A Randomized, Double-Blind, Phase 3 Study of Pembrolizumab/Vibostolimab Coformulation (MK-7684A) in Combination With Chemotherapy Versus Pembrolizumab Plus Chemotherapy as First Line Treatment for Participants With Metastatic Non-Small Cell Lung Cancer (MK-7684A-007/KEYVIBE-007)
Phase: PHASE3
Conditions: Metastatic Non-Small Cell Lung Cancer
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Randomized, Double-Blind, Phase 3 Study of 
Pembrolizumab/Vibostolimab Coformulation 
(MK-7684A) in Combination with Chemotherapy Versus 
Pembrolizumab Plus Chemotherapy as First Line 
Treatment for Participants with Metastatic Non-Small 
Cell Lung Cancer (MK-7684A-007/KEYVIBE-007)
NCT05226598
 22 January 2025

PRODUCT: MK-7684A
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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Randomized, Double-Blind, Phase 3 Study of 
Pembrolizumab/Vibostolimab Coformulation (MK-7684A) in Combination with 
Chemotherapy Versus Pembrolizumab Plus Chemotherapy as First Line Treatment for
Participants with Metastatic Non-Small Cell Lung Cancer (MK-7684A-007/KEYVIBE-007)
Protocol Number: 007-05
Compound Number: MK-7684A
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
05226598
EU CT
2023-506074-12
EudraCT
2021-004564-94
JAPIC-CT
jRCT2031220098
WHO
U1111-1293-2114
UTN
U1111-1293-2114
IND
147424
Approval Date:   22 January 2025
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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 5
22-JAN-2025
The Sponsor has decided to discontinue treatment 
with MK-7684A based on lack of efficacy observed 
in other studies.
Amendment 4
03-JUN-2024
 
 
 
 
 
 
 
 
 
 
the objectives, hypotheses, and statistical analysis 
plan were updated to evaluate participants with PD-
L1 TPS≥1% in addition to all participants.
Amendment 3
16-APR-2024
Revisions to align with Regulation (EU) 536/2014
Amendment 2
17-NOV-2023
 
 
Additionally, interim data recently became 
available from the external Phase 3 
SKYSCRAPER-01 study.
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
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Document
Date of Issue
Overall Rationale
Amendment 1
23-JUN-2022
Clarified the contraception requirements for male 
participants in UK to meet the requirements of UK 
Regulatory Agency.
Original Protocol
11-NOV-2021
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendment:
The Sponsor has decided to discontinue treatment with MK-7684A based on lack of efficacy 
observed in other studies.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 1, 
Protocol 
Summary
Participants receiving MK-7684A will be 
transitioned to pembrolizumab.
The Sponsor has decided to discontinue 
treatment with MK-7684A based on lack of 
efficacy observed in other studies.
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Section 1, 
Protocol 
Summary
A brief summary of new data from MK-7684A 
studies was added. 
To provide context for the discontinuation of the 
MK-7684A clinical program.
Section 1.1, 
Synopsis
Updated the pembrolizumab row(s) in the study 
interventions table to apply to all participants.
Refer to rationale for Section 1 for the 
discontinuation of the MK-7684A clinical 
program.
Section 4, Study 
Design
Section 6, Study 
Intervention
Section 7, 
Discontinuation 
of Study 
Intervention and 
Participant 
Withdrawal
•
This study will be unblinded.
•
Participants receiving MK-7684A plus 
chemotherapy will be transitioned to 
pembrolizumab plus chemotherapy.
•
Pembrolizumab can be sourced locally or 
centrally.
Refer to rationale for Section 1 for the 
discontinuation of the MK-7684A clinical 
program.
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Section Number 
and Name
Description of Change
Brief Rationale
Section 8, Study 
Assessments and 
Procedures
Section 9, 
Statistical 
Analysis Plan
•
Participants with access to approved SOC 
(eg, pembrolizumab plus chemotherapy) 
should be considered for discontinuation 
from the study. Those benefiting from 
pembrolizumab with chemotherapy, but 
unable to access it as SOC outside the 
study, may continue on study and receive 
treatment with pembrolizumab plus 
chemotherapy until discontinuation criteria 
are met. The final required study visit will 
be the Safety Follow-up Visit.
•
Imaging scans should no longer be 
submitted to iCRO nor read by BICR. 
However, for participants who are still on 
study treatment and deriving clinical 
benefit and will continue on study 
treatment until criteria for discontinuation 
are met, local tumor imaging should 
continue per local SOC schedule and local 
SOC method of assessment of imaging. All 
imaging as well as relevant objectives and 
endpoints will be assessed locally.
•
PK/ADA samples will no longer be 
collected.
•
Biomarker/FBR samples will no longer be
collected.
•
ePROs will no longer be collected.
•
Second course treatment of 
pembrolizumab for participants currently 
not on second course treatment will be 
offered. Any participant already receiving 
Second Course treatment will be able to 
complete treatment as planned.
•
Treatment beyond progression will no 
longer be offered. Any participant already 
receiving treatment beyond progression 
will be able to complete treatment as 
planned.
•
Participants who complete study treatment 
or otherwise meet EOT criteria will be 
discontinued from the study after the EOT 
visit and any required safety follow-up 
visit.
•
There will be no follow-up for survival 
status. Participants currently in imaging 
follow-up or survival follow-up are 
considered to have completed the study 
and therefore should obtain imaging and 
further oncological care as per local SOC. 
However, standard safety reporting should 
continue, as applicable.
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Section Number 
and Name
Description of Change
Brief Rationale
•
Those participants remaining on study at 
the time of Amendment 05 should 
continue to be monitored in the study 
through the AE reporting period (Section 
8.4).
•
Assessments listed in the SoA will be done 
per local SOC.
•
Participants may enroll in an extension 
study, if available.
-
Participation in this study is ended 
when the participant is consented for 
an extension study.
-
The overall study ends when the last 
participant completes the last study-
related contact, withdraws consent, or 
is lost to follow-up (Section 7.3), or 
the last participant on active treatment 
is consented in an extension study
-
For participants who enter an 
extension study, all AEs, SAEs, and 
other reportable safety events must be 
reported by the investigator in this 
protocol (parent study) from the time 
of intervention randomization up to 
the time of providing documented 
informed consent for an extension 
study. Note: Once consented to an 
extension study, safety events, 
including those considered related to 
study intervention, will be collected 
as instructed in the extension study.
Section 6.1, 
Study 
Intervention(s) 
Administered
Table 5: updated the pembrolizumab row to 
apply to all participants.
Refer to rationale for Section 1 for the 
discontinuation of the MK-7684A clinical 
program.
Pembrolizumab can be sourced locally or 
centrally.
Refer to rationale for Section 1 for the 
discontinuation of the MK-7684A clinical 
program.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................17
1.2
Schema ..................................................................................................................24
1.3
Schedule of Activities...........................................................................................25
1.3.1
Initial Treatment Period ...............................................................................25
1.3.2
Follow-up Assessments ...............................................................................34
1.3.3
Second Course Treatment............................................................................36
2
INTRODUCTION..........................................................................................................40
2.1
Study Rationale....................................................................................................40
2.2
Background ..........................................................................................................41
2.2.1
Pharmaceutical and Therapeutic Background .............................................42
2.2.1.1
MK-7684 Background .......................................................................43
2.2.1.2
Pembrolizumab Background..............................................................43
2.2.2
Preclinical and Clinical Studies ...................................................................43
2.2.2.1
MK-7684 Preclinical Studies.............................................................43
2.2.2.2
Pembrolizumab Preclinical and Clinical Studies...............................43
2.2.3
Ongoing Clinical Studies.............................................................................44
2.2.3.1
MK-7684A Ongoing Clinical Studies ...............................................44
2.2.3.2
Pembrolizumab Ongoing Clinical Studies.........................................46
2.3
Benefit/Risk Assessment......................................................................................46
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................48
4
STUDY DESIGN............................................................................................................53
4.1
Overall Design......................................................................................................54
4.2
Scientific Rationale for Study Design.................................................................55
4.2.1
Rationale for Endpoints ...............................................................................55
4.2.1.1
Efficacy Endpoint ..............................................................................55
4.2.1.2
Safety Endpoints................................................................................56
4.2.1.3
Patient-reported Outcomes.................................................................56
4.2.1.3.1
EORTC QLQ-C30 ...................................................................57
4.2.1.3.2
EORTC QLQ-LC13.................................................................57
4.2.1.3.3
NSCLC-SAQ ...........................................................................57
4.2.1.3.4
EQ-5D-5L ................................................................................57
4.2.1.4
.........................................58
4.2.1.5
Future Biomedical Research..............................................................59
4.2.2
Rationale for the Use of Comparator/Placebo .............................................60
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4.3
Justification for Dose...........................................................................................60
4.3.1
MK-7684A...................................................................................................60
4.3.2
Pembrolizumab ............................................................................................61
4.3.3
Justification of Chemotherapy Dose............................................................61
4.3.4
Biocomparability of MK-7684 and Pembrolizumab as Sequential 
Infusions Versus Coformulated Product MK-7684A in Solid Tumors .......61
4.4
Beginning and End-of-Study Definition ............................................................62
4.4.1
Clinical Criteria for Early Study Termination .............................................62
5
STUDY POPULATION ................................................................................................63
5.1
Inclusion Criteria.................................................................................................63
5.2
Exclusion Criteria................................................................................................67
5.3
Lifestyle Considerations......................................................................................69
5.3.1
Meals and Dietary Restrictions....................................................................69
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................69
5.3.3
Activity Restrictions ....................................................................................69
5.4
Screen Failures.....................................................................................................69
5.5
Participant Replacement Strategy......................................................................69
6
STUDY INTERVENTION............................................................................................70
6.1
Study Intervention(s) Administered...................................................................71
6.1.1
Treatment .....................................................................................................75
6.1.2
Second Course .............................................................................................75
6.2
Preparation/Handling/Storage/Accountability .................................................76
6.2.1
Dose Preparation..........................................................................................76
6.2.2
Handling, Storage, and Accountability........................................................76
6.3
Measures to Minimize Bias: Randomization and Blinding..............................76
6.3.1
Intervention Assignment..............................................................................76
6.3.2
Stratification.................................................................................................77
6.3.3
Blinding........................................................................................................77
6.4
Study Intervention Compliance..........................................................................77
6.5
Concomitant Therapy..........................................................................................77
6.5.1
Rescue Medications and Supportive Care ...................................................79
6.5.1.1
Pembrolizumab ..................................................................................80
6.5.1.2
Chemotherapy....................................................................................80
6.6
Dose Modification (Escalation/Titration/Other)...............................................80
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................80
6.6.2
Dose Modifications for Chemotherapy........................................................87
6.6.3
Other Allowed Dose Interruption for Study Intervention............................93
6.7
Intervention After the End of the Study............................................................94
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6.8
Clinical Supplies Disclosure................................................................................94
6.9
Standard Policies..................................................................................................94
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................95
7.1
Discontinuation of Study Intervention...............................................................96
7.2
Participant Withdrawal From the Study...........................................................97
7.3
Lost to Follow-up .................................................................................................97
8
STUDY ASSESSMENTS AND PROCEDURES........................................................98
8.1
Administrative and General Procedures .........................................................100
8.1.1
Informed Consent.......................................................................................100
8.1.1.1
General Informed Consent...............................................................100
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research...........................................................................................100
8.1.2
Inclusion/Exclusion Criteria ......................................................................101
8.1.3
Participant Identification Card...................................................................101
8.1.4
Medical History .........................................................................................101
8.1.4.1
Non-small Cell Lung Cancer History ..............................................101
8.1.5
Prior and Concomitant Medications Review.............................................101
8.1.5.1
Prior Medications.............................................................................101
8.1.5.2
Concomitant Medications................................................................102
8.1.6
Assignment of Screening Number.............................................................102
8.1.7
Assignment of Randomization Number.....................................................102
8.1.8
Study Intervention Administration ............................................................102
8.1.8.1
Timing of Dose Administration.......................................................102
8.1.8.1.1
MK-7684A and Pembrolizumab............................................102
8.1.8.1.2
Chemotherapy........................................................................103
8.1.8.1.2.1
Carboplatin (AUC 6 [Squamous] or AUC 5 
[Nonsquamous])...........................................................103
8.1.8.1.2.2
Paclitaxel or Nab-paclitaxel (Squamous).....................104
8.1.8.1.2.3
Pemetrexed (Nonsquamous)........................................104
8.1.8.1.2.4
Cisplatin (Nonsquamous).............................................104
8.1.8.1.3
Antiemetic Therapy ...............................................................105
8.1.8.1.4
Colony-stimulating Factors....................................................105
8.1.9
Discontinuation and Withdrawal ...............................................................105
8.1.9.1
Withdrawal From Future Biomedical Research ..............................105
8.1.10
Participant Blinding/Unblinding................................................................106
8.1.11
Calibration of Equipment...........................................................................106
8.1.12
Tumor Tissue for Biomarker Status...........................................................107
8.2
Efficacy Assessments .........................................................................................107
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8.2.1
Tumor Imaging and Assessment of Disease..............................................107
8.2.1.1
Initial Tumor Scans..........................................................................108
8.2.1.2
Tumor Scans During the Study........................................................109
8.2.1.3
End-of-treatment and Follow-up Tumor Scans ...............................109
8.2.1.4
Second Course (Retreatment) Tumor Scans....................................110
8.2.1.5
RECIST 1.1 Assessment of Disease................................................111
8.2.2
Patient-reported Outcomes.........................................................................112
8.2.3
PD-L1 Status..............................................................................................112
8.3
Safety Assessments.............................................................................................113
8.3.1
Physical Examinations...............................................................................113
8.3.1.1
Full Physical Examination...............................................................113
8.3.1.2
Directed Physical Examination........................................................113
8.3.2
Vital Signs..................................................................................................113
8.3.3
Electrocardiograms ....................................................................................114
8.3.4
Clinical Safety Laboratory Assessments ...................................................114
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)........................................................................................114
8.3.5
Pregnancy Testing......................................................................................114
8.3.6
Performance Assessments..........................................................................115
8.3.6.1
Eastern Cooperative Oncology Group Performance Status.............115
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................115
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................116
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....118
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.118
8.4.4
Regulatory Reporting Requirements for SAE ...........................................118
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................118
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................119
8.4.7
Events of Clinical Interest..........................................................................119
8.5
Treatment of Overdose......................................................................................119
8.6
Pharmacokinetics...............................................................................................120
8.6.1
Blood Collection for Serum MK-7684A and Pembrolizumab ..................120
8.6.1.1
Blood Collection for PK ..................................................................120
8.6.1.2
Blood Collection for Antidrug Antibodies ......................................120
8.7
Pharmacodynamics............................................................................................120
8.8
Biomarkers .........................................................................................................121
8.8.1
Planned Genetic Analysis Sample Collection............................................121
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8.9
Future Biomedical Research Sample Collection.............................................121
8.10
Medical Resource Utilization and Health Economics.....................................121
8.11
Visit Requirements.............................................................................................122
8.11.1
Screening....................................................................................................122
8.11.2
Initial Treatment Period .............................................................................122
8.11.3
Second Course Treatment Period...............................................................122
8.11.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ..............................................................................123
8.11.5
Posttreatment Visit.....................................................................................123
8.11.5.1
Safety Follow-up Visit.....................................................................123
8.11.5.2
Efficacy Follow-up Visits................................................................123
8.11.5.3
Survival Follow-up Contacts ...........................................................124
8.11.6
Vital Status.................................................................................................124
9
STATISTICAL ANALYSIS PLAN ...........................................................................125
9.1
Statistical Analysis Plan Summary...................................................................126
9.2
Responsibility for Analyses/In-house Blinding ...............................................128
9.3
Hypotheses/Estimation ......................................................................................128
9.4
Analysis Endpoints.............................................................................................129
9.4.1
Efficacy Endpoints.....................................................................................129
9.4.2
Safety Endpoints........................................................................................129
9.4.3
Patient-reported Outcomes.........................................................................129
9.5
Analysis Populations..........................................................................................130
9.5.1
Efficacy Analysis Populations...................................................................130
9.5.2
Safety Analysis Populations ......................................................................130
9.5.3
Patient-reported Outcome Analysis Population.........................................131
9.6
Statistical Methods.............................................................................................131
9.6.1
Statistical Methods for Efficacy Analyses.................................................131
9.6.1.1
Overall Survival...............................................................................131
9.6.1.2
Progression-free Survival.................................................................132
9.6.1.3
Objective Response Rate .................................................................133
9.6.1.4
Duration of Response.......................................................................133
9.6.1.5
Analysis Strategy for Efficacy Variables.........................................134
9.6.2
Statistical Methods for Safety Analyses ....................................................135
9.6.2.1
Overall Safety Assessment ..............................................................135
9.6.2.2
Assessment of Safety Topics of Special Interest .............................136
9.6.3
Statistical Methods for Patient-reported Outcome Analyses.....................137
9.6.4
Demographic and Baseline Characteristics ...............................................138
9.7
Interim Analyses ................................................................................................138
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9.7.1
Efficacy Interim Analyses..........................................................................138
9.7.2
Safety Interim Analyses.............................................................................139
9.8
Multiplicity .........................................................................................................139
9.8.1
Progression-free Survival...........................................................................140
9.8.2
Overall Survival.........................................................................................141
9.8.3
Safety Analyses..........................................................................................144
9.9
Sample Size and Power Calculations ...............................................................144
9.10
Subgroup Analyses.............................................................................................146
9.11
Compliance (Medication Adherence)...............................................................146
9.12
Extent of Exposure.............................................................................................146
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................147
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......147
10.1.1
Code of Conduct for Clinical Trials...........................................................147
10.1.2
Financial Disclosure...................................................................................150
10.1.3
Data Protection...........................................................................................151
10.1.3.1
Confidentiality of Data ....................................................................151
10.1.3.2
Confidentiality of Participant Records.............................................151
10.1.3.3
Confidentiality of IRB/IEC Information..........................................152
10.1.4
Committees Structure.................................................................................152
10.1.4.1
External Data Monitoring Committee .............................................152
10.1.4.2
Executive Oversight Committee......................................................152
10.1.5
Publication Policy......................................................................................152
10.1.6
Compliance with Study Registration and Results Posting Requirements .153
10.1.7
Compliance with Law, Audit, and Debarment ..........................................153
10.1.8
Data Quality Assurance .............................................................................154
10.1.9
Source Documents .....................................................................................155
10.1.10
Study and Site Closure...............................................................................155
10.2
Appendix 2: Clinical Laboratory Tests............................................................156
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................158
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................158
10.3.2
Definition of AE ........................................................................................158
10.3.3
Definition of SAE ......................................................................................159
10.3.4
Additional Events Reported in the Same Manner as SAE.........................160
10.3.5
Recording AE and SAE .............................................................................160
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................164
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................165
10.5
Appendix 5: Contraceptive Guidance..............................................................166
10.5.1
Definitions..................................................................................................166
10.5.2
Contraceptive Requirements......................................................................167
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................168
10.7
Appendix 7: Country-specific Requirements..................................................172
10.7.1
Argentina-specific Requirements...............................................................172
10.7.2
China-specific Requirements.....................................................................172
10.7.3
France-specific Requirements....................................................................173
10.7.4
Germany-specific Requirements................................................................174
10.7.5
Japan-specific Requirements .....................................................................175
10.7.6
Spain-specific Requirements .....................................................................175
10.7.7
United Kingdom-specific Requirements....................................................176
10.8
Appendix 8: ECOG Performance Status.........................................................178
10.9
Appendix 9: Abbreviations ...............................................................................179
11
REFERENCES.............................................................................................................186
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LIST OF TABLES
Table 1
Initial Treatment Period Schedule of Activities ..........................................25
Table 2
Follow-up Schedule of Activities................................................................34
Table 3
Second Course Schedule of Activities.........................................................36
Table 4
Adequate Organ Function Laboratory Values .............................................66
Table 5
Study Interventions......................................................................................72
Table 6
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations (MK-7684A) or IO Combinations.....................................82
Table 7
Pembrolizumab Monotherapy, Coformulations (MK-7684A) or IO 
Combinations Infusion Reaction Dose Modification and Treatment 
Guidelines....................................................................................................86
Table 8
Dose-level Modifications for Chemotherapeutic Agents ............................91
Table 9
Recommended Chemotherapy Dose Modifications for Hematological 
Toxicity........................................................................................................92
Table 10
Recommended Chemotherapy Dose Modifications for 
Nonhematological Toxicity .........................................................................92
Table 11
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events ..........................................................................117
Table 12
Censoring Rules for Primary and Sensitivity Analyses of PFS.................133
Table 13
Censoring Rules for DOR .........................................................................134
Table 14
Analysis Strategy for Efficacy Variables...................................................135
Table 15
Analysis Strategy for Safety Endpoints.....................................................136
Table 16
Censoring Rules for Time-to-Deterioration ..............................................138
Table 17
Summary of Interim and Final Analyses Strategy.....................................139
Table 18
Efficacy Boundaries and Properties for PFS Analyses..............................141
Table 19
Non-Binding Futility Bounds and Properties for OS Futility Analysis in 
participants with PD-L1 TPS≥1% at Interim Analysis..............................142
Table 20
Efficacy Boundaries and Properties for OS Analyses in participants 
with PD-L1 TPS≥1%.................................................................................142
Table 21
Efficacy Boundaries and Properties for OS Analyses for all participants.143
Table 22
Protocol-required Safety Laboratory Assessments....................................156
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LIST OF FIGURES
Figure 1
Initial Treatment Period...............................................................................24
Figure 2
Second Course Treatment............................................................................24
Figure 3
Imaging and Treatment for Clinically Stable Participants Treated With 
MK-7684A or Pembrolizumab After First Radiologic Evidence of PD 
Assessed by the Investigator .....................................................................112
Figure 4
Multiplicity Diagram for Type I Error Control .........................................140
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1
PROTOCOL SUMMARY
Four Phase 3 studies met prespecified futility criteria for OS or RFS: MK-7684A-003 in 
metastatic NSCLC with PD-L1 TPS ≥50% 
 
