be performed within 28 days before restarting study intervention treatment 
with 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 a new anticancer treatment, 
pregnancy, withdrawal of consent, death, completion of Second Course, or notification by the 
Sponsor, whichever occurs first.
Imaging should continue to be performed until disease progression, the start of a new 
anticancer treatment, withdrawal of consent, death, 
 
, or notification by the Sponsor, whichever occurs first.
For participants who discontinue Second Course study intervention, tumor imaging should be 
performed at the time of intervention discontinuation (±4-week window). If previous imaging 
was obtained within 4 weeks prior to the date of discontinuation, then imaging at intervention 
discontinuation is not mandatory. For participants who discontinue study intervention due to 
documented disease progression, this is the final required tumor imaging.
For participants who discontinue Second Course study intervention without documented 
disease progression, every effort should be made to continue monitoring their disease status 
by radiologic imaging every 12 weeks (84 days ±7 days) until either the start of a new 
anticancer treatment, disease progression, death, or the end of the study, whichever occurs 
first. 
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 
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immediately to iCRO for BICR verification of progression. After submission of scan(s), the 
iCRO will email the assessment to the site and Sponsor.
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 anti-cancer 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 judgement 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 3 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 3
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. 
 
 
 
 
 
 Additional assessment will occur at Treatment 
Discontinuation Visit and at 30-day Safety Follow-up Visit. Perform ePROs in the following 
order listed: EORTC QLQ-C30 followed by EQ-5D-5L. Note: ePROs will be assessed on 
scheduled cycle visits.
It is best practice and strongly recommended that ePROs are administered to randomized 
participants prior to 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 
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drawn/collected by visit and by sample type per participant, can be found in the 
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
8.3.1.1
Complete 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 complete 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 complete 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.
Note:
 
 
•
•
•
•
•
•
•
•
•
•
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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. The same 
method of temperature measurement must be used for all participants and must remain 
the same for each participant. Height will be measured during the Screening Phase only. 
Weight will be measured during the Screening phase and at every treatment visit.
•
Blood pressure and heart rate measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. The correct size of the blood pressure cuff and correct positioning of the 
participant’s arm are essential to the accuracy of the blood pressure measurement.
•
Blood pressure and heart rate 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 semi-supine 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 the schedule of activities 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
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.
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The investigator or qualified designee will assess ECOG status (see Appendix 10) at 
screening, prior to the administration of each dose of study intervention, and during the 
Follow-up period (Section 1.3).
8.3.5
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 
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.
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.6
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum) should be conducted at every monthly intervals 
during intervention.
-
Pregnancy testing (urine or serum) should be conducted as per SoA 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
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Section 5.1. The length of time required to continue pregnancy testing for each study 
intervention is.
◦
Pembrolizumab 150 days
◦
Chemotherapy 210 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.
Refer to Appendix 7 for country-specific requirements.
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 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 event cause the participant to be excluded from the study, or is the 
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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 following cessation 
of study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention randomization through 90 
days following cessation of study intervention or 30 days following cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention
randomization through 120 days, following cessation of pembrolizumab, 180 days 
following cessation of chemotherapy, or 30 days following 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 of 
the time period 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 he/she 
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 8.
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Table 8
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)
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
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.
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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 towards 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.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) 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), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
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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 monitor aggregated efficacy endpoint events and safety data to ensure the 
safety of the participants in the study. Any suspected endpoint that upon review is not 
progression of the cancer under study will be forwarded to Global Pharmacovigilance as an 
SAE within 24 hours of determination that the event is not progression of the cancer under 
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.
Events of clinical interest for this study include: 
•
An overdose of Sponsor's product, as defined in Section 8.5.
•
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment and 
follow up of these criteria can be found in the Investigator Study File Binder (or equivalent).
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8.4.8
Medical Device and Drug-device Combination Products/Combination 
Medicinal Product - PQCs/Malfunctions
The method of documenting and reporting of such events complaints associated with medical 
devices, drug-device combination product/combination medicinal product including 
PQCs/malfunctions will occur as noted below and in Appendix 4.
To fulfill regulatory reporting obligations worldwide, medical device information (including 
device constituent part information) associated with AEs will be collected and reported to the 
Sponsor in the same time frame as AEs per Section 8.4.1 via CRF (paper or electronic) and 
as per data entry guidelines. All associated person SAEs must be reported to the Sponsor in 
the same time frame as all other SAEs per Section 8.4.1 via CRF and as per data entry 
guidelines. All SAEs due to malfunction will be followed until resolution, stabilization, until 
the event is otherwise explained, or the participant or associated person is lost to follow-up.
PQCs/malfunctions including those that involve a participant or any user/associated person 
must be reported to the Sponsor. Sponsor shall review reported events by the investigator to 
fulfill the legal responsibility of notifying appropriate regulatory authorities and other entities 
about certain safety information relating to medical devices and drug-device combination 
products being used in clinical studies.
8.5
Treatment of Overdose
 
