Clinical trial NCT03664024
Conditions: Non-Small Cell Lung Cancer
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1) Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2) Carcinoma, Non-Small-Cell Lung Adenocarcinoma
Sponsor: Merck Sharp & Dohme LLC
Start date: 2018-10-30; Completion date: 2021-11-05
Enrollment: 118 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Participants with Stage IV nonsquamous non-small cell lung cancer (NSCLC) without prior systemic treatment will be treated with standard of care pembrolizumab combined with platinum-doublet chemotherapy for 4 cycles, then pembrolizumab plus pemetrexed maintenance for up to 31 additional cycles. The platinum doublet would be pemetrexed plus the investigator's choice of either cisplatin or carboplatin. The primary objective is to evaluate if total baseline tumor mutation burden (TMB) in cell-free circulating tumor deoxyribonucleic acid (ctDNA) is predictive of objective response per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by the investigator by estimating the level of association.

Detailed description:

Arms: arm 1: Participants will receive standard of care pembrolizumab combined with platinum-doublet chemotherapy for 4 cycles, then pembrolizumab plus pemetrexed maintenance for up to 31 additional cycles. The platinum doublet would be pemetrexed plus the investigator's choice of either cisplatin or carboplatin.
Interventions: intervention 1: Pembrolizumab intervention 2: Pemetrexed intervention 3: Carboplatin intervention 4: Cisplatin
Intervention descriptions: intervention 1: Pembrolizumab, 200 mg, Day 1 of each 21-day cycle (Q3W), intravenous infusion (IV), standard of care in most countries intervention 2: Pemetrexed, 500 mg/m\^2 infusion, standard of care, Q3W, IV intervention 3: Carboplatin AUC 5 mg/mL/min, IV infusion, Day 1 of each 21-day cycle for 4 cycles (Cycles 1 - 4). Investigator's choice of either cisplatin or carboplatin. intervention 4: Cisplatin, 75 mg/m\^2, IV infusion, Day 1 of each 21-day cycle for 4 cycles (Cycles 1 - 4). Investigator's choice of either cisplatin or carboplatin.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase II Trial to Investigate Genetic Markers of Response to
Pembrolizumab (MK-3475, SCH 900475) Combined with 
Chemotherapy as a First-line Treatment for Non-Small Cell Lung 
Cancer (KEYNOTE-782)
20 AUG 2021
NCT03664024


PRODUCT: MK 3475 SCH 900475
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PROTOCOL/AMENDMENT NO.: 782 02
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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 CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase II Trial to Investigate Genetic Markers of Response to 
Pembrolizumab (MK-3475, SCH 900475) Combined with Chemotherapy as a First-line 
Treatment for Non-Small Cell Lung Cancer (KEYNOTE-782)
Protocol Number: 782-02
Compound Number: MK-3475
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
116833
EUDRACT
2018-002598-22
NCT
NCT03664024
Approval Date: 20 August 2021
Copyright © 2021
Merck & Co., Inc., Kenilworth NJ USA, and its affiliates.
All Rights Reserved
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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 2
20-AUG-2021
To include instruction allowing participants to be enrolled in a pembrolizumab 
extension study upon study completion, add final analysis in the statistical 
analysis plan, and update the Sponsor’s branding information.
Amendment 1
02-APR-2019
To include direction for re-consenting participants upon disease progression, 
move the collection time point of one of the primary endpoint samples, and 
correct errors in the Schedule of Activities.
Original Protocol
12-JUL-2018
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: [782-02]
Overall Rationale for the Amendments:
To include instruction allowing participants to be enrolled in a pembrolizumab extension study upon study completion, add final 
analysis in the statistical analysis plan, and update the Sponsor’s branding information.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title page
Added a copyright statement
To add clarification on copyrights
4.4 Beginning and End of 
Study Definition
Added text of “Upon study completion, 
participants are discontinued and may be 
enrolled in a pembrolizumab extension 
study, if available.” 
To allow participants to be enrolled in a pembrolizumab 
extension study upon study completion for the medical 
benefit of the participants
9.1 Statistical Analysis Plan 
Summary
Added text “Final analysis will occur after 
all participants have received 35 
administrations of pembrolizumab or 
discontinued study intervention.” 
To add final analysis to the summary of the statistical 
analysis plan
9.8 Final Analysis
Added a section for final analysis
To align with the update in Section 9.1
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................16
1.3
Schedule of Activities (SoA)................................................................................17
2
INTRODUCTION..........................................................................................................30
2.1
Study Rationale....................................................................................................30
Rationale for the Trial and Selected Patient Population..............................30
Tumor Mutation Burden ..............................................................................32
Tumor Cell-Free DNA Analysis..................................................................33
Microbiome Modulation of the Immune System and Immunotherapy .......34
2.2
Background ..........................................................................................................36
Pharmaceutical and Therapeutic Background .............................................37
Completed Clinical Studies..........................................................................37
Ongoing Clinical Studies.............................................................................40
2.2.3.1
Pembrolizumab Studies .....................................................................40
2.2.3.2
Ongoing Grail cfNA Biomarker Studies............................................40
2.3
Benefit/Risk Assessment......................................................................................41
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................41
4
STUDY DESIGN............................................................................................................43
4.1
Overall Design......................................................................................................43
4.2
Scientific Rationale for Study Design.................................................................44
Rationale for Endpoints ...............................................................................44
4.2.1.1
Efficacy Endpoints.............................................................................44
4.2.1.1.1
Efficacy Endpoints per RECIST 1.1........................................44
4.2.1.1.2
Modified RECIST for Immune-based Therapeutics 
(iRECIST)................................................................................45
4.2.1.2
Biomarkers.........................................................................................46
4.2.1.2.1
Circulating Free DNA Mutation Burden .................................46
4.2.1.2.2
Tumor Mutation Burden ..........................................................46
4.2.1.2.3
Microbiome and Metabolomics...............................................46
4.2.1.3
Safety Endpoints................................................................................46
4.2.1.4
Pharmacodynamic Endpoints.............................................................46
4.2.1.5
Planned Exploratory Biomarker Research.........................................47
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4.2.1.5.1
Planned Genetic Analysis ........................................................49
4.2.1.6
Future Biomedical Research..............................................................49
4.3
Justification for Dose...........................................................................................50
Pembrolizumab ............................................................................................50
Chemotherapy..............................................................................................50
4.4
Beginning and End of Study Definition .............................................................50
Clinical Criteria for Early Study Termination .............................................50
5
STUDY POPULATION ................................................................................................50
5.1
Inclusion Criteria.................................................................................................50
5.2
Exclusion Criteria................................................................................................53
5.3
Lifestyle Considerations......................................................................................56
Meals and Dietary Restrictions....................................................................56
Caffeine, Alcohol, and Tobacco Restrictions ..............................................56
Activity Restrictions ....................................................................................56
Contraception...............................................................................................56
Pregnancy.....................................................................................................56
Use in Nursing Women................................................................................57
5.4
Screen Failures.....................................................................................................57
5.5
Participant Replacement Strategy......................................................................57
6
STUDY INTERVENTION............................................................................................57
6.1
Study Intervention(s) Administered...................................................................57
6.2
Preparation/Handling/Storage/Accountability .................................................59
Dose Preparation..........................................................................................59
Handling, Storage, and Accountability........................................................59
6.3
Measures to Minimize Bias: Randomization and Blinding..............................60
Intervention Assignment..............................................................................60
Stratification.................................................................................................60
Blinding........................................................................................................60
6.4
Study Intervention Compliance..........................................................................60
6.5
Concomitant Therapy..........................................................................................60
Probiotics and Prebiotics..............................................................................62
Rescue Medications and Supportive Care ...................................................62
6.6
Dose Modification (Escalation/Titration/Other)...............................................63
Dose Modification .......................................................................................64
Dose Modification for Chemotherapy .........................................................70
6.7
Intervention After the End of the Study............................................................70
6.8
Clinical Supplies Disclosure................................................................................71
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DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................71
7.1
Discontinuation of Study Intervention...............................................................71
7.2
Participant Withdrawal From the Study...........................................................72
7.3
Lost to Follow-up .................................................................................................72
8
STUDY ASSESSMENTS AND PROCEDURES........................................................73
8.1
Administrative and General Procedures ...........................................................74
Informed Consent.........................................................................................74
8.1.1.1
General Informed Consent.................................................................74
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................74
Inclusion/Exclusion Criteria ........................................................................75
Participant Identification Card.....................................................................75
Medical History ...........................................................................................75
Prior and Concomitant Medications Review...............................................75
8.1.5.1
Prior Medications...............................................................................75
8.1.5.2
Concomitant Medications..................................................................75
Assignment of Screening Number...............................................................75
Assignment of Treatment/Randomization Number.....................................76
Study Intervention Administration ..............................................................76
8.1.8.1
Timing of Dose Administration.........................................................76
8.1.8.1.1
Timing of Dose Administration of Pembrolizumab ................76
8.1.8.1.2
Timing of Dose Administration of Pemetrexed.......................76
8.1.8.1.3
Timing of Dose of Carboplatin or Cisplatin ............................77
8.1.8.1.3.1
Carboplatin.....................................................................77
8.1.8.1.3.2
Cisplatin.........................................................................77
Discontinuation and Withdrawal .................................................................77
8.1.9.1
Withdrawal From Future Biomedical Research ................................77
Participant Blinding/Unblinding..................................................................78
Calibration of Equipment.............................................................................78
8.2
Efficacy/Immunogenicity Assessments ..............................................................78
Tumor Imaging and Assessment of Disease................................................78
8.2.1.1
Initial Tumor Imaging........................................................................79
8.2.1.2
Tumor Imaging During the Study......................................................79
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging............................80
8.2.1.4
RECIST 1.1 Assessment of Disease..................................................80
8.2.1.5
iRECIST Assessment of Disease.......................................................80
8.3
Safety Assessments...............................................................................................82
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Physical Examinations.................................................................................83
8.3.1.1
Full Physical Examination.................................................................83
8.3.1.2
Directed Physical Examination..........................................................83
Vital Signs....................................................................................................83
Electrocardiograms ......................................................................................83
Clinical Safety Laboratory Assessments .....................................................84
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)..........................................................................................84
8.3.4.2
Pregnancy Test...................................................................................84
Eastern Cooperative Oncology Group (ECOG) Performance Scale ...........85
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................85
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................85
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......88
Follow-up of AE, SAE, and Other Reportable Safety Event Information...88
Regulatory Reporting Requirements for SAE .............................................88
Pregnancy and Exposure During Breastfeeding ..........................................88
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................89
Events of Clinical Interest (ECIs)................................................................89
8.5
Treatment of Overdose........................................................................................89
8.6
Pharmacokinetics.................................................................................................90
8.7
Pharmacodynamics..............................................................................................90
8.8
Future Biomedical Research Sample Collection...............................................90
8.9
Planned Genetic Analysis Sample Collection....................................................90
8.10
Biomarkers ...........................................................................................................91
Tissue Biomarkers .......................................................................................91
8.10.1.1
PD-L1 IHC.........................................................................................91
8.10.1.2
Exploratory Biomarkers.....................................................................91
Blood-based Biomarkers..............................................................................92
Stool-based Biomarkers...............................................................................92
8.11
Health Economics Medical Resource Utilization and Health Economics.......92
8.12
Visit Requirements...............................................................................................92
Screening......................................................................................................93
Treatment Period..........................................................................................93
Discontinued Participants Continuing to be Monitored in the Study ..........93
8.12.3.1
Safety Follow-up Visit.......................................................................93
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8.12.3.2
Follow-up Visits.................................................................................94
8.12.3.3
Survival Follow-up ............................................................................94
Survival Status .............................................................................................94
9
STATISTICAL ANALYSIS PLAN .............................................................................94
9.1
Statistical Analysis Plan Summary.....................................................................95
9.2
Responsibility for Analyses/In-house Blinding .................................................96
9.3
Hypotheses/Estimation ........................................................................................96
9.4
Analysis Endpoints...............................................................................................96
Efficacy Endpoints.......................................................................................96
Biomarker Endpoints ...................................................................................96
Safety Endpoints..........................................................................................97
9.5
Analysis Populations............................................................................................97
9.6
Statistical Methods...............................................................................................97
Statistical Methods for Biomarker/Efficacy Analyses.................................97
Statistical Methods for Safety Analyses ......................................................99
9.7
Interim Analyses ................................................................................................100
9.8
Final Analysis .....................................................................................................100
9.9
Multiplicity .........................................................................................................100
9.10
Sample Size and Power Calculations ...............................................................100
9.11
Subgroup Analyses.............................................................................................101
9.12
Compliance (Medication Adherence)...............................................................101
9.13
Extent of Exposure.............................................................................................101
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................102
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......102
Code of Conduct for Clinical Trials...........................................................102
Financial Disclosure...................................................................................104
Data Protection...........................................................................................104
10.1.3.1
Confidentiality of Data ....................................................................105
10.1.3.2
Confidentiality of Participant Records.............................................105
10.1.3.3
Confidentiality of IRB/IEC Information..........................................105
Committees Structure.................................................................................105
10.1.4.1
Steering Committee .........................................................................105
Publication Policy......................................................................................105
Compliance with Study Registration and Results Posting Requirements .106
Compliance with Law, Audit, and Debarment ..........................................106
Data Quality Assurance .............................................................................107
Source Documents .....................................................................................108
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Study and Site Closure...............................................................................108
10.2
Appendix 2: Clinical Laboratory Tests............................................................109
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................110
Definition of AE ........................................................................................110
Definition of SAE ......................................................................................111
Additional Events Reported in the Same Manner as SAE.........................112
Recording AE and SAE .............................................................................112
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................116
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................118
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................119
Definitions..................................................................................................119
Contraception Requirements......................................................................120
Pregnancy Testing......................................................................................121
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................122
10.7
Appendix 7: Country-specific Requirements..................................................127
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................128
10.9
Appendix 9: Abbreviations ...............................................................................132
10.10 Appendix 10: Eastern Cooperative Oncology Group (ECOG) 
Performance Scale .............................................................................................134
11
REFERENCES.............................................................................................................135
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LIST OF TABLES
Table 1
Study Schedule of Activities.........................................................................17
Table 2
Adequate Organ Function Laboratory Values ..............................................52
Table 3
Study Interventions.......................................................................................58
Table 4
Dose Modifications for Trial Medications....................................................64
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with Pembrolizumab...............................................65
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines .....................................................................................................68
Table 7
Recommended Dose Modifications for Chemotherapy Hematological 
Toxicity.........................................................................................................70
Table 8
Recommended Dose Modifications for Chemotherapy Non-
Hematological Toxicity ................................................................................70
Table 9
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease..........................................................................................................82
Table 10
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events..............................................................................87
Table 11
Analysis Strategy for Primary and Secondary Objectives............................99
Table 12
Mean Fold Increase in the Total Tumor Mutation Burden (TMB) in 
Circulating Free DNA (cfDNA) for Responders Compared to Non-
responders With 80% and 90% Power to Detect a Coefficient for cfDNA 
TMB Greater Than Zero for Varying Objective Response Rates (ORR)...101
Table 13
Protocol-required Safety Laboratory Assessments.....................................109
Table 14
Highly Effective Contraceptive Methods That Have Low User 
Dependency.................................................................................................121
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LIST OF FIGURES
Figure 1
Trial Schema.................................................................................................16
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase II Trial to Investigate Genetic Markers of Response to 
Pembrolizumab (MK-3475, SCH 900475) Combined with Chemotherapy as a First-line 
Treatment for Non-Small Cell Lung Cancer (KEYNOTE-782)
Short Title: Biomarkers of Response to Pembrolizumab Combined with Chemotherapy in 
Non-Small Cell Lung Cancer (KEYNOTE-782) 
Acronym: KEYNOTE-782
Hypotheses, Objectives, and Endpoints:
Participants with Stage IV nonsquamous NSCLC without prior systemic treatment will be 
treated with standard of care pembrolizumab combined with platinum-doublet chemotherapy 
for 4 cycles, then pembrolizumab plus pemetrexed maintenance for up to 31 additional 
cycles.  The platinum doublet would be pemetrexed plus the investigator’s choice of either 
cisplatin or carboplatin.
Objectives/Hypothesis
Endpoints
Primary Objective
•
Objective:  To evaluate if total baseline 
tumor mutation burden (TMB) in cfDNA 
is predictive of objective response per 
Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST 1.1) by the 
investigator by estimating the level of 
association. 
•
Objective response (OR):  Complete 
response (CR) or partial response (PR)
Secondary Objectives