MK-7684A-007 in metastatic NSCLC with PD-L1 TPS ≥1% 
 
, MK-7684A-008 in ES-SCLC (OS HR, 1.26; 95% CI, 1.00-1.59; presented at Society 
for Immunotherapy of Cancer 2024), and MK-7684A-010 in adjuvant melanoma (RFS HR, 
1.25; 95% CI, 0.87-1.80; presented at Society for Melanoma Research 2024) (data on file). 
Overall, the lack of efficacy observed with MK-7684A rendered the risk-benefit balance 
unfavorable, so treatment with this investigational therapy was stopped in all studies.
At implementation of Amendment 05 or upon receipt of investigator letter detailing 
discontinuation of the MK-7684A clinical program, the following changes apply. The 
changes listed below supersede any protocol content/instructions from previous amendments.
•
This study will be unblinded.
•
Participants receiving MK-7684A plus chemotherapy will be transitioned to 
pembrolizumab plus chemotherapy.
•
Pembrolizumab can be sourced locally or centrally.
•
Participants with access to approved SOC (eg, pembrolizumab plus chemotherapy) 
should be considered for discontinuation from the study. Those benefiting from 
pembrolizumab with chemotherapy, but unable to access it as SOC outside the study, 
may continue on study and receive treatment with pembrolizumab plus chemotherapy 
until discontinuation criteria are met. The final required study visit will be the Safety 
Follow-up Visit.
•
Imaging scans should no longer be submitted to iCRO nor read by BICR. However, for 
participants who are still on study treatment and deriving clinical benefit and will 
continue on study treatment until criteria for discontinuation are met, local tumor imaging 
should continue per local SOC schedule and local SOC method of assessment of imaging. 
All imaging as well as relevant objectives and endpoints will be assessed locally.
•
PK/ADA samples will no longer be collected.
•
Biomarker/FBR samples will no longer be collected.
•
ePROs will no longer be collected.
•
Second course treatment of pembrolizumab for participants currently not on second 
course treatment will be offered. Any participant already receiving Second Course 
treatment will be able to complete treatment as planned.
•
Treatment beyond progression will no longer be offered. Any participant already
receiving treatment beyond progression will be able to complete treatment as planned.
•
Participants who complete study treatment or otherwise meet EOT criteria will be 
discontinued from the study after the EOT visit and any required safety follow-up visit.
•
There will be no follow-up for survival status. Participants currently in imaging follow-
up or survival follow-up are considered to have completed the study and therefore should 
obtain imaging and further oncological care as per local SOC. However, standard safety 
reporting should continue, as applicable.
CCI
CCI
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•
Those participants remaining on study at the time of Amendment 05 should continue to 
be monitored in the study through the AE reporting period (Section 8.4).
•
Assessments listed in the SoA will be done per local SOC.
•
Participants may enroll in an extension study, if available.
-
Participation in this study is ended when the participant is consented for an extension 
study.
-
The overall study ends when the last participant completes the last study-related 
contact, withdraws consent, or is lost to follow-up (Section 7.3), or the last participant 
on active treatment is consented in an extension study
-
For participants who enter an extension study, all AEs, SAEs, and other reportable 
safety events must be reported by the investigator in this protocol (parent study) from 
the time of intervention randomization up to the time of providing documented 
informed consent for an extension study. Note: Once consented to an extension study, 
safety events, including those considered related to study intervention, will be 
collected as instructed in the extension study.
Existing protocol content is retained for historical reference.
1.1
Synopsis
Protocol Title: A Randomized, Double-Blind, Phase 3 Study of 
Pembrolizumab/Vibostolimab Coformulation (MK-7684A) in Combination with 
Chemotherapy Versus Pembrolizumab Plus Chemotherapy as First Line Treatment for
Participants with Metastatic Non-Small Cell Lung Cancer (MK-7684A-007/KEYVIBE-007)
Short Title: A Phase 3 study of MK-7684A in combination with chemotherapy in metastatic 
NSCLC
Acronym: MK-7684A-007-05
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
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In males and females with treatment-naïve metastatic NSCLC (squamous or nonsquamous): 
Primary Objective
Primary Endpoint
Objective: To compare MK-7684A in 
combination with chemotherapy to 
pembrolizumab in combination with 
chemotherapy with respect to Overall 
Survival (OS) in participants with PD-L1
TPS ≥1%
Hypothesis (H1): MK-7684A in 
combination with chemotherapy is superior 
to pembrolizumab combination with 
chemotherapy with respect to OS in 
participants with PD-L1 TPS ≥1%
•
OS, defined as the time from 
randomization to the date of death due 
to any cause
Secondary Objectives
Secondary Endpoints
•
Objective: To compare MK-7684A in 
combination with chemotherapy to 
pembrolizumab in combination with 
chemotherapy with respect to OS in all 
participants 
•
Hypothesis (H2): MK-7684A in 
combination with chemotherapy is 
superior to pembrolizumab combination 
with chemotherapy with respect to OS 
in all participants
•
OS, defined as the time from 
randomization to the date of death due 
to any cause
•
Objective: To compare MK-7684A in 
combination with chemotherapy to 
pembrolizumab in combination with 
chemotherapy with respect to 
progression-free survival (PFS) in 
participants with PD-L1 TPS≥1% and in 
all participants per Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 
as assessed by blinded independent 
central review (BICR)
•
Hypothesis (H3): MK-7684A in 
combination with chemotherapy is 
superior to pembrolizumab in 
combination with chemotherapy with 
respect to PFS in all participants per 
RECIST 1.1 as assessed by BICR
•
PFS, defined as the time from 
randomization to the first documented 
disease progression or death due to any 
cause, whichever occurs first
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•
Objective: To evaluate MK-7684A in 
combination with chemotherapy to 
pembrolizumab in combination with 
chemotherapy with respect to Objective 
Response Rate (ORR) in participants 
with PD-L1 TPS≥1% and in all 
participants per RECIST 1.1 as assessed 
by BICR
•
Objective response, defined as a 
confirmed Complete Response (CR) or 
Partial Response (PR)
•
•
•
Objective: To evaluate the mean change 
from baseline in global health 
status/quality of life (QoL), physical 
functioning, role functioning, dyspnea, 
cough, and chest pain for MK-7684A in 
combination with chemotherapy 
compared to pembrolizumab in 
combination with chemotherapy in 
participants with PD-L1 TPS≥1% and in 
all participants
•
Change from baseline in the following 
patient-reported outcomes (PROs) 
scales/items:
-
Global health status/QoL score 
(EORTC QLQ-C30 items 29 and 
30)
-
Physical functioning score (EORTC 
QLQ-C30 items 1-5)
-
Role functioning score (EORTC 
QLQ-C30 items 6-7)
-
Dyspnea score (EORTC QLQ-C30 
item 8)
-
Cough (EORTC QLQ-LC13 item 
31)
•
Chest pain (EORTC QLQ-LC13 item 
40)
•
Objective: To evaluate the time to 
deterioration in global health 
status/QoL, physical functioning, role 
functioning, dyspnea, cough, and chest 
pain for MK-7684A in combination 
with chemotherapy compared to 
pembrolizumab in combination with 
chemotherapy in participants with PD-
L1 TPS≥1% and in all participants
•
Time to deterioration: time from 
baseline to the first onset of a ≥10-point 
(out of 100 points) deterioration from 
baseline in a given scale/subscale/item 
with confirmation at a subsequent visit 
of a ≥10-point deterioration from 
baseline. If the first deterioration is at 
the last patient-reported outcomes 
assessment timepoint, then no 
confirmation is required. Time to 
deterioration in the following 
scales/items:
-
Global health status/QoL score 
(EORTC QLQ-C30 items 29 and 
30)
-
Physical functioning score (EORTC 
QLQ-C30 items 1-5)
-
Role functioning score (EORTC 
QLQ-C30 item 6-7)
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-
Dyspnea score (EORTC QLQ-C30 
item 8)
-
Cough (EORTC QLQ-LC13 item 
31)
•
Chest pain (EORTC QLQ-LC13 item 
40)
•
Objective: To evaluate the safety and 
tolerability of MK-7684A in 
combination with chemotherapy 
compared to pembrolizumab in 
combination with chemotherapy
•
Adverse Events (AEs)
•
Discontinuations of study intervention 
due to an AE
•
Objective: To evaluate DOR per 
RECIST 1.1 as assessed by BICR for 
MK-7684A plus chemotherapy 
compared to pembrolizumab plus 
chemotherapy in participants with PD-
L1 TPS≥1% and in all participants
•
DOR: for participants who demonstrate 
confirmed CR or PR, DOR is defined as 
the time from first documented evidence 
of CR or PR until disease progression or 
death due to any cause, whichever 
occurs first
Note: This study will be considered to have met its success criteria if MK-7684A plus 
chemotherapy is superior to pembrolizumab plus chemotherapy with respect to OS.
Throughout this protocol, the term RECIST 1.1 refers to the modification of RECIST 1.1 to 
include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. 
Refer to Section 4.2.1.1 for further details.
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Non-small cell lung cancer metastatic
Population
Adult participants with metastatic NSCLC 
who are candidates for first-line treatment
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Active Control Without Placebo
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Sponsor
Investigator
Participants or Subjects
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Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 5 years from the time 
the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 700 participants may be enrolled.
Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Treatment 
Period
Use
Arm 1
MK-7684A
MK-7684 200 mg 
+pembrolizumab 
200 mg/20 mL 
vial
200 mg/200 
mg
IV Infusion
Q3W for up 
to 35 cycles
Test 
Product
Arm 1
Carboplatin
10 mg/mL
Squamous: 
AUC 6 
mg/ml/min
Non
squamous: 
AUC 5 
mg/mL/min
IV Infusion
Q3W for 4 
cycles
Background 
Treatment
Arm 1
Cisplatin
1 mg/mL
75 mg/m2
IV Infusion
Q3W for 4 
cycles
Background 
Treatment
Arm 1
Paclitaxel
6 mg/mL
200 mg/m2
IV Infusion
Q3W for 4 
cycles
Background 
Treatment
Arm 1
Nab-paclitaxel
100 mg/vial
100 mg/m2
IV Infusion
Day 1, 8, 
and 15 of 
each 21 day 
cycle for 4 
cycles
Background 
Treatment
Arm 1
Pemetrexed
500 mg/vial
500 mg/m2
IV Infusion
Q3W until 
progression, 
intolerable 
AE, or 
participant 
or physician 
decision
Background 
Treatment
All 
participants
Pembrolizumab
25 mg/mL
200 mg
IV Infusion
Q3W for up 
to 35 cycles
Test 
Product
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Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Treatment 
Period
Use
Arm 2
Carboplatin
10 mg/mL
Squamous 
AUC 6 
mg/mL/min
Non-
squamous: 
AUC 5 
mg/mL//min
IV Infusion
Q3W for 4 
cycles
Background 
Treatment
Arm 2
Cisplatin
1 mg/mL
75 mg/m2
IV Infusion
Q3W for 4 
cycles
Background 
Treatment
Arm 2
Paclitaxel
6 mg/mL
200 mg/m2
IV Infusion
Q3W for 4 
cycles
Background 
Treatment
Arm 2
Nab-paclitaxel
100 mg/vial
100 mg/m2
IV Infusion
Day 1, 8, 
and 15 of 
each 21 day 
cycle for 4 
cycles
Background 
Treatment
Arm 2
Pemetrexed
500 mg/vial
500 mg/m2
IV Infusion
Q3W until 
progression, 
intolerable 
AE, or 
participant 
or physician 
decision
Background 
Treatment
Abbreviations: AE=adverse event; AUC=area under the curve; IV=intravenous; Q3W=every 3 weeks.
a. MK-7684A = coformulated as 200 mg MK-7684 and 200 mg pembrolizumab.
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Total Number of Intervention Groups/Arms
2
Duration of Participation
Each participant will participate in the study 
from the time the participant provides 
documented informed consent 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 one of the 
conditions for discontinuation of study 
intervention is met.
Participants who complete study 
intervention after receiving 35 
administrations of MK-7684A or 
pembrolizumab (4 cycles in combination 
with chemotherapy and up to 31 cycles of 
MK-7684A or pembrolizumab treatment 
[including pemetrexed for participants with 
nonsquamous NSCLC]), may be eligible for 
up to 17 additional administrations of MK-
7684A or pembrolizumab (approximately 1 
year). There is no treatment duration limit 
for pemetrexed in nonsquamous NSCLC.
After the end of treatment, each participant 
will be followed for the occurrence of 
adverse events and spontaneously reported 
pregnancy.
Participants who discontinue for reasons 
other than BICR-verified radiographic 
disease progression will have posttreatment 
follow-up imaging for disease status until 
any of the conditions for discontinuation of 
imaging are met.
All participants will be followed for overall 
survival until death, withdrawal of consent, 
or the end of the study.
Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
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Study Accepts Healthy Participants:   
No
A list of abbreviations is in Appendix 9.
1.2
Schema
The study design is depicted in Figure 1 and Figure 2.
Figure 1
Initial Treatment Period
Abbreviations: ECOG=Eastern Cooperative Oncology Group; N=sample size; NSCLC=non-small cell lung cancer; PD-L1=programmed 
cell death ligand 1; PS=performance status; Q3W=every 3 weeks; TPS=tumor proportion score; vs=versus.
Figure 2
Second Course Treatment
Abbreviations: CR=complete response; PR=partial response; Q3W=every 3 weeks; RECIST=Response Evaluation Criteria in Solid 
Tumors; SD=stable disease.
CCI
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1.3
Schedule of Activities
1.3.1
Initial Treatment Period
Table 1
Initial Treatment Period Schedule of Activities
Study Period:
Screening
Treatment (21-Day Cycles)
Notes
Each cycle consists of 3 weeks 
(21 calendar days)
Visit Timing / Cycle Number
-28 to -1
1
2
3
4
5
6
7
8
9
10 to 35
>36
Cycle Day
1
1
1
1
1
1
1
1
1
1
1
Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Informed Consent
X
Documented informed consent must 
be obtained before any protocol-
specific screening procedures are 
performed. Additional consent is 
required to continue study 
intervention beyond PD.
Informed Consent for Future 
Biomedical Research
X
This is optional for the participant.
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
Update with randomization number 
at C1D1.
Demographics and Medical 
History
X
Data collection will follow local 
regulations where applicable. See 
Section 8.1.4 for specific 
requirements.
Prior and Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
See Section 6.5 for specific 
requirements.
NSCLC Disease Details and 
Prior Treatment
X
See Section 8.1.4.1 for specific 
requirements.
Randomization
X
Obtain allocation number using IRT. 
Study intervention is required to 
begin within 3 days of 
randomization.
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Study Period:
Screening
Treatment (21-Day Cycles)
Notes
Each cycle consists of 3 weeks 
(21 calendar days)
Visit Timing / Cycle Number
-28 to -1
1
2
3
4
5
6
7
8
9
10 to 35
>36
Cycle Day
1
1
1
1
1
1
1
1
1
1
1
Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Study Intervention Administration
See Section 8.1.8.1 for details 
regarding order of study intervention 
administration.
MK-7684A or Pembrolizumab
X
X
X
X
X
X
X
X
X
X
Platinum Doublet for 
Nonsquamous Histology 
(Carboplatin or Cisplatin) 
Administration
X
X
X
X
Investigator choice of carboplatin or 
cisplatin. See Appendix 7 for 
country-specific requirements.
Pemetrexed Administration
(Nonsquamous only)
X
X
X
X
X
X
X
X
X
X
X
Pemetrexed administration is to be 
completed at least 30 minutes before 
the initiation of carboplatin or 
cisplatin during Cycles 1 to 4. 
Premedication is to be dosed per the 
approved product labels.
Pemetrexed treatment will continue 
as per standard care beyond C35 for 
participants who remain progression-
free and tolerate treatment.
See Table 5 for premedication 
requirements.
Platinum Doublet for 
Squamous Histology 
(Carboplatin/Taxane 
Administration)
X
X
X
X
Investigator choice of paclitaxel or 
nab-paclitaxel as taxane.
Participants receiving nab-paclitaxel 
are dosed on Days 1, 8 (±1 day), and 
15 (±1 day) of each 21-day cycle.
Carboplatin is to be administered 
immediately after taxane.
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Study Period:
Screening
Treatment (21-Day Cycles)
Notes
Each cycle consists of 3 weeks 
(21 calendar days)
Visit Timing / Cycle Number
-28 to -1
1
2
3
4
5
6
7
8
9
10 to 35
>36
Cycle Day
1
1
1
1
1
1
1
1
1
1
1
Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Efficacy Assessments
See Section 8.2.1 for further details.
Brain Scan
X
X
Brain scans are required for all 
participants at Screening.
For participants with brain 
metastases at Screening (treated or 
untreated), on-study brain scans are 
to be acquired at Week 6 and as 
clinically indicated. Participants with 
brain metastases at Screening require 
brain scans to confirm CR.
For those with no brain metastases at 
Screening, on-study brain scans are 
to be acquired only if clinically 
indicated.
Bone Scan
X
Bone scans are required at screening 
for participants with history of bone 
metastases or signs/symptoms 
suggestive of bone metastases. On-
study bone scans are to be acquired 
as clinically indicated or to confirm a 
CR when bone metastases were 
present at Screening.
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Study Period:
Screening
Treatment (21-Day Cycles)
Notes
Each cycle consists of 3 weeks 
(21 calendar days)
Visit Timing / Cycle Number
-28 to -1
1
2
3
4
5
6
7
8
9
10 to 35
>36
Cycle Day
1
1
1
1
1
1
1
1
1
1
1
Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Tumor Scans (chest, abdomen, 
and pelvis)
X
X
X
Screening scans are to be captured 
within 28 days before randomization. 
All time points are calculated from 
the date of randomization. Scans will 
be captured at Week 6 (42 days ±7 
days), Week 12 (84 days ±7 days), 
Week 18 (126 days ±7 days), and 
subsequently every 9 weeks (63 days 
±7 days). After 63 weeks (441 days 
±7 days), participants who remain on 
treatment will have scans performed 
every 12 weeks (84 days ±7 days). 
Scan timing will follow calendar 
days and should not be adjusted for 
delays in study intervention. Imaging 
will continue to be performed until 
progressive disease is documented by 
the investigator and verified by 
BICR, the start of new anticancer 
treatment, withdrawal of consent, 
pregnancy, or death, whichever 
occurs first.
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Study Period:
Screening
Treatment (21-Day Cycles)
Notes
Each cycle consists of 3 weeks 
(21 calendar days)
Visit Timing / Cycle Number
-28 to -1
1
2
3
4
5
6
7
8
9
10 to 35
>36
Cycle Day
1
1
1
1
1
1
1
1
1
1
1
Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Patient-reported Outcomes
EORTC QLQ-C30
X
X
X
X
X
X
X
X
X
X
PROs are assessed before dosing at 
every cycle through C17, then every 
other cycle through C35 (ie, Cycles 
1-17, 19, 21, 23, 25, 27, 29, 31, 33, 
and 35). PROs should be performed 
at the scheduled study visit until 
treatment discontinuation. PROs are 
to be administered by trained study 
personnel and completed 
electronically by participants.
 