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.
8.6
Pharmacokinetics
8.6.1
Blood Collection for PK
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the 
. PK samples should be drawn according to the PK collection schedule 
for all participants (Section 1.3). Every effort should be taken to collect samples at 30 days 
after end of study intervention.
8.6.2
Blood Collection for Antidrug Antibodies
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the 
. ADA samples should be drawn according to the ADA collection 
schedule for all participants (Section 1.3). Every effort should be taken to collect samples at 
30 days after end of study intervention for ADA. Simultaneous PK sampling is required for 
interpretation of ADA analysis.
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8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants as specified in the SoA:
•
Archival or newly obtained tumor tissue
•
Blood for genetic analysis
•
Blood for ctDNA analysis
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the 
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant 
provides documented informed consent for future biomedical research. If the planned genetic 
analysis is not approved, but future biomedical research is approved and consent is given, 
this sample will be collected for the purpose of future biomedical research.
Sample collection, storage, and shipment instruction for planned genetic analysis samples 
will be provided in the 
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for future biomedical research, the 
following specimens will be obtained as part of future biomedical research:

Leftover samples listed in Section 8.8 (including any extracted material from samples)
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8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Approximately 28 days prior to intervention randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5.
Documented consent must be obtained prior to performing any protocol-specific procedure. 
Results of a test performed prior to 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 prior to the first dose of 
study intervention except for the following:
•
Laboratory tests are to be performed within 10 days prior to the first dose of study 
intervention. An exception is hepatitis and HIV testing which may be done up to 28 days 
prior to the first dose of study intervention if required by the local health authority.
•
Evaluation of ECOG is to be performed within 7 days prior to randomization.
•
A WOCBP must have a negative highly sensitive pregnancy test (as required by local 
regulations) within 24 hours for urine or within 72 hours for serum before the first dose 
of study intervention. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required (performed by the local study site laboratory). Additional 
pregnancy testing can be conducted if required by local regulations or clinically 
indicated.
Participants may be rescreened one time 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. Rescreening is permitted as long as the study is still open for enrollment.
8.11.2
Treatment Period (Intervention Phase)
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1. Unless otherwise specified, assessments/procedures are to be 
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performed prior to the first dose of study intervention for each cycle, and the window for 
each visit is ±1 day for Cycles 1 through 7 and ±3 days for Cycle 8+.
8.11.2.1
Optional Home Health Visits for PK Sampling
A global home health vendor is available to be utilized for participants in both the SC and IV 
arms who must have additional
 
 
 
.
If the visiting nurse service is utilized 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.
8.11.3
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 8.11.4).
8.11.4
Post-Treatment (Post-Intervention) Visit
At the end of study intervention, each participant will be followed for a minimum of 30 days 
for AE monitoring. Serious AEs occurring within 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, will be collected.
Participants will have posttreatment follow-up for disease status, including radiographic 
imaging, until initiating a nonstudy anticancer treatment, experiencing disease progression, 
death, withdrawing consent, becoming lost to follow-up, or end of study.
All participants will be followed for overall survival until death, withdrawal of consent, or 
the end of the study.
8.11.4.1
Safety Follow-up Visits
The mandatory 30-day Safety Follow-up Visit must be conducted approximately 30 days 
after the last dose of study intervention or before the 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. 
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Participants who are eligible for Second Course retreatment with pembrolizumab may have 
up to 2 safety follow-up visits, 1 after the Intervention Phase and 1 after the Second Course 
Retreatment.
8.11.4.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than documented disease progression will 
move into the Efficacy Follow-up Phase. Follow-up visits after treatment discontinuation 
must coincide with the imaging schedule until disease progression, death, or end of study. 
Participants who completed all efficacy assessments and/or will not have further efficacy 
assessments must enter the Survival Follow-up Phase.
Every effort must be made to collect imaging until the start of new anticancer therapy, 
confirmed PD, or death. Information regarding poststudy anticancer treatment will be 
collected if new treatment is initiated. Participants who are eligible to receive retreatment 
with pembrolizumab according to the criteria in Section 6.6.3 will move from the Efficacy 
Follow-up Phase to the Second Course Retreatment Phase when they experience disease 
progression. Details are provided in the SoA (Section 1.3) for retreatment with 
pembrolizumab.
8.11.4.3
Survival Follow-up Assessments
Participant survival follow-up status will be assessed by telephone approximately every 12 
weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
The first survival follow-up assessment should be scheduled as described below:
For participants who discontinue treatment intervention and who will not enter the Efficacy 
Follow-up Phase, the first survival follow-up assessment will be scheduled 12 weeks after the 
discontinuation visit and/or Safety Follow-up visit (whichever is last).
For participants who completed assessments in the Efficacy Follow-up Phase, the first 
survival follow-up assessment will be scheduled 12 weeks after the last efficacy assessment 
follow-up visit has been performed.
8.11.5
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 time period will be 
contacted for their vital status.
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9
STATISTICAL ANALYSIS PLAN
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 E-9). Changes 
to exploratory or other non-confirmatory analyses made after the protocol has been finalized, 
but prior to unblinding/final database lock, will be documented in an sSAP and referenced in 
the CSR for the study. Post hoc exploratory analyses will be clearly identified in the CSR. 
The PRO analysis plan will also be included in the sSAP. 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 9.2-9.12. See Appendix 7 for country-specific information.
Study Design 
Overview
A Randomized, Phase 3, Open-label Study to Investigate the Pharmacokinetics and 
Safety of Subcutaneous Pembrolizumab versus Intravenous Pembrolizumab, 
Administered with Platinum Doublet Chemotherapy, in the First-Line Treatment of 
Participants with Metastatic Squamous or Nonsquamous Non-Small-Cell Lung Cancer
Treatment
Assignment
Participants will be randomized 
 