Objective: To evaluate if total baseline 
TMB in cfDNA is predictive of 
progression-free survival (PFS) per 
RECIST 1.1 by investigator review or
overall survival (OS) by estimating the 
level of association. 
•
PFS is defined as the time from the start 
of treatment to the first documented 
progressive disease (PD) or death due to 
any cause, whichever occurs first. 
•
OS is defined as the time from the start 
of treatment to death due to any cause.
•
Objective:  To evaluate the safety and 
tolerability of pembrolizumab + 
investigator choice chemotherapy.
•
Adverse events (AEs)
•
Discontinuations due to AEs.
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Non-Small Cell Lung Cancer
Population
Male/Female participants with nonsquamous NSCLC who 
have not received prior systemic chemotherapy treatment 
for stage IV NSCLC, are at least 18 years of age, and in 
whom epidermal growth factor receptor (EGFR-), 
anaplastic lymphoma kinase (ALK-), c-ros oncogene 1 
(ROS1), or B isoform of rapidly accelerated fibrosarcoma 
(B-RAF) -directed therapy is not indicated will be enrolled 
in this trial.
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study.
Type of Control
No treatment control
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 3 years from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
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Number of Participants:
Approximately 100 participants will be enrolled in this study as described in Section 9.9.
Intervention Groups and Duration:
Interventio
n Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Regimen/ 
Treatment 
Period/ 
Use
1
Pembrolizumab
200 mg
Q3W
IV 
infusion
Day 1 of 
each 21 day 
cycle
SOCa
Pemetrexed
500 mg/m2
Q3W
IV 
infusion
Day 1 of 
each 21 day 
cycle
SOC
Carboplatin
OR
Cisplatin
AUC 
5 mg/mL/m
in
75 mg/m2
Q3W
IV 
infusion
Day 1 of
each 
21-day 
cycle for 
4 cycles 
(Cycles 1 –
4)
SOC
Abbreviations: IV  intravenous; Q3W  every 3 weeks; SOC  standard of care.
a May not be SOC in some countries.
Total 
Number
1
Duration of 
Partici-
pation
Each participant will participate in the study from the time the participant signs 
the Informed Consent Form (ICF) through the final protocol-specified contact.
After a screening phase of up to 28 days, each participant will be assigned to 
receive study intervention until disease progression is radiographically 
documented and , when clinically appropriate, confirmed by the site per 
modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics (iRECIST) for participants treated with pembrolizumab, 
unacceptable adverse event(s) (AEs), intercurrent illness that prevents further 
administration of treatment, investigator’s decision to discontinue the 
participant, noncompliance with study intervention or procedure requirements or 
administrative reasons requiring cessation of treatment, or until the participant 
has received 35 administrations of pembrolizumab (approximately 2 years).
After the end of treatment, each participant will be followed for the occurrence 
of AEs and spontaneously reported pregnancy as described under Section 8.4.
Participants who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease status until 
disease progression is documented radiographically per RECIST 1.1 , and 
confirmed by the site per iRECIST (for participants treated with 
pembrolizumab), initiating a non-study cancer treatment, withdrawing consent, 
or becoming lost to follow-up. All participants will be followed by telephone for 
overall survival until death, withdrawal of consent, or the end of the study.
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Study Governance Committees:
Steering Committee
Yes
Executive Oversight Committee
No
Data Monitoring Committee
No
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 9.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Trial Schema
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1.3
Schedule of Activities (SoA)
Table 1
Study Schedule of Activities
Trial Period
Screening
Treatment Cycles (3-week cycles)
EOT
Post Treatment
Notes
Visit/Cycle
C1
D1
C2
D1
C3
D1
C4
D1
C5
D1
C6
D1
Cycle 7 
and 
beyond
Safety 
FU
Follow-up 
Visits
Survival 
FU
Scheduled Time Point and 
Window
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
At DC±7
30 Days 
Post DC
±7
Q9W to 
Wk 48, 
then Q12W
± 14 days
Q12W
± 14 days
Administrative Procedures
Informed Consent
X
X
Additional consent 
is required at disease 
progression
Informed Consent for Future 
Biomedical Research (optional)
X
Participant Identification Card
X
Update card once 
participant is
allocated.
Inclusion/Exclusion Criteria
X
Demographics and Medical 
History
X
Prior/Concomitant Medication 
Review (including any prebiotic 
or probiotic use)
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications may 
need to be reported 
beyond 30 days if 
related to an SAE.
NSCLC Disease Details and Prior 
Treatment
X
Obtain Allocation Number using 
IVRS
X
Request after 
eligibility is 
confirmed and prior 
to first treatment.
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PRODUCT: MK 3475 SCH 900475
18
PROTOCOL/AMENDMENT NO.: 782 02
MK 3475 782 02 FINAL PROTOCOL
20 AUG 2021
Trial Period
Screening
Treatment Cycles (3-week cycles)
EOT
Post Treatment
Notes
Visit/Cycle
C1
D1
C2
D1
C3
D1
C4
D1
C5
D1
C6
D1
Cycle 7 
and 
beyond
Safety 
FU
Follow-up 
Visits
Survival 
FU
Scheduled Time Point and 
Window
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
At DC±7
30 Days 
Post DC
±7
Q9W to 
Wk 48, 
then Q12W
± 14 days
Q12W
± 14 days
Subsequent Antineoplastic 
Therapy Status
X
X
X
Survival Status
Participants may be 
contacted for 
survival status at 
any time during the 
course of the study.
Study Treatment Administration-
Pembrolizumab 200 mg
X
X
X
X
X
X
X
Pembrolizumab 
dosed Q3W.
Pemetrexed 500 mg/m2
X
X
X
X
X
X
X
Participants may 
receive maintenance 
pemetrexed at the 
discretion of the 
investigator if 
participant 
discontinues 
treatment with 
pembrolizumab
during the study.
Carboplatin AUC 5 
OR
Cisplatin (75 mg/m2)
X
X
X
X
Dosed Q3W for the 
first 4 cycles.
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PRODUCT: MK 3475 SCH 900475
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PROTOCOL/AMENDMENT NO.: 782 02
MK 3475 782 02 FINAL PROTOCOL
20 AUG 2021
Trial Period
Screening
Treatment Cycles (3-week cycles)
EOT
Post Treatment
Notes
Visit/Cycle
C1
D1
C2
D1
C3
D1
C4
D1
C5
D1
C6
D1
Cycle 7 
and 
beyond
Safety 
FU
Follow-up 
Visits
Survival 
FU
Scheduled Time Point and 
Window
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
At DC±7
30 Days 
Post DC
±7
Q9W to 
Wk 48, 
then Q12W
± 14 days
Q12W
± 14 days
Clinical Procedures / Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
Report non serious 
AEs occurring 
within 30 days after 
the last dose of 
study treatment. 
Report SAEs 
occurring within 90 
days after the last 
dose of study 
treatment, or 
30 days after the last 
dose of study 
treatment if a new 
anticancer therapy is 
initiated, whichever 
is earlier.
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
X
X
Vital Signs and Weight 
X
X
X
X
X
X
X
X
X
Height at screening 
only.
Electrocardiogram
X
Additional ECGs 
may be performed
as clinically 
indicated.
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
For eligibility, 
assess within 10 
days of the first 
dose.
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PRODUCT: MK 3475 SCH 900475
20
PROTOCOL/AMENDMENT NO.: 782 02
MK 3475 782 02 FINAL PROTOCOL
20 AUG 2021
Trial Period
Screening
Treatment Cycles (3-week cycles)
EOT
Post Treatment
Notes
Visit/Cycle
C1
D1
C2
D1
C3
D1
C4
D1
C5
D1
C6
D1
Cycle 7 
and 
beyond
Safety 
FU
Follow-up 
Visits
Survival 
FU
Scheduled Time Point and 
Window
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
At DC±7
30 Days 
Post DC
±7
Q9W to 
Wk 48, 
then Q12W
± 14 days
Q12W
± 14 days
Laboratory Procedures / Assessments: Analysis Performed by Local Laboratory
Pregnancy Test Urine or Serum 
β HCG 5
X
X
X
X
X
X
X
X
X
WOCBP requires 
negative test within 
72 hours prior to 
first dose in study. 
Pregnancy testing 
will be performed 
every cycle during 
the treatment period
and at end of 
treatment as 
described in Section 
10.5.3, and as 
required locally.
PT/INR and aPTT/PTT
X
Perform eligibility 
labs within 10 days 
prior to C1D1. 
Hepatitis B & C Serology
X
Hepatitis B surface 
antigen, HBV DNA, 
HCV RNA (or HCV 
antibody if HCV
RNA is not the local 
SOC). May use 
central lab only if 
local lab is not 
capable. Only 
required if mandated 
by local health 
authority.
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PROTOCOL/AMENDMENT NO.: 782 02
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20 AUG 2021
Trial Period
Screening
Treatment Cycles (3-week cycles)
EOT
Post Treatment
Notes
Visit/Cycle
C1
D1
C2
D1
C3
D1
C4
D1
C5
D1
C6
D1
Cycle 7 
and 
beyond
Safety 
FU
Follow-up 
Visits
Survival 
FU
Scheduled Time Point and 
Window
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
At DC±7
30 Days 
Post DC
±7
Q9W to 
Wk 48, 
then Q12W
± 14 days
Q12W
± 14 days
HIV Testing
X
Not required unless 
mandated by local 
health authority.
CBC with Differential
X
X
X
X
X
X
X
X
X
Perform eligibility 
labs within 10 days 
prior to C1D1. After 
C1D1, may collect 
Hematology Panel 
up to 3 days prior to 
dosing.
Comprehensive Chemistry Panel
X
X
X
X
X
X
X
X
X
Perform eligibility 
labs within 10 days 
prior to C1D1. 
Urinalysis
X
X
X
X
X
X
X
Perform within 
10 days prior to 
C1D1, then C2D1, 
C4D1, and C6D1, 
then every 6th cycle 
thereafter.
T3 or FT3, FT4, and TSH
X
X
X
X
X
X
X
Perform within 10 
days prior to C1D1,
then C2D1, C4D1, 
and C6D1, then 
every second cycle 
thereafter. May use 
central lab only if 
local lab is not 
capable.
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PRODUCT: MK 3475 SCH 900475
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PROTOCOL/AMENDMENT NO.: 782 02
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20 AUG 2021
Trial Period
Screening
Treatment Cycles (3-week cycles)
EOT
Post Treatment
Notes
Visit/Cycle
C1
D1
C2
D1
C3
D1
C4
D1
C5
D1
C6
D1
Cycle 7 
and 
beyond
Safety 
FU
Follow-up 
Visits
Survival 
FU
Scheduled Time Point and 
Window
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
At DC±7
30 Days 
Post DC
±7
Q9W to 
Wk 48, 
then Q12W
± 14 days
Q12W
± 14 days
Blood Samples for Analysis Performed by Central Laboratory
Whole Blood for cfDNA Analyses
X
X
X
X
X
X
Blood for cfDNA 
 will be 
collected 
pretreatment at 
Screening, C2D1, 
C3D1, C4D1, and 
C5D1, on first 
radiographically 
confirmed Partial 
Response (PR), at 
second 
radiographically 
confirmed PR, at 
first 
radiographically 
confirmed Complete 
Response (CR), and 
at radiographically 
or clinically 
confirmed 
Progressive Disease
(PD).
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PRODUCT: MK 3475 SCH 900475
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20 AUG 2021
Trial Period
Screening
Treatment Cycles (3-week cycles)
EOT
Post Treatment
Notes
Visit/Cycle
C1
D1
C2
D1
C3
D1
C4
D1
C5
D1
C6
D1
Cycle 7 
and 
beyond
Safety 
FU
Follow-up 
Visits
Survival 
FU
Scheduled Time Point and 
Window
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
At DC±7
30 Days 
Post DC
±7
Q9W to 
Wk 48, 
then Q12W
± 14 days
Q12W
± 14 days
Serum for Cytokine Analysis
X
X
X
X
X
Blood to be 
collected 
pretreatment, 
pembrolizumab 
infusion for C1D1,
C2D1, C4D1, and 
C12D1, on first 
radiographically 
confirmed Partial 
Response (PR), at 
second 
radiographically 
confirmed PR, at 
first 
radiographically 
confirmed Complete 
Response (CR), and 
at radiographically 
or clinically 
confirmed 
Progressive Disease
(PD).
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20 AUG 2021
Trial Period
Screening
Treatment Cycles (3-week cycles)
EOT
Post Treatment
Notes
Visit/Cycle
C1
D1
C2
D1
C3
D1
C4
D1
C5
D1
C6
D1
Cycle 7 
and 
beyond
Safety 
FU
Follow-up 
Visits
Survival 
FU
Scheduled Time Point and 
Window
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
At DC±7
30 Days 
Post DC
±7
Q9W to 
Wk 48, 
then Q12W
± 14 days
Q12W
± 14 days
Blood for Genetic Analysis
X
Collect 
pretreatment. This 
sample should be 
drawn for planned 
analysis of the 
association between 
genetic variants in 
DNA and drug 
response. Leftover 
extracted DNA will 
be stored for future 
biomedical research 
if the participant 
signs the future 
biomedical research 
consent. 
Blood for RNA Analysis
X
Collect 
pretreatment.
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PRODUCT: MK 3475 SCH 900475
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Trial Period
Screening
Treatment Cycles (3-week cycles)
EOT
Post Treatment
Notes
Visit/Cycle
C1
D1
C2
D1
C3
D1
C4
D1
C5
D1
C6
D1
Cycle 7 
and 
beyond
Safety 
FU
Follow-up 
Visits
Survival 
FU
Scheduled Time Point and 
Window
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
At DC±7
30 Days 
Post DC
±7
Q9W to 
Wk 48, 
then Q12W
± 14 days
Q12W
± 14 days
Plasma for Metabolomics 
Analysis
X
X
X
X
X
Blood to be 
collected before 
infusion of 
pembrolizumab and 
after completing 
chemotherapy 
infusion at C1D1, 
C2D1, C4D1, and 
C12D1, on first 
radiographically 
confirmed Partial 
Response (PR), at 
second 
radiographically 
confirmed PR, at 
first 
radiographically 
confirmed Complete 
Response (CR), and 
at radiographically 
or clinically 
confirmed 
Progressive Disease
(PD).
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PRODUCT: MK 3475 SCH 900475
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20 AUG 2021
Trial Period
Screening
Treatment Cycles (3-week cycles)
EOT
Post Treatment
Notes
Visit/Cycle
C1
D1
C2
D1
C3
D1
C4
D1
C5
D1
C6
D1
Cycle 7 
and 
beyond
Safety 
FU
Follow-up 
Visits
Survival 
FU
Scheduled Time Point and 
Window
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
At DC±7
30 Days 
Post DC
±7
Q9W to 
Wk 48, 
then Q12W
± 14 days
Q12W
± 14 days
Stool Samples for Analysis Performed by Central Laboratory
Stool Microbiome Analysis
X
X
X
X
X
Collected by 
participant at home 
using a kit and 
returned to clinic at 
next study visit. 
Two separate stool 
collections within 1 
week prior to first 
dose of therapy 
C1D1. A single 
stool collection
within 5 days prior 
to each of the 
following study 
visits: C2D1, 
C4D1, C12D1, and 
at radiographically 
or clinically 
confirmed 
Progressive Disease
(PD). Final 
collection may be 
returned to clinic at 
30 day FU visit if it 
cannot be provided 
at progression.
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PRODUCT: MK 3475 SCH 900475
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20 AUG 2021
Trial Period
Screening
Treatment Cycles (3-week cycles)
EOT
Post Treatment
Notes
Visit/Cycle
C1
D1
C2
D1
C3
D1
C4
D1
C5
D1
C6
D1
Cycle 7 
and 
beyond
Safety 
FU
Follow-up 
Visits
Survival 
FU
Scheduled Time Point and 
Window
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
At DC±7
30 Days 
Post DC
±7
Q9W to 
Wk 48, 
then Q12W
± 14 days
Q12W
± 14 days
Tumor Tissue Collection
Newly Obtained/Archival Tissue 
Sample or Biopsy for Biomarker 
Analysis, such as: WES, RNA, 
genetic analysis, and exploratory 
biomarkers
X
May use archival 
tissue sample that 
was obtained prior 
to screening period 
as part of the 
participant’s 
standard care. If 
archived tissue of 
sufficient quality is 
not available, fresh 
core biopsy is 
required. Newly 
obtained tumor 
tissue may be 
obtained within 90 
days of treatment 
initiation. Fine 
needle aspiration 
(FNA) samples will 
not be accepted.
EGFR, ALK, B RAF, and ROS 
Molecular Status
X
May send tumor 
tissue to central lab 
for molecular testing 
if status is unknown 
and cannot be 
determined locally.
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Trial Period
Screening
Treatment Cycles (3-week cycles)
EOT
Post Treatment
Notes
Visit/Cycle
C1
D1
C2
D1
C3
D1
C4
D1
C5
D1
C6
D1
Cycle 7 
and 
beyond
Safety 
FU
Follow-up 
Visits
Survival 
FU
Scheduled Time Point and 
Window
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
At DC±7
30 Days 
Post DC
±7
Q9W to 
Wk 48, 
then Q12W
± 14 days
Q12W
± 14 days
PD L1 Molecular Status
X
Not required for 
eligibility, but 
collected as part of 
pre treatment biopsy
analyses.
Tumor Imaging
Imaging and RECIST 
Assessments (see Section 8.2.1)
X
X
X
See note
X
X
Perform imaging at 
Baseline, C3D1, 
C5D1, C8D1, , then 
Q9W through Week 
48, then Q12W 
subsequently (all
imaging after 
baseline has a ±7
day window). 
Schedule should be 
followed regardless 
of treatment delays.
If imaging was 
obtained within 4 
weeks prior to DC, 
scan at DC is not 
mandatory.
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Trial Period
Screening
Treatment Cycles (3-week cycles)
EOT
Post Treatment
Notes
Visit/Cycle
C1
D1
C2
D1
C3
D1
C4
D1
C5
D1
C6
D1
Cycle 7 
and 
beyond
Safety 
FU
Follow-up 
Visits
Survival 
FU
Scheduled Time Point and 
Window
-28 
to -1
+3
± 3
± 3
± 3
± 3
± 3
± 3
At DC±7
30 Days 
Post DC
±7
Q9W to 
Wk 48, 
then Q12W
± 14 days
Q12W
± 14 days
AE
adverse events; ALK
anaplastic lymphoma kinase; aPTT
activated PTT; AUC
area under the curve; β HCG
beta human chorionic gonadotropin; C
cycle; CBC 
 complete blood count; cfDNA  circulating free DNA; D
day; DC
discontinuation; DNA  deoxyribonucleic acid; ECG  Electrocardiogram; ECOG
Eastern 
Cooperative Oncology Group; EGFR
epidermal growth factor receptor; EOT  end of treatment; FT3
free T3; FT4
free thyroxine; FU  follow up; HBV
hepatitis B 
virus; HCV  hepatitis C virus; HIV  human immunodeficiency virus; INR
international normalized ratio; IVRS
interactive voice response system; iRECIST
modified 
Response Evaluation Criteria in Solid Tumors 1.1 for immune based therapeutics; KRAS  a proto oncogene derived from Kirsten RAt Sarcoma virus; NSCLC
non small 
cell lung cancer; PD L1
programmed cell death ligand 1; PI
principal investigator; PT
prothrombin time; PTT
partial thromboplastin time; Q  Every; 
RECIST
Response Evaluation Criteria in Solid Tumors; RNA  ribonucleic acid; ROS 1
c ros oncogene 1; SAE
serious adverse event; SOC
standard of care; 
T3
triiodothyronine; TSH
thyroid stimulating hormone; W/Wk
Week; WES
whole exome sequencing; WOCBP
women of childbearing potential.
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2
INTRODUCTION
2.1
Study Rationale
Rationale for the Trial and Selected Patient Population
Multiple programmed cell death 1 (PD-1) receptor/programmed cell death ligand 1 (PD-L1)-
based combination therapies show promise in the clinic.  However, it is not clear which 
patients are most likely to respond to which pembrolizumab-based combinations.  This study 
will evaluate the value of TMB, as measured by cfDNA, in predicting the response to 
pembrolizumab and chemotherapy in NSCLC, assess the utility of cfDNA as an emerging 
technology that can allow exploration of the mechanisms of progression on and resistance to 
pembrolizumab and chemotherapy, and assess the role of the metagenomics (microbiome) 
and metabolomics in response to pembrolizumab + chemotherapy in NSCLC. 
The global incidence of lung cancer was 1.8 million in 2012, resulting in an estimated 
1.6 million deaths [World Health Organization 2012]. In the United States, the 2016 
estimated incidence of new diagnoses was 224,400 and estimated number of deaths was 
158,100 [National Cancer Institute 2016]. NSCLC represents approximately 80% to 85% of 
all lung cancers. Of the patients with NSCLC, tumor histology is approximately 46% 
adenocarcinoma, 16% squamous, 5% other (including neuroendocrine), and the rest, “not 
otherwise specified” [Sulpher, J. A., et al 2013].
The standard of care (SOC) for metastatic NSCLC has changed in recent years with the 
development of immunotherapy agents. Two important trials, KEYNOTE-024 and 
KEYNOTE-042, have demonstrated pembrolizumab monotherapy efficacy in the first-line 
setting versus chemotherapy.  In the Phase 3 study KEYNOTE-024, pembrolizumab, a PD-1 
receptor inhibitor, showed statistically significant increases in overall survival (OS) and 
progression-free survival (PFS) compared to SOC platinum-based chemotherapy for 
treatment-naïve participants with metastatic NSCLC whose tumors expressed high levels of 
PD-L1 (tumor proportion score [TPS] ≥50%) with no epidermal growth factor receptor 
(EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations, leading to 
regulatory approval for this indication in the US and other countries around the world.
Approximately 30% of patients with newly diagnosed, advanced NSCLC have tumors that 
highly express PD-L1 to a TPS ≥50% [Reck, M., et al 2016].
KEYNOTE-042 is an international, open-label, Phase 3 study designed to compare OS 
between pembrolizumab and standard of care platinum-doublet chemotherapy as first-line 
therapy in patients with advanced or metastatic NSCLC that expresses PD-L1 in ≥1% of 
tumor cells.  In 2018, an interim analysis conducted by the independent Data Monitoring 
Committee (DMC) demonstrated that treatment with pembrolizumab resulted in significantly 
longer OS than platinum-based chemotherapy (carboplatin plus paclitaxel or carboplatin plus 
pemetrexed) in patients with a PD-L1 TPS ≥1%. As part of a prespecified analysis plan, OS 
was sequentially tested and was significantly improved in patients with a TPS ≥50%, with a 
TPS ≥20%, and then in the entire study population with a TPS ≥1% [Lopes, G., et al 2018]. 
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The safety profile of pembrolizumab in this trial was consistent with that observed in 
previously reported monotherapy studies involving patients with advanced NSCLC.  
Prior to the approval of pembrolizumab, the SOC for first-line metastatic NSCLC has been 
platinum-doublet chemotherapy. Studies evaluating different pembrolizumab combinations 
in anti-PD-1/PD-L1 naïve participants have shown preliminary evidence of clinical activity 
in participants with recurrent and/or metastatic disease. To evaluate the activity of the 
combination of pembrolizumab and chemotherapy, 2 pivotal studies were initiated,
KEYNOTE-021 and the follow-up study, KEYNOTE-189 (see Section 2.2.2).  In the Phase 
1/2 study KEYNOTE-021 Cohort G, pembrolizumab plus pemetrexed and carboplatin 
showed statistically significant increases in objective response rate (ORR) compared to 
pemetrexed and carboplatin alone in participants with nonsquamous advanced NSCLC, 
regardless of PD-L1 status, although the ORR was higher in the TPS ≥50% subgroup. These
results established pembrolizumab plus chemotherapy as an efficacious option for first-line 
therapy in patients with NSCLC; these findings were further evaluated in the Phase 3 study 
KEYNOTE-189 (nonsquamous histology).  In KEYNOTE-189, pembrolizumab plus
investigator choice platinum agent and pemetrexed chemotherapy had a statistically
significant increase in OS over the platinum agent and pemetrexed alone in advanced 
NSCLC [Lopes, G., et al 2018].
However, for these studies not all NSCLC patients have shown benefit from anti-PD-1 
antibody therapy, either alone or in combination with chemotherapy, presumably due to 
multiple inherent or acquired immune-mediated resistance mechanisms that are active at the 
level of the host, including microbiome, or the tumor microenvironment. Moreover, many 
patients ultimately progress, indicating the need for identifying those mechanisms to increase