 
 
 
EORTC QLQ-LC13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety Assessments
All assessments should be performed 
predose.
Full Physical Examination
X
Other system-based examinations 
should be included if clinically 
indicated.
Directed Physical Examination
X
X
X
X
X
X
X
X
X
X
X
Review of new clinically significant 
abnormal findings.
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
If >10% change in body weight 
occurs, weight-based therapy should 
be readjusted.
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
Measure temperature, RR, pulse, and 
BP after 5 minutes rest.
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Study Period:
Screening
Treatment (21-Day Cycles)
Notes
Each cycle consists of 3 weeks 
(21 calendar days)
Visit Timing / Cycle Number
-28 to -1
1
2
3
4
5
6
7
8
9
10 to 35
>36
Cycle Day
1
1
1
1
1
1
1
1
1
1
1
Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
12-lead ECG
X
After Screening Visit, repeat if 
clinically indicated.
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
X
Performed within 7 days before 
randomization.
AE/SAE Review
X
X
X
X
X
X
X
X
X
X
X
X
Record all AEs occurring from time 
of consent to within 30 days after last 
dose of study intervention. After 
30 days, record all SAEs occurring 
up to 90 days after last dose of study 
intervention or 30 days after last dose 
if the participant initiates new 
anticancer therapy, whichever comes 
first. See Sections 1.3.2 and 8.4.3 for 
FU details.
Laboratory Assessments
Analysis performed by local 
laboratory.
Archival or Newly Obtained 
Tissue Collection
X
Absence of EGFR, ALK and ROS1 
sensitizing genetic aberrations are 
required for inclusion in the study. 
See Section 8.1.12 for details.
Sample must be submitted to Central 
Laboratory and results obtained for 
determination of PD-L1 status before 
randomization.
The sample will also be utilized for 
EGFR, ALK, and ROS1 testing prior 
to randomization if this testing 
cannot be performed locally for 
subjects with predominantly 
nonsquamous histology.
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Study Period:
Screening
Treatment (21-Day Cycles)
Notes
Each cycle consists of 3 weeks 
(21 calendar days)
Visit Timing / Cycle Number
-28 to -1
1
2
3
4
5
6
7
8
9
10 to 35
>36
Cycle Day
1
1
1
1
1
1
1
1
1
1
1
Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Hematology, Serum 
Chemistry
X
X
X
X
X
X
X
X
X
X
X
See Appendix 2 for parameters.
Screening samples to be collected 
and results reviewed within 10 days 
before the first dose of study 
intervention. After C1, collect within 
3 days before dosing.
Urinalysis is to be performed at 
Cycles 5, 9, and every 4 cycles 
thereafter.
Urinalysis
X
X
X
X
X
INR or PT and aPTT/PTT
X
Screening samples to be collected 
within 10 days before first dose of 
study intervention. Additional testing 
to be conducted as clinically 
indicated for participants taking 
anticoagulant therapy.
Pregnancy Test (WOCBP 
only)
X
X
X
X
X
X
X
X
X
X
X
X
WOCBP require negative serum test 
within 72 hours or negative urine test 
within 24 hours before each dose of 
study intervention. Pregnancy testing 
will also be conducted at the end of 
relevant systemic exposure as 
outlined in Section 8.3.5.
Refer to Appendix 7 for country-
specific requirements.
FSH (WONCBP)
X
To confirm WONCBP status if 
applicable. See Appendix 5.
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Study Period:
Screening
Treatment (21-Day Cycles)
Notes
Each cycle consists of 3 weeks 
(21 calendar days)
Visit Timing / Cycle Number
-28 to -1
1
2
3
4
5
6
7
8
9
10 to 35
>36
Cycle Day
1
1
1
1
1
1
1
1
1
1
1
Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Thyroid function (T3, T4, and 
TSH)
X
X
X
X
X
X
Screening samples to be collected 
within 10 days before the first dose 
of study intervention. Performed D1 
of every other cycle starting from C2. 
Participants may be dosed in 
subsequent cycles after C1 while 
thyroid function tests are pending.
Free T3 and free T4 are acceptable.
Infection Testing (HBV / HCV
/ HIV)
X
Required at Screening if mandated by 
local health authority
Refer to Appendix 2 for details and 
Appendix 7 for country-specific 
requirements.
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Study Period:
Screening
Treatment (21-Day Cycles)
Notes
Each cycle consists of 3 weeks 
(21 calendar days)
Visit Timing / Cycle Number
-28 to -1
1
2
3
4
5
6
7
8
9
10 to 35
>36
Cycle Day
1
1
1
1
1
1
1
1
1
1
1
Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Abbreviations: ADA=antidrug antibodies; AE=adverse event; ALK=anaplastic lymphoma kinase; aPTT=activated partial thromboplastin time; BICR=blinded 
independent central review; BP=blood pressure; C=Cycle; CR=complete response: ctDNA=circulating tumor deoxyribonucleic acid; D=Day; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EGFR=endothelial growth factor receptor; EORTC QLQ=European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire; FSH=follicle-stimulating hormone; FU=follow-up; HBV=hepatitis B virus; HCV=hepatitis C 
virus; HIV=human immunodeficiency virus; INR= international normalized ratio; IRT=intervention randomization system; NSCLC=non-small cell lung 
cancer; PD=progressive disease; PD-L1=programmed cell death ligand 1; PK=pharmacokinetic; PROs=patient-reported outcomes; PT=prothrombin time; 
PTT=partial thromboplastin time; ROS1=c-ros oncogene 1; RR=respiratory rate; SAE=serious adverse event; SAQ=Symptom Assessment Questionnaire; 
T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing 
potential.
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1.3.2
Follow-up Assessments
Table 2
Follow-up Schedule of Activities
Study Period:
Follow-up
Notes
End of Treatment
Safety FU
Efficacy FU
Survival 
FU
Follow-up visits are required for participants who complete 35 cycles of treatment 
without disease progression.
Efficacy FU visits are required for participants who withdraw from treatment 
without BICR-verified radiographic disease progression and have not received 
new anticancer therapy.
Survival FU visits are required for participants that withdraw from treatment for 
BICR-verified radiographic disease progression or have started other anticancer 
therapy.
Visit:
At treatment 
Discontinuation
30 Days Post 
Discontinuation
See Notes
Every 12 
weeks
Window (days):
±14
±7
±14
Efficacy Assessments
For participants who discontinued study intervention without disease progression.
Tumor Scans (chest, 
abdomen, and pelvis)
X
X
EOT scans are not required if obtained within 4 weeks before the EOT visit.
Follow-up visits may be scheduled to coincide with the scan schedule. If 
discontinuation is not due to BICR-verified disease progression, then tumor scans 
are to continue on the initial treatment period schedule. See Section 8.2 for details.
Vital Status
X
On Sponsor request, participants may be contacted for survival information at any 
time during the study.
Patient-reported Outcomes 
Not applicable to participants receiving Second Course Treatment.
EORTC QLQ-C30
X
X
If the Treatment Discontinuation Visit occurs 30 days from the last dose of study 
intervention, at the time of the mandatory Safety Follow-up Visit, PROs do not 
need to be repeated
PROs are to be administered by trained study personnel and completed 
electronically by participants.
 
 
EORTC QLQ-LC13
X
X
X
X
 
X
X
Safety Assessments
ECOG Performance 
Status
X
X
Vital signs and 
Weight
X
X
Temperature, RR, pulse, and BP are to be measured after 5 minutes rest.
Complete Physical 
Examination
X
Directed Physical 
Examination
X
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Study Period:
Follow-up
Notes
End of Treatment
Safety FU
Efficacy FU
Survival 
FU
Follow-up visits are required for participants who complete 35 cycles of treatment 
without disease progression.
Efficacy FU visits are required for participants who withdraw from treatment 
without BICR-verified radiographic disease progression and have not received 
new anticancer therapy.
Survival FU visits are required for participants that withdraw from treatment for 
BICR-verified radiographic disease progression or have started other anticancer 
therapy.
Visit:
At treatment 
Discontinuation
30 Days Post 
Discontinuation
See Notes
Every 12 
weeks
Window (days):
±14
±7
±14
AE/SAE Review
X
X
Record all AEs occurring within 30 days after last dose of study intervention. 
After 30 days, record all SAEs occurring up to 90 days after last dose of study 
intervention or 30 days after last dose if the participant initiates new anticancer 
therapy, whichever comes first. Any treatment-related SAEs must be reported 
regardless of time they occur.
Anticancer Therapy 
Status
X
X
X
X
Concomitant 
Medication
X
X
See Section 6.5 for specific requirements.
Laboratory Assessments
Pregnancy Test 
(WOCBP only)
X
X
Refer to Appendix 7 for country-specific requirements.
Hematology, Serum 
Chemistry
X
X
Urinalysis
X
X
Thyroid Function (T3, 
T4, and TSH)
X
X
Free T3 and free T4 are acceptable.
Biomarker
Abbreviations: ADA=antidrug antibodies; AE=adverse event; BICR=blinded independent central review; BP=blood pressure; ctDNA=circulating tumor deoxyribonucleic acid; 
ECOG=Eastern Cooperative Oncology Group; EORTC QLQ=European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; EOT=end of 
treatment; FU=follow-up; NSCLC=non-small cell lung cancer; PK=pharmacokinetic; PRO=patient-reported outcomes; RR=respiratory rate; SAQ=Symptom Assessment 
Questionnaire; SAE=serious adverse event; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; WOCBP=women of childbearing potential.
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1.3.3
Second Course Treatment
Table 3
Second Course Schedule of Activities
Study Period:
Second Course Treatment
Follow-up
Notes
Visit Timing / Cycle 
number
1
2
3
4
5
6
7 to 17
End of 
Treatment
Safety FU
Efficacy 
FU
Survival 
FU
Each cycle consists of 3 weeks 
(21 calendar days).
Cycle Day
1
1
1
1
1
1
1
Every 
Cycle
At Treatment 
Discontinuation
30 Days Post 
Discontinuation Every 12 
Weeks
Every 12 
Weeks
Window (days):
±3
±3
±3
±3
±3
±3
±14
±7
±14
Administrative Procedures
Eligibility Criteria
X
Only participants who achieved SD, 
PR, or CR followed by disease 
progression as assessed by the 
investigator and verified by BICR as 
per RECIST 1.1 will be eligible for a 
Second Course of treatment.
Concomitant Medication
X
X
X
X
X
X
X
X
X
See Section 6.5 for specific 
requirements.
Study Intervention 
Administration 
(MK-7684A or 
Pembrolizumab)
X
X
X
X
X
X
X
Participants will receive the same 
study intervention allocated in the 
initial treatment phase. 
Anticancer Therapy Status
X
X
X
X
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Study Period:
Second Course Treatment
Follow-up
Notes
Visit Timing / Cycle 
number
1
2
3
4
5
6
7 to 17
End of 
Treatment
Safety FU
Efficacy 
FU
Survival 
FU
Each cycle consists of 3 weeks 
(21 calendar days).
Cycle Day
1
1
1
1
1
1
1
Every 
Cycle
At Treatment 
Discontinuation
30 Days Post 
Discontinuation Every 12 
Weeks
Every 12 
Weeks
Window (days):
±3
±3
±3
±3
±3
±3
±14
±7
±14
Efficacy Assessments
Tumor scans (chest, 
abdomen, and pelvis)
X
X
X
X
X*
Second Course Screening scans are 
to be captured within 28 days before 
Second Course C1. Scans will be 
captured Q12W (±7 days) from 
Second Course C1 (Weeks 12, 24, 
36, and 48). Scan timing will follow 
calendar days and should not be 
adjusted for delays in study 
intervention. Images are for 
investigator assessment of disease 
status only and are not to be sent to 
the iCRO, Refer to Section 8.2.1.4.
If scans were obtained within 4 
weeks before DC, scans at DC are 
not mandatory.
*For participants discontinuing 
Second Course for reasons other than 
PD, follow-up visits and scans 
continue until PD is documented by 
the investigator, the start of new 
anticancer treatment, withdrawal of 
consent, pregnancy, or death, 
whichever occurs first.
Brain Scans
X
Second Course Screening scans need 
to be captured within 28 days before 
planned C1D1 for participants who 
had brain metastases at Screening or 
before entering Second Course, or 
those where it is clinically indicated. 
Brain scans during the Second 
Course are to be performed as 
clinically indicated.
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Study Period:
Second Course Treatment
Follow-up
Notes
Visit Timing / Cycle 
number
1
2
3
4
5
6
7 to 17
End of 
Treatment
Safety FU
Efficacy 
FU
Survival 
FU
Each cycle consists of 3 weeks 
(21 calendar days).
Cycle Day
1
1
1
1
1
1
1
Every 
Cycle
At Treatment 
Discontinuation
30 Days Post 
Discontinuation Every 12 
Weeks
Every 12 
Weeks
Window (days):
±3
±3
±3
±3
±3
±3
±14
±7
±14
Safety Assessments
All assessments are to be collected 
predose.
Complete Physical 
Examination
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
Review of new clinically significant 
abnormal findings. 
Weight
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
Measure temperature, RR, pulse, and 
BP after 5 minutes rest.
12-lead ECG
12-lead ECG is only required where 
clinically indicated.
AE/SAE review
X
X
X
X
X
X
X
X
X
Record all AEs occurring within 30 
days after last dose of study 
intervention. After 30 days, record all 
SAEs occurring up to 90 days after 
last dose of study intervention or 
30 days after last dose if the 
participant initiates new anticancer 
therapy, whichever comes first. 
Laboratory Procedures
Analysis Performed by Local 
laboratory.
Hematology, Serum 
Chemistry
X
X
X
X
X
X
X
X
X
Performed within 10 days before first 
dose. After C1, collect within 3 days 
before dosing. 
Urinalysis is to be performed every 4 
cycles thereafter (C5, C9, etc.). See 
Appendix 2 for parameters.
Urinalysis
X
X
X
X
X
Pregnancy Test (WOCBP 
only)
X
X
X
X
X
X
X
X
X
WOCBP require negative serum test 
within 72 hours or negative urine test 
within 24 hours before each dose of 
study intervention. See Appendix 7 
for country-specific requirements.
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Study Period:
Second Course Treatment
Follow-up
Notes
Visit Timing / Cycle 
number
1
2
3
4
5
6
7 to 17
End of 
Treatment
Safety FU
Efficacy 
FU
Survival 
FU
Each cycle consists of 3 weeks 
(21 calendar days).
Cycle Day
1
1
1
1
1
1
1
Every 
Cycle
At Treatment 
Discontinuation
30 Days Post 
Discontinuation Every 12 
Weeks
Every 12 
Weeks
Window (days):
±3
±3
±3
±3
±3
±3
±14
±7
±14
INR or PT and aPTT/PTT
X
Required at C1. Additional testing to 
be conducted as clinically indicated 
for participants taking anticoagulant 
therapy.
Thyroid Function (T3, T4, 
and TSH)
X
X
X
X
X
Perform within 10 days before 
Second Course C1. To be performed 
D1 of every other cycle starting from 
C3. Participants may be dosed in 
subsequent cycles after C1 while 
thyroid function tests are pending.
Free T3 and free T4 are acceptable.
Biomarker
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; BICR=blinded independent central review; BP=blood pressure; C=Cycle; CR=complete response; ctDNA=circulating 
tumor deoxyribonucleic acid; D=Day; DC=discontinuation; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; FU=follow-up; iCRO=imaging contract research organization; 
INR= international normalized ratio; PD=progressive disease; PR=partial response; PT=prothrombin time; PTT=partial thromboplastin time; Q12W=every 12 weeks; RECIST=Response Evaluation 
Criteria in Solid Tumors; RR=respiratory rate; SAE=serious adverse event; SD=stable disease; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; WOCBP=women of 
childbearing potential.
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2
INTRODUCTION
MK-7684A is a coformulation of MK-7684 and pembrolizumab. MK-7684 is a humanized, 
antagonist mAb that binds to the immune checkpoint receptor, TIGIT, and blocks the 
interaction between TIGIT and its ligands. Pembrolizumab is a potent humanized IgG4 mAb 
with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction with 
PD-L1 and PD-L2. Effective antitumor immunity depends on presentation of a tumor 
antigen, activation of protective T-cell responses, and the ability to overcome tumor-based 
blockade of antitumor responses, and therefore rationale exists to develop anti-PD-1 and 
anti-TIGIT combination therapies. The coformulation of MK-7684A is being developed as a 
cancer immunotherapeutic with the potential to be used to increase benefit to patients with 
metastatic NSCLC.
2.1
Study Rationale
The global incidence of lung cancer was 2.2 million cases in 2020, resulting in an estimated 
1.8 million deaths, representing the second most frequently diagnosed cancer and the leading 
cause of cancer death in 2020 [Sung, H., et al 2021]. NSCLC represents approximately 84% 
of all lung cancers [National Cancer Institute 2020]. Of patients with NSCLC, tumor 
histology is approximately 46% adenocarcinoma, 16% squamous, and the remainder “not 
otherwise specified” [Sulpher, J. A., et al 2013], though histology varies somewhat by 
geographic region. At the time of diagnosis, approximately 80% of patients in the US with 
lung cancer have locally advanced or metastatic disease, and the 5-year relative survival for 
patients with metastatic lung cancer is only approximately 6% [National Cancer Institute 
2020a].
The therapeutic landscape in metastatic NSCLC was dramatically changed with approvals of 
immunotherapy agents, particularly immune checkpoint inhibitors targeting the PD-1/PD-L1 
pathway (pembrolizumab, nivolumab, and atezolizumab) for both treatment-naïve and 
previously treated disease, irrespective of histology. KEYNOTE-024 and KEYNOTE-042 
established pembrolizumab monotherapy as first-line therapy for patients with metastatic 
NSCLC whose tumors express PD-L1 with a TPS ≥50% or and TPS ≥1% (in some 
countries), respectively, with no EGFR or ALK genomic tumor aberrations [Brahmer, J. R., 
et al 2017] [Mok, T. S. K., et al 2019]. Following this, the positive results from KEYNOTE-
189 and KEYNOTE-407 led to the approval of pembrolizumab in combination with 
pemetrexed and platinum chemotherapy for first-line treatment of patients with metastatic 
nonsquamous NSCLC whose tumors have no EGFR or ALK genomic tumor aberrations and 
pembrolizumab in combination with carboplatin and paclitaxel/nab-paclitaxel for first-line 
treatment of patients with metastatic squamous NSCLC [Gandhi, L., et al 2018] [Gandhi, L., 
et al 2018a] [Paz-Ares, L., et al 2018].
Despite the significant progress made with the introduction of checkpoint inhibitors either as 
monotherapy or in combination with chemotherapy, most patients with metastatic NSCLC 
will still succumb to the disease within 3 years of their diagnosis [Goldstraw, P., et al 2016]. 
Therefore, there is still substantial unmet medical need for novel therapies that can potentiate 
the clinical benefit of IO therapies, extend the benefit to a broader population of patients, and 
further improve treatment response and survival in patients with metastatic NSCLC.
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Thus far, the therapeutic benefit of immunotherapy was largely achieved by blocking the 
inhibitory receptors PD-1/PD-L1 or CTLA-4. However, it is believed that concurrent or 
sequential blockade of novel checkpoints within the intricate immune regulatory network 
could further improve the efficacy of immunotherapy. Recently, dual immunotherapies 
(IO/IO) either alone or in combination with chemotherapy have also been approved for the 
treatment of advanced NSCLC [Hellmann, M. D., et al 2019] [Reck, M., et al 2020]. Several 
other IO/IO combinations and regimens including PD-1/PD-L1 checkpoint inhibitors are 
under investigation.
Enhancing the proven anti-PD-1 immune stimulatory mechanism through a novel mechanism 
of action is, therefore, an attractive scientific concept. One avenue for further investigation is 
the T-cell stimulatory/inhibitory network TIGIT (PVRIG/TACTILE)-CD226 (DNAM1) 
pathway. Antibody blockade of TIGIT, a T-cell inhibitory receptor within this network, has 
shown promising activity in preclinical cancer models, as well as in clinical studies. 
MK-7684 is a humanized IgG1 that blocks the inhibitory checkpoint receptor TIGIT 
expressed on T cells and NK cells. Preclinical data has shown that anti-TIGIT antibodies on 
the mIgG2a backbone (with high affinity FcR binding) are more efficacious than anti-TIGIT 
antibodies on the IgG1 D265A backbone (without FcR binding) as single agents and in 
combination with mDX400 (anti-mPD-1 antibody) in multiple preclinical tumor models. 
Therefore, a strong rationale exists to develop anti-PD-1 and anti-TIGIT combination 
therapies. MK-7684 is being developed in combination with pembrolizumab in advanced 
solid tumors. Preliminary data of MK-7684 as monotherapy or coformulated with 
pembrolizumab (MK-7684A) in advanced solid tumors shows promising activity in 
PD-1/PD-L1 naïve NSCLC (see Section 2.2.3.1).
In conclusion, there remains a great unmet need to develop newer, more efficacious, well 
tolerated therapies for the treatment of patients with metastatic NSCLC. Given the substantial 
clinical benefit that pembrolizumab has brought to patients with NSCLC, the concept of 
extending this benefit to a broader population by combining pembrolizumab with an anti-
TIGIT agent is a promising avenue to investigate. Promising efficacy and safety data 
observed in participants with metastatic NSCLC in Study MK-7684-001 show a potential 
opportunity to improve upon the current standard of care in NSCLC (see Section 2.2.3.1 for 
further details). Therefore, the present study is designed to further evaluate the safety and 
efficacy of MK-7684A (a fixed dose coformulation of MK-7684 with pembrolizumab) when 
administered in combination with chemotherapy for the treatment of metastatic NSCLC.
2.2
Background
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. KEYTRUDA® (pembrolizumab) is 
indicated for the treatment of patients across several indications. Refer to the MK-7684/
MK-7684A IB and the pembrolizumab IB for detailed background information on 
MK-7684A and pembrolizumab, respectively.
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2.2.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T cells and the ratio 
of CD8+ effector T cells/FoxP3+ regulatory T cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer, hepatocellular carcinoma, malignant melanoma, and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling on engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
TIGIT forms part of a costimulatory network that consists of a positive (CD226) and 
negative (TIGIT) immunomodulatory receptor on T cells, and ligands (CD155 and CD112) 
expressed on tumor cells and antigen presenting cells [Levin, S. D., et al 2011]. Whereas 
CD226 is widely expressed on most immune cells, TIGIT is highly expressed on memory T 
cells, T-regs, NK cells, and NKT cells [Dardalhon, V., et al 2005] [Stanietsky, N., et al 
2013]. CD155/PVR and CD112/PVRL-2 are 2 nectin family members that are widely 
expressed both on cells of the hematopoietic system and on fibroblasts and endothelial cells. 
Functionally, these receptor ligands are involved in cell adhesion and motility. CD155 is 
reported to be overexpressed in several tumor types and has been found to be induced by Ras 
activation and genotoxic stress [Carlsten, M., et al 2007] [Hirota, T., et al 2005] [Masson, D., 
et al 2001][Soriani, A., et al 2009] [Stanietsky, N., et al 2009].
In addition, TIGIT is highly coexpressed with PD-1 on both CD4+ and CD8+ TILs including 
T-regs, in mouse and human tumors, and has been reported to be coexpressed with PD-1 and 
Tim-3 on the TILs with the most exhausted phenotype [Chauvin, J. M., et al 2015] [Johnston, 
R. J., et al 2014]. Furthermore, enhanced antitumor efficacy is observed in preclinical models 
when an anti-TIGIT antibody is used with an anti-PD-1 antibody to decrease inhibitory 
signaling in T cells. We hypothesize, therefore, that combining MK-7684 with 
pembrolizumab will offer substantially augmented antitumor efficacy.
Interim data recently became available from the external Phase 3 SKYSCRAPER-01 study 
evaluating the investigational anti-TIGIT mAb tiragolumab plus atezolizumab versus 
atezolizumab alone as an initial (first-line) treatment for people with PD-L1-high locally 
advanced or metastatic NSCLC. This study showed minimal benefit to PFS, and the median 
overall survival estimates were 22.9 months (95% CI: 17.5, NE) in the anti-TIGIT mAb 
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tiragolumab plus atezolizumab arm, and 16.7 months (95% CI: 14.6, 20.2) in the 
atezolizumab monotherapy arm, yielding an HR of 0.81 (95% CI: 0.63, 1.03). 
2.2.1.1
MK-7684 Background
MK-7684 is a humanized, antagonist mAb that binds to the immune checkpoint receptor, 
TIGIT, and blocks the interaction between TIGIT and its ligands. This human IgG1 antibody 
is being developed as a cancer immunotherapeutic with the potential to be used as 
monotherapy or to be combined with pembrolizumab (a humanized anti-PD-1 receptor 
antibody) to increase benefit to patients with various tumor types.
TIGIT is an immunomodulatory receptor expressed primarily on activated CD4+ and CD8+ 
T cells, T-regs, NK cells, and NKT cells. Its structure reveals a single extracellular 
immunoglobulin domain, a transmembrane region, an immunoglobulin tail tyrosine-like 
phosphorylation motif, and an immunoreceptor tyrosine based inhibitory motif.
2.2.1.2
Pembrolizumab Background
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical and clinical safety profile as an IV 
immunotherapy for advanced malignancies. KEYTRUDA® (pembrolizumab) is indicated for 
the treatment of patients across several indications. For more details on specific indications 
refer to the IB.
2.2.2
Preclinical and Clinical Studies
2.2.2.1
MK-7684 Preclinical Studies
Refer to the MK-7684/MK-7684A IB for detailed background information on MK-7684A.
Although preclinical studies with anti-TIGIT as monotherapy or in combination with anti-
PD-1 are limited, preliminary efficacy has been shown for the combination. Using A20 
lymphoma cells in Balb/c mice as B-cell NHL model, the study showed prolonged survival 
with anti-TIGIT and anti-PD-1 combination therapy compared with either anti-TIGIT or anti-
PD-1 monotherapy [Sunseri, N., et al 2019]. In MM mouse models, Vk12653 and Vk12598 
cell lines, TIGIT blockage prolonged survival in preclinical studies [Guillerey, C., et al 2018] 
[Minnie, S. A., et al 2018].
2.2.2.2
Pembrolizumab Preclinical and Clinical Studies
Refer to the IB for preclinical and clinical study data for pembrolizumab.
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2.2.3
Ongoing Clinical Studies
2.2.3.1
MK-7684A Ongoing Clinical Studies
Numerous interventional clinical studies involving MK-7684/MK-7684A are currently 
ongoing in a number of advanced solid tumor indications, as well as hematological 
malignancies. Sponsored clinical studies are ongoing which include participants with 
NSCLC; ie, MK-7684-001, MK-3475-U01, MK-7684A-002, and MK-7684A-003. 
Preliminary data are available for MK-7684-001 and MK-3475-U01 studies.
Study MK-7684-001
MK-7684-001 is a first-in-human, safety, tolerability, PK, pharmacodynamic, and efficacy 
study examining MK-7684 as monotherapy and in combination with pembrolizumab or with 
pembrolizumab plus chemotherapy in adults with metastatic solid tumors for which there are 
no available therapies expected to convey clinical benefit. This study consists of a Part A 
dose escalation phase and a Part B expansion phase.
Part A of this study is a dose escalation and confirmation phase to evaluate safety and 
estimate the RP2D for MK-7684 monotherapy or in combination with pembrolizumab plus 
chemotherapy.
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Study MK-3475-U01
MK-3475-U01 is a Phase 2, umbrella study with rolling arms of investigational agents with 
either pembrolizumab in combination with chemotherapy or with pembrolizumab alone in 
participants with advanced NSCLC. In Substudy 01A, treatment-naïve participants with 
advanced or metastatic (squamous or nonsquamous) NSCLC will receive pembrolizumab 
plus chemotherapy in combination with MK-7684 followed by treatment with 
pembrolizumab and MK-7684.
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Study MK-7684A-002
MK-7684A-002 is a Phase 2, multicenter, randomized study to compare the efficacy and 
safety of MK-7684A or MK-7684A plus docetaxel versus docetaxel monotherapy in the 
treatment of participants with metastatic NSCLC with progressive disease after treatment 
with a platinum doublet chemotherapy and immunotherapy. The study is ongoing.
Study MK-7684A-003
MK-7684A-003 is a Phase 3, multicenter, randomized, double-blind study of MK-7684A 
versus pembrolizumab monotherapy as first-line treatment for participants with PD-L1 
positive metastatic NSCLC. No results are currently available.
Additional details regarding other ongoing studies of MK-7684A may be found in the 
MK-7684/MK-7684A IB.
2.2.3.2
Pembrolizumab Ongoing Clinical Studies
Numerous interventional clinical studies involving pembrolizumab are currently ongoing in a 
number of advanced solid tumor indications, as well as in hematological malignancies. 
Additional details regarding other ongoing studies of pembrolizumab and specific benefits 
and risks for participants treated with pembrolizumab may be found in the pembrolizumab 
IB.
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.
Despite the substantial improvement in PFS and OS observed with pembrolizumab 
monotherapy in combination with chemotherapy in KEYNOTE-189 and KEYNOTE-407 in 
participants with metastatic NSCLC, an unmet medical need remains for safe and efficacious 
treatments offering added benefit for this patient population.
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Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In males and females with treatment-naïve metastatic NSCLC (squamous or nonsquamous): 
Primary Objective
Primary Endpoint
Objective: To compare MK-7684A in 
combination with chemotherapy to 
pembrolizumab in combination with 
chemotherapy with respect to Overall 
Survival (OS) in participants with PD-L1
TPS ≥1%
Hypothesis (H1): MK-7684A in 
combination with chemotherapy is superior 
to pembrolizumab combination with 
chemotherapy with respect to OS in 
participants with PD-L1 TPS ≥1%
•
OS, defined as the time from 
randomization to the date of death due 
to any cause
Secondary Objectives
Secondary Endpoints
•
Objective: To compare MK-7684A in 
combination with chemotherapy to 
pembrolizumab in combination with 
chemotherapy with respect to OS in all 
participants 
•
Hypothesis (H2): MK-7684A in 
combination with chemotherapy is 
superior to pembrolizumab combination 
with chemotherapy with respect to OS 
in all participants
•
OS, defined as the time from 
randomization to the date of death due 
to any cause
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•
Objective: To compare MK-7684A in 
combination with chemotherapy to 
pembrolizumab in combination with 
chemotherapy with respect to 
progression-free survival (PFS) in 
participants with PD-L1 TPS≥1% and in 
all participants per Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 
as assessed by blinded independent 
central review (BICR)
•
Hypothesis (H3): MK-7684A in 
combination with chemotherapy is 
superior to pembrolizumab in 
combination with chemotherapy with 
respect to PFS in all participants per 
RECIST 1.1 as assessed by BICR
•
PFS, defined as the time from 
randomization to the first documented 
disease progression or death due to any 
cause, whichever occurs first
•
Objective: To evaluate MK-7684A in 
combination with chemotherapy to 
pembrolizumab in combination with 
chemotherapy with respect to Objective 
Response Rate (ORR) in participants 
with PD-L1 TPS≥1% and in all 
participants per RECIST 1.1 as assessed 
by BICR
•
Objective response, defined as a 
confirmed Complete Response (CR) or 
Partial Response (PR)
•
•
•
Objective: To evaluate the mean change 
from baseline in global health 
status/quality of life (QoL), physical 
functioning, role functioning, dyspnea, 
cough, and chest pain for MK-7684A in 
combination with chemotherapy
compared to pembrolizumab in 
combination with chemotherapy in 
participants with PD-L1 TPS≥1% and in 
all participants
•
Change from baseline in the following 
patient-reported outcomes (PROs) 
scales/items:
-
Global health status/QoL score 
(EORTC QLQ-C30 items 29 and 
30)
-
Physical functioning score (EORTC 
QLQ-C30 items 1-5)
-
Role functioning score (EORTC 
QLQ-C30 items 6-7)
-
Dyspnea score (EORTC QLQ-C30 
item 8)
-
Cough (EORTC QLQ-LC13 item 
31)
•
Chest pain (EORTC QLQ-LC13 item 
40)
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•
Objective: To evaluate the time to 
deterioration in global health 
status/QoL, physical functioning, role 
functioning, dyspnea, cough, and chest 
pain for MK-7684A in combination 
with chemotherapy compared to 
pembrolizumab in combination with 
chemotherapy in participants with PD-
L1 TPS≥1% and in all participants
•
Time to deterioration: time from 
baseline to the first onset of a ≥10-point 
(out of 100 points) deterioration from 
baseline in a given scale/subscale/item 
with confirmation at a subsequent visit 
of a ≥10-point deterioration from 
baseline. If the first deterioration is at 
the last patient-reported outcomes 
assessment timepoint, then no 
confirmation is required. Time to 
deterioration in the following 
scales/items:
-
Global health status/QoL score 
(EORTC QLQ-C30 items 29 and 
30)
-
Physical functioning score (EORTC 
QLQ-C30 items 1-5)
-
Role functioning score (EORTC 
QLQ-C30 item 6-7)
-
Dyspnea score (EORTC QLQ-C30 
item 8)
-
Cough (EORTC QLQ-LC13 item 
31)
•
Chest pain (EORTC QLQ-LC13 item 
40)
•
Objective: To evaluate the safety and 
tolerability of MK-7684A in 
combination with chemotherapy 
compared to pembrolizumab in 
combination with chemotherapy
•
Adverse Events (AEs)
•
Discontinuations of study intervention 
due to an AE
•
Objective: To evaluate DOR per 
RECIST 1.1 as assessed by BICR for 
MK-7684A plus chemotherapy 
compared to pembrolizumab plus 
chemotherapy in participants with PD-
L1 TPS≥1% and in all participants
•
DOR: for participants who demonstrate 
confirmed CR or PR, DOR is defined as 
the time from first documented evidence 
of CR or PR until disease progression or 
death due to any cause, whichever 
occurs first
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Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
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Note: This study will be considered to have met its success criteria if MK-7684A plus 
chemotherapy is superior to pembrolizumab plus chemotherapy with respect to OS in 
participants with PD-L1 TPS≥1%.
Throughout this protocol, the term RECIST 1.1 refers to the modification of RECIST 1.1 to 
include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. 
Refer to Section 4.2.1.1 for further details.
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4
STUDY DESIGN
At implementation of Amendment 05 or upon receipt of investigator letter detailing 
discontinuation of the MK-7684A clinical program, the following changes apply. The 
changes listed below supersede any protocol content/instructions from previous amendments.
•
This study will be unblinded.
•
Participants receiving MK-7684A plus chemotherapy will be transitioned to 
pembrolizumab plus chemotherapy.
•
Pembrolizumab can be sourced locally or centrally.
•
Participants with access to approved SOC (eg, pembrolizumab plus chemotherapy) 
should be considered for discontinuation from the study. Those benefiting from 
pembrolizumab with chemotherapy, but unable to access it as SOC outside the study, 
may continue on study and receive treatment with pembrolizumab plus chemotherapy 
until discontinuation criteria are met. The final required study visit will be the Safety 
Follow-up Visit.
•
Imaging scans should no longer be submitted to iCRO nor read by BICR. However, for 
participants who are still on study treatment and deriving clinical benefit and will 
continue on study treatment until criteria for discontinuation are met, local tumor imaging 
should continue per local SOC schedule and local SOC method of assessment of imaging. 
All imaging as well as relevant objectives and endpoints will be assessed locally.
•
PK/ADA samples will no longer be collected.
•
Biomarker/FBR samples will no longer be collected.
•
ePROs will no longer be collected.
•
Second course treatment of pembrolizumab for participants currently not on second 
course treatment will be offered. Any participant already receiving Second Course 
treatment will be able to complete treatment as planned.
•
Treatment beyond progression will no longer be offered. Any participant already
receiving treatment beyond progression will be able to complete treatment as planned.
•
Participants who complete study treatment or otherwise meet EOT criteria will be 
discontinued from the study after the EOT visit and any required safety follow-up visit.
•
There will be no follow-up for survival status. Participants currently in imaging follow-
up or survival follow-up are considered to have completed the study and therefore should 
obtain imaging and further oncological care as per local SOC. However, standard safety 
reporting should continue, as applicable.
•
Those participants remaining on study at the time of Amendment 05 should continue to 
be monitored in the study through the AE reporting period (Section 8.4).
•
Assessments listed in the SoA will be done per local SOC.
•
Participants may enroll in an extension study, if available.
-
Participation in this study is ended when the participant is consented for an extension 
study.
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-
The overall study ends when the last participant completes the last study-related 
contact, withdraws consent, or is lost to follow-up (Section 7.3), or the last participant 
on active treatment is consented in an extension study
-
For participants who enter an extension study, all AEs, SAEs, and other reportable 
safety events must be reported by the investigator in this protocol (parent study) from 
the time of intervention randomization up to the time of providing documented 
informed consent for an extension study. Note: Once consented to an extension study, 
safety events, including those considered related to study intervention, will be 
collected as instructed in the extension study.
Existing protocol content is retained for historical reference.
4.1
Overall Design
This is a Phase 3, randomized, active-controlled, parallel-group, multisite, double-blind study 
of MK-7684A plus chemotherapy versus pembrolizumab plus chemotherapy in participants 
with metastatic NSCLC. Participants must have newly diagnosed, untreated Stage IV 
NSCLC, an ECOG PS of 0 to 1, and no current pneumonitis or interstitial lung disease at 
enrollment.
Overall, approximately 700 participants will be randomized 1:1 to receive either:
•
MK-7684A in combination with chemotherapy (Arm 1), or
•
Pembrolizumab in combination with chemotherapy (Arm 2)
Participants will be stratified by ECOG PS, histology, PD-L1 status, and geographic region, 
as described in Section 6.3.2.
Treatment with MK-7684A or pembrolizumab in combination with chemotherapy will be 
administered for 4 cycles followed by up to 31 cycles of MK-7684A or pembrolizumab 
treatment (including pemetrexed for participants with nonsquamous histology), until a 
discontinuation criterion is met (see Section 7.1).
The investigator will select the platinum chemotherapy regimen before randomization (see 
Table 5).
Participants who have completed the first course (achieve SD, PR, or CR) and who go on to 
progress may be eligible for up to an additional 17 cycles of the assigned treatment 
(MK-7684A or pembrolizumab) if there is BICR-verified progressive disease by RECIST 1.1 
after initial treatment (see Section 6.1.2).
Participants will be evaluated with radiographic imaging to assess response to study 
intervention at Week 6, Week 12, and Week 18 from randomization, then every 9 weeks 
through 63 weeks, and subsequently every 12 weeks until BICR-verified radiographic PD, 
initiation of a new anticancer regimen, withdrawal of consent, pregnancy, or death. All scans 
obtained during the initial treatment phase of the study will be submitted to the iCRO for 
BICR, which will assess the images using RECIST 1.1 for determination of PFS, ORR, and 
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DOR. Tumor imaging showing site-assessed PD is to be submitted immediately for 
verification by BICR before study intervention discontinuation. Once disease progression is 
verified centrally, subsequent imaging (if acquired) is not to be submitted to the iCRO.
Participants receiving MK-7684A or pembrolizumab may be permitted to continue study 
intervention beyond PD-verified by BICR per RECIST 1.1 if the treating investigator 
considers that the participant may experience clinical benefit with continued treatment and 
the participant is clinically stable and tolerating study intervention; however, this decision 
must be approved by the Sponsor. If the investigator recommends continuation of study 
intervention beyond disease progression, the participant or legally acceptable representative 
will be asked to provide a new documented informed consent.
Participants who discontinue study intervention for reasons other than BICR-verified PD will 
have long-term follow-up for disease status (including imaging), until BICR-verified PD, 
initiation of a new anticancer therapy, withdrawal of informed consent, or becoming lost to 
follow-up. After BICR-verified PD, each participant will be contacted approximately every 
12 weeks (± 14 days) to assess for survival status until withdrawal of consent, becoming lost 
to follow-up, death, or the end of the study, whichever occurs first.
No treatment crossover is planned for the study. The study design is shown in Figure 1
(Initial Treatment) and Figure 2 (Second Course).
AE monitoring will be ongoing throughout the study. AEs will be graded in severity 
according to the guidelines outlined in the NCI CTCAE 5.0.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8. See Appendix 7 for country-specific requirements.
4.2
Scientific Rationale for Study Design
This study is being conducted to compare the efficacy and safety of MK-7684A plus 
chemotherapy to pembrolizumab plus chemotherapy in participants with metastatic NSCLC 
in a randomized, double-blinded fashion.
4.2.1
Rationale for Endpoints
Endpoint definitions are provided in Section 9.4.
4.2.1.1
Efficacy Endpoint
The primary endpoint for this study is OS. 
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures. 
Although original RECIST 1.1 publication recommends a maximum of 5 target lesions in 
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total and 2 per organ, this protocol has implemented an adjustment to RECIST 1.1 to allow a 
maximum of 10 target lesions in total and 5 per organ, if a larger number of target lesions is 
needed to adequately represent the tumor burden. Refer to Section 8.2.1.5 for additional 
detail.
Overall Survival
OS has been recognized as the gold standard for the demonstration of superiority of a new 
antineoplastic therapy in randomized clinical studies.
Progression-free Survival
This study will use PFS based on RECIST 1.1 criteria as assessed by BICR as a secondary
endpoint. 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 BICR and 
RECIST 1.1 to assess PFS is typically considered acceptable by regulatory authorities. 
Images will be submitted to an iCRO and read by an independent central review blinded to 
treatment assignment to minimize bias in the response assessments. In addition, the final 
determination of radiologic progression will be based on the central assessment of 
progression, rather than a local site investigator/radiology assessment. Expedited verification 
of radiologic progression as determined by central review will be communicated to the site.
Objective Response Rate and Duration of Response
The secondary efficacy endpoints of ORR and DOR based on RECIST 1.1 and assessed by 
BICR is accepted by regulatory authorities and the oncology community.
4.2.1.2
Safety Endpoints
The safety and tolerability of MK-7684A will be assessed by clinical evaluation of AEs and 
inspection of other study parameters including vital signs, physical examination, and 
laboratory safety tests at time points specified in the SoA. AEs will be assessed as defined by 
NCI CTCAE 5.0 and recorded according to Section 8.4 and Appendix 3.
Safety parameters frequently used for evaluating investigational-systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs, and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version 5.0.
4.2.1.3
Patient-reported Outcomes
Symptomatic improvement is considered a clinical benefit and accepted by health authorities 
as additional evidence of the risk-benefit profile of any new study intervention.
 