 
 

Arm B – Participants will receive up to 35 cycles of 200 mg pembrolizumab IV 
Q3W administered with platinum doublet chemotherapy
 
 
 
Analysis 
Populations

PK (primary): Per-protocol Set

Efficacy: ITT

Safety: APaT

PRO: PRO FAS
Primary 
Endpoint(s)
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Secondary 
Endpoints

ORR



Safety and tolerability 

PFS

OS

DOR

ADA
Statistical 
Methods for Key 
Immunogenicity/ 
Pharmacokinetic 
Analyses
Statistical 
Methods for Key 
Safety Analyses
For Tier 2 endpoints, 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 method [Miettinen, O. and Nurminen, M. 1985]
Interim Analysis
Multiplicity
By using the graphical approach of Maurer and Bretz [Maurer, W. and Bretz, F. 2013], 
if one hypothesis is rejected, the alpha will be shifted to the other hypothesis.
The futility assessment at the IA1 is non-binding.
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Sample Size and 
Power 
The planned sample size is ~512 participants.
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 is being 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 treatment 
assignment and randomization will be implemented by an IVRS vendor. 
Although the trial is open label, analyses or summaries generated by randomized intervention 
assignment, or actual intervention received will be limited and documented.
Blinding issues related to the planned interim analysis are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Pharmacokinetics, safety, and efficacy endpoints that will be evaluated for within- and/or 
between-treatment differences are listed below.
9.4.1
Pharmacokinetics Endpoints
The methodological details for assessment of model-based PK parameters 
 