and maintain benefit. Such resistance mechanisms are likely to be heterogeneous and multi-
factorial; therefore, identifying new biomarkers of response to differentiate potential 
responders or non-responders will enable further development of more sophisticated patient 
selection criteria and potential combination therapies, either up front or upon progression. 
Furthermore, taking a more holistic approach, markers of a microbiome conducive or 
detrimental to PD-1 therapy may point to possible microbiome augmentation or modulation 
to enhance anti-PD-1 therapy and/or reduce associated drug toxicity. To elucidate this 
biology, it is best considered where PD-1 has established efficacy either alone or in 
combination with other agents.
PD-L1 has been established as a validated predictive biomarker for response to 
pembrolizumab monotherapy in first-line NSCLC [Reck, M., et al 2016].  We are interested 
in exploring other potential markers of PD-1 and chemotherapy activity. 
Data from NSCLC studies have demonstrated that treatment with a combination of 
pembrolizumab and chemotherapy has clinical benefit over chemotherapy alone [Gandhi, L., 
et al 2018]. Chemotherapy adds another layer of complexity to PD-1 intervention due to its 
multitude of effects on the patient’s physiology, tumor, and immune system.
In return, other elements may modulate chemotherapy function such as the microbiome,
which comprises the eukaryote and prokaryote microorganisms that occupy distinct 
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ecological niches. Advances in the study of the microbiome have indicated a range of 
physiological effects are manifested by these organisms. The microbiome has been shown to 
modulate the function of a variety of chemotherapies through immune- and non-immune-
mediated mechanisms.  
Pembrolizumab has been combined with chemotherapy in several tumor types, yet little is 
known about the biological mechanisms of the interactions between these therapies. The 
deep interrogation of response and resistance mechanisms to pembrolizumab in combination 
with chemotherapy has the potential to establish tumor-agnostic markers of response and/or 
resistance. 
Understanding the relationship between tumor genetics, the immune system, microbiome, 
and response to anti-PD-1 therapy is best determined in participants who have not received 
several lines of prior systemic therapy, surgery, or radiation due to potential detrimental 
effects on immune and microbiome compartment function when considered alone or the 
relationships between them.  Furthermore, an appropriate treatment niche is where benefit of 
pembrolizumab combination therapy has been established.  Consequently, a first-line
NSCLC setting such as used for KEYNOTE-21 Cohort G and KEYNOTE-189 represents an 
appropriate population to undertake these exploratory genetic and biomarker analyses to 
further understand patient selection and mechanisms of drug action and resistance. Validated 
biomarkers may ultimately be needed to guide patients, physicians, and payers through an 
expanding armamentarium of combination options.
Tumor Mutation Burden
Tumor rejection antigens allow tumors sufficiently distinct from normal tissue to activate the 
immune system and induce an efficient antitumor response. Tumor-mutated specific antigens 
(neoantigens) are major tumor rejection antigens [Schumacher, T. N. 2015] [Castle, J. C., et 
al 2012]. The recent development of innovative deep sequencing technologies (at an 
affordable cost) along with advances in bioinformatics has enabled systemic analysis of 
nonsynonymous somatic TMB and identification of potentially immunogenic neoantigens. 
The genetic landscape and the full spectrum of genomic alterations in each individual tumor 
provide the guidance for personalized cancer immunotherapy [Yuan, J. 2016].
Two pilot studies in mouse models first demonstrated that whole exome sequencing is able to 
identify neoantigen-specific cluster of differentiation (CD)8+ T-cells associated with tumor 
response [Matsushita, H., et al 2012] [Castle, J. C., et al 2012]. Several clinical studies 
demonstrated the feasibility and importance of understanding the immunogenicity of 
neoantigens and their potential clinical application in patients treated with tumor-infiltrating 
lymphocyte adoptive cell therapy [Robbins, P. F., et al 2013] [Tran, E. 2014] [Linnemann, 
C., et al 2015]. Tumor mutational burden was associated with clinical outcome to immune 
checkpoint blockade cancer immunotherapy in patients with advanced melanoma and
NSCLC [Snyder, A., et al 2014] [Rizvi, N. A., et al 2015] [Van Allen, E. M., et al 2015]. 
Patients with mismatch repair deficient tumors likewise had high rates of clinical response to 
PD-1 blockade [Le, D., et al 2015].  The recent 2017 FDA approval of pembrolizumab in 
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microsatellite instability (MSI)-high tumors highlights this relationship between DNA repair 
abrogation, neoantigens, and response to checkpoint inhibitors.
Recent data have shown a relationship between TMB and monotherapy response to 
pembrolizumab in NSCLC [Rizvi, N. A., et al 2015].  Checkmate 227 was a multi-arm 
randomized trial aimed at analysis of checkpoint inhibition in first-line NSCLC. The 
statistical design was modified during trial execution to include TMB for patient stratification
independent of PD-L1-status. Selective trial data were presented at the 2018 annual 
American Association for Cancer Research meeting [Hellmann, M. D., et al 2018] and 
indicated that the combination of a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
inhibitor, ipilimumab, and the PD-1 inhibitor nivolumab had superior PFS compared to 
chemotherapy for participants with high TMB defined at >10 mutations per megabase of 
genomic DNA. 
Data from KEYNOTE-189 have indicated that regardless of PD-L1 status, pembrolizumab 
and chemotherapy had superior OS compared to chemotherapy alone in the first-line
nonsquamous NSCLC setting. TMB has not been prospectively interrogated in this 
population as an exploratory marker, and several significant questions remain around 
relationship between PD-L1 status, TMB, and whether TMB itself is predictive of response
in the setting of an anti-PD-1/PD-L1 agent and chemotherapy.
This trial is intended to extend these studies to investigate TMB as one of several exploratory 
genetic markers for response to pembrolizumab in combination with chemotherapy in the 
first-line NSCLC setting.
Tumor Cell-Free DNA Analysis
Tumor genetics and TMB have been historically interrogated using next-generation 
sequencing technologies using formalin-fixed paraffin embedded tissue (FFPE), with DNA 
sequencing being whole genome, whole exome, or defined gene panels. For many tumor 
types, biopsies have inherent risk to the patient, notwithstanding patient logistical and 
financial costs. While biopsies for diagnosis do constitute a standard of care, for a variety of 
technical reasons, including having reliable tissue for DNA sequencing, blood-based markers 
offer a variety of advantages.  Furthermore, biopsies are usually undertaken at diagnosis,
whereas blood-based markers have the advantage of being interrogated over the course of 
therapy and importantly at progression.
Through mechanisms that are not well understood, small fragments of tumor DNA appear in 
systemic circulation. An increasing body of evidence demonstrates that these fragments, 
known as cell-free circulating tumor DNA (cfDNA), directly encode genetic features of the 
tumors from which they are derived (http://www.grail.com). cfDNA can be interrogated at 
the whole-genome level or using defined gene panels. The latter offers several advantages,
including cost and reduced sequencing and analysis time, both of which are important in a 
clinical setting. Gene panels can be constructed to interrogate several features of a tumor’s 
genetics and can obtain the same depth of genetic information as can be obtained from 
whole-genome analyses.
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The complexity of tumors suggests that measurements that capture the breadth of the 
heterogeneous cancer genomes represent the best and most direct signature of disease 
biology. High-intensity sequencing assays can readily detect the low fraction of cfDNA in 
the bloodstream, which is very small compared to DNA from non-cancerous cells.  This 
necessitates the ability to distinguish faint signals and tumor genetics of early-stage through 
advanced tumors from a background of wild-type genomic DNA. cfDNA technology 
represents a unique capability for deciphering tumor genetics without the need for invasive 
and potentially detrimental tumor biopsies. 
Biopsy-dependent markers have the detriment of limited samplings over the course of 
therapy. Consequently, there is little temporal information that can be obtained to identify 
tumor genetic evolution over the course of therapy.  Furthermore, the ability to predict 
response and/or progression is constrained by a defined time point analysis of the tumor-
immune interaction, which is not relevant to the stochastic relationship between an evolving 
tumor and the immune system. Therefore, a blood-based cfDNA assay offers the advantage 
as a read-out of these temporal changes, with the prospect of kinetic assessment of tumor 
fraction cfDNA being predictive for early response and/or progression to immunotherapy. In 
addition, the ability to assess temporal changes in tumor genetics will give insight into tumor 
clonal evolution and immune editing of specific neoantigens.
Therefore, as cfDNA represents the genomic diversity of cancer throughout the body, 
cfDNA-based tests have the potential to deliver sensitive and specific tests for early cancer 
detection, analysis of TMB and tumor genetics, mechanisms of resistance to immunotherapy, 
and importantly, determination of tumor response to therapy. This trial will assess these 
exploratory genetic markers, including TMB, in collaboration with GRAIL Inc. 
(http://www.grail.com), a company specializing in tumor cfDNA analysis. These analyses 
will be performed using a proprietary gene panel and bioinformatics pipeline aimed at a 
focused assessment of NSCLC genetics and immune activity. 
This study will investigate the utility of cfDNA technology to assess tumor genetics as 
predictive for response or resistance to pembrolizumab plus chemotherapy in study 
participants with stage IV NSCLC without prior systemic therapy. The study will also 
investigate other exploratory cellular and genetic markers of immune response.
Microbiome Modulation of the Immune System and Immunotherapy
The human body is host to large numbers of bacteria and other microorganisms, primarily 
colonizing epithelial surfaces with the highest densities within the lower GI tract. 
Microbiome components have both local and physiological effects that are mediated via 
microbiome-immune co-evolution and microbiome production of metabolites [Belkaid, Y. 
2017]. These commensals play an important homeostatic role in a variety of human body 
systems, including the immune system and endocrine systems. The microbiota play a 
fundamental role in the induction, evolution, function, and modulation of the host immune 
system. Likewise, the host immune system has evolved mechanisms to maintain this 
symbiotic relationship with the microbiome. The maintenance of this communication allows 
the induction of protective responses to pathogenic organisms and the utilization of immune 
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regulatory pathways involved in the sustained tolerance to innocuous antigens. This ability of 
the microbiome components to set the systemic immunological tone requires complex 
feedback loops between innate and adaptive components of the immune system. 
The largest component of the microbiome in numbers and biological complexity is within the 
gut environment. These commensals have systemic immune-stimulatory and 
immune-regulatory effects, which suggest the gut microbiome impacts the systemic immune 
system through a broad range of immune functions [Haase, S., et al 2018].  The lung is one 
such tissue impacted by this distant microbiome ecology [Shukla, S. D., et al 2017]. Chronic 
respiratory diseases, namely asthma, chronic obstructive pulmonary disease (COPD) and 
cystic fibrosis, all have been demonstrated to be impacted by the gut microbiota (reviewed in 
[Shukla, S. D., et al 2017] [Lloyd, C. M. 2017]). The gut lung cross-talk is considered to be 
mediated by resident microbes, microbiome-generated metabolites, and patrolling immune 
cells. This relationship between the systemic effects of the gut microbiome and the immune 
system suggests a combined impact on the development of cancer and its evasion of the 
immune system.  
The microbiome may modulate systemic T cell-mediated tumoricidal activity, as 
administration of antibiotics severely reduced the efficacy of adoptive T-cell transfer in 
several mouse models of cancer [Luo, A., et al 2017].  The microbiome-mediated modulation 
of the immune system impacts cancer at all of its developmental stages, including 
development, elimination, equilibrium, and escape [Zitvogel, L., et al 2018] [Kim, C. H. 
2018] [Rea, D., et al 2018]. Some tumors themselves have been reported to have a resident 
microbiome population, suggesting that effects may sometimes be more direct [Hooper, S. J., 
et al 2007] [Chanudet, E., et al 2007] [Hubbard, A. L., et al 1998] [Silva-Valenzuela, C. A., 
et al 2016]. Microorganism presence in tumor tissue can be directly related to tumorigenesis, 
as exemplified by Helicobacter pylori in gastric cancer [Wroblewski, L. E., et al 2010], or 
may represent a coincidental infection.
However, our understanding of this biological interaction between microbiome and tumor 
immunology is limited.  Evidence suggests for some cancers, such as GI cancer, that gut 
dysbiosis is a direct contributing factor to cancer development and immune evasion [Meng, 
C., et al 2018].  Identifying defined mechanisms of microbiome-induced immune evasion of 
cancer will help to determine how that microbiome may also be directed to be “pro-
tumorigenic” versus “tumor-protective”.  Furthermore, the microbiome has an additional 
cancer-related effect, which is modulation of the effectiveness of chemotherapy and 
immunotherapy. So, identifying how to alter microbiome elements to increase therapy 
effectiveness may be a new element in cancer therapy. 
The recent advances in the use of immunotherapy in the first-line lung cancer space have
indicated the rationale for combination of chemotherapy with immune agents. The concept 
that the microbiome may independently modulate these modalities individually and in 
combination indicates a need to understand these effects. Evidence from mouse models 
suggests links between the effectiveness of platinum-based cytotoxic compounds and the 
microbiome [Iida, N., et al 2013] [Alexander, J. L., et al 2017]. However, there are limited 
clinical data on microbiome and standard of care chemotherapies. 
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Recent work has indicated a possible involvement of microbiome in influencing the efficacy 
of checkpoint inhibitor treatment strategies for both CTLA-4- and PD-1-targeting checkpoint 
inhibitors. Mouse models indicated direct links between various bacterial genera and T-cell 
components associated with checkpoint inhibitors [Vetizou, M., et al 2015].  Three recent 
investigations into the microbiome and the PD-1/PD-L1 axis have provided clinical data that 
the gut microbiome modulates the response to inhibitors of PD-1/PD-L1 axis
[Gopalakrishnan, V., et al 2018] [Matson, V., et al 2018] [Routy, B., et al 2018]. Overall, 
they indicated that a healthier, highly diverse microbiota and the presence of certain bacterial 
species favor the establishment of an anti-tumor immune response at baseline that may be 
enhanced by the anti-PD-1 axis treatment, leading to a more favorable clinical response. 
These studies reported the importance of defined gut microbiota on response to PD-1 
therapy, but highlighted different bacterial players between the studies. Many factors 
modulate microbiome composition, such as geographical location, socioeconomic factors, 
antibiotic or other drug use, early childhood exposure, stress, and diet. Furthermore, the 
taxonomic identification of bacterial species by shotgun metagenomics has several 
limitations, including incomplete databases of full bacterial genomic sequences and analysis 
pipelines. In addition, the effects of the microbiota on therapy are likely due to changes in the 
population ecology and metabolism of the gut microbiota that together affect cancer 
immunity. Presumably, the effects on the immune system may not be wholly dependent on 
the bacterial composition per se but more potentially on the metabolites they produce
[Cummings, J. H., et al 1987] [Rooks, M. G. 2016] [Stockinger, B., et al 2014]. So,
understanding the element of bacterial-produced metabolites through metabolomics analysis 
in conjunction with microbiome assessment will help us to further understand the 
relationship with response to anti-PD-1 therapy.
This trial will investigate, as exploratory markers, the role of the microbiome and 
metabolomics in response to pembrolizumab plus chemotherapy in treatment-naïve NSCLC 
participants. A first-line lung population is the more suitable niche, as prior lines of therapy 
are likely to have perturbed the microbiota due to the therapy itself, AEs such as GI toxicity, 
or the management of AEs such as use of antibiotics in infections.
2.2
Background
Pembrolizumab is a potent humanized immunoglobulin (Ig)G4 monoclonal antibody (mAb) 
with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction with 
PD-L1 and programmed cell death ligand 2 (PD-L2).  Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1.  
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an intravenous (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 Investigator’s Brochure (IB).
In this study, pembrolizumab will be administered in combination with pemetrexed and 
either cisplatin or carboplatin.   Refer to the prescribing information for cisplatin, carboplatin, 
and pemetrexed.
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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 to 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]. 
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 Ig-variable type (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 CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (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 NSCLC.
Completed Clinical Studies
Six completed, company-sponsored, clinical studies were conducted to evaluate the efficacy 
of pembrolizumab monotherapy and pembrolizumab combination therapy in the treatment of 
NSCLC: KEYNOTE-001, KEYNOTE-010, KEYNOTE-021, KEYNOTE-024, 
KEYNOTE-042, and KEYNOTE-189.  Several additional studies are in progress.  Refer to 
the current pembrolizumab IB for a description of KEYNOTE-001 and KEYNOTE-010.  
The results of KEYNOTE-010 indicate that in previously treated participants with NSCLC 
with PD-L1 TPS ≥1%, and disease progression following platinum-containing 
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chemotherapy, pembrolizumab provides a statistically significant and clinically meaningful 
OS benefit compared to standard docetaxel chemotherapy. Furthermore, the PD-L1 selection 
employed in KEYNOTE-010 identified participants more likely to benefit from 
pembrolizumab and resulted in favorable HR in OS compared to docetaxel.
Overall, the results from KEYNOTE-001 and KEYNOTE-010 demonstrated that 
pembrolizumab provided substantial, clinically meaningful benefits in OS, PFS, and ORR in 
participants with NSCLC who progressed after platinum-containing chemotherapy and 
whose tumor cells expressed PD-L1. The 2 key clinical studies for this trial population are 
KEYNOTE-021 Cohort G and KEYNOTE-189.
KEYNOTE–021
In the Phase 1/2 Cohort A of KEYNOTE-021, 25 participants with treatment-naïve, 
advanced/metastatic NSCLC, regardless of PD-L1 expression and without treatable EGFR or 
ALK aberrations, were treated with 4 cycles of carboplatin, paclitaxel, and pembrolizumab 
(randomized 1:1 to 2 mg/kg or 10 mg/kg) followed by pembrolizumab Q3W [Langer, C. J., 
et al 2016]. The primary endpoint of the cohort was to determine the recommended Phase 2 
dose for pembrolizumab in combination with chemotherapy in participants with unresectable 
or metastatic NSCLC.
No dose-limiting toxicities were observed, no treatment-related deaths occurred, and no 
treatment-related discontinuations occurred. Grade 3/4 AE were observed in 56% of 
participants and potential irAEs were observed in 16% of participants.
After a median duration of follow-up of 13 months (range, 2-21 months), the confirmed ORR 
was 52% (13/25; 95% CI: 31 to 72) per blinded independent central review (BICR). Median 
PFS was 10.3 months (95% CI: 3.7 to not reached [NR]) per BICR and OS was NR (95% CI: 
11.0 to NR). Responses were seen in both PD-L1-positive and PD-L1-negative participants 
[Gadgeel, S., et al 2016]
In the Phase 2 Cohort G study KEYNOTE-021, pembrolizumab plus pemetrexed plus 
carboplatin demonstrated a statistically significant increase in ORR and PFS compared to 
pemetrexed plus carboplatin alone for participants with treatment-naïve advanced NSCLC in 
whom EGFR- or ALK-directed therapy is not indicated. The magnitude of benefit observed 
in this PD-L1 unselected nonsquamous NSCLC population has not been observed in 
randomized studies adding a third agent to standard chemotherapy and subsequently led to 
FDA-accelerated approval of the combination for the first-line treatment of participants with 
metastatic nonsquamous NSCLC, contingent upon verification and description of clinical 
benefit in a confirmatory study [Langer, C. J., et al 2016].
Cohort G included participants with treatment-naïve, nonsquamous, stage IIIB/IV NSCLC, 
irrespective of PD-L1 expression and without treatable EGFR mutations or ALK 
translocations, randomized 1:1 to receive pembrolizumab plus pemetrexed plus carboplatin 
OR pemetrexed plus carboplatin alone.
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The cohort enrolled 123 participants, with 60 randomly assigned to the pembrolizumab plus 
chemotherapy arm and 63 to the chemotherapy alone group. For the primary endpoint of 
ORR, 33/60 participants (55%; 95% CI: 42 to 68) in the pembrolizumab plus chemotherapy 
group achieved an objective response compared with 18/63 participants (29%; 95% CI: 18 to 
41) in the chemotherapy-alone group (estimated treatment difference: 26% [95% CI: 9 to 
42]; p 0.0016).
Progression-free survival was significantly longer with pembrolizumab plus chemotherapy 
compared with chemotherapy alone (HR 0.53 [95% CI: 0.31 to 0.91]; p 0.010). Median PFS 
was 13.0 months (95% CI: 8.3 to NR) for pembrolizumab plus chemotherapy and 8.9 months 
(95% CI: 4.4 to 10.3) for chemotherapy alone. At the time of data cutoff, no difference in 
survival was noted between treatment groups (HR 0.90 [95% CI: 0.42 to 1.91]), though the 