 
 
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4.2.1.3.1
EORTC QLQ-C30
EORTC QLQ-C30 is a psychometrically and clinically validated instrument appropriate for 
assessing HRQoL in oncology studies [Aaronson, N. K., et al 1993]. The EORTC QLQ-C30 
is the most widely used cancer-specific HRQoL instrument, which contains 30 items and 
measures 5 functional dimensions (physical, role, emotional, cognitive, and social), 3 
symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, sleep 
disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health 
and QoL scale [Aaronson, N. K., et al 1993]. For the global health status or QoL and function 
scales, a higher value indicates a better level of function; for symptom scales and items, a 
higher value indicates increased severity of symptoms. TTD and mean change from baseline 
in global health status or QoL scale of the EORTC QLQ-C30, will be evaluated as secondary 
objectives.
4.2.1.3.2
EORTC QLQ-LC13
The EORTC QLQ-LC13, a supplemental lung cancer-specific module used in combination 
with QLQ-C30, is composed of multi-item and single-item measures of lung cancer-
associated symptoms (cough, hemoptysis, dyspnea, and site-specific pain) and treatment-
related symptoms (sore mouth, dysphagia, peripheral neuropathy, and alopecia) [Bergman, 
B., et al 1994]. It is scored on a 4-point scale (l = not at all, 2 = a little, 3 = quite a bit, and 4 = 
very much) and has been translated and validated into more than 60 languages.
The EORTC QLQ-C30 and QLQ-LC13 are the most frequently used and reported PRO 
measures in lung cancer clinical studies. The reliability, validity, and practicality of these 
instruments have been reported [Bergman, B., et al 1994] [Aaronson, N. K., et al 1993].
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4.2.2
Rationale for the Use of Comparator/Placebo
The comparator arm for this study will include pembrolizumab in combination with 
chemotherapy. The type of chemotherapy will depend on the histology type.
Pembrolizumab in combination with chemotherapy is approved as first-line treatment for 
patients with metastatic NSCLC regardless of tumor PD-L1 expression and is considered the 
standard of care for patients who are not candidates for targeted therapies. The chemotherapy 
regimens used in this study are well-established standards for first-line treatment of 
squamous (carboplatin with paclitaxel or nab-paclitaxel) or nonsquamous (pemetrexed and 
carboplatin or cisplatin) NSCLC. These regimens are also identical to the regimens used in 
KEYNOTE-189 and KEYNOTE-407.
4.3
Justification for Dose
4.3.1
MK-7684A
Based on the totality of available data, including clinical PK, pharmacodynamics, safety, and 
efficacy from the dose escalation and confirmation portion of Study MK-7684-001, the 
selected dose of MK-7684 is 200 mg, to be administered as MK-7684A (a coformulation 
with 200 mg pembrolizumab) as a 30-minute IV infusion Q3W.
CCI
CCI
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Further information is provided in the MK-7684/MK-7684A IB.
4.3.2
Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg Q3W.
 