will be summarized in a separate MAP.
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Primary
Secondary
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.
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•
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 pembrolizumab SC and pembrolizumab IV.
9.4.5
PRO Endpoints
The predefined PRO endpoints in this study are mean change from baseline in EORTC QLQ-
C30 global health/QoL scale (Items 29 and 30) and physical functioning domain score (Items 
1 through 5), role functioning domain scores (Items 6 and 7) and mean score change from 
baseline in EQ-5D VAS. Exploratory PRO endpoints as described in Section 4.2.1.4 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. 
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Any participants or data values excluded from the analyses will be identified, along with the 
reasons for exclusion, in the CSR. 
9.5.2
Safety Analysis Populations
Safety Analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least one 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 one laboratory, vital sign, or ECG measurement obtained subsequent to at least one 
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.
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9.5.3
Efficacy Analysis Populations
The ITT population will serve as the population for efficacy analysis. All randomized 
participants will be included in this population. Participants will be included in the treatment 
group to which they are randomized. 
9.5.4
PRO Analysis Populations
The PRO analyses are based on the PRO FAS population, defined for each PRO endpoint 
respectively as randomized participants who have at least one PRO assessment available and 
have received at least one dose of study medication. Participants will be analyzed in the 
treatment group to which they are randomized.
9.6
Statistical Methods
9.6.1
Statistical Methods for Pharmacokinetics Analyses
The primary objectives are to compare GMR between pembrolizumab SC and 
pembrolizumab IV based on 
. These 
objectives will be assessed via the following non-inferiority (NI) hypothesis:
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9.6.2
Statistical Methods for Safety Analyses
The primary safety analyses will include only events that occur prior to Second Course 
Retreatment.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 9). The tiers differ with 
respect to the analyses that will be performed. AEs (specific terms as well as system organ 
class terms) are either prespecified as “Tier 1” endpoints, or will be classified as belonging to 
"Tier 2" or "Tier 3" based on the observed proportions of participants with an event.
Tier 1 Events
Safety parameters or AEs of special interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance with p-
values and 95% CIs to be provided for between-treatment differences in the proportion of 
participants with events; these analyses will be performed using the unstratified Miettinen 
and Nurminen method (1985), an unconditional, asymptotic method [Miettinen, O. and 
Nurminen, M. 1985]. There are no safety events that are considered Tier 1 for this protocol. 
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method, an 
unconditional, asymptotic method [Miettinen, O. and Nurminen, M. 1985].
Membership in Tier 2 requires that at least 10% of participants in any treatment group show 
the event; all other AEs and predefined limits of change will belong to Tier 3. The threshold 
of at least 10% of participants was chosen for Tier 2 events 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, 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 be considered Tier 2 endpoints. 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.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. The broad AE 
categories consisting of the proportion of participants with any AE, a drug-related AE, a 
serious AE, an AE which is both drug-related and serious, a Grade 3 to 5 AE, a drug-related 
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Grade 3 to 5 AE, and discontinuation due to an AE will be considered Tier 3 endpoints. Only 
point estimates by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format. 
Table 9
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE (incidence ≥10% of participants in one of 
the treatment groups)
X
X
Any Serious AE (incidence ≥2% of participants in 
one of the treatment groups)
X
X
Any Grade 3-5 AE (incidence ≥5% of participants 
in one of the treatment groups)
X
X
Tier 3
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 due to AE
X
Death
X
Specific AEs, SOCs (incidence > 0% of participants 
in all of the treatment groups)
X
Change from Baseline Results (Lab Toxicity Grade, 
Vital Signs)
X
AE=adverse event; CI=confidence interval; SOC=system organ class.
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, the stratified log-rank 
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test, 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 Retreatment.
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 will also be used for 
comparison of the ORR between 2 treatment groups. The ratio of ORR and its 95% CI using 
the normal approximation on the logarithmic scale will be reported as applicable. 
The stratification factors used for randomization (see Section 6.3.2) will be applied to the 
stratified analysis specified above. 
Additional sensitivity analyses will be conducted excluding all the participants enrolled from 
Russia and Ukraine. The details of the sensitivity analyses will be specified in the sSAP.
9.6.3.2
Progression-free Survival
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron's method of tie handling will be 
used to assess the magnitude of the treatment difference (ie, hazard ratio) between the 
treatment arms. The hazard ratio 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 both the 
stratified log-rank test and the stratified Cox model. 
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. 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. Death is always considered a confirmed PD event.
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 
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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 10.
9.6.3.3
Overall Survival
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test. A stratified 
Cox proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (ie, the hazard ratio). The hazard ratio and its 95% 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 both the 
stratified log-rank test and 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 11. 
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.
9.6.3.5
Analysis Strategy for Key Efficacy Variables
Efficacy will be assessed only once, at the time of FA. A summary of the primary analysis 
strategy for the key efficacy endpoints is provided in Table 12.
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Table 12
Analysis Strategy for Key Efficacy Variables
Endpoint/
Variable
Statistical Method
Analysis 
Population
Missing Data Approach
ORR per 
RECIST 1.1 
by BICR
P-value: stratified Miettinen and 
Nurminen method,
 
Estimation: stratified Miettinen and 
Nurminen method, stratified CMH 
method
ITT
Participants with missing data 
are considered nonresponders
PFS per 
RECIST 1.1
by BICR
P-value: stratified log-rank test
Estimation: stratified Cox model with 
Efron’s tie handling method 
ITT
Censored according to rules in
Table 10
OS
P-value: stratified log-rank test
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
Changes from baseline in the following exploratory PRO endpoints will be assessed:
•
Global health status/QoL score (QLQ C30 Items 29 and 30)
•
Physical functioning domain score (QLQ C30 Items 1 through 5)
•
Role functioning domain score (QLQ C30 Items 6 and 7)
•
EQ-5D-5L VAS score
Treatment effect on PRO score change from baseline will primarily be evaluated at 
predefined timepoint or the latest time point where the overall completion/compliance rates 
are ~60%/~80%, respectively, and will be based on a constrained longitudinal data analysis 
model. The difference in the least square mean change from baseline between arms will be 
reported at the predefined primary analysis time point. 
Descriptive analyses will assess the empirical mean change (with 95% CIs) from baseline 
across all time points for each endpoint.
The detailed analysis plan will be specified in sSAP.
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 
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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.
9.7
Interim Analysis
The eDMC will serve as the primary reviewer of the results of the interim 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 of the interim analysis will be documented by the 
unblinded statistician. Additional logistical details will be provided in the eDMC Charter. 
Treatment-level results from the interim 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 analysis.
Although the trial 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
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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. 
 