survival analysis may be premature and participants progressing on the chemotherapy-only 
arm were permitted to crossover to pembrolizumab monotherapy on study as well as receive 
immunotherapy subsequently.
Treatment-related AEs occurred in 55/59 (93%) participants in the as-treated pembrolizumab 
plus chemotherapy group and 56/62 (90%) participants in the as-treated chemotherapy alone 
group, including 23 (39%) and 16 (26%) participants, respectively, who had events of 
Grade 3 or worse severity. The rate of treatment discontinuation because of treatment-related 
AEs was similar between groups, with 6/59 (10%) participants in the pembrolizumab plus 
chemotherapy group and 8/62 (13%) participants in the chemotherapy-alone group.
The addition of pembrolizumab to carboplatin and pemetrexed significantly improved the 
proportion of participants who achieved an objective response compared with carboplatin 
and pemetrexed alone in participants with chemotherapy-naïve, advanced nonsquamous 
NSCLC. In addition, this combination significantly prolonged PFS in this population. These 
data suggest that the combination of pembrolizumab, carboplatin, and pemetrexed provides a 
significant and clinically relevant improvement in antitumor activity compared with 
chemotherapy alone for treatment-naïve, nonsquamous, advanced NSCLC. These results 
subsequently led to the FDA-accelerated approval of the combination for the first-line 
treatment of participants with metastatic nonsquamous NSCLC, contingent upon verification 
and description of clinical benefit in a confirmatory study KEYNOTE-189.
KEYNOTE-189
KEYNOTE-189 is a Phase 3, randomized, double-blinded, active-controlled, multicenter 
study of pembrolizumab plus pemetrexed and platinum (carboplatin or cisplatin) versus 
pemetrexed and platinum in participants with treatment-naïve, metastatic, nonsquamous 
NSCLC. The primary endpoint is PFS per RECIST 1.1 as assessed by BICR. 
The results of the KEYNOTE-189 demonstrated an OS benefit of pembrolizumab plus 
platinum-based doublet chemotherapy to platinum-doublet chemotherapy alone [Gandhi, L., 
et al 2018]. After a median follow-up of 10.5 months, the estimated survival at 12 months 
was 69.2% (95% CI: 64.1 to 73.8) in the pembrolizumab-containing group versus 49.4% 
(95% CI: 42.1 to 56.2) in the placebo-combination group, with an HR for death 0.49 (95% 
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CI: 0.38 to 0.64; p<0.001).  There was an improvement in OS seen across all PD-L1 groups 
that were evaluated. The median PFS was 8.8 months (95% CI: 7.6 to 9.2) in the 
pembrolizumab-containing group and 4.9 months (95% CI: 4.7 to 5.5) in the placebo-
combination group, with an HR for disease progression or death 0.52 (95% CI: 0.43 to 0.64; 
p<0.001). The KEYNOTE-189 data indicate that the combination of a checkpoint inhibitor 
and chemotherapy is a viable therapeutic option for first-line NSCLC treatment.
The overall response rate assed by BICR was 47.6% (95 CI: 42.6 to 52.5) in the 
pembrolizumab-combination group and 18.9% 95% CI: 13.8 to 25.0) in the placebo-
combination group (p<0.001). The disease control rate (the proportion of patients with a 
confirmed complete or partial response or stable disease) was 84.6% in the pembrolizumab 
combination group and 70.4% in the placebo-combination group. The median duration of 
response was 11.2 months (range, 1.1+ to 18.0+) in the pembrolizumab-combination group 
and 7.8 months (range, 2.1+ to 16.4+) in the placebo-combination group. The response rate 
in the pembrolizumab-containing arm was higher in all categories of PD-L1 tumor proportion 
score, with the greatest difference in patients with TPS ≥50% (61.4% vs 22.9%).
Adverse events of any cause regardless of attribution occurred in 99.8% of the patients in the 
pembrolizumab-combination group and in 99.0% of those in the placebo-containing group. 
The events were Grade 3 or higher in 67.2% and 65.8% of the patients, respectively. 
Discontinuation of all trials drugs because of AEs occurred in 13.8% of patients in the 
pembrolizumab-combination group and in 7.9% of the placebo-containing group. 
Discontinuation of pembrolizumab and placebo were 20.2% and 10.4%, respectively. 
These results have confirmed that KEYNOTE-21 Cohort G and KEYNOTE-189 have 
demonstrated the increased clinical efficacy of pembrolizumab and platinum-containing 
doublet chemotherapy versus platinum-containing doublet across all categories of PD-L1 
expression.  The data from KEYNOTE-021 and KEYNOTE-189 demonstrate there is still a 
need to understand the biology of resistance to PD-1 inhibitors and exploratory markers of 
pembrolizumab and chemotherapy response.
Ongoing Clinical Studies
2.2.3.1
Pembrolizumab Studies
Pembrolizumab is under evaluation in participants with NSCLC as monotherapy and in 
combination with chemotherapy, immunotherapy, and targeted therapies. A full list of 
ongoing company-sponsored studies can be found in the current IB of pembrolizumab.
2.2.3.2
Ongoing Grail cfNA Biomarker Studies
There are 2 ongoing GRAIL-sponsored oncology studies using cfDNA to interpret tumor 
genetics.  NCT02889978 titled “The Circulating Cell-free Genome Atlas Study (CCGA)” is a 
study aimed at mapping the cell-free tumor genome of early cancer patients. This study will 
collect biological samples from donors with a new diagnosis of cancer (blood and tumor 
tissue) and from donors who do not have a diagnosis of cancer (blood) in order to 
characterize the population heterogeneity in cancer and non-cancer participants and to 
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develop and validate models for distinguishing cancer from non-cancer.  The purpose of the 
CCGA Study is to characterize the landscape of cell-free nucleic acid (cfNA) profiles in 
individuals with and without cancer, and develop an assay to detect early cancer in blood. 
The observational CCGA Study will enroll approximately 10,500 individuals with newly 
diagnosed cancer (treatment naïve) and approximately 4500 individuals without cancer, 
interrogating the biology of both tumor biopsy tissue samples and the circulating, tumor-
derived nucleic acids in blood. cfNAs in the blood are an emerging biomarker for earlier 
cancer detection. Clinical outcomes data will be collected on the enrolled participants at least 
annually for up to 5 years. The result will be a detailed atlas of cancer genetics that GRAIL 
will use to support its product development goals. The database, upon analysis, may be 
expanded to enroll additional individuals with specific cancers or without cancer. Initial 
results from a substudy of approximately 1650 participants from CCGA were presented at 
the 2018 Annual American Association for Cancer Research Conference [Aravanis, A. A., et 
al 2018].
NCT03085888 is an observational breast cancer study titled “The STRIVE Study: Breast 
Cancer Screening Cohort for Development of Assays for Early Cancer Detection”. The aim 
of this study is to use high-intensity sequencing of circulating cfNAs to support the 
development of a test for detection of invasive breast cancer. STRIVE is a multi-center, 
longitudinal, prospective, observational study that will enroll approximately 120,000 women 
at the time of their screening mammogram.     
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.  Results from KEYNOTE-189 
show that treatment with pembrolizumab plus platinum-doublet chemotherapy provides a 
substantial benefit in this patient population [Gandhi, L., et al 2018]. Additional details 
regarding specific benefits and risks for participants participating in this clinical study may 
be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Participants with Stage IV nonsquamous NSCLC without prior systemic treatment will be 
treated with standard of care pembrolizumab combined with platinum-doublet chemotherapy 
for 4 cycles, then pembrolizumab plus pemetrexed maintenance for up to 31 additional 
cycles.  The platinum doublet would be pemetrexed plus the investigator’s choice of either 
cisplatin or carboplatin.
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Objectives
Endpoints
Primary Objective
•
Objective: To evaluate if total baseline 
TMB in cfDNA is predictive of objective 
response per RECIST 1.1 by the 
investigator by estimating the level of 
association.
•
Objective response (OR):  Complete 
response (CR) or partial response (PR)
Secondary Objectives
•
Objective: To evaluate if total baseline 
TMB in cfDNA is predictive of PFS per 
RECIST 1.1 by investigator review or OS
by estimating the level of association. 
•
PFS is defined as the time from the start 
of treatment to the first documented 
progressive disease (PD) or death due to 
any cause, whichever occurs first.   
•
OS is defined as the time from the start of 
treatment to death due to any cause.
•
Objective:  To evaluate the safety and 
tolerability of pembrolizumab + 
investigator choice chemotherapy
•
AEs 
•
Discontinuations due to AEs
Tertiary/Exploratory Objectives
•
Objective:  To evaluate whether total 
baseline TMB in cfDNA or whole exome 
sequencing (WES) of tumor 
biopsy/sample is predictive of OR and
PFS per iRECIST 1.1 by investigator
review
•
OR:  Complete response (CR) or partial 
response (PR)
•
PFS is defined as the time from the start 
of treatment to the first documented PD 
or death due to any cause, whichever 
occurs first.   
•
Objective:  To characterize kinetic 
profiles of tumor fraction in cfDNA and 
evaluate whether they are predictive of 
OR and PFS per RECIST 1.1 by 
investigator review and OS
•
OR:  Complete response (CR) or partial 
response (PR)
•
PFS is defined as the time from the start 
of treatment to the first documented PD 
or death due to any cause, whichever 
occurs first.   
•
OS is defined as the time from the start of 
treatment to death due to any cause.
•
Objective: To identify molecular 
(genomic, metabolic, and/or proteomic) 
biomarkers that may be indicative of 
clinical response/resistance, safety, 
pharmacodynamics activity, and/or the 
mechanism of action of chemotherapy or 
pembrolizumab
•
Germline genetic variation, genetic 
(DNA) mutations from tumor, tumor and 
blood RNA variation, proteomics and 
immunohistochemistry (IHC), and other 
blood-derived biomarkers
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Objectives
Endpoints
•
Objective:  To estimate the concordance 
between baseline WES-based TMB of 
tumor biopsy or FFPE sample and 
baseline TMB in cfDNA
•
Baseline TMB in cfDNA (blood)
•
WES-based TMB of tumor FFPE
biopsy/sample
•
Objective:  To evaluate the impact of pre-
treatment (baseline) and on-treatment gut 
microbiome signatures associated with 
OR and PFS per RECIST 1.1 by 
investigator review and OS
•
OR:  Complete response (CR) or partial 
response (PR)
•
PFS is defined as the time from the start 
of treatment to the first documented PD 
or death due to any cause, whichever 
occurs first.   
•
OS is defined as the time from the start of 
treatment to death due to any cause.
•
Objective: To evaluate whether
metabolomics components are associated 
with OR and PFS per RECIST 1.1 by 
investigator review and OS
•
OR:  Complete response (CR) or partial 
response (PR)
•
PFS is defined as the time from the start 
of treatment to the first documented PD 
or death due to any cause, whichever 
occurs first.   
•
OS is defined as the time from the start of 
treatment to death due to any cause.
4
STUDY DESIGN
4.1
Overall Design
This is a nonrandomized, multi-site, open-label study of pembrolizumab + platinum-doublet
chemotherapy (pemetrexed plus investigator’s choice of either cisplatin or carboplatin) as 
first-line treatment in participants with stage IV NSCLC who have not previously received 
systemic therapy for their metastatic disease and in whom EGFR-, ALK-, B-RAF-, or ROS1-
directed therapy is not indicated.  Treatment will include pembrolizumab combined with a 
platinum-doublet chemotherapy for 4 cycles then pembrolizumab plus pemetrexed 
maintenance for up to 31 additional cycles.  The platinum-doublet will be pemetrexed plus 
the investigator’s choice of either cisplatin or carboplatin.
Participants will be evaluated with radiographic imaging to assess response to treatment at 
6 weeks (42 ± 7 days) and 12 weeks (84 ± 7 days) and then every 9 weeks (63 ± 7 days) for 
the first 48 weeks and every 12 weeks (84 ± 7 days) subsequently.  Imaging will continue on 
this schedule until documented disease progression, unacceptable AE(s), intercurrent illness 
that prevents further administration of treatment, investigator’s decision to discontinue the 
participant, participant withdraws consent, pregnancy of the participant, noncompliance with 
trial treatment or procedure requirements, or administrative reasons, or initiation of a new 
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anticancer regimen requiring cessation of treatment. All imaging obtained on the study will 
be assessed by the investigator using RECIST 1.1 and iRECIST 1.1 (see Section 8.2) for 
determination of objective response of complete or partial response (CR or PR, respectively) 
and PFS. 
AE monitoring will be ongoing throughout the study and graded in severity according to the 
guidelines outlined in the National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE) v4.0.
Study treatment will continue until 35 administrations of pembrolizumab (approximately 
2 years), documented PD, unacceptable AEs, intercurrent illness that prevents further 
administration of treatment, investigator’s decision to discontinue the participant, participant 
withdrawal of consent, pregnancy of the participant, or administrative reasons requiring the 
cessation of treatment.  Optionally, participants with a confirmed CR who have received at 
least 8 cycles of pembrolizumab may discontinue treatment (Section 7.1).
All participants will be followed by telephone for OS until death, withdrawal of consent, or 
the end of the study.
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
This clinical trial will test the utility of TMB and other exploratory markers of response in a 
treatment-naïve nonsquamous NSCLC population.  The treatment regimen of pembrolizumab 
in combination with platinum-doublet chemotherapy has been previously tested with positive 
efficacy results in a randomized, Phase 3 trial, KEYNOTE-189.
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
4.2.1.1.1 Efficacy Endpoints per RECIST 1.1
Objective response by RECIST 1.1 criteria is considered preliminary evidence of efficacy
and is a reasonable endpoint in a Phase 2 study.
OS has been recognized as the gold standard for the demonstration of superiority of a new 
antineoplastic therapy in randomized clinical studies.
PFS is an acceptable measure of clinical benefit for a late-stage study that demonstrates 
superiority of a new antineoplastic therapy, especially if the magnitude of the effect is large 
and the therapy has an acceptable risk/benefit profile. The use of RECIST 1.1 to assess PFS 
is typically considered acceptable by regulatory authorities. 
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This study will use objective response based on RECIST 1.1 criteria as assessed by the 
investigator as the primary endpoint, and PFS, as assessed by the investigator, and OS as 
secondary endpoints. Objective response is defined a confirmed CR or confirmed PR per 
RECIST 1.1 as assessed by investigator recorded between the start of treatment and disease 
progression or death due to any cause, whichever occurs first. 
RECIST 1.1 will be used when assessing images for efficacy measures and by the local site 
when determining eligibility (Section 8.2.1.4). 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.
4.2.1.1.2
Modified RECIST for Immune-based Therapeutics (iRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab (Section 8.2.1.5). Immunotherapeutic agents such 
as pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific 
immune responses. The response patterns seen with such an approach may extend beyond the 
typical time course of responses seen with cytotoxic agents, and patients treated with 
pembrolizumab may manifest a clinical response after an initial increase in tumor burden or 
even the appearance of new lesions. Thus, standard RECIST 1.1 may not provide an accurate 
response assessment of immunotherapeutic agents such as pembrolizumab. Based on an 
analysis of participants with melanoma enrolled in KEYNOTE-001 (KN001), 7% of 
evaluable participants experienced delayed or early tumor pseudo-progression. Of note, 
participants who had progressive disease (PD) by RECIST 1.1 but not by the immune-related 
response criteria [Wolchok, J. D., et al 2009] had longer overall survival than participants 
with PD by both criteria [Hodi, F. S., et al 2014]. Additionally, the data suggest that RECIST 
1.1 may underestimate the benefit of pembrolizumab in approximately 15% of participants. 
These findings support the need to apply a modification to RECIST 1.1 that takes into 
account the unique patterns of atypical responses in immunotherapy and enables treatment 
beyond initial radiographic progression, if the participant is clinically stable.
Modified RECIST 1.1 for immune-based therapeutics (iRECIST) assessment has been 
developed and published by the RECIST Working Group, with input from leading experts 
from industry and academia, along with participation from the US Food and Drug 
Administration and the European Medicines Agency [Seymour, L., et al 2017]. The 
unidimensional measurement of target lesions, qualitative assessment of nontarget lesions, 
and response categories are identical to RECIST 1.1, until progression is seen by RECIST 
1.1. However, if a participant is clinically stable, additional imaging may be performed to 
confirm radiographic progression. iRECIST will be used by investigators to assess tumor 
response and progression and make treatment decisions .
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4.2.1.5
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/PD biomarkers and generate information that may better guide single-agent and 
combination therapy with immuno-oncology drugs. To identify novel biomarkers, 
biospecimens (ie, blood components, tumor material) will be collected to support analyses of 
cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations. In addition to studying 
variation across the human genome, cfDNA-based technologies enable blood-based 
interrogation of tumor genetics, including total TMB, tumor immune-editing, and tumor 
evolution.  cfDNA analysis represents a more complete snapshot of total tumor genetics of 
primary and metastatic lesions over single-site, biopsy-based analyses. cfDNA technologies 
allows interrogation of tumor genetics without the risk of invasive biopsies and being a blood 
marker enables routine tumor genetics assessment over the course of therapy. Finally, 
microsatellite instability (MSI) may be evaluated as this is an important biomarker for some 
cancers (ie, colorectal cancer).
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Thus, genome-wide approaches may be used for this 
effort. Note that in order to understand tumor-specific mutations, it is necessary to compare 
the tumor genome with the germline genome. Microsatellite instability may also be evaluated 
as this is an important biomarker for some cancers (ie, colorectal cancer). Circulating tumor 
DNA and/or RNA may also be evaluated from blood samples.
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Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with pembrolizumab or other immunotherapies. 
Pembrolizumab induces a response in tumors that likely reflects an inflamed/immune 
phenotype. Specific immune-related gene sets (ie, those capturing interferon-gamma 
transcriptional pathways) may be evaluated and new signatures may be identified. Individual 
genes related to the immune system may also be evaluated (eg, IL-10). MicroRNA profiling 
may also be pursued as well as exosomal profiling.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic (IVD) device 
has been developed for use with pembrolizumab in NSCLC. Preliminary data indicates that 
this association may also be true in additional cancer types (ie, triple negative breast cancer, 
head and neck, and gastric). Additional tumor or blood-derived proteins may also correlate 
with response to pembrolizumab. Therefore, tumor tissue may be subjected to proteomic 
analyses using a variety of platforms that could include but are not limited to immunoassays 
and liquid chromatography/mass spectrometry. This approach could identify novel protein 
biomarkers that could aid in patient selection for pembrolizumab (MK-3475) therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as enzyme-linked immunoassay 
(ELISA) measure such proteins in serum. Correlation of expression with response to 
pembrolizumab therapy may identify new approaches for predictive biomarkers in blood, 
representing a major advance from today’s reliance on assessing tumor biomarkers. This 
research would serve to develop such assays for future clinical use.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
Microbiome analysis of stool
Stool samples from this study will be collected to assess the microbiome associated with 
clinical activity. This research may help identify factors predictive of pembrolizumab 
response and resistance and novel targets for cancer immunotherapy.
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Metabolomics
Blood samples from this study will be collected to assess the metabolomics profiles 
associated with clinical activity. This research may help identify factors predictive of 
pembrolizumab response and resistance and novel targets for cancer immunotherapy.
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research substudy are presented in Appendix 6.
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4.3
Justification for Dose
Pembrolizumab
Pembrolizumab 200 mg IV Q3W is the approved dose for the NSCLC indication per the 
current label.
Chemotherapy
This study will use SOC dosing for carboplatin at AUC 5 mg•min/mL ≤50 mg, cisplatin at 
75 mg/m2, and pemetrexed at 500 mg/m2 in participants with NSCLC. Refer to the 
carboplatin, cisplatin, and pemetrexed prescribing information for more information.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, 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.
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Male/female participants with metastatic NSCLC who have received no systemic anticancer 
therapy for their metastatic NSCLC and who are at least 18 years of age 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
To be eligible for inclusion in this study, the participant must:
1. Have a histologically-confirmed or cytologically confirmed diagnosis of stage IV (M1a,
M1b, or M1c [AJCC 8th edition]) nonsquamous NSCLC.
2. Have confirmation that epidermal growth factor receptor (EGFR-), anaplastic 
lymphoma kinase (ALK-), c-ros oncogene 1 (ROS1), or B isoform of rapidly 
accelerated fibrosarcoma (BRAF) directed therapy is not indicated as primary therapy. 