 
 As outlined below, this dose is justified by:
•
Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg Q2W representing an approximate 5- to 7.5-fold exposure range (refer to IB, 
Section 5.2.2)
•
Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W 
•
Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications
•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W
4.3.3
Justification of Chemotherapy Dose
The chemotherapy treatments used in this study are well-established regimens for squamous 
(carboplatin with paclitaxel or nab-paclitaxel) or nonsquamous (pemetrexed and carboplatin 
or cisplatin) NSCLC, as described above. See Section 6.1 for information on the order in 
which study interventions are to be administered.
4.3.4
Biocomparability of MK-7684 and Pembrolizumab as Sequential Infusions 
Versus Coformulated Product MK-7684A in Solid Tumors
CCI
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Further details are provided in the MK-7684/MK-7684A IB.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3), or the last participant on active treatment is consented in the extension study. For 
purposes of analysis and reporting, the overall study ends when the Sponsor receives the last 
laboratory test result or at the time of final contact with the last participant, whichever comes 
last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
The Sponsor estimates that the maximum duration of the study from first participant entered 
through long-term follow-up will be 5 years (~3 years after study intervention has been 
completed) to attain the final assessment of the study (eg, to evaluate safety and/or long-term 
efficacy) for all evaluable participants. Refer to the Synopsis, Section 1.1, for the duration of 
participation of participants.
4.4.1
Clinical Criteria for Early Study Termination
Early study termination will be the result of the following specified criteria:
•
Incidence or severity of emerging effects/clinical endpoints is such that the risk/benefit 
ratio for the study population as a whole is unacceptable.
•
Plans to modify or discontinue the development of the study drug.
Ample notification will be provided in the event of Sponsor decision to no longer supply 
MK-7684A or pembrolizumab.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Section 10.1.1), our studies include 
people of varying age, race, ethnicity, and sex. The collection and use of these demographic 
data are to follow all local laws and guidelines in keeping with the needs for participant 
confidentiality while supporting the study of the disease, its related factors, and the IMP 
under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Has a histologically or cytologically confirmed diagnosis of Stage IV (T any, N any, 
M1a, M1b, M1c - AJCC eighth Edition) squamous or nonsquamous NSCLC.
2. Note: Mixed tumors will be characterized by the predominant cell type; if small cell 
elements are present, the participant is ineligible.
3. Has measurable disease based on RECIST 1.1, as determined by the local site 
assessment.
4. Note: Measurable disease is defined as having at least 1 measurable lesion by CT or 
MRI per RECIST 1.1. Lesions that appear measurable but are situated in a previously 
irradiated area can be considered measurable (eligible for selection as target lesions) 
if they have shown documented growth since the completion of radiation.
5. Has provided tumor tissue (post diagnosis of metastatic disease is preferred) for 
determination of PD-L1 status before randomization.
6. Note: Assessment of PD-L1 expression must be made from provided archival tumor 
tissue sample or newly obtained core or incisional or excisional biopsy of a tumor 
lesion not previously irradiated. FFPE tissue blocks are preferred to slides. Details 
pertaining to tumor tissue submission can be found in the laboratory manual.
7. Has confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as 
primary therapy (documentation of the absence of tumor-activating EGFR mutations 
[eg, DEL19 or L858R], AND absence of ALK and ROS1 gene rearrangements OR 
presence of a KRAS mutation).
8. Note: If participant’s tumor is known to have a predominantly squamous histology, 
molecular testing for EGFR mutation and ALK and ROS1 translocations will not be 
required, as this is not part of current diagnostic guidelines.
9. Has not received prior systemic treatment for metastatic NSCLC.
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Demographics
10. Is male or female, from ≥18 years of age inclusive, at the time of signing the 
informed consent.
11. Has an ECOG PS of 0 or 1 assessed within 7 days before randomization.
12. Has a life expectancy of at least 3 months.
Male Participants
13. If male, agrees to the following during the intervention period and for at least the time 
needed to eliminate each study intervention after the last dose of study intervention. 
The length of time required to continue contraception for each study intervention is as 
follows:
Chemotherapy: at least 95 days from the last dose
Refrain from donating sperm
a.
PLUS either:
Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on 
a long-term and persistent basis) and agrees to remain abstinent
OR
Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to 
medical cause), documented from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview as detailed below:
Uses a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: Men with 
a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile-vaginal penetration.
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions is more stringent than 
the requirements above, the local label requirements are to be followed.
Female Participants
14. A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies:
Not a WOCBP
OR
Is a WOCBP and:
Uses a contraceptive method that is highly effective (with a failure rate of <1% per year), 
with low user dependency, or be abstinent from heterosexual intercourse as their 
preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described 
in Appendix 5 during the intervention period and for at least the time needed to eliminate 
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each study intervention after the last dose of study intervention and agrees not to donate 
eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of 
reproduction during this period. The length of time required to continue contraception for 
each study intervention is as follows:
MK-7684A/pembrolizumab: 120 days
Chemotherapy: 180 days
The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study intervention. 
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions is more stringent than 
the requirements above, the local label requirements are to be followed.
Has a negative highly sensitive pregnancy test (as required by local regulations) within 
24 hours for urine or within 72 hours for serum before the first dose of study intervention. 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive. Additional requirements for 
pregnancy testing during and after study intervention are in Section 8.3.5.
Abstains from breastfeeding during the study intervention period and for at least 120 days 
after the last dose of study intervention.
Medical history, menstrual history, and recent sexual activity has been reviewed by the 
investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
Informed Consent
15. The participant (or legally acceptable representative) has provided documented 
informed consent/assent for the study. The participant may also provide 
consent/assent for FBR. However, the participant may participate in the study without 
participating in FBR.
Additional Categories
16. Has adequate organ function as defined in Table 4. Specimens must be collected 
within 10 days before the start of study intervention.
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Table 4
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Estimated creatinine clearance using the 
Cockcroft-Gault equationb
To initiate treatment with carboplatin or cisplatin, 
CrCl must be ≥60 mL/min
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
Abbreviations: ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); ANC=absolute 
neutrophil count; AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase);Crcl= creatinine 
clearance ULN=upper limit of normal.
a.
Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion 
within last 2 weeks.
b
Estimated creatinine clearance using Cockcroft-Gault:
(140-age [years] × weight (kg) (×F)*
Serum creatinine (mg/dL) × 72
*where F = 0.85 for females and F = 1 for males
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements 
are to be adapted according to local regulations and guidelines for the administration of specific chemotherapies.
See Appendix 7 for country-specific requirements for inclusion criteria.
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Known additional malignancy that is progressing or has required active treatment 
within the past 3 years.
2. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have 
undergone potentially curative therapy are not excluded.
3. Known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, (ie, without evidence of progression) for at least 4 weeks as confirmed by 
repeat imaging performed during study screening, are clinically stable and have not 
required steroid treatment for at least 14 days before the first dose of study 
intervention. Participants with asymptomatic brain metastases (ie, no neurological 
symptoms, no requirements for corticosteroids, no or minimal surrounding edema, 
and no lesion >1.5 cm) may participate.
4. Severe hypersensitivity (≥Grade 3) to MK-7684, MK-7684A, pembrolizumab, 
chemotherapy components, and/or any of its excipients.
5. 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 before the first dose of study medication.
6. Active autoimmune disease that has required systemic treatment in past 2 years, 
except replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid).
7. History of (noninfectious) pneumonitis/interstitial lung disease that required steroids 
or has current pneumonitis/interstitial lung disease.
8. Note: Lymphangitic spread of the NSCLC is not exclusionary.
9. Active infection requiring systemic therapy.
10. Known history of HIV infection. No HIV testing is required unless mandated by local 
health authority.
11. Has a known history of hepatitis B (defined as HBsAg reactive) or known active 
hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
12. Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority.
13. History or current evidence of any condition, therapy, or laboratory abnormality, or 
other circumstance that might confound the results of the study or interfere with the 
participant’s participation for the full duration of the study, such that it is not in the 
best interest of the participant to participate, in the opinion of the treating 
investigator.
14. Known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
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Prior/Concomitant Therapy
15. Received prior therapy with an anti-TIGIT, anti-PD-1, anti-PD-L1, or anti-PD-L2 
agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor 
(eg, CTLA-4, OX-40, CD137).
16. Received prior systemic anticancer therapy for metastatic disease.
Note: Participants who received adjuvant or neoadjuvant therapy are eligible if the 
adjuvant/neoadjuvant therapy was completed at least 12 months before the 
development of metastatic disease.
17. If the participant had major surgery, the participant must have recovered adequately 
from the procedure and/or any complications from the operation before starting study 
intervention.
18. Received prior radiotherapy within 2 weeks of start of study intervention or have had 
a history of radiation pneumonitis.
Note: Participants must have recovered from all radiation-related toxicities and not 
require corticosteroids. A 1-week washout is permitted for palliative radiation (≤2 
weeks of radiotherapy) to non-CNS disease.
19. Received radiation therapy to the lung that is >30 Gray within 6 months of the first 
dose of study intervention.
20. Received a live or live-attenuated vaccine within 30 days before the first dose of 
study intervention. Administration of killed vaccines are allowed.
Pemetrexed-Specific Concomitant Therapy
21. Is unable to interrupt aspirin or other NSAIDs, other than an aspirin dose ≤1.3 g/day, 
for a 5-day period (8-day period for long-acting agents, such as piroxicam).
22. Is unable or unwilling to take folic acid or vitamin B12 supplementation.
Prior/Concurrent Clinical Study Experience
23. Currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks before the first dose of study 
intervention.
24. 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.
Other Exclusions
25. History of allogeneic tissue/solid organ transplant.
See Appendix 7 for country-specific requirements for exclusion criteria.
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5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
No restrictions are required.
5.3.3
Activity Restrictions
No restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
Participants who fail screening may be rescreened one time for eligibility.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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6
STUDY INTERVENTION
At implementation of Amendment 05 or upon receipt of investigator letter detailing 
discontinuation of the MK-7684A clinical program, the following changes apply. The 
changes listed below supersede any protocol content/instructions from previous amendments.
•
This study will be unblinded.
•
Participants receiving MK-7684A plus chemotherapy will be transitioned to 
pembrolizumab plus chemotherapy.
•
Pembrolizumab can be sourced locally or centrally.
•
Participants with access to approved SOC (eg, pembrolizumab plus chemotherapy) 
should be considered for discontinuation from the study. Those benefiting from 
pembrolizumab with chemotherapy, but unable to access it as SOC outside the study, 
may continue on study and receive treatment with pembrolizumab plus chemotherapy 
until discontinuation criteria are met. The final required study visit will be the Safety 
Follow-up Visit.
•
Imaging scans should no longer be submitted to iCRO nor read by BICR. However, for 
participants who are still on study treatment and deriving clinical benefit and will 
continue on study treatment until criteria for discontinuation are met, local tumor imaging 
should continue per local SOC schedule and local SOC method of assessment of imaging. 
All imaging as well as relevant objectives and endpoints will be assessed locally.
•
PK/ADA samples will no longer be collected.
•
Biomarker/FBR samples will no longer be collected.
•
ePROs will no longer be collected.
•
Second course treatment of pembrolizumab for participants currently not on second 
course treatment will be offered. Any participant already receiving Second Course 
treatment will be able to complete treatment as planned.
•
Treatment beyond progression will no longer be offered. Any participant already
receiving treatment beyond progression will be able to complete treatment as planned.
•
Participants who complete study treatment or otherwise meet EOT criteria will be 
discontinued from the study after the EOT visit and any required safety follow-up visit.
•
There will be no follow-up for survival status. Participants currently in imaging follow-
up or survival follow-up are considered to have completed the study and therefore should 
obtain imaging and further oncological care as per local SOC. However, standard safety 
reporting should continue, as applicable.
•
Those participants remaining on study at the time of Amendment 05 should continue to 
be monitored in the study through the AE reporting period (Section 8.4).
•
Assessments listed in the SoA will be done per local SOC.
•
Participants may enroll in an extension study, if available.
-
Participation in this study is ended when the participant is consented for an extension 
study.
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-
The overall study ends when the last participant completes the last study-related 
contact, withdraws consent, or is lost to follow-up (Section 7.3), or the last participant 
on active treatment is consented in an extension study
-
For participants who enter an extension study, all AEs, SAEs, and other reportable 
safety events must be reported by the investigator in this protocol (parent study) from 
the time of intervention randomization up to the time of providing documented 
informed consent for an extension study. Note: Once consented to an extension study, 
safety events, including those considered related to study intervention, will be 
collected as instructed in the extension study.
Existing protocol content is retained for historical reference.
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study treatments provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 5. Country-specific 
differences are noted in Appendix 7.
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Table 5
Study Interventions
Arm 
Nam
e
Arm Type Intervention 
Name
Intervention 
Type
Dose 
Formulati
on
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administrati
on
Regimen/Treat
ment Period
Use
IMP or 
NIMP/
AxMP
Sourci
ng
Arm 
1
Experimen
tal
MK-7684A
Biological/
Vaccine
Solution
MK-7684 200 
mg 
+pembrolizu
mab 200 
mg/20 mL 
vial
200 
mg/200 
mg
IV Infusion
Q3W for up to 35 
cycles
Test 
Product
IMP
Central
Arm 
1
Experimen
tal
Carboplatin
Drug
Solution
10 mg/mL
Squamous
: AUC 6 
mg/ml/
min
Non
squamous
: AUC 
5 mg/mL/
min
IV Infusion
Q3W for 4 cycles Backgrou
nd 
Treatment
NIMP/Ax
MP
Local 
or 
Central
Arm 
1
Experimen
tal
Cisplatin
Drug
Solution
1 mg/mL
75 mg/m2
IV Infusion
Q3W for 4 cycles Backgrou
nd 
Treatment
NIMP/Ax
MP
Local 
or 
Central
Arm 
1
Experimen
tal
Paclitaxel
Drug
Solution
6 mg/mL
200 
mg/m2
IV Infusion
Q3W for 4 cycles Backgrou
nd 
Treatment
NIMP/Ax
MP
Local 
or 
Central
Arm 
1
Experimen
tal
Nab-
paclitaxel
Drug
Powder, 
For 
Solution
100 mg/vial
100 
mg/m2
IV Infusion
Day 1, 8, and 15 
of each 21 day 
cycle for 4 cycles
Backgrou
nd 
Treatment
NIMP/Ax
MP
Local 
or 
Central
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Arm 
Nam
e
Arm Type Intervention 
Name
Intervention 
Type
Dose 
Formulati
on
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administrati
on
Regimen/Treat
ment Period
Use
IMP or 
NIMP/
AxMP
Sourci
ng
Arm 
1
Experimen
tal
Pemetrexed
Drug
Powder, 
For 
Solution
500 mg/vial
500 
mg/m2
IV Infusion
Q3W until 
progression, 
intolerable AE, or 
participant or 
physician 
decision
Backgrou
nd 
Treatment
NIMP/Ax
MP
Local 
or 
Central
All 
parti
cipa
nts
Active 
Comparato
r
Pembrolizu
mab
Biological/Vacc
ine
Solution
25 mg/mL
200 mg
IV Infusion
Q3W for up to 35 
cycles
Test 
Product
IMP
Local 
or 
Central
Arm 
2
Active 
Comparato
r
Carboplatin
Drug
Solution
10 mg/mL
Squamous 
AUC 6 
mg/mL/m
in
Non-
squamous
: AUC 5 
mg/mL//
min
IV Infusion
Q3W for 4 cycles Backgrou
nd 
Treatment
NIMP/Ax
MP
Local 
or 
Central
Arm 
2
Active 
Comparato
r
Cisplatin
Drug
Solution
1 mg/mL
75 mg/m2
IV Infusion
Q3W for 4 cycles Backgrou
nd 
Treatment
NIMP/Ax
MP
Local 
or 
Central
Arm 
2
Active 
Comparato
r
Paclitaxel
Drug
Solution
6 mg/mL
200 
mg/m2
IV Infusion
Q3W for 4 cycles Backgrou
nd 
Treatment
NIMP/Ax
MP
Local 
or 
Central
Arm 
2
Active 
Comparato
r
Nab-
paclitaxel
Drug
Powder, 
For 
Solution
100 mg/vial
100 
mg/m2
IV Infusion
Day 1, 8, and 15 
of each 21 day 
cycle for 4 cycles
Backgrou
nd 
Treatment
NIMP/Ax
MP
Local 
or 
Central
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Arm 
Nam
e
Arm Type Intervention 
Name
Intervention 
Type
Dose 
Formulati
on
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administrati
on
Regimen/Treat
ment Period
Use
IMP or 
NIMP/
AxMP
Sourci
ng
Arm 
2
Active 
Comparato
r
Pemetrexed
Drug
Powder, 
For 
Solution
500 mg/vial
500 
mg/m2
IV Infusion
Q3W until 
progression, 
intolerable AE, or 
participant or 
physician 
decision
Backgrou
nd 
Treatment
NIMP/Ax
MP
Local 
or 
Central
Abbreviations:  AE=adverse event; AUC=area under the curve; BID=bis in die (twice daily); EEA=European Economic Area; IM=intramuscular; IMP=investigational medicinal 
product; MASCC=Multinational Association of Supportive Care in Cancer; NIMP/AxMP=noninvestigational medicinal product/auxiliary medicinal product; PO=per oral.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
MK-7684A = coformulated as 200 mg MK-7684 and 200 mg pembrolizumab
For commercially available supplies, the unit dose strength or formulation may vary, depending on market availability.
All participants taking pemetrexed are to receive the appropriate supplementation of vitamin B12, folic acid, and corticosteroid prophylaxis, as listed below (or as per local label):
•
Folic acid 350-1000 μg PO: at least 5 doses of folic acid must be taken during the 7 days preceding the first dose of pemetrexed, and folic acid dosing must continue 
during the full course of therapy and for 21 days after the last dose of pemetrexed.
•
Vitamin B12 1000 μg IM injection in the week preceding the first dose of pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be 
given on the same day as pemetrexed administration.
•
Dexamethasone prophylaxis 4 mg, PO BID (or equivalent). Taken the day before, day of, and day after pemetrexed administration. Higher or additional doses are 
permitted for antiemetic prophylaxis during Cycles 1 through 4, but not to exceed the doses in the MASCC guidelines.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 5 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary, or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Treatment
The Initial Treatment or First Course of MK-7684A plus chemotherapy or pembrolizumab 
plus chemotherapy consists of 4 cycles (Q3W) of treatment followed by up to 31 cycles 
(Q3W) of MK-7684A or pembrolizumab treatment, including pemetrexed for participants 
with nonsquamous NSCLC. Note: The number of treatments is calculated starting with the 
first dose.
The investigator will select the platinum chemotherapy regimen before randomization.
The platinum chemotherapy regimen will be selected based on histological subtype:
•
Squamous: carboplatin with taxane (investigators choice of paclitaxel/nab-paclitaxel)
•
Nonsquamous: pemetrexed with platinum (cisplatin/carboplatin) followed by pemetrexed 
maintenance until progression, intolerable AE, participant or investigator decision. There 
is no treatment duration limit for pemetrexed in nonsquamous histology.
These participants may be eligible for Second Course described in Section 6.1.2.
6.1.2
Second Course
All participants who have completed the first course may be eligible for up to an additional 
17 cycles of MK-7684A or pembrolizumab if there is BICR-verified progressive disease by 
RECIST 1.1 after initial treatment. This retreatment is the Second Course of this study.
Participants may enter the Second Course if all of the following criteria are met:
1. The participant received MK-7684A or pembrolizumab, determined on unblinding if 
applicable
2. No new anticancer treatment was administered after the last dose of study intervention
3. The participant meets all of the inclusion criteria and none of the exclusion criteria
4. The study is ongoing
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Participants will receive the same study intervention that was allocated in the initial treatment 
phase (MK-7684A or pembrolizumab).
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of MK-7684A and pembrolizumab are provided in 
the Pharmacy Manual. Carboplatin, cisplatin, paclitaxel, nab-paclitaxel, and pemetrexed will 
be prepared and administered as per the approved product labels.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 2 study 
intervention arms. Participants will be assigned randomly in a 1:1 ratio to MK-7684A plus 
chemotherapy or pembrolizumab plus chemotherapy.
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6.3.2
Stratification
6.3.3
Blinding
A double-blinding technique will be used. MK-7684A and pembrolizumab will be prepared 
and/or dispensed in a blinded fashion by an unblinded pharmacist or qualified study-site 
personnel. The participant, the investigator, and Sponsor personnel or delegate(s) who are 
involved in the study intervention administration or clinical evaluation of the participants are 
unaware of the intervention assignments. The chemotherapy agents will be open-label.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption or infusion/injection cessation of study 
intervention will be documented in the participant’s medical record.
Refer to Section 6.6.1 for Dose Modification and Toxicity Management Guidelines for irAEs 
associated with pembrolizumab monotherapy, coformulations, or IO combinations and for 
other allowed dose interruptions.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant ID will be confirmed at the time of 
dosing by a member of the study-site staff other than the person administering the study 
intervention.
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 intervention may be required. The 
investigator is to discuss prohibited medication/vaccination 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 
CCI
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participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
The following medications and vaccinations are prohibited during the study: (See Appendix 
7 for country-specific requirements):
•
Antineoplastic systemic chemotherapy or biological therapy
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
•
Investigational agents other than MK-7684A or pembrolizumab
•
Radiation therapy for disease control.
Note: Palliative radiotherapy is permitted for nontarget lesions if considered medically 
necessary by the treating physician and upon discussion with the Sponsor.
•
Surgery for tumor control
•
Anticancer hormonal therapy (eg, androgen deprivation, androgen receptor blockade, 
anti-estrogens)
Note: Hormonal replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is allowed.
•
Live or live attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study.
Note: Killed vaccines are allowed.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated 
just as any other concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
•
Systemic glucocorticoids except when used for the following purposes:
-
To modulate symptoms of an AE that is suspected to have an immunologic etiology
-
For the prevention of emesis
-
To premedicate for IV contrast allergies
-
To treat asthma or COPD exacerbations (only short-term oral or IV use in doses 
>10 mg/day prednisone equivalent)
-
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent
•
Other glucocorticoid use except when used for the following purposes:
-
For topical use or ocular use
-
Intraarticular joint use
-
For inhalation in the management of asthma or COPD
•
Phenytoin during therapy with cisplatin/carboplatin.
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If the investigator determines that a participant requires any of the aforementioned treatments 
for any reason, study intervention (all combination treatments) must be discontinued.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medications will be recorded on the eCRF including all 
prescriptions, OTC products, herbal supplements, and IV medications, and fluids. If changes 
occur during the study period, documentation of drug dosage, frequency, route, and date 
should also be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.4.
If a participant receives additional anticancer therapies, this will be judged to represent 
evidence of PD, and study intervention will be discontinued. These participants are required 
to complete all end-of-treatment assessments and continue to be followed for survival in the 
follow-up period.
Investigators must always refer to the up-to-date label of chemotherapeutics agents used in 
this study (ie, paclitaxel, nab-paclitaxel, pemetrexed, cisplatin and carboplatin) regarding the 
use of concomitant medications to address adequately the drug interaction potential.
•
Caution must be exercised when administering pemetrexed together with ibuprofen in 
patients with mild to moderate renal impairment. Monitor patients more frequently for 
myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of 
ibuprofen cannot be avoided.
•
Caution and increased monitoring must be exercised when administering paclitaxel 
concomitantly with known substrates or inhibitors of the CYP2C8 and CYP3A4.
•
Caution must be exercised when administering cisplatin or carboplatin together with 
other nephrotoxic agents (eg, aminoglycosides, diuretics, antihypertensives, other 
chemotherapy specified in the study).
•
Caution and increased monitoring must be exercised when administering cisplatin with 
other ototoxic agents (eg, aminoglycosides, loop diuretics).
6.5.1
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.
Refer to Appendix 7 for country-specific requirements.
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6.5.1.1
Pembrolizumab
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
Suggested supportive care measures for the management of AEs with potential immunologic 
etiology are outlined along with the dose modification guidelines in Section 6.6.
6.5.1.2
Chemotherapy
For supportive care measures for the management of AEs that may result from treatment with 
chemotherapy, refer to the approved product labels for these agents.
For all agents and all administration, antiemetic therapy should follow MASCC guidelines 
(http://www.mascc.org/antiemetic - guidelines/; [Roila, F., et al 2016]) and should include a 
5-HT3 receptor antagonist, dexamethasone (or equivalent) and/or aprepitant as per the
MASCC guidelines.
Prior to paclitaxel infusion, all participants should be premedicated with oral or IV 
corticosteroids, diphenhydramine, and H2 antagonists according to the approved product 
label and/or standard practice, see Section 8.1.8.1.2.2.
Prior to pemetrexed infusion, all participants should receive the appropriate supplementation 
of vitamin B12, folic acid, and dexamethasone; see Section 8.1.8.1.2.3.
In addition, all participants should receive the appropriate corticosteroid premedications as 
per the local approved label.
Additional premedications and pre- and post-cisplatin hydration should be administered as 
per standard practice.
6.6
Dose Modification (Escalation/Titration/Other)
Dose modifications for chemotherapy components are to follow the recommendation detailed 
in the prescribing information for the relevant product.
Toxicity events may be attributed to MK-7684A, pembrolizumab, individual chemotherapy 
agents, or to the combination of MK-7684A plus chemotherapy or pembrolizumab plus 
chemotherapy.
Refer to Appendix 7 for country-specific dose modification requirements.
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
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AEs associated with pembrolizumab monotherapy, coformulation, or IO combination 
exposure may represent an immune-related response. These irAEs may occur shortly after 
the first dose or several months after the last dose of pembrolizumab monotherapy, 
coformulation, or IO combination treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab monotherapy, coformulation, or IO 
combination administration of corticosteroids and/or other supportive care. For suspected 
irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional 
procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of 
the evaluation.
Attribution of Toxicity:
When study interventions are administered in combination, attribution of an adverse event to 
a single component is likely to be difficult. Therefore, while the investigator may attribute a 
toxicity event to pembrolizumab monotherapy, coformulations, or IO combinations, 
pembrolizumab monotherapy, coformulations, or IO combinations must be held according to 
the criteria in the Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events.
Holding Study Interventions:
When study interventions are administered in combination and if the AE is considered 
immune-related, pembrolizumab monotherapy, coformulations, or IO combinations should 
be held according to recommended Dose Modification criteria.
If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from pembrolizumab monotherapy, coformulations, or IO 
combinations.
Restarting Study Interventions:
Participants may restart pembrolizumab monotherapy, coformulations, or IO combinations as 
described below:
If the toxicities do resolve and conditions are aligned with what is defined in the Dose 
Modification and Toxicity Management Guidelines for irAEs, pembrolizumab monotherapy, 
coformulations, or IO combinations may be restarted at the discretion of the investigator.
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 6.
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Table 6
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations (MK-7684A) or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the irAEs 
are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not 
≤10 mg/day within 12 weeks of the last treatment.
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after 
corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Add prophylactic antibiotics 
for opportunistic infections
Monitor participants for signs and symptoms 
of pneumonitis
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
Recurrent Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
Diarrhea/Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without 
fever) and of bowel perforation (ie, 
peritoneal signs and ileus)
Participants with ≥Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST or ALT Elevation 
or Increased Bilirubin
Grade 2 a
Withhold
Administer corticosteroids 
(initial dose of 0.5 to 
1 mg/kg prednisone or 
equivalent) followed by 
taper
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable)
Grade 3 b or 4 c
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold d
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer 
antihyperglycemic in 
participants with 
hyperglycemia
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hyperthyroidism
Grade 2
Continue
Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue d
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2, 3 or 4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
Monitor for signs and symptoms of thyroid 
disorders
Nephritis:
grading according to 
increased creatinine or 
acute kidney injury
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by 
taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Neurological 
Toxicities
Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Asymptomatic 
cardiac enzyme 
elevation with 
clinical suspicion of 
myocarditis 
(previously CTCAE 
v4.0 Grade 1)
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm 
etiology or exclude other causes
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
All Other irAEs
PersistentGrade2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm 
etiology or exclude other causes
Grade 3
Withhold or 
discontinue based on 
the event e
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; 
DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; IR=immune-related; IV=intravenous; 
SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 
10.0 x baseline if baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the 
investigator or treating physician. If control achieved or ≤Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing 
cholangitis).
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab Monotherapy, Coformulations (MK-7684A) or IO Combinations 
Pembrolizumab monotherapy, coformulations (MK-7684A) or IO combinations 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 monotherapy, coformulations (MK-7684A) or IO 
combinations associated infusion reaction are provided in Table 7.
Table 7
Pembrolizumab Monotherapy, Coformulations (MK-7684A) or IO 
Combinations 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 h
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/h to 50 mL/h). Otherwise,
dosing will be held until symptoms 
resolve and the participant should be 
premedicated for the next scheduled 
dose.
Participants who develop Grade 2 
toxicity despite adequate 
premedication should be permanently 
discontinued from further study 
intervention.
Participant may be 
premedicated 1.5 h (±30 min) 
prior to infusion of study 
intervention with:
Diphenhydramine 50 mg PO 
(or equivalent dose of 
antihistamine).
Acetaminophen 500 to 
1000 mg PO (or equivalent 
dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms after 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (eg, renal 
impairment, pulmonary infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop 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 
intervention.
No subsequent dosing
h=hour; IV=intravenous; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer 
Institute; NSAIDs= nonsteroidal anti-inflammatory drugs.
Note:  Appropriate resuscitation equipment should be available at the bedside and a physician readily 
available during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) 
at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab Monotherapy, Coformulations, 
or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations may be interrupted for 
situations other than treatment-related AEs such as medical or surgical events and/or 
unforeseen circumstances not related to study intervention. However, study intervention is to 
be restarted within 3 weeks (21 days) of the originally scheduled dose and within 42 days of 
the previously administered dose, unless otherwise discussed with the Sponsor. The reason 
for study intervention interruption is to be documented in the participant’s study record.
6.6.2
Dose Modifications for Chemotherapy
If a participant experiences a >10% weight change from baseline, the doses of paclitaxel/nab-
paclitaxel, pemetrexed, cisplatin, or carboplatin are to be recalculated.
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Dose modifications due to AEs will depend on the investigator’s assessment of causality. If 
appropriate, the investigator may attribute each toxicity event to paclitaxel, nab-paclitaxel, 
pemetrexed, cisplatin, carboplatin, MK-7684A or pembrolizumab alone, or to the 
combination, and use a stepwise dose modification (Table 8, Table 9, Table 10). Reduction 
of 1 chemotherapy agent and not the other agent is appropriate if, in the opinion of the 
investigator, the toxicity is clearly related to one of the treatments. If, in the opinion of the 
investigator, the toxicity is related to the combination of both chemotherapy agents, both 
agents are to be reduced according to recommended dose modifications.
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 chemotherapy throughout the course of the study for toxicities. Participants 
who require a third dose modification to any particular component will have that intervention 
discontinued. If a participant experiences several toxicities and there are conflicting 
recommendations, the most conservative recommended dose adjustment is to be followed (ie, 
the dose reduction appropriate to the most severe toxicity). Once the dose has been 
decreased, it should remain reduced for all subsequent administrations or be further reduced, 
if necessary. There will be no dose escalations in this study.
If the toxicity is related to the combination of 3 agents (MK-7684A/pembrolizumab, taxane, 
and platinum agents), all 3 agents are to be reduced (chemotherapy only), interrupted, or 
discontinued according to the recommended dose modifications. If all 3 agents are 
discontinued due to a toxicity, the participant must be discontinued from the study. 
MK-7684A and pembrolizumab dose reductions are not permitted. MK-7684A and 
pembrolizumab treatment may be delayed/interrupted for a maximum of 12 weeks for an AE
(see Section 6.6.1).
Study intervention-related toxicities must be resolved to baseline or Grade ≤1 (with the 
exception of alopecia, Grade 2 fatigue, Grade 2 peripheral neuropathy, Grade 2 anemia, 
endocrine-related AEs (Grade ≤2) requiring treatment or hormone replacement and creatinine 