 
9.8
The study uses the graphical method of Maurer and Bretz [Maurer, W., et al 2011] to provide 
strong multiplicity control for multiple hypotheses as well as the interim analysis. 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 4 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.
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9.8.1
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9.8.2
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9.9
Sample Size and Power Calculations
The study will randomize approximately 512 participants 
 into the 
pembrolizumab SC and pembrolizumab IV arms. 
are primary endpoints for the study, with ORR as a secondary endpoint. 
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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 KEYNOTE-555 Cohort A data for SC. 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 KEYNOTE-555 Cohort A.
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The sample size and power calculations were performed using R.
9.10
Subgroup Analyses
Subgroup analysis will not be performed for 
given that historical data 
from Keytruda development program has consistently shown that there is no clinically 
relevant impact of covariates in PK.
9.11
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
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 medication. 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 Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of 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 local and/or national regulations (including all applicable data protection regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also 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. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
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.
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 fraud, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees 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.
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. 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. 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.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. 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.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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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 chart 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 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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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 prior to transmission to the Sponsor.
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.
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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 Interim 
Analysis) 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.
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 International Committee 
of Medical Journal Editors 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 trial Directive 2001/20/EC, 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 or other local registries. MSD, as Sponsor of this study, will 
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review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive 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 directive, 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, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 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. 
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.
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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 
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 
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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 16 will be performed by the local laboratory.
•
All on-treatment samples will be collected prior to administration of study intervention.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2 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.
Table 16
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN) 
or ureaa
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT)
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of normal)
Albumin
Carbon dioxide 
(CO2 or 
Bicarbonate)b
Chloride
Phosphorous
Creatinine or 
creatinine 
clearancec
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT)
Total Protein
Glucose 
(nonfasting)
Calcium
Alkaline phosphatase
Lactate 
dehydrogenase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase 
by dipstick

Microscopic examination (if blood or protein is abnormal)
Pregnancy 
Testing

Highly sensitive serum or urine hCG pregnancy test (as needed for WOCBP)
Other 
Screening 
Tests

Follicle-stimulating hormone (as needed in women of nonchildbearing potential only)

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody) as required by local health authority or institutional regulations. Refer to 
Appendix 7 for country-specific information.

Coagulation factors (PT or INR, and aPTT/PTT). Additional testing to be conducted as 
clinically indicated for participants taking anticoagulation therapy.

Thyroid-stimulating hormone (TSH), free thyroxine (FT4), triiodothyronine (T3) 
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Laboratory 
Assessments
Parameters
aPTT=activated partial thromboplastin time; FT4=free thyroxine; GFR=glomerular filtration rate; HIV=human 
immunodeficiency virus; INR=international normalized ratio; MCH=mean corpuscular hemoglobin; MCV=mean 
corpuscular volume; PT=prothrombin time; PTT=partial thromboplastin time; RBC = red blood cell; T3 = 
triiodothyronine; TSH=thyroid-stimulating hormone; WBC=white blood cell; WOCBP=women of child bearing 
potential.
NOTES:
a.
BUN is preferred; if not available, urea may be tested.
b.
Performed only if considered the local standard of care.
c.
GFR (measured or calculated) or creatinine clearance can be used in place of creatinine.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
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 (also referred to as Sponsor’s 
product) 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 pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
Note: Congenital disorders (eg, present from birth) not detected or diagnosed prior to 
study intervention administration do not qualify for reporting as AE.
•
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 
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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 pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
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.
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 pre-existing condition that has not 
worsened is not an SAE.) A pre-existing 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.
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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.
10.3.3
Additional Events Reported in the Same Manner as SAE
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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10.3.4
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. 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 Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product 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 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
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(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) Sponsor’s 
product(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 SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT 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 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
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 his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
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•
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.
10.3.5
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.
•
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.
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•
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 e-mail 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, Drug-Device Combination Product/Combination 
Medicinal Product: Definitions, Collection, and Documentation
The recording and follow-up procedures described in this protocol apply to all medical 
devices as described below. For purposes of this section, medical devices in scope for device 
information collection include devices intended to be used by a participant according to the 
study protocol, that are manufactured by the Sponsor or for the Sponsor by a third party, 
licensed by the Sponsor for human use and/or drug-device combination product/combination 
medicinal product as listed in Section 6.1.1. Product Quality Complaints/Malfunctions must 
be reported to the Sponsor.
Note: See Appendix 7 for country-specific information.
Definitions
Combination Product – A product composed of any combination of a drug, a device and a 
biological product. Each drug, device, and biological product included in a combination 
product is referred to as a “constituent part” of the combination product.
Complaint - Any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device 
after it is released for distribution. See also AE and PQC.
Note: A complaint does not necessarily need to involve a user or any other person.
Malfunction - The failure of a device constituent part or the device product as a whole to 
meet its performance specifications or otherwise perform as intended. Performance 
specifications include all claims made in the labeling for the device/device constituent part. 
The intended performance of a device refers to the intended use for which the device is 
labeled or marketed.
Medical Device – An instrument, apparatus, implement, machine, contrivance, implant, in 
vitro reagent, or other similar or related article, including a component part, or accessory 
which is intended for use in the diagnosis of disease or other conditions, or in the cure, 
mitigation, treatment, or prevention of disease, in man or other animals, or intended to affect 
the structure or any function of the body of man or other animals, and which does not achieve 
any of its primary intended purposes through chemical action within on the body of man or 
other animals and which is not dependent upon being metabolized for the achievement of any 
of its primary intended purposes.
PQC - Any communication that describes a potential defect related to the identity, strength, 
quality, purity or performance of a product identified by external customers. This includes 
potential device or device component malfunctions. Note: A report of Lack or Limited 
Efficacy is considered an AE rather than a PQC.
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Serious Deterioration of Health/Serious Injury/Serious Illness
This includes:
•
Life-threatening illness, even if temporary in nature
•
Results in permanent impairment of a body function or permanent damage to a body 
structure
•
Fetal distress, fetal death or any congenital abnormality or birth defects
•
A condition necessitating medical or surgical intervention, including hospitalization or 
prolonged hospitalization, to prevent one of the above
•
Cases that are considered medically significant
The specific definitions for Japan are described in Appendix 7, Country-specific 
requirements.
Recording
•
When a complaint including PQC/malfunction occurs, it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory reports, 
and diagnostic reports) related to the event.
•
Events occurring during the study will be recorded in the participant’s medical records, in 
accordance with the investigator’s normal clinical practice, and on the appropriate CRF 
(paper or electronic) as per instructions provided in the data entry guidelines. Medical 
device/device constituent part of drug-device combination product/combination 
medicinal product information will be collected and reported to the Sponsor in the same 
time frame as SAEs as per Section 8.4.1 via CRF (paper or electronic). 
PQCs/malfunctions must be reported to the Sponsor.
•
It is important that the investigator provides his/her assessment of causality (relationship) 
to the medical device/device constituent part) at the time of the initial report.
The specific recording of Malfunctions for Japan are described in Appendix 7, Country-
specific requirements.
Assessing Causality
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship.
•
The investigator will use clinical judgment to determine the relationship.
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•
Alternative causes such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration should be considered and investigated.
Follow-up
•
The investigator will perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Sponsor to elucidate the 
nature and/or causality of the event as complete as possible.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile 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.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
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 female
-
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 women 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.
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only subdermal contraceptive implantb,c