Documentation of the absence of tumor activating EGFR mutations, BRAF mutations, 
ALK gene rearrangements, and ROS1 gene rearrangements is required. 
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3. Have measurable disease based on RECIST 1.1 as determined by the local site 
investigator/radiology assessment.  Target lesions situated in a previously irradiated area 
are considered measurable if progression has been demonstrated in such lesions.
4. Have not received prior systemic treatment for their advanced/metastatic NSCLC. 
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.
5. Have provided sufficient evaluable Stage IV, archival, solid tumor tissue sample or newly 
obtained core or excisional biopsy of a tumor lesion (that was not previously irradiated) 
for biomarker analysis (Fine Needle Aspiration [FNA] samples will not be accepted).
Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly 
obtained biopsies are preferred to archived tissue. (See Procedures Manual for specific 
details.)
Demographics
6. Participant is ≥18 yearsof age inclusive, at the time of signing the informed consent.
7. Have an ECOG performance status of 0 or 1 within 10 days prior to the first dose of 
study treatment. 
Male Participants
8. Agree to use a contraception as detailed in Appendix 5 of this protocol during the 
treatment period and for at least 120 days, corresponding to time needed to eliminate any 
study intervention(s) (pembrolizumab and/or any active comparator/combination) plus an 
additional 90 days (a spermatogenesis cycle) for study interventions where there is risk of 
clinically relevant genotoxicity after the last dose of study intervention and refrain from 
donating sperm during this period.
Female Participants
9. Not be pregnant (Appendix 5) or breastfeeding, and at least 1 of the following conditions 
applies:
a) Not be a woman of childbearing potential (WOCBP) as defined in Appendix 5.
OR
b) A WOCBP must agree to follow the contraceptive guidance in Appendix 5 during 
the treatment period and for at least 120 days (corresponding to time needed to 
eliminate any study intervention(s) (pembrolizumab and or any active 
comparator/combination) after the last dose of pembrolizumab.
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Informed Consent
13. The participant (or legally acceptable representative if applicable) provides written 
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.
Laboratory Values
14. Have adequate organ function as indicated by the laboratory values in Table 2. 
Specimens must be collected and reviewed within 10 days prior to the start of study 
treatment.
Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematologic
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/La
Renal
Creatinine OR
Measured or calculated CrCl b
(GFR can also be used in place of creatinine or CrCl)
≤1.5 × ULN OR
≥30 mL/min for participants with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin (serum)
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels >1.5 × ULN.
If there is no institutional ULN, then direct bilirubin 
must be <40% of total bilirubin to be eligible. Note: 
In no case can the total bilirubin exceed 3 x ULN.
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN or ≤5 × ULN for participants with liver 
metastases
Coagulation
International normalized ratio or prothrombin time 
(PT)
Activated partial thromboplastin time (aPTT) or 
partial thromboplastin time (PTT)c
≤1.5 × ULN unless the participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
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.
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within 
2 weeks of the screening test. Participants can be on stable dose of erythropoietin (≥ approximately 3 months).
b CrCl should be calculated per institutional standard.
c PTT may be performed if the local lab is unable to perform aPTT.
Abbreviations: ALT (SGPT)
alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)
aspartate aminotransferase (serum glutamic oxaloacetic transaminase); CrCl 
creatinine clearance; GFR
glomerular 
filtration rate; ULN upper limit of normal.
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15. Has provided blood for cfDNA analysis that has been received and determined to be of 
sufficient quality and quantity by the designated laboratory for the primary endpoint.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has predominantly squamous cell histology NSCLC. Mixed tumors will be categorized 
by the predominant cell type.
2. Has small cell elements present in NSCLC tumor.
3. Is a WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment 
(see Appendix 5). If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.
Note:  In the event that 72 hours have elapsed between the screening pregnancy test and 
the first dose of study treatment, another pregnancy test (urine or serum) must be 
performed and must be negative in order for participant to start receiving study 
medication.
4. Has clinically active diverticulitis, intra-abdominal abscess, GI obstruction, peritoneal
carcinomatosis.
5. Has a known history of prior malignancy except if the participant has undergone 
potentially curative therapy with no evidence of that disease recurrence for 2 years since 
initiation of that therapy.  
Note: The time requirement for no evidence of disease for 2 years does not apply to the 
NSCLC tumor for which a participant is enrolled in the study.  The time requirement also 
does not apply to participants who underwent successful definitive resection of basal cell 
carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in 
situ cervical cancer, or other in situ cancers.
6. Has symptomatic ascites or pleural effusion. A participant who is clinically stable 
following treatment for these conditions (including therapeutic thoraco- or paracentesis) 
is eligible.
Prior/Concomitant Therapy
7. If participant received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting study intervention.
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8. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants 
must have recovered from all radiation-related toxicities, not require corticosteroids, and 
not have had radiation pneumonitis. A 1-week washout is permitted for palliative 
radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
9. Has received prior therapy with a PD-1/PD-L1 receptor inhibitor.
10. Is expected to require any other form of antineoplastic therapy while on study (including 
maintenance therapy with another agent for NSCLC, radiation therapy, and/or surgical 
resection).
11. Has received a live vaccine within 30 days prior to treatment. Examples of live vaccines 
include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster 
(chicken pox), yellow fever, rabies, Bacillus Calmette Guérin (BCG), and typhoid 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and 
are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines and are not allowed.
12. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients or 
to another monoclonal antibody.
13. Has a known sensitivity to any component of cisplatin, carboplatin or pemetrexed.
14. Has 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.
15. Is on chronic systemic steroids. Participants with asthma that require intermittent use of 
bronchodilators, inhaled steroids, or local steroid injections would not be excluded from 
the study. 
16. Is unable or unwilling to take folic acid or vitamin B12 supplementation.
Prior/Concurrent Clinical Study Experience
17. 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.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
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Diagnostic Assessments
18. 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 drug.
19. Has a known additional malignancy that is progressing or has required active treatment 
within the past 2 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin,or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
20. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, (ie, without evidence of progression) for at least 4 weeks by repeat imaging (note 
that the repeat imaging should be performed during study screening), clinically stable and 
without requirement of steroid treatment for at least 14 days prior to first dose of study 
intervention.
21. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
22. Has an active infection requiring systemic therapy.
23. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing 
is required unless mandated by local health authority.
24. 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.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority.
25. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant's participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
26. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
Other Exclusions
27. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days after 
the last dose of study intervention.
28. Has had an allogenic tissue/solid organ transplant.
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5.3
Lifestyle Considerations
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
Caffeine, Alcohol, and Tobacco Restrictions
During each dosing session, participants will abstain from alcohol from 24 hours before the 
start of dosing until after collection of the metabolomic sample. Ethanol and its metabolites 
are also products of bacterial metabolism and alcohol use may interfere with the translational 
metabolomics analyses.
Activity Restrictions
Participants will abstain from strenuous exercise (eg, swimming, running, or any gym 
workout) for 4 hours before each blood collection for cfDNA and metabolomics analysis.
Participant may resume normal activity following blood draw, as per investigator’s 
instructions. Participants should wait to have all blood samples collected at the visits before 
exercise.  Participants may participate in light recreational activities during studies (eg, 
watching television, reading).
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Refer to Appendix 5 for 
approved methods of contraception.
Participants should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study, participants of childbearing potential must adhere to the contraception 
requirement (Appendix 5) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 
120 days after the last dose of study medication. If there is any question that a participant of 
childbearing potential will not reliably comply with the requirements for contraception, that 
participant should not be entered into the study.
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study intervention. The site will contact 
the participant at least monthly and document the participant’s status until the pregnancy has 
been completed or terminated. The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (eg, death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The study Investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
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Sponsor. If a male participant impregnates his female partner, the study personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
followed as described in Section 8.4.1.
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, participants who are breastfeeding are not eligible for enrollment.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (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.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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.
Centrally sourced Clinical supplies (study interventions provided by the Sponsor) will be 
packaged to support enrollment .  These Clinical supplies will be affixed with a clinical label 
in accordance with regulatory requirements.
Locally sourced clinical supplies will be provided locally by the study site as described in 
Section 6.1.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 3.
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Table 3
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/Treatment 
Period/Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
NA
Other
pembrolizumab
(MK-3475)
Biological/
Vaccine
Solution for 
Infusion
25 mg / mL
200 mg
IV 
Infusion
Day 1 of each 21-day 
cycle
SOC
IMP
Central 
NA
Other
pemetrexed
Drug
Lyophilized 
Powder
500 mg
500 
mg/m2
IV 
Infusion
Day 1 of each 21-day 
cycle
SOC
NIMP
US: 
Local
ex-US: 
Central 
NA
Other
carboplatin
Drug
Solution for 
Infusion
10 mg / mL
AUC 5 
mg/mL/
min
IV 
Infusion
Day 1 of each 21-day 
cycle for 4 cycles  
(Cycles 1 – 4)
SOC
NIMP
US: 
Local
ex-US: 
Central 
NA
Other
cisplatin
Drug
Solution for 
Infusion
1 mg/ mL
75
mg/m2
IV 
Infusion
Day 1 of each 21-day 
cycle for 4 cycles 
(Cycles 1 – 4)
SOC
NIMP
US: 
Local
ex-US: 
Central 
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) are based on guidance issued by the European 
Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed. SOC = 
Standard of care.
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The chemotherapy doublet must include pemetrexed plus the investigator’s choice of either 
cisplatin or carboplatin.  Upon IVRS allocation, the investigator will assign each participant 
to either cisplatin or carboplatin, as determined by the investigator.
All study interventions will be administered on an outpatient basis.
All products indicated in Table 3 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. Concomitant chemotherapeutic/immunotherapeutic agents will be prepared and 
administered as per the approved product label(s).
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.
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The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
Intervention Assignment
Participants in this study will be allocated by nonrandom assignment.
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the interventions administered.
6.4
Study Intervention Compliance
Administration of study medication(s) will be witnessed by the investigator and/or study 
staff. The total volume of study medication infused will be compared with the total volume 
prepared to determine compliance with each dose administered.
Interruptions from the protocol-specified treatment plan for ≥21 days require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study therapy or vaccination may be required. 
The investigator should discuss any questions regarding this with the Sponsor's Clinical 
Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
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Below is a list of specifically prohibited medications or devices for this study:
•
Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol
Note: denosumab is permitted.
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
•
Investigational agents other than pembrolizumab
•
Radiation therapy
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion, provided the lesions were not previously defined by the 
site as target lesions.
•
Live vaccines within 30 days prior to the first dose of study intervention and while 
participating in the study
Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are allowed; 
however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and 
are not allowed.
•
Prolonged therapy with systemic glucocorticoids (>7 days) for any purpose other than to
modulate symptoms from an AE, SAE, or ECI or for use as a premedication for
chemotherapy or in participants with a known history of an IV contrast allergy
administered as part of CT radiography. Brief, limited use of systemic corticosteroids (≤7
days) are permitted where such use is considered SOC (eg, for COPD exacerbation).
•
Replacement doses of steroids (eg, prednisone 5 to 7.5 mg daily) are permitted while on
study, as is the use of local steroids.
Participants who, in the assessment of the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.
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, over-the-counter (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.
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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 events of clinical interest (ECIs) as defined in Section 
8.4.7.
Probiotics and Prebiotics
Use of commercially available prebiotics and probiotic supplements will be monitored on 
study. Any prebiotic or probiotic use should be recorded in the concomitant medications 
eCRF. Examples of representative prebiotic and probiotics are listed below. The list is not 
comprehensive.  
•
Probiotics may include products containing any of the following:
•
Bifidobacterium spp.
•
Saccharomyces boulardii
•
Lactobacillus spp.
Prebiotics are dissacharide containing supplements including lactulose; oligosaccharides,
including fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), isomalto-
oligosaccharides, xylo-oligosaccharides, transgalacto-oligosaccharides (TGOS), and soybean 
oligosaccharides; and polysaccharides, such as the fructan inulin, reflux starch, cellulose, 
hemicellulose or pectin.
Rescue Medications and Supportive Care
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, Table 4. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to  in Section 6.6 for 
guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
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6.6
Dose Modification (Escalation/Titration/Other)
If appropriate, the investigator may attribute each toxicity event to cisplatin/carboplatin, 
pemetrexed, or pembrolizumab alone or to the combination and use a stepwise dose 
modification according to Table 5 through Table 8.  Dose modifications must be based on the 
maximum toxicity experienced during a cycle. Toxicity needs to resolve to Grade ≤1 or 
baseline prior to resuming subsequent cycle. For individual participants requiring a dose 
modification, treatment for each new cycle may be delayed if the scheduled off-drug periods 
are not adequate to allow for recovery to Grade ≤1 or the baseline status of the participant.  
Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
interrupted or discontinued due to toxicity. If a dose reduction for toxicity occurs with any 
agent, the dose may not be re-escalated. 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 dose adjustment recommended should 
be followed (dose reduction appropriate to the most severe toxicity). Participants who require 
a third dose modification to any particular component will have that agent discontinued.
Reduction of one chemotherapy agent and not the other agent is appropriate if, in the opinion 
of the investigator, the toxicity is clearly related to one of the treatments. If, in the opinion of 
the investigator, the toxicity is related to the combination of both chemotherapy agents, both 
drugs should be reduced according to recommended dose modifications. If the toxicity is 
related to the combination of 3 agents, all 3 agents should be reduced (if applicable), 
interrupted, or discontinued according to the recommended dose modifications. Participants
may have chemotherapy discontinued and continue on pembrolizumab alone.  Similarly,
participants may discontinue pembrolizumab and continue on chemotherapy alone, if 
appropriate, through the duration of study participation (ie, up to 35 total cycles).
Chemotherapy may be interrupted for a maximum of 6 weeks from last dose; pembrolizumab 
may be interrupted for a maximum of 12 weeks from last dose.
The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) must be 
used to grade the severity of adverse events. All dose modifications should be based on the 
AE requiring the greatest dose modification. Dose modifications are detailed in Table 5
through Table 8.
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Table 4
Dose Modifications for Trial Medications
Dose Level 0
Dose Level -1
Dose Level -2
Dose Level -3
Cisplatin
75 mg/m2
56 mg/m2
38 mg/m2
Discontinue
Carboplatin
AUC 5
Maximum dose 
750 mg
AUC 3.75
Maximum dose 
562.5 mg
AUC 2.5
Maximum dose 
375 mg
Discontinue
Pemetrexed
500 mg/m2
375 mg/m2
250 mg/m2
Discontinue
Pembrolizumab
200 mg fixed dose
Dose reductions 
are not permitted.
Dose reductions 
are not permitted.
Dose reductions 
are not permitted
Dose Modification
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than 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. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 5.
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Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has 
been tapered. Pembrolizumab must be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to 
≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 
•
Administer corticosteroids (initial dose 
of 1-2 mg/kg prednisone or 
equivalent) followed by taper
•
Monitor participants for signs and 
symptoms of pneumonitis
•
Evaluate participants with suspected 
pneumonitis with radiographic imaging 
and initiate corticosteroid treatment
•
Add prophylactic antibiotics for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
•
Administer corticosteroids (initial dose 
of 1-2 mg/kg prednisone or 
equivalent) followed by taper
•
Monitor participants for signs and 
symptoms of enterocolitis (ie, diarrhea, 
abdominal pain, blood or mucus in stool 
with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
•
Participants with ≥Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis
•
Participants with diarrhea/colitis should 
be advised to drink liberal quantities of 
clear fluids. If sufficient oral fluid intake 
is not feasible, fluid and electrolytes 
should be substituted via IV infusion.
Grade 4
Permanently 
discontinue
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
Bilirubin
Grade 2
Withhold
•
Administer corticosteroids (initial dose 
of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper
•
Monitor with liver function tests 
(consider weekly or more frequently until 
liver enzyme value returned to baseline or
is stable)
Grade 3 or 4 
Permanently 
discontinue
•
Administer corticosteroids (initial dose 
of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
New onset T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold
•
Initiate insulin replacement therapy for 
participants with T1DM
•
Administer anti-hyperglycemic in 
participants with hyperglycemia
•
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
•
Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated
•
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue
•
Treat with non-selective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate
•
Monitor for signs and symptoms of 
thyroid disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue
•
Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care
•
Monitor for signs and symptoms of 
thyroid disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold
•
Administer corticosteroids (prednisone 
1-2 mg/kg or equivalent) followed by 
taper
•
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Myocarditis
Grade 1 or 2
Withhold
•
Based on severity of AE administer 
corticosteroids
•
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All Other 
immune-related 
AEs
Intolerable/persistent 
Grade 2
Withhold
•
Based on severity of AE administer 
corticosteroids
•
Ensure adequate evaluation to confirm 
etiology or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of event. 