clearance, for which the guidelines provided below may be followed) before administering 
the subsequent cycle. Participants must not receive the next cycle of chemotherapy if any of 
the following apply:
•
Absolute neutrophil count <1500/mm3
•
Platelet count <100,000/mm3
•
Hemoglobin level <8 g/dL
•
Total bilirubin level >1.5 × ULN
•
AST and ALT levels ≥2.5 × ULN, or ≥5 × ULN if liver metastases are present
•
CrCl will be based on the Cockcroft-Gault formula.
-
For participants receiving cisplatin, the scheduled dose of cisplatin may only be 
administered if the calculated CrCl is ≥50 mL/min.
If CrCl falls to <50 mL/min, delay the start of that cycle for ≤21 days. In the interim, monitor 
renal function weekly and consider IV hydration. When CrCl improves to ≥50mL/min, 
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decrease cisplatin to DL-1 (Table 8). Alternatively, if in the investigator’s judgment it is in 
the best interest of the participant, cisplatin can be switched to carboplatin if the calculated 
CrCl is appropriate, and in consultation with the Sponsor.
•
At the second occurrence of CrCl <50 mL/min, decrease cisplatin to DL-2 upon 
improvement of CrCl to ≥50 mL/min. Alternatively, if in the investigator’s judgment it is 
in the best interest of the participant, cisplatin can be switched to carboplatin if the 
calculated CrCl is appropriate, and in consultation with the Sponsor.
•
At the third occurrence of CrCl <50 mL/min, cisplatin is to be discontinued. If in the 
investigator’s judgment it is in the best interest of the participant, cisplatin can be 
switched to carboplatin if the calculated CrCl is appropriate, at the discretion of the 
investigator and in consultation with the Sponsor.
-
For participants receiving carboplatin, the scheduled dose of carboplatin may only be 
administered if the calculated CrCl is ≥40 mL/min.
If CrCl falls to <40 mL/min, delay the start of that cycle for ≤21 days. In the interim, monitor 
renal function weekly and consider IV hydration. When CrCl improves to ≥40 mL/min, 
decrease carboplatin to DL-1 (Table 8).
•
At the second occurrence of CrCl <40 mL/min, decrease carboplatin to DL-2 (Table 8) 
upon improvement of CrCl to ≥40mL/min.
•
At the third occurrence of CrCl <40 mL/min, carboplatin is to be discontinued.
During concurrent chemotherapy treatment:
•
If paclitaxel/nab-paclitaxel or pemetrexed dosing is delayed or interrupted on Day 1, the 
platinum agent and MK-7684A/pembrolizumab will also be delayed/interrupted. If 
paclitaxel/nab-paclitaxel or pemetrexed is delayed or interrupted during Cycles 1 through 
4, participants are to be seen weekly until toxicity resolves.
•
If platinum dosing is delayed or interrupted on Day 1, MK-7684A/pembrolizumab and 
pemetrexed/paclitaxel/nab-paclitaxel will also be delayed/interrupted. If platinum agent is 
delayed or interrupted during Cycles 1 through 4, participants are to be seen weekly until 
toxicity resolves.
•
If MK-7684A/pembrolizumab dosing is delayed or interrupted, platinum agent, 
pemetrexed/paclitaxel/nab-paclitaxel can continue as scheduled. 
MK-7684A/pembrolizumab administration is to be attempted at the next cycle of therapy.
•
Each chemotherapy cycle may not be delayed by more than 3 weeks (>21 days) despite 
supportive treatment. If only one of the agents is thought to be causing the specified 
toxicity leading to a 21-day delay of administration of the next cycle, that 
chemotherapeutic agent can be withheld and treatment can continue with 
MK-7684A/pembrolizumab and the remaining chemotherapy drug. 
MK-7684A/pembrolizumab dosing can continue with 1 agent or as monotherapy.
The reason for the dose interruption or reduction is to be captured on the appropriate eCRF.
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A participant is allowed to switch from cisplatin to carboplatin if the participant develops 
unexpected toxicities with the use of cisplatin (including hearing loss), becomes ineligible for 
further cisplatin therapy, and/or the investigator considers switching to carboplatin to be in 
the best interest of the participant. This switch from cisplatin to carboplatin requires 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision.
A participant may be allowed to switch from paclitaxel to nab-paclitaxel if the participant 
experiences an infusion reaction to paclitaxel and the investigator considers switching to be 
in the best interest of the participant. This switch from paclitaxel to nab-paclitaxel requires 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision.
The CTCAE 5.0 must be used to grade the severity of AEs. All dose modifications are to be 
based on the AE requiring the greatest dose modification. Dose modifications are detailed in 
Table 8, Table 9, and Table 10. These serve as a guide and do not replace investigator 
judgment and applicable local label recommendations, if more stringent.
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Table 8
Dose-level Modifications for Chemotherapeutic Agents
Nonsquamous: Pemetrexed Plus Platinum-based Chemotherapy
Squamous: Carboplatin Plus Taxane
(Paclitaxel or Nab-paclitaxel)
Pemetrexed
Carboplatin
Cisplatin
Carboplatin
Paclitaxel
Nab-paclitaxel
Dose Level 0 
(starting dose)
500 mg/m2
AUC 5 mg/mL/min
75 mg/m2
AUC 
6 mg/mL/min
200 mg/m2
100 mg/m2
Dose Level -1
375 mg/m2
AUC 3.75 
mg/mL/min
56 mg/m2
AUC 
4.5 mg/mL/min
150 mg/m2
75 mg/m2
Dose Level -2
250 mg/m2
AUC 2.5 
mg/mL/min
38 mg/m2
AUC 
3 mg/mL/min
100 mg/m2
50 mg/m2
Dose Level -3
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
Abbreviation: AUC=area under the curve.
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Recommended dose modifications for key chemotherapy toxicities are outlined in Table 9
and Table 10. These serve as a guide and do not replace investigator judgment and applicable 
local label recommendations, if more stringent. These data are based on Day 1 cell counts.
Table 9
Recommended Chemotherapy Dose Modifications for Hematological Toxicity
Drug-related Toxicitya
Cisplatin
Carboplatin
Paclitaxel
Nab-
paclitaxel
Pemetrexed
Dose Level from Table 8
Neutrophils (ANC) <500/mm3
without fever
DL-1
DL-1
DL-1
DL-1
DL-1
Febrile neutropenia (fever 
≥38.5C 
and ANC <1,000/mm3)
DL-1
DL-1
DL-1
DL-1
DL-1
Platelets <50,000/mm3 without 
significant bleeding or 
requiring 
blood transfusion
DL-1
DL-1
DL-1
DL-1
DL-1
Platelets <50,000/mm3 with 
Grade ≥2 hemorrhage or 
requiring blood transfusion
DL-2
DL-2
DL-2
DL-2
DL-2
Grade 4 hemoglobin
DL-1
DL-1
DL-1
DL-1
DL-1
Abbreviations: ANC=absolute neutrophil count; DL=dose level
Note: If toxicity can clearly be attributed to one of the drugs, the investigator may choose to only reduce the 
dose of one of the chemotherapy agents. Investigators may decide to use supportive measures/treatment 
and/or secondary prophylaxis as per institutional standards (eg, filgrastim, pegfilgrastim, transfusions) 
instead of dose reductions for the next dose, if considered in the best interest of the participant.
a
Should the hematologic toxicity recur; the dose of the agent could be reduced further. However, not 
more than 2 dose reductions per chemotherapy agent are permitted.
Table 10
Recommended Chemotherapy Dose Modifications for Nonhematological 
Toxicity
Drug-Related Toxicitya
CTCAE 
Grade
Cisplatin
Carboplatin
Paclitaxel
Nab-
paclitaxel
Pemetrexed
Dose Level from Table 8
Nausea/vomiting
Grade ≥3b
DL-1
DL-1
DL-1
DL-1
No 
modification
Mucositis
Grade ≥3b
DL-1
DL-1
DL-1
DL-1
DL-2
Diarrhea
Grade ≥3b
DL-1
DL-1
DL-1
DL-1
DL-1
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Drug-Related Toxicitya
CTCAE 
Grade
Cisplatin
Carboplatin
Paclitaxel
Nab-
paclitaxel
Pemetrexed
Peripheral neuropathy
Grade 2
DL-1c
No 
modification
DL-1
DL-1
No 
modification
Grade 3
Discontinued
DL-1
Discontin
ue
Disconti
nue
DL-1
Grade 4
Discontinue
DL-1
Discontin
ue
Disconti
nue
DL-1
Total bilirubin
Grade 2
No 
modification
No 
modification
DL-2
DL-2
No 
modification
Grade 3
No 
modification
No 
modification
Discontin
ue
Disconti
nue
No 
modification
Grade 4
No 
modification
No 
modification
Discontin
ue
Disconti
nue
No 
modification
AST or ALT Elevation
Grade 3
DL-1
DL-1
Discontinu
e
Discontin
ue
DL-1
Grade 4
Discontinue
Discontinue
Discontinu
e
Discontin
ue
Discontinue
Other nonhematologic 
toxicity (except fatigue 
and transient arthralgia 
and myalgia)
Grade≥3
DL-1
DL-1
DL-1
DL-1
DL-1
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=common 
terminology criteria for adverse events; DL=dose level.
Note: If considered in the best interest of the participant, and consistent with local practice, investigators may 
decide to use supportive measures/treatment, and/or secondary prophylaxis instead of dose reductions for the 
next dose. Also, if toxicity can clearly be attributed to one of the drugs, the investigator may choose to only 
reduce the dose of one of the chemotherapy agents.
a
Should the toxicity recur; the dose of the agent could be reduced further. However, not more than 2 dose 
reductions per chemotherapy agent are permitted.
b
The first occurrence of Grade ≥3 nausea/vomiting, mucositis, and diarrhea is to be managed 
symptomatically with optimal medical therapy and improve to Grade ≤1 before proceeding with 
additional therapy. Should these events recur despite aggressive management, a dose modification can 
be used once the AE improves to Grade ≤1.
c
If Grade 2 neurotoxicity recurs after DL -1, drug will be given at DL -2 or switch can be made to the 
appropriate dose of carboplatin at the discretion of the investigator in consultation with the Sponsor. If 
Grade 2 neurotoxicity persists after 2 dose level reductions and 21-day hold, switch can be made to the 
appropriate dose of carboplatin at the discretion of the investigator in consultation with the Sponsor.
d
If Grade 3 neurotoxicity occurs, cisplatin will be discontinued, and, upon improvement, a switch can be 
made to the appropriate dose of carboplatin at the discretion of the investigator in consultation with the 
Sponsor.
6.6.3
Other Allowed Dose Interruption for Study Intervention
Pembrolizumab, MK-7684A, or chemotherapy may be interrupted for situations other than 
treatment-related AEs such as medical or surgical events and/or unforeseen circumstances 
not related to study intervention. However, study intervention is to be restarted within 
3 weeks (21 days) of the originally scheduled dose and within 42 days of the previously 
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administered dose, unless otherwise discussed with the Sponsor. The reason for study 
intervention interruption is to be documented in the participant’s study record.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
This study is blinded, but supplies are provided open label; therefore, an unblinded 
pharmacist or qualified study-site personnel will be used to blind supplies. Study intervention 
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention randomization system (IRT) should be used to unblind participants 
and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
At implementation of Amendment 05 or upon receipt of investigator letter detailing 
discontinuation of the MK-7684A clinical program, the following changes apply. The 
changes listed below supersede any protocol content/instructions from previous amendments.
•
This study will be unblinded.
•
Participants receiving MK-7684A plus chemotherapy will be transitioned to 
pembrolizumab plus chemotherapy.
•
Pembrolizumab can be sourced locally or centrally.
•
Participants with access to approved SOC (eg, pembrolizumab plus chemotherapy) 
should be considered for discontinuation from the study. Those benefiting from 
pembrolizumab with chemotherapy, but unable to access it as SOC outside the study, 
may continue on study and receive treatment with pembrolizumab plus chemotherapy 
until discontinuation criteria are met. The final required study visit will be the Safety 
Follow-up Visit.
•
Imaging scans should no longer be submitted to iCRO nor read by BICR. However, for 
participants who are still on study treatment and deriving clinical benefit and will 
continue on study treatment until criteria for discontinuation are met, local tumor imaging 
should continue per local SOC schedule and local SOC method of assessment of imaging. 
All imaging as well as relevant objectives and endpoints will be assessed locally.
•
PK/ADA samples will no longer be collected.
•
Biomarker/FBR samples will no longer be collected.
•
ePROs will no longer be collected.
•
Second course treatment of pembrolizumab for participants currently not on second 
course treatment will be offered. Any participant already receiving Second Course 
treatment will be able to complete treatment as planned.
•
Treatment beyond progression will no longer be offered. Any participant already
receiving treatment beyond progression will be able to complete treatment as planned.
•
Participants who complete study treatment or otherwise meet EOT criteria will be 
discontinued from the study after the EOT visit and any required safety follow-up visit.
•
There will be no follow-up for survival status. Participants currently in imaging follow-
up or survival follow-up are considered to have completed the study and therefore should 
obtain imaging and further oncological care as per local SOC. However, standard safety 
reporting should continue, as applicable.
•
Those participants remaining on study at the time of Amendment 05 should continue to 
be monitored in the study through the AE reporting period (Section 8.4).
•
Assessments listed in the SoA will be done per local SOC.
•
Participants may enroll in an extension study, if available.
-
Participation in this study is ended when the participant is consented for an extension 
study.
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-
The overall study ends when the last participant completes the last study-related 
contact, withdraws consent, or is lost to follow-up (Section 7.3), or the last participant 
on active treatment is consented in an extension study
-
For participants who enter an extension study, all AEs, SAEs, and other reportable 
safety events must be reported by the investigator in this protocol (parent study) from 
the time of intervention randomization up to the time of providing documented 
informed consent for an extension study. Note: Once consented to an extension study, 
safety events, including those considered related to study intervention, will be 
collected as instructed in the extension study.
Existing protocol content is retained for historical reference.
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period regimen will still continue to be monitored in this study and participate in the study 
visits and procedures as specified in Section 1.3 and Section 8.11.5 unless the participant has 
withdrawn from the study Section 7.2.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
Interruption of chemotherapy (carboplatin and/or taxane [paclitaxel/nab-paclitaxel] for 
squamous NSCLC; pemetrexed and/or carboplatin/cisplatin for nonsquamous NSCLC) 
for more than 6 weeks. Participants may continue on study upon consultation with 
Sponsor.
•
Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Section 6.6.1, require 
Sponsor consultation prior to restarting treatment. If treatment will not be restarted, the 
participant will continue to be monitored in the study and the reason for discontinuation 
of study intervention will be recorded in the medical record.
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•
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.
•
The participant is taking any prohibited medications noted in Section 6.5.
•
Radiographic disease progression outlined in Section 8.2.1.5 (after obtaining informed 
consent addendum and Sponsor communication, the investigator may elect to continue 
treatment beyond BICR-verified disease progression).
•
Any progression or recurrence of malignancy, or any occurrence of another malignancy 
that requires active treatment.
•
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in Section
6.6.
For participants who are discontinued from study intervention, but continue to be monitored
in the study, all visits and procedures, as outlined in the SoA, should be completed.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
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.
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8
STUDY ASSESSMENTS AND PROCEDURES
At implementation of Amendment 05 or upon receipt of investigator letter detailing 
discontinuation of the MK-7684A clinical program, the following changes apply. The 
changes listed below supersede any protocol content/instructions from previous amendments.
•
This study will be unblinded.
•
Participants receiving MK-7684A plus chemotherapy will be transitioned to 
pembrolizumab plus chemotherapy.
•
Pembrolizumab can be sourced locally or centrally.
•
Participants with access to approved SOC (eg, pembrolizumab plus chemotherapy) 
should be considered for discontinuation from the study. Those benefiting from 
pembrolizumab with chemotherapy, but unable to access it as SOC outside the study, 
may continue on study and receive treatment with pembrolizumab plus chemotherapy 
until discontinuation criteria are met. The final required study visit will be the Safety 
Follow-up Visit.
•
Imaging scans should no longer be submitted to iCRO nor read by BICR. However, for 
participants who are still on study treatment and deriving clinical benefit and will 
continue on study treatment until criteria for discontinuation are met, local tumor imaging 
should continue per local SOC schedule and local SOC method of assessment of imaging. 
All imaging as well as relevant objectives and endpoints will be assessed locally.
•
PK/ADA samples will no longer be collected.
•
Biomarker/FBR samples will no longer be collected.
•
ePROs will no longer be collected.
•
Second course treatment of pembrolizumab for participants currently not on second 
course treatment will be offered. Any participant already receiving Second Course 
treatment will be able to complete treatment as planned.
•
Treatment beyond progression will no longer be offered. Any participant already
receiving treatment beyond progression will be able to complete treatment as planned.
•
Participants who complete study treatment or otherwise meet EOT criteria will be 
discontinued from the study after the EOT visit and any required safety follow-up visit.
•
There will be no follow-up for survival status. Participants currently in imaging follow-
up or survival follow-up are considered to have completed the study and therefore should 
obtain imaging and further oncological care as per local SOC. However, standard safety 
reporting should continue, as applicable.
•
Those participants remaining on study at the time of Amendment 05 should continue to 
be monitored in the study through the AE reporting period (Section 8.4).
•
Assessments listed in the SoA will be done per local SOC.
•
Participants may enroll in an extension study, if available.
-
Participation in this study is ended when the participant is consented for an extension 
study.
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-
The overall study ends when the last participant completes the last study-related 
contact, withdraws consent, or is lost to follow-up (Section 7.3), or the last participant 
on active treatment is consented in an extension study
-
For participants who enter an extension study, all AEs, SAEs, and other reportable 
safety events must be reported by the investigator in this protocol (parent study) from 
the time of intervention randomization up to the time of providing documented 
informed consent for an extension study. Note: Once consented to an extension study, 
safety events, including those considered related to study intervention, will be 
collected as instructed in the extension study.
Existing protocol content is retained for historical reference.
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before providing documented informed consent, may be used for 
screening or baseline purposes provided the procedures meet the protocol-specified 
criteria and were performed within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
The maximum amount of blood collected from each participant over the duration of the 
study can be found in the Procedures Manual.
•
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
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
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8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout, or run-in treatment including placebo run-in).
8.1.4.1
Non-small Cell Lung Cancer History
The investigator or qualified designee will obtain prior and current details regarding the 
participant’s NSCLC. This information will include, but is not limited to, date of diagnosis, 
stage, histology, location(s) of primary lesions, location(s) of metastases and prior treatment.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the study. Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.
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8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit. In addition, new medications started 
during the Second Course through the Second Course Safety Follow-up Visit are to be 
recorded.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Specific details on the screening/rescreening visit requirements are in Section 8.11.1.
8.1.7
Assignment of Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the Pharmacy Manual.
Study intervention should begin within 3 days of intervention randomization.
8.1.8.1
Timing of Dose Administration
For in-clinic dosing, study intervention will be administered after all procedures and 
assessments have been performed. When administering MK-7684A or pembrolizumab in 
combination with chemotherapy, administer treatments in the following order:
•
MK-7684A or pembrolizumab
•
Chemotherapy
8.1.8.1.1
MK-7684A and Pembrolizumab
MK-7684A and pembrolizumab will be administered using a 30-minute IV infusion every 
3 weeks. 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 25 to 40 minutes). The Pharmacy 
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Manual contains specific instructions for MK-7684A and pembrolizumab reconstitution, 
preparation of the infusion fluid, and administration.
After Cycle 1 Day 1, MK-7684A or pembrolizumab will be administered up to 3 days before 
or after the scheduled Day 1 of each subsequent cycle for administrative reasons.
8.1.8.1.2
Chemotherapy
Unless there is a change in weight >10%, the same dose of chemotherapy can be used 
throughout the 4 cycles of the Intervention Phase (provided there are no additional toxicities).
8.1.8.1.2.1
Carboplatin (AUC 6 [Squamous] or AUC 5 [Nonsquamous])
Carboplatin (AUC 6 [mg/mL/min] squamous; AUC 5 [mg/mL/min] nonsquamous) will be 
administered as an IV infusion over approximately 60 minutes Q3W on Day 1 for each of the 
4 cycles (Intervention Phase) and after MK-7684A or pembrolizumab as per local practice 
and labels. The carboplatin dose is to be calculated using the Calvert Formula (see below) 
and is not to exceed 900 mg (squamous) or 750 mg (nonsquamous).
Calvert Formula (Squamous dose):
•
Total dose (mg) = (target AUC) × (CrCl + 25)
•
The estimated CrCl in the Calvert Formula is not to exceed 125 mL/min
•
Maximum carboplatin dose (mg) = target AUC 6 × (125 + 25)
= 6 × 150
= 900 mg
Calvert Formula (Nonsquamous dose):
•
Total dose (mg) = (target AUC) × (CrCl + 25)
•
The estimated CrCl in the Calvert Formula is not to exceed 125 mL/min
•
Maximum carboplatin dose (mg) = target AUC 5 × (125 + 25)
= 5 × 150
= 750 mg
Creatinine clearance must be calculated using either the Cockcroft-Gault formula or another 
acceptable standard formula for estimating CrCl in mL/min based on serum creatinine:
•
Male: [(140 - age (y)) × weight (kg)]/[72 × serum creatinine (mg/dL)]
•
Female: [(140 - age (y)) × weight (kg)] × 0.85/[72 × serum creatinine (mg/dL)]
Note: Dose may be rounded to the nearest 50 mg at the discretion of the investigator, and 
according to institutional standards.
Additional premedications are to be administered as per standard practice.
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8.1.8.1.2.2
Paclitaxel or Nab-paclitaxel (Squamous)
Paclitaxel or nab-paclitaxel will be administered immediately after MK-7684A or 
pembrolizumab and is to be completely administered before initiating the carboplatin dose.
•
Paclitaxel (200 mg/m2 Q3W) will be administered as an IV infusion over 3 hours for 4 
cycles as per local practice and labels. All participants are to be premedicated with oral or 
IV steroid and antihistamines according to the approved product label and/or standard 
practice. Additional premedications are to be administered as per standard practice.
•
Nab-paclitaxel (100 mg/m2) will be administered at as an IV infusion over 30 minutes for 
4 cycles as per local practice and labels. Participants will be dosed on Day 1, 8 (±1 day), 
and 15 (±1 day) of each 3-week cycle.
A participant may be allowed to switch from paclitaxel to nab-paclitaxel if the participant 
experiences an infusion reaction to paclitaxel and the investigator considers switching to be 
in the best interest of the participant. This switch from paclitaxel to nab-paclitaxel requires 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision.
8.1.8.1.2.3
Pemetrexed (Nonsquamous)
Pemetrexed (500 mg/m2 Q3W) will be administered as an IV infusion over 10 minutes. 
Pemetrexed administration is to be completed at least 30 minutes before the initiation of 
carboplatin or cisplatin. All participants are to receive the appropriate supplementation of 
vitamin B12, folic acid, and corticosteroid prophylaxis as listed below (or as per local label):
•
Folic acid 350 to 1000 μg PO: at least 5 doses of folic acid must be taken during the 
7 days preceding the first dose of pemetrexed, and folic acid dosing must continue during 
the full course of therapy and for 21 days after the last dose of pemetrexed.
•
Vitamin B12 1000 μg IM injection in the week preceding the first dose of pemetrexed 
and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the 
same day as pemetrexed administration.
•
Dexamethasone prophylaxis 4 mg PO BID (or equivalent). Taken the day before, day of, 
and day after pemetrexed administration. Higher or additional doses are permitted for 
antiemetic prophylaxis during Cycles 1-4 but not to exceed doses in MASCC guidelines 
(Section 8.1.8.1.3).
8.1.8.1.2.4
Cisplatin (Nonsquamous)
Cisplatin (75 mg/m2 Q3W) will be administered as an IV infusion over 30 to 180 minutes on 
Day 1 for up to 4 cycles (Intervention Phase) and after MK-7684A or pembrolizumab as per 
local practice and labels.
Participants are allowed to switch from cisplatin to carboplatin if the participant becomes 
ineligible for further cisplatin therapy according to local guidelines and the investigator 
considers switching to carboplatin to be in the best interest of the participant. This switch 
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from cisplatin to carboplatin requires consultation between the investigator and the Sponsor 
and written documentation of the collaborative decision.
8.1.8.1.3
Antiemetic Therapy
Antiemetic therapy should follow the MASCC guidelines. In each cycle of treatment during 
the Intervention Phase, antiemetic therapy should include a 5-HT3 receptor antagonist, 
dexamethasone (or equivalent), and/or aprepitant [Roila, F., et al 2016].
8.1.8.1.4
Colony-stimulating Factors
The use of CSFs when administering chemotherapy is highly recommended as primary 
prophylaxis to reduce the risk of febrile neutropenia in this patient population, especially as 
many participants have multiple comorbidities and advanced disease. Granulocyte-CSF 
should not be used within 14 days before randomization.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period 
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.4.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
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8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the
intensity/toxicity grade of the AEs observed, the relation to study intervention, the reason 
thereof, etc, in the medical record. If it is not possible to record this assessment in the 
medical record before the unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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8.1.12
Tumor Tissue for Biomarker Status
During the screening period, a tumor sample for each participant is required and is to be:
•
A newly obtained core, incisional, or excisional biopsy of a tumor lesion, which was not 
previously irradiated
Or
•
An archival tumor tissue sample if a new biopsy is unavailable (depending on protocol 
requirements)
FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived 
tissue.
Details pertaining to tumor tissue submission can be found in the Procedures Manual.
The central laboratory will use the tissue sample to ascertain PD-L1 status using the PD-L1 
IHC 22C3 pharmDx (Investigational Use Only) diagnostic kit. The diagnostic test is identical 
to the US FDA-approved PD-L1 IHC 22C3 pharmDx diagnostic kit except it is labeled IUO. 
The PD-L1 IHC 22C3 pharmDx assay kit is currently approved to assess PD-L1 status in 
participants with NSCLC for treatment with pembrolizumab.
The PD-L1 result will be masked to the site.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
Throughout this section, the term ‘scan’ refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, or other methods as specified in this protocol.
In addition to survival, efficacy will be assessed based on evaluation of scan changes in 
tumor burden over time, until the participant is discontinued from the study or goes into 
survival follow-up. The process for scan collection and transmission to the iCRO can be 
found in the SIM. Tumor scans by CT are strongly preferred. For the abdomen and pelvis, 
contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or 
when mandated by local practice. The same scan technique should be used in a participant 
throughout the study to optimize the reproducibility of the assessment of existing and new 
tumor burden and improve the accuracy of the response assessment based on scans.
Note: For the purposes of assessing tumor scans, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer at the site or at an offsite facility. 
Magnetic resonance imaging is preferred for brain scans; however, CT imaging with IV 
contrast will be acceptable, if MRI is medically contraindicated.
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Bone scans may be performed to evaluate bone metastases. Any supplemental scans 
performed to support a positive or negative bone scan, such as plain x-rays acquired for 
correlation, should also be submitted to the iCRO.
Other imaging modalities that may be collected, submitted to the iCRO, and included in the 
response assessment include PET-CT. Other types of medical imaging (such as ultrasound) 
should not be submitted to the iCRO and will not be included in response assessment.
All scheduled scans for participants will be submitted to the iCRO. In addition, a scan that is 
obtained at an unscheduled time point, for any reason (including suspicion of progression or 
other clinical reason), is also to be submitted to the iCRO if it shows disease progression, or 
if it is used to support a response assessment. All scans acquired within the protocol-
specified window of time around a scheduled scan visit are to be classified as pertaining to 
that visit.
Further details are provided in the SIM.
8.2.1.1
Initial Tumor Scans
The screening scans must be submitted to the iCRO for retrospective review.
Tumor scans performed as part of routine clinical management are acceptable for screening if 
they are of acceptable diagnostic quality and performed within 28 days of randomization and 
can be assessed by the iCRO.
Bone scans are required at Screening for participants with history of bone metastases or 
signs/symptoms suggestive of bone metastases. Bone scan refers to imaging methods used to 
assess bone metastasis. The specific methods permitted for this study are described in the 
SIM.
Brain scans are required for all participants at Screening. Participants with treated brain 
metastases (eg, whole brain radiation treatment, stereotactic radiosurgery, or equivalent) may 
participate only if they satisfy all of the following:
•
Have no evidence of new or enlarging brain metastases confirmed by posttreatment 
repeat brain imaging (using the same modality) performed at least 4 weeks after 
pretreatment brain imaging, and
•
Are neurologically stable without the need for steroids for at least 14 days before first 
dose of study treatment as per local site assessment. This exception does not include 
carcinomatous meningitis, as participants with carcinomatous meningitis are excluded 
regardless of clinical stability.
•
Have asymptomatic brain metastases (ie, no neurological symptoms, no requirements for 
corticosteroids, no or minimal surrounding edema, and no lesion >1.5 cm).
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8.2.1.2
Tumor Scans During the Study
The first on-study scan should be performed at 6 weeks (42 days ±7 days) from the date of 
randomization followed by Week 12 (84 days ±7 days) and Week 18 (126 days ±7 days) 
from the date of randomization. Subsequent tumor scans should be performed every 9 weeks 
(63 days ±7 days) or more frequently if clinically indicated. After 63 weeks (441 days ±7 
days), participants who remain on treatment will have scans performed every 12 weeks (84 
days ±7 days). Scan timing should follow calendar days and should not be adjusted for delays 
in cycle starts.
Scans are to be performed until disease progression is identified by the investigator and 
verified by the BICR, or until the start of new anticancer treatment, pregnancy, withdrawal of 
consent, or death, whichever occurs first.
Objective response should be confirmed by a repeat scan performed at least 4 weeks after the 
first indication of a response is observed. Participants will then return to the regular scan 
schedule, starting with the next scheduled time point. Participants who receive additional 
scans for confirmation do not need to undergo the next scheduled scan if it is fewer than 4 
weeks later; scans may resume at the subsequent scheduled time point.
On-study bone scans should be performed if clinically indicated or to confirm CR (if other 
lesions indicate CR and bone lesions existed at baseline).
For participants with brain metastases at Screening (whether treated or untreated), on-study 
brain scans are to be acquired at Week 6 and as clinically indicated. For participants with no
brain metastases at Screening, on-study brain scans are to be acquired only if clinically 
indicated. All participants with brain metastases at Screening require brain scans to confirm 
CR.
8.2.1.3
End-of-treatment and Follow-up Tumor Scans
If participants discontinue study intervention, tumor scans should be performed at the time of 
discontinuation (±4-week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to documented disease 
progression, this is the final required tumor scan.
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans using the same 
schedule calculated from the date of randomization (refer to Section 8.2.1.2).
Scans are to be continued until one of the following conditions are met:
•
disease progression as defined by RECIST 1.1 verified by BICR
•
the start of a new anticancer treatment
•
pregnancy
•
death
•
withdrawal of consent
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•
the end of the study
Follow-up visits may be scheduled to coincide with the scan schedule. If discontinuation is 
not due to BICR-verified disease progression, then tumor scans should continue on the initial 
treatment period schedule.
8.2.1.4
Second Course (Retreatment) Tumor Scans
Tumor scans must be performed within 28 days before restarting study intervention with 
MK-7684A or pembrolizumab.
If disease progression has been verified by BICR for the First Course, the Second Course 
may be initiated. The disease progression scan may be used as the Second Course baseline 
scan if performed within 4 weeks prior to dosing and meets scan standards.
The first scan should be performed at 12 weeks (84 day ±7 days) after restarting study 
intervention. Subsequent tumor scans are to be performed every 12 weeks (84 days ±7 days) 
or more frequently, if clinically indicated.
Scans are to be performed until:
•
disease progression,
•
the start of a new anticancer treatment,
•
pregnancy,
•
withdrawal of consent,
•
death,
•
completion of Second Course,
•
or notification by the Sponsor, whichever occurs first
Response assessments and PD in the Second Course are determined by site assessment only. 
No scans from the Second Course Phase should be provided to the central vendor, except for 
the Second Course Phase Screening scan if this scan is also the final scan for the initial 
treatment phase.
For participants who discontinue Second Course study intervention, tumor imaging is to be 
performed at the time of intervention discontinuation (±4-week window). If previous imaging 
was obtained within 4 weeks before the date of discontinuation, then imaging at intervention 
discontinuation is not mandatory. For participants who discontinue study intervention due to 
documented disease progression, this is the final required tumor imaging.
For participants who discontinue Second Course study intervention without documented 
disease progression, every effort should be made to continue monitoring their disease status 
by radiologic imaging every 12 weeks (84 days ±7 days) until either the start of a new 
anticancer treatment, disease progression, death, or the end of the study, whichever occurs 
first.
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8.2.1.5
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all protocol guidelines related to disease status (eg, 
discontinuation of study intervention). Although RECIST 1.1 references a maximum of 5 
target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions in 
total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
Upon investigator-assessed disease progression, the indicative scans are to be submitted 
immediately to iCRO for BICR verification of progression. After submission of scan(s), the 
iCRO will email the assessment to the site and Sponsor.
If disease progression is not verified, the process continues as follows:
•
If participant is clinically stable, continue study intervention per protocol
-
resume imaging per protocol schedule (≥4 weeks to next scan)
-
send scans to iCRO
-
continue local assessment
-
do not change investigator assessment of progression
-
if subsequent scan(s) indicate progression, submit scan(s) to iCRO to request 
verification
•
If the participant is not clinically stable, best medical practice is to be applied
Before stopping study intervention or imaging or starting new anticancer therapy in a 
participant who is clinically stable, communication with the Sponsor is required.
If disease progression is verified, the process continues as follows:
•
investigator judgment will determine action
•
if the participant is clinically stable and study intervention is to continue, communication 
with the Sponsor is required and a reconsent addendum must be signed
•
obtain scans locally per original protocol schedule
•
do not send scans to iCRO
Figure 3 illustrates the study intervention decision process involving verification of disease 
progression for participants.
•
For the purpose of this decision process, lack of clinical stability is defined as:
-
unacceptable toxicity
-
clinical signs or symptoms indicating clinically significant disease progression
-
decline in performance status
-
rapid disease progression or threat to vital organs or critical anatomical sites (eg, CNS 
metastasis, respiratory failure due to tumor compression, spinal cord compression) 
requiring urgent alternative medical intervention
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Figure 3
Imaging and Treatment for Clinically Stable Participants Treated With 
MK-7684A or Pembrolizumab After First Radiologic Evidence of PD Assessed by the 
Investigator
8.2.2
Patient-reported Outcomes
 