IUSc,d

Non-hormonal IUD

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner 
of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study 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
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c
Male condoms must be used in addition to female participant hormonal contraception.
d
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
Note: See Appendix 7 for country-specific requirements.
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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.
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 
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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 are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between 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 utilizing 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. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
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6. Withdrawal From Future Biomedical Research3,4
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main 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 main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
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 prior to 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.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main 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 main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
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
Brazil
Section 4.1 Overall Design, Section 7.1 Discontinuation of Study Intervention, Section 
8.2.1.2 Tumor Imaging During the Study, Section 8.2.1.5 RECIST 1.1 Assessment of 
Disease
All information regarding treatment beyond progression is documented in the Main ICF 
and signed by the participant at the start of screening. Informed consent addendum for 
treatment beyond progression will not be collected per local regulations.
10.7.2
Colombia
Section 1.3.1 Screening and Intervention Phase
HIV, Hepatitis B, and C testing during the screening is required to determine 
participant´s eligibility for the study.
10.7.3
France
Section 1.3.1 Screening and Intervention Phase
Audiogram to be completed at screening and at the beginning of each cycle for 
participants taking cisplatin.
Monthly and end-of-treatment pregnancy testing must be conducted as per local 
regulations.
Section 1.3.3 End-of-intervention and Long-term Follow-up
Monthly and end-of-treatment pregnancy testing must be conducted as per local 
regulations.
Section 5.2 Exclusion Criteria
Carboplatin / Paclitaxel only:
a.
Participants who experience hemorrhage from tumor
b. Participants who use phenytoin or fosphenytoin
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Cisplatin / Pemetrexed only: 
a.
Participants with a hearing impairment
b. Participants with pathologies that are a contraindication to hyperhydration prior to 
chemotherapy administration
c.
Participants who are unable to tolerate use of phenytoin
Section 6.5 Concomitant Therapy
Investigators must refer to the up-to-date SmPC of registered products used in this study, 
regarding forbidden medications or medications to be used with precaution.
Section 6.6.2.1 Dose Modification and Toxicity Management for Immune-related AEs 
Associated with Pembrolizumab
Participants should be discontinued from study treatment if any of the following AEs 
occur:
•
Grade 4 skin rash
•
Stevens-Johnson syndrome
•
Toxic epidermal necrolysis
Section 8.3.6 Pregnancy Testing
•
Monthly and end-of-treatment pregnancy testing must be conducted as per local 
regulations.
Section 10.5 Appendix 5: Contraceptive Guidance
Monthly and end-of-treatment pregnancy testing must be conducted as per local 
regulations.
10.7.4
Guatemala
Section 1.3.1 Screening and Intervention Phase
Prior to start in the study, a serum pregnancy test is required as per local regulations. 
Additional evaluations/testing may be deemed necessary by the investigator and/or the 
Sponsor for reasons related to participant safety. In some cases, such evaluations/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. 
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Section 8.3.6 Pregnancy Testing
Prior to start in the study, a serum pregnancy test is required as per local regulations. 
10.7.5
Japan
Section 1.3.1 Screening and Intervention Phase – footnotes
For the assistance to early diagnosis of pneumonitis/interstitial lung disease in study 
participants, the following items, such as pulse oximetry monitoring (peripheral capillary 
oxygen saturation [SpO2]), C-reactive protein (CRP), Krebs von den Lungen-6 (KL-6), 
and surfactant protein-D (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, End of 
Intervention, 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 5.1 Inclusion Criteria
In addition to Inclusion Criterion 8, patients who stop breastfeeding at the start of the 