Events that require 
discontinuation 
include and not 
limited to: Guillain-
Barre Syndrome, 
encephalitis
Grade 4 or recurrent 
Grade 3
Permanently 
discontinue
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.
NOTE:
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE 
resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 6.
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of the 
investigator
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs
Stop Infusion
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the 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). 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 
of pembrolizumab with:
Diphenhydramine 50 mg 
PO (or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 
mg PO (or equivalent dose 
of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
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 Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the 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 v4.0 (CTCAE) 
at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the participant's study record.
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Dose Modification for Chemotherapy
Recommended dose modifications for key chemotherapy toxicities are outlined in Table 7
and Table 8. These serve as a guide and do not replace investigator judgment and applicable 
local label recommendations if more stringent.
Table 7
Recommended Dose Modifications for Chemotherapy Hematological Toxicity
Pemetrexed
Cisplatin/Carboplatin
Platelets
ANC
Dose level (DL) from Table 3
≥50,000/mcL  AND
≥500/mcL
DL 0
DL 0
≥50,000/mcL  AND
<500/mcL
DL -1
DL -1
<50,000/mcL without 
bleeding AND
ANY
DL -1
DL -1
<50,000/mcL with Grade ≥2 
bleeding AND
ANY
DL -2
DL -2
ANY 
<1000/mcL + fever 
≥38.5°C (101°F)
DL -1
DL -1
Table 8
Recommended Dose Modifications for Chemotherapy Non-Hematological 
Toxicity
Pemetrexed
Cisplatin
Carboplatin
Event
CTC Grade
Dose level (DL) from Table 3
Nausea or vomiting
Grade 3or 4
DL 0
DL 0
DL 0
Diarrhea
Grade 3or 4
DL -1
DL -1
DL 0
Mucositis
Grade 3or 4
DL -2
DL 0
DL 0
Neurotoxicity
Grade 2
DL 0
DL -2
DL 0
Grade 3or 4
DL -1
Discontinue
DL -1
Transaminase elevation
Grade 3
DL -1
DL -1
DL -1
Grade 4
Discontinue
Discontinue
Discontinue
Other non-hematological
toxicity
Grade 3or 4
DL -1
DL -1
DL -1
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
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6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
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 
period will still continue to participate in the study as specified in Section 1.3 (SoA) and 
Section 8.12.3.
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.
•
The participant interrupts study intervention administration for more than 12 consecutive 
weeks, unless approved with written documentation from Sponsor.
•
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.
•
If the investigator performs a drug screen at his/her discretion and the participant has a 
positive urine drug screen at any time during the course of the study.
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•
Confirmed radiographic disease progression outlined in Section 8.2.1.2 (exception if the 
Sponsor approves treatment continuation)
•
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
•
Noncompliance with study intervention or procedure requirements
•
Recurrent Grade 2 pneumonitis
•
Discontinuation of treatment may be considered for participants who have attained a 
confirmed complete response (CR) and have been treated for at least 8 cycles (at least 
24 weeks), receiving at least 2 cycles of the combination including 2 doses of 
pembrolizumab and at least 80% of the planned doses of pemetrexed beyond the date 
when the initial CR was declared. 
•
Completion of 35 treatments (approximately 2 years) with pembrolizumab
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.
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.
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•
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.
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 or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized 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.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
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8.1
Administrative and General Procedures
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a 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 consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(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 dated 
signature or by the participant’s legally acceptable representative’s dated signature.
The participant or his/her legally acceptable representative will be asked to sign consent at 
the point of initial radiographic disease progression.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to the future biomedical research substudy. 
A copy of the informed consent will be given to the participant.
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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.
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 written informed consent. At the time of intervention
allocation/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 healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
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 significant. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the study. Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up visit.
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 intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
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Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. The 
assigned screening number will become the participants’ treatment/randomization number. 
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.
Study Intervention Administration
Administration of IV study medication (pembrolizumab and chemotherapy) will be 
witnessed by the investigator and/or study staff.
Study treatment should begin on the day of treatment allocation or as close as possible to the 
date on which the participant is allocated/assigned.
8.1.8.1
Timing of Dose Administration
Study interventions will generally be administered in the following order:  pembrolizumab, 
premedications, pemetrexed, and then carboplatin or cisplatin.  Details of administering the 
individual components are discussed below.
8.1.8.1.1
Timing of Dose Administration of Pembrolizumab
Study treatment with pembrolizumab should be administered on Day 1 of each 21-day cycle 
after all procedures/assessments have been completed as detailed in the SoA (Section 1.3). 
All study treatments will be administered on an outpatient basis. Study treatment of 
pembrolizumab may be administered up to 3 days before or after the scheduled Day 1 of each 
21-day cycle due to administrative reasons except for Cycle 1 Day 1, where the window is 
+3 days from randomization.
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion. 
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 min/+10 min).
The Pharmacy Manual contains specific instructions for pembrolizumab reconstitution, 
preparation of the infusion fluid, and administration.
8.1.8.1.2
Timing of Dose Administration of Pemetrexed
Pemetrexed 500 mg/m2 will be administered as an IV infusion over 10 minutes on Day 1 of 
the 21-day cycle. All participants should be premedicated with steroids as per the approved 
label and local standard practices. In addition, all participants must take a folic acid 
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preparation or multivitamin with folic acid containing between 350 to 1000 µg daily. At least 
5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of 
pemetrexed and dosing should continue during the full course of therapy and for 21 days 
after the last dose of pemetrexed.
Participants must also receive 1 intramuscular injection of vitamin B12 1000 µg during the 
week preceding the first dose of pemetrexed and every 3 cycles thereafter. Subsequent 
vitamin B12 injections may be given the same day as pemetrexed.
For additional details, refer to approved product labels for details regarding dose calculation, 
reconstitution, preparation of the infusion fluid, and administration for each of the standard 
of care chemotherapies.
8.1.8.1.3
Timing of Dose of Carboplatin or Cisplatin
8.1.8.1.3.1
Carboplatin
Carboplatin AUC 5 will be administered as an IV infusion over 30 to 60 minutes on Day 1 of 
every 21-day cycle following pemetrexed infusions, for a maximum of 4 administrations.
8.1.8.1.3.2
Cisplatin
Cisplatin 75 mg/m2 will be administered as an IV infusion over a recommended time of 
60 minutes. However, cisplatin may be administered over 30 to 150 minutes to accommodate 
local SOC. Treatment will be administered after pemetrexed on Day 1 of the 21-day cycle, 
for a maximum of 4 administrations.
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA (Section 1.3) and Section 8.12.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit should be performed (at the time of withdrawal). Any AEs
that are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
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 principal 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 
. 
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 
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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. 
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy/Immunogenicity Assessments
Tumor Imaging and Assessment of Disease
All imaging will be completed and read locally per clinical SOC. 
Tumor imaging is strongly preferred to be acquired by CT. For the abdomen and pelvis, 
contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or 
when mandated by local practice. MRI is the strongly preferred modality for imaging the 
brain. The same imaging technique regarding modality, ideally the same scanner, and the use 
of contrast should be used in a participant throughout the study to optimize the 
reproducibility of the assessment of existing and new tumor burden and improve the 
accuracy of the assessment of response or progression based on imaging. Note: for the 
purposes of assessing tumor imaging, the term “investigator” refers to the local investigator 
at the site and/or the radiological reviewer at the site or at an offsite facility.
Participant eligibility will be determined using local assessment (investigator assessment) 
based on RECIST 1.1.
Brain imaging is only required for participants with existing or suspected CNS metastases 
and/or carcinomatous meningitis. MRI is preferred; however, CT imaging with contrast will 
be acceptable, if MRI is medically contraindicated. Bone scans are also required for 
participants with a history of bone metastases and/or for those participants with new bone 
pain. 
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8.2.1.1
Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 28 days prior to the date of
allocation.  
Tumor imaging performed as part of routine clinical management are acceptable for use as 
screening tumor imaging if they are of diagnostic quality and performed within 28 days prior 
to the date of allocation. If brain imaging is performed to document the stability of existing 
metastases, MRI should be used if possible. If MRI is medically contraindicated, CT with 
contrast is an acceptable alternative.
8.2.1.2
Tumor Imaging During the Study
The first on-study imaging assessment should be performed at 6 weeks (42 days ±7 days) 
from the date of randomization.  The second on-study imaging assessment should be 
performed at 12 weeks (84 days ±7 days) from the date of randomization.  Subsequent tumor 
imaging should be performed every 9 weeks (63 days ±7 days) through Week 48 or more 
frequently if clinically indicated.  After 48 weeks, participants who remain on treatment will 
have imaging performed every 12 weeks (84 days ±7 days).  Imaging timing should follow 
calendar days and should not be adjusted for delays in cycle starts.  Imaging should continue 
to be performed until disease progression is identified by the investigator (unless the site PI 
elects to continue treatment and follow iRECIST), the start of new anticancer treatment, 
withdrawal of consent, or death or notification by the Sponsor, whichever occurs first.  
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 (ie, 9 or 12 weeks 
later) if it is less than 4 weeks later; tumor imaging may resume at the subsequent scheduled 
imaging time point. 
Per iRECIST (Section 8.2.1.5), disease progression in participants treated with 
pembrolizumab should be confirmed by the site 4 to 8 weeks after site-assessed first 
radiologic evidence of PD in clinically stable participants.  Participants who have 
unconfirmed disease progression may continue on treatment at the discretion of the site 
investigator until progression is confirmed by the site, provided they have met the conditions 
detailed in Section 8.2.1.5.  Participants who obtain a confirmation scan do not need to 
undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may 
resume at the subsequent scheduled imaging time point if clinically stable. Participants who 
have confirmed disease progression, as assessed by the site, will discontinue study treatment.  
Exceptions are detailed in Section 8.2.1.5.
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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 if the investigator elects not to 
implement iRECIST.
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 (every 9 weeks in Year 1 or 12 weeks 
after Year 1) until the start of a new anticancer treatment, disease progression, pregnancy, 
death, withdrawal of consent, or the end of the study, whichever occurs first.
8.2.1.4
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.
8.2.1.5
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and make treatment decisions. When clinically stable, participants 
should not be discontinued until progression is confirmed by the investigator, working with 
local radiology, according to the rules outlined in Appendix 8. This allowance to continue
treatment despite initial radiologic PD takes into account the observation that some 
participants can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. This data will be captured 
in the clinical database.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of disease
•
No decline in ECOG performance status
•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
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Any participant deemed clinically unstable should be discontinued from study intervention at
investigator verification of site-assessed first radiologic evidence of PD, and is not required 
to have repeat tumor imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment.
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study intervention may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
intervention.
If a participant has confirmed radiographic progression (iCPD) as defined in  Appendix 8, 
study intervention should be discontinued; however, if the participant is achieving a 
clinically meaningful benefit, an exception to continue study intervention may be considered 
following consultation with the Sponsor. In this case, if study intervention is continued, 
tumor imaging should continue to be performed following the intervals as outlined in 
Section 1.3 (SoA).
A description of the adaptations and iRECIST process is provided in Appendix 8, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 9.
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Table 9
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1.
Repeat imaging at 
4 to 8 weeks to 
confirm PD.
May continue study 
intervention at the 
investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
iRECIST.
Repeat imaging at 4 
to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment.
Repeat tumor 
imaging confirms PD 
(iCPD) by iRECIST 
per investigator 
assessment.
No additional 
imaging required.
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
Sponsor).
No additional 
imaging required
Not applicable.
Repeat tumor 
imaging shows iUPD 
by iRECIST per 
investigator 
assessment.
Repeat imaging at 
4 to 8 weeks to 
confirm PD. May 
occur at next 
regularly 
scheduled 
imaging visit.
Continue study 
intervention at the 
investigator’s 
discretion.
Repeat imaging at 4 
to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment.
Repeat tumor 
imaging shows iSD, 
iPR, or iCR by 
iRECIST per 
investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments.
Continue study 
intervention at the 
investigator’s 
discretion.
Continue regularly 
scheduled imaging 
assessments.
May restart study 
intervention if 
condition has 
improved and/or 
clinically stable per 
investigator’s 
discretion. Next 
tumor imaging 
should occur 
according to the 
regular imaging 
schedule.
iCPD iRECIST confirmed progressive disease; iCR iRECIST complete response; iRECIST modified Response Evaluation 
Criteria in Solid Tumors 1.1 for immune based therapeutics; iSD iRECIST stable disease; iUPD iRECIST unconfirmed 
progressive disease; PD progressive disease; RECIST 1.1 Response Evaluation Criteria in Solid Tumors 1.1; 
VOP verification of progression.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Procedures 
Manual.
Planned time points for all safety assessments are provided in the SoA.
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Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard. Height (at 
screening only) and weight will also be measured and recorded.
A brief directed physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical exam during the 
Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 1.3 (SoA). After the 
first dose of study intervention, new clinically significant abnormal findings should be 
recorded as AEs.
8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical exam as defined in Section 1.3 (SoA), the 
investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to the administration of the study intervention. New clinically significant 
abnormal findings should be recorded as AEs.
Vital Signs
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, pulse, and respiratory rate.
Electrocardiograms
Single 12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. 
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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 case report form 
(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 Procedures Manual and the SoA.
•
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Study 
Procedures Manual. Refer to the SoA (Section 1.3) for the timing of laboratory assessments.
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.4.2
Pregnancy Test
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 72 hours or the 
first dose of study intervention. If a urine test is positive or not evaluable, a serum test will be 
required. Participants must be excluded/discontinued from the study in the event of a positive 
test result. Repeated pregnancy test (such as clinic visit testing) may be conducted if required 
by local regulation.
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Eastern Cooperative Oncology Group (ECOG) Performance Scale
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 as specified in the SoA (Section 1.3).
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), 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.
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.
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 consent form is signed 
but before intervention allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.
All AEs from the time of intervention allocation/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 allocation/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 
allocation/randomization through 120 days following cessation of study intervention, or 30 
days following cessation of study intervention if the participant initiates new anticancer 
therapy must be reported by the investigator.
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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 drug-related.
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 10.
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Table 10
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:
Nonserious Adverse 
Event (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
Serious Adverse 
Event (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:
- due to 
intervention
- causes 
exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- potential drug-
induced liver 
injury (DILI)
- require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (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
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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.
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, events of clinical interest (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.
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 wth 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 suspected unexpected serious adverse 
reactions (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.
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. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
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serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints, as described in Section 9.4.1, will not be reported to MSD.  
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
MSD will monitor efficacy endpoint events and safety data to ensure the safety of the 
participants in the study.  Any suspected endpoint which upon review is not progression of 
the cancer under study will be forwarded to MSD as an SAE within 24 hours of 
determination that the event is not progression of the cancer under study.
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
1) An overdose of Sponsor's product, as defined in Section 8.5, that is not associated 
with clinical symptoms or abnormal laboratory results.
2) An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. The study site guidance 
for assessment and follow up of these criteria can be found in the Investigator Study 
File Binder (or equivalent).
8.5
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater (≥5 times the indicated dose).
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.
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8.6
Pharmacokinetics
Pharmacokinetic parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic markers will be evaluated to gain a better understanding of response and 
resistance biology. Blood samples for a variety of exploratory biomarkers and planned 
genetic analysis will be collected at baseline, prior to and/or following treatment per the SoA 
(Section 1.3), at response if it occurs, and at end of treatment/progression.  Detailed 
endpoints are described below in the biomarker section (Section 8.10).
8.8
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of future biomedical research:

Leftover DNA for future research

Leftover main study plasma from metabolomics analysis stored for future research

Leftover main study serum from cytokine analysis stored for future research

Leftover main study RNA

Leftover main study tumor stored for future research

Leftover main study stool stored for future research
8.9
Planned Genetic Analysis Sample Collection
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be provided in the Procedures Manual.  
Samples should be collected for planned analysis of associations between genetic variants in 
germline/tumor DNA and drug response. If a documented law or regulation prohibits (or 
local IRB/Independent Ethics Committee [IEC] does not approve) sample collection for these 
purposes, then such samples should not be collected at the corresponding sites. Leftover 
DNA extracted from planned genetic analysis samples will be stored for future biomedical 
research only if participant signs the Future Biomedical Research consent.
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8.10
Biomarkers
Collection of samples for biomarker analysis supports primary endpoint, secondary 
endpoints, and exploratory endpoints in this study, as shown below. The following samples 
for biomarker research are required and will be collected from all participants in this study as 
specified in the SoA:

Whole blood for the following analyses:
•
cfDNA (primary endpoint and secondary endpoint)
•
Cytokine analysis (exploratory endpoint)
•
Genetic analysis (exploratory endpoint)
•
RNA analysis (exploratory endpoint)
•
Metabolomics analysis (exploratory endpoint)

Archival or newly obtained Stage IV tumor tissue for the following analyses:
•
PD-L1 molecular status (exploratory endpoint)  
•
WES for TMB (exploratory endpoint)
•
Other, eg: RNA, genetic, or other exploratory biomarkers 
•
Stool for microbiome analysis (exploratory endpoint)
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the Merck Procedures Manual for this study.
Tissue Biomarkers
8.10.1.1
PD-L1 IHC
Although not required for determining eligibility, pre-treatment PD-L1 status of tumor tissue 
will be recorded for each participant.  If PD-L1 results are not available from a participant’s 
diagnostic biopsy, PD-L1 IHC must be performed.  Analysis may be performed locally using 
PharmDx kit (Agilent, FDA approved for NSCLC), which uses the 22C3 antibody.  
Otherwise, adequate tumor tissue must be sent to the central tissue lab, Covance, for this 
analysis. Sample requirements, collection, storage, and shipment instructions are provided in 
the Procedures Manual.
8.10.1.2
Exploratory Biomarkers
To be eligible to participate in the study, participants must provide sufficient evaluable Stage 
IV, archival solid tumor tissue sample or newly obtained core or excisional biopsy of a tumor 
lesion (that was not previously irradiated) for biomarker analysis (Fine Needle Aspiration 
[FNA] samples will not be accepted). Formalin-fixed, paraffin embedded (FFPE) tissue 
blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. The 
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Merck Procedures Manual for this study specifies the definitions for what is considered 
sufficient and evaluable tissue.  This sufficient and adequate tissue must be provided to the 
central lab prior to Randomization.  
The planned Exploratory Biomarker tissue analyses will include the following:

WES for TMB (exploratory endpoint)

Other, eg: RNA, genetic, or other exploratory biomarkers 
Tissue sample requirements, collection, storage, and shipment instructions are provided in 
the Merck Procedures Manual for this study.
Blood-based Biomarkers
Whole blood will be collected for primary and secondary endpoints, and exploratory 
biomarker analyses.  These collections are shown in the SoA and include: whole blood for 
cfDNA analysis, serum for cytokine analysis, blood for genetic analysis, blood for RNA 
analysis, and plasma for metabolomics analysis.
The Merck Procedures Manual details the requirements for sample collection, processing, 
storage and shipment for each of the blood-based biomarkers.
The Screening cfDNA collection is required for analyzing the primary endpoint of this study.  
For this most critical sample, please ensure that the Merck Procedures Manual is followed 
exactly for the collection, processing, storage, and shipment of this sample.  All cfDNA 
shipments must be shipped the same day of collection, via overnight expedited shipping in 
extreme ambient shipping kits.
Stool-based Biomarkers
Stool samples will be collected for microbiome analysis per the SoA.  Of note, two (2) 
separate stool collections are required within 1 week prior to first dose of therapy on C1D1. 
A single stool collection is required within 5 days prior to each of the designated on-
treatment study visits.  Sites should provide the participant with adequate stool collection kits 
and instructions for at-home collection of stool prior to the designated study visit. 
Stool sample collection, storage, and shipment instructions are provided in the Merck 
Procedures Manual.
8.11
Health Economics Medical Resource Utilization and Health Economics
Not applicable.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3 (SoA). Specific procedure-related details are 
provided in Section 8.
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Screening
Written 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 testing, which may be done up to 28 days prior to 
the first dose of study intervention.
•
Evaluation of ECOG is to be performed within 10 days prior to the first dose of study 
intervention.
•
For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 72 hours prior to 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).
•
Archival tumor sample collection is not required to be obtained within 28 days prior to 
the first dose of study intervention. Newly obtained tumor tissue may be obtained within 
90 days of treatment initiation.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criterion is met. Participants who are rescreened will retain their original 
screening number.
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.
Discontinued Participants Continuing to be Monitored in the Study
8.12.3.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first.
All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Participants with 
an AE of Grade >1 will be followed until the resolution of the AE to Grade 0-1 or until the 
beginning of a new anticancer therapy, whichever occurs first. SAEs that occur within 90 
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days of the end of treatment or before initiation of a new anticancer treatment should also be 
followed and recorded.
8.12.3.2
Follow-up Visits
Participants who discontinue study treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed approximately every 12 weeks to 
monitor disease status.  The Sponsor may request survival status to be assessed at additional 
time points during the course of the study (not to exceed approximately 12 weeks).  Every 
effort should be made to collect information regarding disease status until the start of new 
anticancer therapy, disease progression, death, or end of study as detailed in Section 1.3 
(SoA).  Information regarding post-study anticancer treatment will be collected if new 
treatment is initiated.
8.12.3.3
Survival Follow-up
Participants who experience confirmed disease progression or start a new anticancer therapy 
will move into the Survival Follow-up Phase and should be contacted by telephone 
approximately every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first.
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (eDMC) review, 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 survival status (excluding 
participants that have a previously recorded death event in the collection tool).
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  Changes 
to analyses made after the protocol has been finalized, but prior to final database lock, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report for 
the study. Details around the analysis approach for biomarker endpoints related to the 
exploratory objectives are deemed out of scope for this SAP, but may be the subject of 
sSAPs.
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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 to 9.12.  
Study Design Overview
A Phase II Trial to Investigate Genetic Markers of Immune Response 
to Pembrolizumab Combined with Chemotherapy in First-Line Non-
Small Cell Lung Cancer (KEYNOTE-782)
Treatment Assignment