 
The questionnaires are to be administered before dosing at every cycle through 
Cycle 17, then every other cycle through Cycle 35 (eg, Cycles 1-17, 19, 21, 23, 25, 27, 29, 
31, 33, and 35), at the Treatment Discontinuation Visit, and at the 30-day Safety Follow-up 
Visit.
If the Treatment Discontinuation Visit occurs 30 days from the last dose of study 
intervention, at the time of the mandatory Safety Follow-up Visit, the ePROs do not need to 
be repeated.
It is best practice and strongly recommended that ePROs are administered to randomized 
participants before drug administration, AE evaluation, and disease status notification. If the 
participant does not complete the ePROs at a scheduled time point, the MISSMODE form 
must be completed to capture the reason the assessment was not performed.
8.2.3
PD-L1 Status
The results of PD-L1 status are required before randomization.
CCI
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Laboratory 
or Study Procedures Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. Height and weight 
will also be measured and recorded.
A brief directed physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 1.3. After the first 
dose of study intervention, new clinically significant abnormal findings should be recorded 
as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated prior to study intervention administration. New clinically significant abnormal 
findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
Vital signs will be recorded after 5 minutes of rest and include systolic and diastolic blood 
pressure, temperature, pulse, and respiration rate. Vital signs will be assessed at the visits 
designated in the SoA (Section 1.3) by a validated method.
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8.3.3
Electrocardiograms
A standard 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 pulse rate, QRS, and QT
intervals. Refer to Appendix 3 for evaluation and potentially significant findings.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
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 Laboratory or 
Study Procedures Manual. Refer to the Schedule of Activities (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.
8.3.5
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1. Refer 
to Appendix 7 for country-specific requirements.
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Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted for the time required to eliminate systemic exposure after the last dose of 
each study intervention(s) as noted in Section 5.1. The length of time required to 
continue pregnancy testing for each study intervention is as follows:
◦
MK-7684A/pembrolizumab: 120 days
◦
Chemotherapy: 180 days
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
8.3.6
Performance Assessments
8.3.6.1
Eastern Cooperative Oncology Group Performance Status
The ECOG PS is standardized criteria to measure how cancer impacts level of functioning 
(performance status) in terms of ability to care for oneself, daily activity, and physical ability 
(walking, working, etc.) with Grades 0 to 5.
The investigator or qualified designee will assess ECOG PS (see Appendix 8) at screening, 
before the administration of each dose of study intervention and during the follow-up period 
as specified in the SoA (Section 1.3).
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6 
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention randomization, must be reported by 
the investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event causes the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
•
All AEs from the time of intervention randomization through 30 days after cessation of 
study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention randomization through 
90 days after cessation of study intervention or 30 days after cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention 
randomization through the time required to eliminate systemic exposure after cessation of 
study intervention as described in Sections 5.1 and 8.3.5, or 30 days after cessation of 
study intervention if the participant initiates new anticancer therapy must be reported by 
the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside the 
time specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 11.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 11
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
NSAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE including 
Cancer and Overdose
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
– drug/vaccine 
related.
(Follow 
ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
– participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout,
or run-in treatment 
including placebo 
run-in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously 
reported – Follow 
to completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (requiring
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– requiring
regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
ECI (does not require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 
5 calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse event.
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. SAEs and other reportable safety events, including 
pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be followed 
until resolution, stabilization, until the event is otherwise explained, or the participant is lost 
to follow-up (as defined in Section 7.3). The investigator will also make every attempt to 
follow nonserious AEs that occur in randomized participants for outcome. Further 
information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Note: To meet EU CTR requirements, the Sponsor will report SUSARs to the Eudravigilance 
database via E2B(R3) electronic ICSR form in compliance with CTR 536/2014.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
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The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3× the ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2× the ULN and, at the same time, an alkaline phosphatase laboratory 
value that is less than 2× the ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
8.5
Treatment of Overdose
For this study, an overdose of MK-7684A will be defined as any dose exceeding 3 times or 
300% the prescribed dose. For pembrolizumab, an overdose will be defined as any dose 
1000 mg.
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No specific information is available on the treatment of overdose of pembrolizumab or 
MK-7684A. In the event of overdose, the participant should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated.
CCI
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8.10
Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency department visits must be reported in the eCRF,
from the time of treatment randomization through 90 days after cessation of study 
intervention, or 30 days after cessation of study intervention, if the participant initiates new 
anticancer therapy, whichever is earlier.
CCI
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Medical resource utilization and health economics data, associated with medical encounters, 
will be collected in the CRF by the investigator and study-site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to conduct exploratory economic analyses and will include:
•
Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient)
•
Duration of hospitalization (total days or length of stay, including duration by wards [eg, 
intensive care unit])
•
Number and type of diagnostic and therapeutic tests and procedures
•
Outpatient medical encounters and treatments (including physician or emergency 
department visits, tests and procedures, and medications).
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Documented informed consent must be provided before performing any protocol-specific 
procedure. Results of a test performed before the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame.
Screening procedures are to be completed within 28 days before the first dose of study 
intervention or sooner as indicated in the SoA (Section 1.3).
Participants may be rescreened one time after initially failing to meet the inclusion/exclusion 
criteria. Results from assessments during the initial screening period are acceptable in lieu of 
a repeat screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
8.11.2
Initial Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Sections 8.1, 8.2, and 8.3.
8.11.3
Second Course Treatment Period
See Sections 1.3.3 and 6.1.2 for details concerning Second Course Treatment.
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8.11.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Participants who discontinue study intervention due to BICR-verified disease progression or 
start of a new anticancer therapy will have Safety Follow-up and then proceed directly to 
survival follow-up Phase as described in Section 8.11.5.
The End of Treatment Visit is to occur at the time study intervention is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study intervention, at 
the time of the mandatory Safety Follow-up Visit, the Discontinuation Visit procedures and 
any additional Safety Follow-up procedures are to be performed.
8.11.5
Posttreatment Visit
At the end of study intervention, each participant will be followed for a minimum of 30 days 
for AE monitoring. Serious AEs occurring within 90 days after cessation of study 
intervention, or 30 days after cessation of study intervention if the participant initiates new 
anticancer therapy, whichever is earlier, will be collected.
Participants will have posttreatment follow-up for disease status, including radiographic 
imaging, until initiating a nonstudy anticancer treatment, experiencing BICR-verified disease 
progression, death, withdrawing consent, becoming lost to follow-up, or end of study.
All participants will be followed for OS until death, withdrawal of consent, or the end of the 
study.
8.11.5.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer treatment, whichever 
comes first.
Participants who are eligible for retreatment with MK-7684A or pembrolizumab may have 
up to 2 safety follow-up visits: 1 after the Initial Treatment or First Course and 1 after the 
Second Course.
8.11.5.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than BICR-verified disease progression will 
begin Efficacy Follow-up and are to be assessed using the same schedule calculated from the 
date of randomization. Imaging will continue to be collected in the Efficacy Follow-up Phase 
(see Section 8.2.1.3). Every effort should be made to collect information regarding disease 
status until BICR-verified disease progression, the start of new anticancer therapy, 
pregnancy, death, withdrawal of consent, or the end of the study. Information regarding 
poststudy anticancer treatment will be collected if new treatment is initiated. Participants 
who complete all efficacy assessments and/or will not have further efficacy assessments must 
enter survival follow-up.
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Participants who are eligible to receive retreatment with MK-7684A or pembrolizumab 
according to the criteria in Section 6 will move from Efficacy Follow-up to the Second
Course when they experience disease progression. Details are provided in the SoA (Section 
1.3) for retreatment with MK-7684A or pembrolizumab.
8.11.5.3
Survival Follow-up Contacts
Participant survival follow-up status will be assessed approximately every 12 weeks to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
The first survival follow-up assessment are to be scheduled as described below:
•
For participants who discontinue treatment intervention and who will not enter Efficacy 
Follow-up, the first survival follow-up contact will be scheduled 12 weeks after the 
Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).
•
For participants who complete assessments in Efficacy Follow-up, the first survival 
follow-up contact will be scheduled 12 weeks after the last efficacy assessment follow-up 
visit has been performed.
8.11.6
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an eDMC review, 
interim and/or final analysis. Upon Sponsor notification, all participants who do not/will not 
have a scheduled study visit or study contact during the Sponsor-defined period will be 
contacted for their vital status.
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9
STATISTICAL ANALYSIS PLAN
At implementation of Amendment 05 or upon receipt of investigator letter detailing 
discontinuation of the MK-7684A clinical program, the following changes apply. The 
changes listed below supersede any protocol content/instructions from previous amendments.
•
This study will be unblinded.
•
Participants receiving MK-7684A plus chemotherapy will be transitioned to 
pembrolizumab plus chemotherapy.
•
Pembrolizumab can be sourced locally or centrally.
•
Participants with access to approved SOC (eg, pembrolizumab plus chemotherapy) 
should be considered for discontinuation from the study. Those benefiting from 
pembrolizumab with chemotherapy, but unable to access it as SOC outside the study, 
may continue on study and receive treatment with pembrolizumab plus chemotherapy 
until discontinuation criteria are met. The final required study visit will be the Safety 
Follow-up Visit.
•
Imaging scans should no longer be submitted to iCRO nor read by BICR. However, for 
participants who are still on study treatment and deriving clinical benefit and will 
continue on study treatment until criteria for discontinuation are met, local tumor imaging 
should continue per local SOC schedule and local SOC method of assessment of imaging. 
All imaging as well as relevant objectives and endpoints will be assessed locally.
•
PK/ADA samples will no longer be collected.
•
Biomarker/FBR samples will no longer be collected.
•
ePROs will no longer be collected.
•
Second course treatment of pembrolizumab for participants currently not on second 
course treatment will be offered. Any participant already receiving Second Course 
treatment will be able to complete treatment as planned.
•
Treatment beyond progression will no longer be offered. Any participant already
receiving treatment beyond progression will be able to complete treatment as planned.
•
Participants who complete study treatment or otherwise meet EOT criteria will be 
discontinued from the study after the EOT visit and any required safety follow-up visit.
•
There will be no follow-up for survival status. Participants currently in imaging follow-
up or survival follow-up are considered to have completed the study and therefore should 
obtain imaging and further oncological care as per local SOC. However, standard safety 
reporting should continue, as applicable.
•
Those participants remaining on study at the time of Amendment 05 should continue to 
be monitored in the study through the AE reporting period (Section 8.4).
•
Assessments listed in the SoA will be done per local SOC.
•
Participants may enroll in an extension study, if available.
-
Participation in this study is ended when the participant is consented for an extension 
study.
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The overall study ends when the last participant completes the last study-related 
contact, withdraws consent, or is lost to follow-up (Section 7.3), or the last participant 
on active treatment is consented in an extension study
-
For participants who enter an extension study, all AEs, SAEs, and other reportable 
safety events must be reported by the investigator in this protocol (parent study) from 
the time of intervention randomization up to the time of providing documented 
informed consent for an extension study. Note: Once consented to an extension study, 
safety events, including those considered related to study intervention, will be 
collected as instructed in the extension study.
Existing protocol content is retained for historical reference.
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized will be documented in a sSAP and 
referenced in the CSR for the study.
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below. The comprehensive plan is provided in 
Section 9.2 through Section 9.12.
Study Design 
Overview
A Randomized, Double-Blind, Phase 3 Study of Pembrolizumab/Vibostolimab 
Coformulation (MK-7684A) in Combination with Chemotherapy Versus 
Pembrolizumab Plus Chemotherapy in Participants with Metastatic Non-Small 
Cell Lung Cancer (MK-7684A-007/KEYVIBE-007)
Treatment 
Assignment
Approximately 700 participants will be randomized in a 1:1 ratio between 
2 treatment arms: (1) MK-7684A plus chemotherapy and (2) pembrolizumab plus 
chemotherapy.
Analysis Populations
Efficacy: ITT
Safety: APaT
Primary Endpoints