study but wish to resume breastfeeding thereafter during participation in the study are not 
eligible.
Section 6.1 Study Intervention(s) Administered 
Table 2 Study Interventions
Pembrolizumab IV used in this study is categorized as “product(s) used in the clinical 
trial other than test product(s)” in Japan local regulation.
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Section 10.4 Appendix 4: Medical Device, Drug-Device Combination 
Product/Combination Medicinal Product: Definitions, Collection, and Documentation
Definitions
Medical Device - Devices, etc, (other than regenerative medicine products) intended for use 
in the diagnosis, treatment or prevention of disease in humans or animals, or intended to 
affect the structure or functions of the body of humans or animals.
Combination Medicinal Product - A product comprised of 2 or more regulated 
components, ie, a drug and a device; a device and a cellular and tissue-based products; a 
cellular and tissue-based products and a drug; or a drug, a device, and a cellular and tissue-
based products according to Japan regulations.
Malfunction - Failure of quality, safety and performance, etc, of investigational device in a 
broad sense such as damage or operational failure.
Malfunction which may lead to Serious Adverse Events - Any malfunction of a medical 
device which might have led to the death of a participant and/or the associated person or to a 
serious deterioration in his/her state of health. “Which might have led to” means that there is 
the possibility that death or a serious deterioration might have occurred in a participant 
and/or the associated person, although these cases have not actually occurred.
Recording - Combination medicinal product malfunction which could have resulted in SAEs 
will be reported to the Sponsor within 5 calendar days of learning of the information via a 
paper reporting form.
10.7.6
Peru
Section 1.3.1 Screening and Intervention Phase
HIV, Hepatitis B, and C testing during the screening is required to determine 
participant´s eligibility for the study.
Pregnancy testing in WOCBP is required at screening and within 24 hours prior to 
administration of each cycle of study treatment. Urine or Serum β-HCG is acceptable; if 
urine pregnancy test cannot be confirmed as negative, a serum pregnancy test is required. 
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166
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12-JUL-2023
10.7.7
Romania
Section 1.3.1 Screening and Intervention Phase
HBV, HCV, and HIV testing at screening is mandatory.
Pregnancy testing must be performed monthly by WOCBP during treatment with study 
interventions and 30 days after last dose of study intervention.
Section 1.3.3 End-of-intervention and Long-term Follow-up
Pregnancy testing must be performed monthly by WOCBP during treatment with study 
interventions and 30 days after last dose of study intervention.
Section 5.2 Exclusion Criteria
Has a known history of HIV infection. HIV testing is required as mandated by local 
regulation.
Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection. Testing for Hepatitis B and Hepatitis C is required at screening.
10.7.8
South Africa
Section 1.3.1 Screening and Intervention Phase
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.
Section 5.2 Exclusion Criteria
Has a known history of HIV infection. HIV testing is required at screening as mandated 
by local regulation.
Has known active tuberculosis (TB; Bacillus tuberculosis) infection requiring systemic 
therapy. Testing for active tuberculosis is required at screening and every 6 months 
during treatment as mandated by local regulation.
08GSPF
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12-JUL-2023
10.7.9
Spain
Section 1.3.1 Screening and Intervention Phase
Monthly and end-of-treatment pregnancy testing must be conducted as per local 
regulations.
HBV, HCV, and HIV testing at screening is mandatory.
Tuberculosis (TB; Bacillus tuberculosis) testing at screening is a required evaluation for 
study entry and needs to be performed in order to evaluate eligibility. This testing can be 
performed at any time during the Screening Period.
Section 1.3.3 End-of-intervention and Long-term Follow-up
Monthly and end-of-treatment pregnancy testing must be conducted as per local 
regulations.
Section 5.2 Exclusion Criteria
Has a known history of HIV infection. HIV testing is required at screening as mandated 
by local regulation.
Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection. Testing for Hepatitis B and Hepatitis C is required at screening.
Has known active tuberculosis (TB; Bacillus tuberculosis). Testing for tuberculosis is 
required at screening. 
Section 6.5 Concomitant Therapy
Investigators must refer to the up-to-date SmPC of registered products used in this study, 
regarding forbidden medications or medications to be used with precaution.
Live vaccines must not be administered for 90 days after the last dose of study 
intervention.