Participants will receive: 
(1) Pembrolizumab 200 mg Q3W in combination with 
carboplatin AUC 5 mg/mL/min Q3W IV and 
pemetrexed 500 mg/m2 Q3W IV for 4 cycles followed 
by pembrolizumab monotherapy 200 mg Q3W IV with 
pemetrexed maintenance 500 mg/m2 Q3W IV.
OR
(2) Pembrolizumab 200 mg Q3W in combination with 
cisplatin 75mg/m2 Q3W IV and pemetrexed 500 mg/m2
Q3W IV for 4 cycles followed by pembrolizumab 
monotherapy 200 mg Q3W IV with pemetrexed 
maintenance 500 mg/m2 Q3W IV.
Analysis Populations
All Subjects as Treated (ASaT)
Primary Efficacy Endpoint
1)
Objective response (OR):  Complete response (CR) or partial 
response (PR)
Primary Biomarker 
Endpoint
1)
Baseline tumor mutation burden (TMB) in circulating cell-free 
DNA (cfDNA) (blood)
Key Secondary Endpoints
1)
PFS is defined as the time from the start of treatment to the first 
documented progressive disease (PD) or death due to any cause, 
whichever occurs first.   
2)
OS is defined as the time from the start of treatment to death due 
to any cause.
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
For the primary objective, the posterior probability that the coefficient 
for baseline TMB in cfDNA is greater than zero in a logistic regression 
model of objective response (yes/no) will be used to estimate the level of 
association of baseline TMB in cfDNA and objective response in 
NSCLC participants treated with pembrolizumab + platinum-doublet
chemotherapy.
Statistical Methods for Key 
Safety Analyses
Descriptive summary statistics will be provided.
Interim Analyses
A preliminary analysis of the primary objective: an evaluation of the 
level of association of TMB in cfDNA and objective response will occur 
approximately 16 weeks after last patient enrolled (LPE).
Final analysis will occur after all participants have received 35 
administrations of pembrolizumab or discontinued study intervention.
Multiplicity
No multiplicity adjustment
Sample Size and Power
This estimation study will enroll approximately 100 participants.
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9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Early Clinical Development Statistics Department of the Sponsor.
This trial is being conducted as an unblinded, 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.
Biomarker assays used to assess the primary, secondary, and tertiary/exploratory objectives 
in this study will be performed by personnel blinded to participants’ clinical outcome data.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy Endpoints
Primary Efficacy Endpoint
1) Objective Response:  defined as confirmed CR or PR between the start of the study 
treatment and disease progression/recurrence (or death due to any cause, whichever 
occurs first) as assessed by the investigator using RECIST 1.1. A treated participant
will be designated as a ‘responder’ if he/she achieves a confirmed CR or confirmed 
PR and designed as a ‘non-responder’ otherwise. Participants with missing response
data are considered non-responders.
Secondary Efficacy Endpoints
2) Progression-Free Survival (PFS):  defined as the time from start of treatment to the 
first documented PD (per investigator assessed RECIST 1.1) or death due to any 
cause, whichever occurs first. 
3) Overall Survival (OS):  defined as the time from start of treatment to death due to any 
cause. 
Biomarker Endpoints
Primary and Secondary Biomarker Endpoints
The primary and secondary biomarker endpoint is baseline TMB in cfDNA from blood 
detailed in Section 4.2.1.1.1.
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Exploratory Biomarker Endpoints
Details around other biomarker-related endpoints associated with the exploratory objectives, 
including additional genomic, metabolic, proteomic, radiomic, and microbiome endpoints, as 
well as details for the processing and normalization of these complex data sources, are 
deemed out of scope for this SAP, but may be the subject of supplementary SAPs.
Safety Endpoints
Refer to Section 4.2.1.3 for the description of safety measures.
9.5
Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of the primary, 
secondary, and exploratory objectives. The ASaT population consists of all subjects who 
received at least 1 dose of study treatment. Subjects will be included in the treatment group 
corresponding to the study treatment they actually received for the analysis of primary, 
secondary, and exploratory objectives using the ASaT population.
9.6
Statistical Methods
Statistical Methods for Biomarker/Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in supplemental 
SAPs.
Those generating the biomarker data will remain blinded to a participant’s clinical status as a 
responder or non-responder per RECIST 1.1 (investigator-assessed) in order to preserve an 
objective evaluation of the study objectives. Demographic and baseline characteristics of 
responders and non-responders will be tabulated.
Primary Objective
Logistic regression modeling of responders (CR or PR) and non-responders will be used to 
estimate the level of association of baseline TMB in cfDNA and objective response in 
NSCLC participants treated with pembrolizumab + investigator choice platinum-doublet 
chemotherapy (pemetrexed plus investigator choice of either cisplatin or carboplatin). The 
logistic regression model will include a term for independent variable:  continuous log10
transformed TMB in cfDNA and dependent variable:  objective response (yes/no). The 
posterior probability that the coefficient for cfDNA TMB is greater than zero in the logistic 
regression model will be reported. In addition, logistic regression models adjusting for 
ECOG performance status, smoking status, and other relevant clinical variables will be 
evaluated to assess the importance of these prognostic factors and support the robustness of 
TMB in cfDNA findings. Sensitivity analyses using raw scale and square root 
transformations of TMB in cfDNA will be explored to handle any zero-inflation in the TMB 
in cfDNA data. The association of baseline TMB in cfDNA with objective response will also 
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be evaluated using the area under the ROC curve (AUROC). The distribution of baseline 
TMB in cfDNA will be graphically displayed and summarized (mean, median, and standard 
deviation) by responders (CR or PR) versus non-responders.
Secondary Objectives
Cox regression modeling will be used to estimate the level of association of baseline TMB in 
cfDNA and survival (PFS or OS). The Cox regression models will include a term for the 
independent variable:  continuous log10 transformed TMB in cfDNA and dependent 
variables:  PFS or OS. Participants without documented progression or death at the time of 
analysis will be censored at the date of the last adequate assessment. The posterior 
probability that the coefficients for cfDNA TMB are less than zero in the Cox regression 
models will be reported. In addition, Cox regression models adjusting for ECOG 
performance status, smoking status, and other relevant clinical variables will be evaluated to 
assess the importance of these prognostic factors and support the robustness of TMB in 
cfDNA findings. Sensitivity analyses using raw scale and square root transformations of 
TMB in cfDNA will be explored to handle any zero-inflation in the TMB in cfDNA data.
Exploratory Objectives
Details around the analysis approach for biomarker endpoints related to the exploratory 
objectives are deemed out of scope for this SAP, but will be the subject of supplemental 
SAPs.
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Table 11 summarizes the estimation strategy for the primary and secondary objectives 
detailed above.
Table 11
Analysis Strategy for Primary and Secondary Objectives
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach1
Statistical Method2
Analysis 
Population
Missing Data 
Approach
Primary Objective
Objective Response (OR)
P
Posterior probability of 
TMB coefficient in 
logistic regression3
ASaT
Study 
participants with 
missing data are 
considered non-
responders.
Objective Response (OR)
S
AUROC
ASaT
Study 
participants with 
missing data are 
considered non-
responders.
Secondary Objective
Progression-free survival (PFS)
P
Posterior probability of 
TMB coefficient in 
Cox regression4
ASaT
Censored at the 
date of last 
adequate 
assessment
Overall survival (OS)
P
Posterior probability of 
TMB coefficient in 
Cox regression4
ASaT
Censored at the 
date of last 
follow-up
  1
ASaT All Subjects as Treated; cfDNA circulating free deoxyribonucleic acid; P Primary approach; 
PFS progression free survival; S Supportive approach; TMB tumor mutation burden.
  2
Statistical models are described in further detail below:
  3
Logistic regression model, including term for independent variable baseline cfDNA TMB and dependent variable 
OR (yes/no CR or PR). The posterior probability of the TMB coefficient in logistic regression models adjusting for 
ECOG performance status, smoking status, and other relevant clinical variables will be evaluated as a supportive 
approach.
  4
Cox regression model, including term for independent variable baseline cfDNA TMB and dependent variables PFS 
or OS. The posterior probability of the TMB coefficient in Cox regression models adjusting for ECOG performance 
status, smoking status, and other relevant clinical variables will be evaluated as a supportive approach.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters,
including AEs, SAEs, laboratory tests, vital signs, etc.
Descriptive summary statistics will be provided for safety endpoints. For continuous 
measures such as changes from baseline in laboratory tests and vital signs, summary statistics 
for baseline, on-treatment, and change from baseline values will be provided in table format.
Additional safety endpoints may also be summarized as deemed clinically appropriate.
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9.7
Interim Analyses
A preliminary analysis of the primary objective:  an evaluation of the level of association of 
TMB in cfDNA and objective response will occur approximately 16 weeks after last patient 
enrolled (LPE).
9.8
Final Analysis
The final analysis of the primary objective will occur after all participants have received 35 
administrations of pembrolizumab or discontinued study intervention.
9.9
Multiplicity
No multiplicity adjustment will be applied to the primary or secondary analyses. 
9.10
Sample Size and Power Calculations
This study will enroll approximately 100 participants. This provides 80% power to detect a 
coefficient for cfDNA TMB greater than zero in a logistic regression model for objective 
response with type I error rate of 5% (one-sided) and with mean fold increase in median 
cfDNA TMB for responders versus non-responders of 1.78, assuming a 50% ORR. 50% 
ORR is consistent with data from KEYNOTE-021G and KEYNOTE-189, where in the same 
treatment setting response rates of 56.7% and 47.6%, respectively, were observed.
Historically, an approximate 60% increase in the median WES TMB for responders 
compared to non-responders to pembrolizumab monotherapy has been observed in bladder 
and head and neck squamous cell carcinoma (HNSCC), indications which are most similar to 
NSCLC. Recent NSCLC pembrolizumab monotherapy-treated WES TMB data are in 
alignment with historical data. A linear relationship between WES TMB data and TMB in 
cfDNA data is assumed. 
While historical data provide evidence of a 60% increase in the median WES TMB for 
responders compared to non-responders, it is important to note the fold increase is in 
reference to response to treatment with pembrolizumab monotherapy. The fold increase in 
the median TMB for responders versus non-responders treated with pembrolizumab plus 
chemotherapy may lessen from that expected for pembrolizumab monotherapy if 
chemotherapy generates objective responses independent of the level of the biomarker, TMB. 
Table 12 shows the mean fold increase of median TMB in cfDNA for responders compared 
to non-responders from 10,000 simulated datasets with 80% and 90% power to detect a
coefficient for TMB in cfDNA greater than zero with type I error rate of 5% (one-sided) for 
varying objective response rates (ORR). The simulations used to generate Table 12 make the 
following assumptions:  TMB in cfDNA is normally distributed on the log10 scale with equal 
variance between responders and non-responders, the mean TMB in cfDNA of responders is 
a positive shift from the mean TMB in cfDNA of non-responders, and the variance of TMB 
in cfDNA is 0.24 on the log10 scale. First, the power was calculated as the proportion of 
10,000 datasets with logistic regression coefficient for TMB in cfDNA Wald-test p-value less 
than or equal to one-sided α 0.05 using logistic regression models for objective response. 
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Then, the geometric mean of the paired fold-difference in median TMB in cfDNA for 
responders versus non-responders for the 10,000 datasets was estimated. 
With limitations in the ability to detect a statistically significant association at one-sided
α 0.05 with underlying fold-change (responders/non-responders) less than 1.78 (closer to the 
historical 1.60), an estimation approach to the primary and secondary study objectives was 
taken.
Table 12
Mean Fold Increase in the Total Tumor Mutation Burden (TMB) in Circulating 
Free DNA (cfDNA) for Responders Compared to Non-responders With 80% and 90% Power 
to Detect a Coefficient for cfDNA TMB Greater Than Zero for Varying Objective Response 
Rates (ORR)
N
Response 
Rate (%)
Mean Fold Increase in TMB in cfDNA
Responders vs. Non-Responders
with 80% Power1
Mean Fold Increase in TMB in cfDNA
Responders vs. Non-Responders
with 90% Power1
100
40
1.78
1.98
45
1.78
1.97
50
1.78
1.95
55
1.78
1.95
1Based on 10,000 generated datasets; power evaluated from logistic regression models at α=0.05 (one-sided)
9.11
Subgroup Analyses
Not applicable.
9.12
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study.  Any 
deviation from protocol-directed administration will be reported.
9.13
Extent of Exposure
The extent of exposure to study treatment will be evaluated by summary statistics (eg, N, 
mean, median, standard deviation, etc.) for duration of treatment in cycles.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (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 of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, 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 (ie, 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 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 general principles of 
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, scientific/research misconduct, or serious GCP noncompliance is suspected, the issues 
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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 primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified 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. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
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 representative), 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.
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.
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MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review 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 (eg, 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.
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.
Data Protection
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.
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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.
Committees Structure
10.1.4.1
Steering Committee
This study will be conducted in consultation with a Steering Committee. The Steering 
Committee is composed of Sponsor personnel and representatives of GRAIL, Inc.
The Steering Committee will provide guidance on the operational aspects of the study.
Specific details regarding responsibilities and governance of the Steering Committee will be 
described in a separate charter.
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 
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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.
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the 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 
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.
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 Conference on Harmonization 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 Studies.
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.
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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.
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.
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Records and documents, including signed ICF, 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.
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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 will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 13 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 13
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)
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
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose 
(nonfasting)
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
•
Follicle-stimulating hormone (as needed in women of nonchildbearing potential only)
•
β human chorionic gonadotropin (β hCG) pregnancy test (as needed for WOCBP)
within 72 hours of first dose
Thyroid panel: TSH, FT4, FT3/T3Serology
NOTES:
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
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, 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.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
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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.
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.
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.
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•
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.
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
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.
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•
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 Common Terminology for Adverse Events 
(CTCAE), version 4. 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 activities of daily living (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.
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 
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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’  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.
(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 
IRB/IEC.
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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 CRFs/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.
The causality assessment is one 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 are sufficient data to support full attribution 
of the AE to the single agent.
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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.
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 electronic data collection 
(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.
•
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).
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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: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
•
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormone replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range is 
required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 1 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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Contraception Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 of the following during the protocol-defined time frame in Section 5.1:
•
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
•
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant.
-
The following are not acceptable methods of contraception:
•
Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea
method (LAM).
•
Male condom with cap, diaphragm, or sponge with spermicide.
•
Male and female condom cannot be used together.
-
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration. 
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
consistent and correct use of a highly effective method of contraception that has a low user 
dependency as described in Table 14 during the protocol-defined time frame in Section 5.1.
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Table 14
Highly Effective Contraceptive Methods That Have Low User Dependency
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●Progestogen only contraceptive implanta,b
●Intrauterine hormone-releasing system (IUS)b
●Intrauterine device (IUD)
●Bilateral tubal occlusion
●Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. 
●Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study 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.
Notes:
Use should be consistent with local regulations regarding the use of contraceptive methods for participants of 
clinical studies.
a
If locally required, in accordance with Clinical Trial Facilitation Group guidelines, acceptable 
contraceptive implants are limited to those which inhibit ovulation.
b
If hormonal contraception efficacy is potentially decreased due to interaction with study intervention, 
condoms must be used in addition to the hormonal contraception during the intervention period and for at 
least 120 days (corresponding to time needed to eliminate study intervention plus 30 days for study 
interventions with genotoxic potential)  after the last dose of study intervention.
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test and in accordance with local requirements. This test should be repeated a maximum of 
72 hours before the first dose.
Following initiation of treatment, additional pregnancy testing will be performed at every 
study visit during the treatment period and at 180 days for study interventions with risk of 
evidence of genotoxicity at any dose, after the last dose of study intervention, and as required 
locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research

Definitions
1.
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
2.
Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
3.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
4.
DNA: Deoxyribonucleic acid.
5.
RNA: Ribonucleic acid.

Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 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 drugs/vaccines may interact with
◦
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.
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
Summary of Procedures for Future Biomedical Research.
1. Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy
2. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
3. 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.
4. 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.

Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' 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 gender, 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.
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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.

Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (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 this substudy. Future biomedical research 
specimens remaining with the third party after specific analysis is performed will be 
reported to the Sponsor.

Withdrawal From Future Biomedical Research
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 principal 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 
. 
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.

Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
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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.

Data Security
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.

Reporting of Future Biomedical Research Data to Participants
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.

Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.

Risks Versus Benefits of Future Biomedical Research
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.
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
Questions
Any questions related to the future biomedical research should be emailed directly to 

References
3) National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid 45618
4) International Conference on Harmonization [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 
5) 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/ 
6) 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
Not applicable.     
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study 
intervention until repeat imaging is obtained using iRECIST for participant management (see 
Table 9). This decision by the investigator should be based on the participant’s overall 
clinical condition.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of disease
•
No decline in ECOG performance status
•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study intervention at     
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:
•
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
Note: The iRECIST publication uses the terminology “sum of measurements,” but “sum 
of diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology.
•
Unequivocal progression of nontarget lesion(s) identified at baseline
•
Development of new lesion(s)
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iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions Target. 
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
•
Any of the factors that were the basis for the iUPD at the previous visit show worsening
-
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point
-
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
-
For new lesions, worsening is any of these:
◦
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time 
point
◦
Visible growth of new nontarget lesions
◦
The appearance of additional new lesions
•
Any new factor appears that would have triggered PD by RECIST 1.1
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Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
•
None of the progression-confirming factors identified above occurs AND
•
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
•
None of the progression-confirming factors identified above occurs, AND
•
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset.” This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
intervention may be considered following consultation with the Sponsor. In this case, if study 
intervention is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 1.3 and submitted to the central imaging vendor.
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Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:
•
Target lesions
-
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression. The nadir 
is always the smallest sum of diameters seen during the entire study, either before or 
after an instance of pseudo-progression.
•
Nontarget lesions
-
If nontarget lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD.
-
If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole.
•
New lesions
-
New lesions appear for the first time
-
Additional new lesions appear
-
Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum
-
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: If new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
ADL
activities of daily living
AE
adverse event
ALK
anaplastic lymphoma kinase
aPTT
activated partial thromboplastin time
ASaT
All Subjects as Treated
AUC
area under the time-concentration curve
BICR
blinded independent central review
B-RAF
B isoform of rapidly accelerated fibrosarcoma
C1D1
Cycle 1 Day 1
CBC
complete blood count
CCGA
Circulating Cell-free Genome Atlas Study
CD
cluster of differentiation
cfDNA
circulating free DNA
cfNA
cell-free nucleic acid
CI
confidence interval
CNS
central nervous system
CR
complete response
CRF
case report form
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DC
discontinuation
DILI
drug-induced liver injury
DL
dose level
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data collection 
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
EOT
end of treatment
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed paraffin embedded
FSH
Follicle stimulating hormone 
GCP
Good Clinical Practice 
GI
gastrointestinal
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
HR
hazard ratio
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
Ig
immunoglobulin
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Abbreviation
Expanded Term
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IND
Investigational New Drug
INR
international normalized ratio
irAE
immune-related adverse event
IRB
Institutional Review Board 
iRECIST
immune-related Response Evaluation Criteria in Solid Tumors
IUD
intrauterine device
IV
intravenous
IVRS
interactive voice response system
KRAS
a proto-oncogene derived from Kirsten RAt Sarcoma virus
mAb
monoclonal antibody
MRI
magnetic resonance imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MSI
microsatellite instability
NR
not reached
NSCLC
non-small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
PD
progressive disease
PD-1
programmed cell death 1 receptor
PD-L1
programmed cell death ligand 1
PFS
progression-free survival
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
Q3W
Every 3 weeks
RECIST 
Response Evaluation Criteria in Solid Tumors version 1.1
RNA
ribonucleic acid
ROS1
c-ros oncogene 1
SAE
serious adverse event 
SAP
statistical analysis plan
SoA
schedule of activities
SOC
standard of care
sSAP
supplemental statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
TMB
tumor mutation burden
TPS
tumor proportion score
ULN
upper limit of normal
WES
whole exome sequencing
WOCBP
woman/women of childbearing potential 
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10.10 Appendix 10: Eastern Cooperative Oncology Group (ECOG) Performance Scale
Developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group 
Chair.* 
GRADE
ECOG Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, eg, light house work, office work
2
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
Capable of only limited self-care; confined to bed or chair more than 50% 
of waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed 
or chair
5
Dead
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;5:649-655.
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