Section 8.3.6 Pregnancy Testing
Monthly and end-of-treatment pregnancy testing must be conducted as per local 
regulations.
Section 10.2 Appendix 2: Clinical Laboratory Tests 
Other screening tests: serology (HIV-RNA, Hepatitis B surface antigen, Hepatitis C virus 
antibody, and tuberculosis), amylase, lipase.
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Section 10.5 Appendix 5: Contraceptive Guidance
Monthly and end-of-treatment pregnancy testing must be conducted as per local 
regulations.
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
Not applicable.
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10.9
Appendix 9: Other Medical Device: Complaints Including Product Quality 
Complaints/Malfunction, Serious Injury, Death, Fetal Distress/Fetal Death and 
Congenital Anomaly: Definitions and Reporting
Not applicable.
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10.10 Appendix 10: Eastern Cooperative Oncology Group
Grade
Performance Status
0
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry 
out any work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair.
5
Dead 
[ECOG ACRIN Cancer Research Group 2016]
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
1L
First Line
AE
Adverse event
ADA
Antidrug Antibodies
ADL
Activities of daily living
ALT
Alanine aminotransferase
ALK
Anaplastic lymphoma kinase
ANC
Absolute neutrophil count
APaT
All-participants-as-treated
aPTT
Activated partial thromboplastin time
AUC
Area under the curve
AST
Aspartate aminotransferase
β-HCG
Beta human chorionic gonadotropin
BCG
Bacillus Calmette-Guérin
BICR
Blinded independent central review
Cavg
Average concentration
CI
Confidence interval
Cmax
Maximal concentration
CNS
Central nervous system
COPD
Chronic obstructive pulmonary disease
COVID-19
Coronavirus disease 2019
CR
Complete response
CrCl
Calculated creatinine clearance
CRF
Case report form
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
ctDNA
Circulating tumor deoxyribonucleic acid
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
Ctrough
Minimal concentration
CV
Coefficient of variation
DILI
Drug-induced liver injury
DMC
Data Monitoring Committee
DOR
Duration of response
ECI
Events of clinical interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic data collection
EGFR
epidermal growth factor receptor 
ELISA
Enzyme-linked immunosorbent assay
EOC
Executive Oversight Committee 
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-Cancer 30
ePRO
Electronic patient-reported outcome
FA
Final analysis
FAS
Full analysis set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FFPE
Formalin-fixed, paraffin embedded
FSH
Follicle stimulating hormone 
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Abbreviation
Expanded Term
FT4
Free thyroxine
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GM
Geometric mean
GMR
Geometric mean ratio
HA
health authority
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B
HCV
Hepatitis C
HIV
Human immunodeficiency virus
IA1
Interim Analysis 1
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgG4
Immunoglobulin G4
IHC
Immunohistochemistry
INR
International normalized ratio
irAEs
Immune-related adverse events
IRB
Institutional Review Board
IRT
Interactive response technology
ITT
intent-to-treat 
IUD
Intrauterine device
IV
Intravenous
IVRS
Interactive voice response system
MAP
modeling analysis plan
mAb
Monoclonal antibody
MASCC
Multinational Association of Supportive Care in Cancer
MRI
Magnetic resonance imaging
MSI
Microsatellite instability
Nab-paclitaxel
Nano particle albumin-bound paclitaxel 
NCI
National Cancer Institute
NI
Non-Inferiority
NSCLC
Non-small cell lung cancer (NSCLC)
OR
Objective response
ORR
Objective response rate
OS
Overall survival
OTC
Over-the-counter
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PET
Positron emission tomography
PFS
Progression-free survival
PK
Pharmacokinetic
PP
Per protocol
PQC
Product quality complaint
PRO
Patient-reported outcome 
PR
Partial response
PTT
Partial thromboplastin time
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Abbreviation
Expanded Term
QoL
Quality of life
RECIST
Response Evaluation Criteria in Solid Tumors RECIST 1.1
RNA
Ribonucleic acid
SAE
Serious adverse events
SAP
Statistical analysis plan
SC
Subcutaneous
SD
Stable disease
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SoA
Schedule of activities
SOC
Standard of care
sSAP
Supplementary statistical analysis plan
SUSAR
Suspected unexpected serious adverse reaction
TPS
Tumor proportion score
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
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12-JUL-2023
08GSPF
CCI
08J3ZK

PRODUCT:  MK-3475  
176
PROTOCOL/AMENDMENT NO.:  A86-07
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12-JUL-2023
08GSPF
CCI
08J3ZK

PRODUCT:  MK-3475  
177
PROTOCOL/AMENDMENT NO.:  A86-07
MK-3475-A86-07 FINAL PROTOCOL
12-JUL-2023
08GSPF
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11
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