OS in participants with PD-L1 TPS≥1%
CCI
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Secondary Endpoints

OS in all participants

PFS per RECIST 1.1 as assessed by BICR in participants with PD-L1 
TPS≥1% and all participants

ORR per RECIST 1.1 as assessed by BICR in participants with PD-L1 
TPS≥1% and all participants

DOR per RECIST 1.1 as assessed by BICR in participants with PD-L1 
TPS≥1% and all participants

Change from baseline in global health status/QoL, cough, chest pain, 
dyspnea, role functioning, and physical functioning scores in participants with 
PD-L1 TPS≥1% and all participants

TTD in global health status/QoL, cough, chest pain, dyspnea, role 
functioning, and physical functioning in participants with PD-L1 TPS≥1% 
and all participants

Safety and tolerability
Statistical Methods 
for Key Efficacy 
Analyses
The primary and key secondary hypotheses testing of OS in participants with PD-
L1 TPS≥1% and all participants, and PFS in all participants will be evaluated by 
comparing the MK-7684A plus chemotherapy treatment arm with the 
pembrolizumab plus chemotherapy treatment arm using a stratified log-rank test. 
The HR will be estimated using a stratified Cox regression model. Event rates 
over time will be estimated within each treatment group using the Kaplan-Meier 
method. 
Statistical Methods 
for Key Safety 
Analyses
For analyses in which 95% CIs will be provided for between-treatment differences 
in the percentage of participants with events, these analyses will be performed 
using the M&N method [Miettinen, O. and Nurminen, M. 1985].
Interim Analyses
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Multiplicity
The overall Type I error over the primary and key secondary hypotheses is 
strongly controlled at 2.5% (1-sided), 
 
 
 
 
[Lan, K. K. G. and 
DeMets, D. L. 1983] [O'Brien, P. C. and Fleming, T. R. 1979].
Sample Size and 
Power
 
articipants per treatment arm will be used for study planning 
purposes.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IRT.
An eDMC will serve as the primary reviewer of the results of the interim analysis of the 
study and will make recommendations for discontinuation of the study or protocol 
modifications to the study EOC. Treatment-level results of the interim analyses will be 
provided by the unblinded statistician to the eDMC. If the eDMC recommends modifications 
to the design of the protocol or discontinuation of the study, the EOC (and potentially other 
limited Sponsor personnel) may be unblinded to results at the treatment level to act on these 
recommendations. The extent to which individuals are unblinded with respect to results of 
interim analyses will be documented by the unblinded team. Additional logistical details will 
be provided in the eDMC charter. Key aspects of the interim analyses are described in 
Section 9.7.
Before final study unblinding, the unblinded statistician will not be involved in any 
discussions regarding modifications to the protocol or statistical methods, identification of 
protocol deviations, or data validation efforts.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are outlined in Section 3.
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9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below, followed by the 
descriptions of the derivations of selected endpoints.
9.4.1
Efficacy Endpoints
Primary Efficacy Endpoints
•
Overall Survival
OS is defined as the time from randomization to death due to any cause.
Secondary Efficacy Endpoints
•
Progression-free survival
PFS is defined as the time from randomization to the first documented disease 
progression per RECIST 1.1 by BICR or death due to any cause, whichever occurs 
first.
•
Objective Response Rate
The ORR is defined as the percentage of participants who achieve a confirmed CR or PR per 
RECIST 1.1 as assessed by BICR.
•
Duration of Response
For participants who demonstrate confirmed CR or PR, DOR is defined as the time from the 
first documented evidence of CR or PR until disease progression or death due to any cause, 
whichever occurs first.
9.4.2
Safety Endpoints
Safety and tolerability of study treatment will be assessed by clinical review of all relevant 
parameters including AEs, laboratory tests, and vital signs. AEs will be assessed as defined 
by NCI CTCAE 5.0. A description of safety measures is provided in Section 8.3.
9.4.3
Patient-reported Outcomes
The following secondary PRO endpoints will be evaluated as described in Section 4.2.1.3 
and analyzed as described in Section 9.6.3:
Change from baseline in
1. Global health status/QoL score (QLQ-C30 items 29-30)
2. Single-item symptom scores: cough (QLQ-LC13 item 31), chest pain (QLQ-LC13 item 
40), and dyspnea (QLQ-C30 item 8)
3. Functioning scores: physical functioning (QLQ-C30 items 1-5) and role functioning 
(QLQ-C30 items 6-7)
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Time to deterioration in
4. Global health status/QoL score (QLQ-C30 items 29-30)
5. Single-item symptom scores: cough (QLQ-LC13 item 31), chest pain (QLQ-LC13 item 
40), and dyspnea (QLQ-C30 item 8)
6. Functioning scores: physical functioning (QLQ-C30 items 1-5) and role functioning 
(QLQ-C30 items 6-7)
Based on prior literature [Osoba, D., et al 1998] [King, M. T. 1996], a 10-point or greater 
worsening from baseline for each scale represents a clinically relevant deterioration. TTD is 
defined as the time to the first onset of a 10-point or more (out of 100 points) deterioration 
from baseline in a given scale/subscale/item with confirmation at a subsequent visit of a 10-
point or more deterioration from baseline. If the first deterioration is at the last PRO 
assessment timepoint (in the current database lock), then no confirmation is required.
These analyses and other supportive PRO analyses will be described in the sSAP.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The ITT population will serve as the population for primary efficacy analysis. All 
randomized participants will be included in this population. Participants will be included in 
the treatment group to which they are randomized.
The analysis population for DOR consists of participants in the analysis population of OR 
who demonstrate confirmed CR or PR.
9.5.2
Safety Analysis Populations
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all randomized participants who received at least one dose of study 
treatment. Participants will be included in the treatment group corresponding to the study 
treatment they actually received for the analysis of safety data using the APaT population. 
For most participants this will be the treatment group to which they are randomized. 
Participants who take incorrect study treatment for the entire treatment period will be 
included in the treatment group corresponding to the study treatment actually received. Any 
participants who receive the incorrect study medication for one cycle but receives the correct 
treatment for all other cycles will be analyzed according to the participant’s randomized 
treatment group and a narrative will be provided for any events that occur during the cycle 
for which the participant was incorrectly dosed.
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At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
9.5.3
Patient-reported Outcome Analysis Population
The PRO analyses are based on the PRO FAS population, defined as all randomized 
participants who have at least one PRO assessment available for the specific endpoint and 
have received at least one dose of the study intervention. Participants will be analyzed in the 
treatment group to which they are randomized.
9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
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9.6.2
Statistical Methods for Safety Analyses
The primary safety analyses will include only events that occur prior to Second Course 
Treatment.
9.6.2.1
Overall Safety Assessment
The overall safety evaluation will include a summary by treatment group of the number and 
percentage of participants with at least one AE, a drug-related AE, a serious AE, a serious 
drug-related AE, a Grade 3-5 AE, a drug-related Grade 3-5 AE, a discontinuation from study 
intervention due to an AE, and an AE resulting in death. Point estimates and 95% CIs for the 
differences between treatment groups in the percentages of participants with the event will be 
provided based on the criteria described below. 
Point estimate and 95% CIs for the difference between treatment groups in the percentage of 
participants with specific AEs will be provided for AEs that occur in at least 10% of 
participants in any treatment group. The threshold of at least 10% of participants was chosen 
because the population enrolled in this study is in critical condition and usually experiences 
various AEs of similar types regardless of treatment; events reported less frequently than 
10% of participants would obscure the assessment of the overall safety profile and add little 
to the interpretation of potentially meaningful treatment differences. In addition, difference in 
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the percentage of participants with specific Grade 3 to 5 AEs (≥5% of participants in 1 of the 
treatment groups) and SAEs (≥5% of participants in 1 of the treatment groups) will also be 
summarized by point estimate and 95% CIs.
CIs for between treatment group differences will be provided using the M&N method 
[Miettinen, O. and Nurminen, M. 1985]. Because many 95% CIs may be provided without 
adjustment for multiplicity, the CIs should be regarded as a helpful descriptive measure to be 
used in safety review, not as a formal method for assessing the statistical significance of the 
between-group differences.
9.6.2.2
Assessment of Safety Topics of Special Interest
AEs that are immune-mediated or potentially immune-mediated will be evaluated separately. 
These events have been characterized consistently throughout the pembrolizumab clinical 
development program. Point estimates and 95% CIs for between-group difference is not 
expected to add value to the safety evaluation, and hence only number and percentage of 
participants with such pembrolizumab AEOSI will be provided, as well as the number and 
percentage of participants with corticosteroids administration to treat an AEOSI. Summary 
statistics will be provided for the analysis of time from first dose to the onset of an AEOSI.
Table 15 summarizes the analysis strategy for safety endpoints in this study.
Table 15
Analysis Strategy for Safety Endpoints
Analysis Part
Safety Endpoint
Descriptive Statistics
95% Between-group 
CI (Graphical 
Display)
Overall Safety 
Assessment
Specific AEs (incidence 10% of 
participants in one of the treatment 
groups)
X
X
Specific Grade 3-5 AE (incidence 
≥5% of participants in one of the 
treatment groups)
X
X
Specific serious AE (incidence ≥5% 
of participants in one of the treatment 
groups)
X
X
Any AE
X
Any Grade 3-5 AE
X
Any serious AE 
X
Any drug-related AE
X
Any serious and drug-related AE
X
Any Grade 3-5 and drug-related AE
X
Discontinuation study treatment due to 
AE
X
AE that resulted in death
X
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Analysis Part
Safety Endpoint
Descriptive Statistics
95% Between-group 
CI (Graphical 
Display)
AE that led to dose interruption
X
AE that led to dose reduction
X
Specific AEs, system organ classes
(incidence <10% of participants in all 
of the treatment groups)
X
Change from Baseline Results 
(laboratory toxicity shift, vital signs)
X
Assessment of 
safety topics of 
special interest
Pembrolizumab AEOSI
X
Abbreviations: AE=adverse event; AEOSI=adverse event of special interest; CI=confidence interval.
9.6.3
Statistical Methods for Patient-reported Outcome Analyses
This section describes the planned analyses for the PRO endpoints.
Change from Baseline
The time point for the change from baseline will be determined based on blinded data review 
prior to the database lock for any PRO analysis and documented in the sSAP.
To assess the treatment effects on the PRO score change from baseline in the PRO endpoint 
(global health status/QoL, physical functioning, role functioning, dyspnea, cough, chest pain) 
defined in Section 9.4.3, a constrained longitudinal data analysis model proposed by Liang 
and Zeger [Liang, K-Y. and Zeger, S. L. 2000] will be applied, with the PRO score as the 
response variable, and treatment, time, the treatment by time interaction, and stratification 
factors used for randomization (see Section 6.3.2) as covariates. The treatment difference in 
terms of LS mean change from baseline will be estimated from this model together with 95% 
CI. Model-based LS mean with 95% CI will be provided by treatment group for PRO scores 
at baseline and postbaseline time point.
Time to Deterioration
For the TTD endpoint defined in Section 9.4.3, the Kaplan-Meier method will be used to 
estimate the TTD curve for each treatment group. The estimate of median TTD and its 95% 
CI will be obtained from the Kaplan-Meier estimates. The treatment difference in TTD will 
be assessed by the stratified log-rank test. A stratified Cox proportional hazard model with 
Efron’s method of tie handling and with a single treatment covariate will be used to assess 
the magnitude of the treatment difference (ie, HR). The HR and its 95% CI will be reported. 
The same stratification factors used for randomization (see Section 6.3.2) will be used as the 
stratification factors in both the stratified log-rank test and the stratified Cox model. Table 16
provides censoring rule for TTD analysis.
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Table 16
Censoring Rules for Time-to-Deterioration
Scenario
Outcome
Deterioration confirmed
Event observed at time of assessment
(first deterioration)
Ongoing or discontinued from study without confirmed 
deterioration
If the first deterioration is at the last assessment timepoint, 
then event observed at time of assessment (first 
deterioration); otherwise, right censored at time of last 
assessment
No baseline assessments
Right censored at treatment start date
9.6.4
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables, baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables.
9.7
Interim Analyses
The eDMC will serve as the primary reviewer of the results of the interim analysis and will 
make recommendations for discontinuation of the study or modification to the EOC of the 
Sponsor. If the eDMC recommends modifications to the design of the protocol or 
discontinuation of the study, this EOC and potentially other limited Sponsor personnel may 
be unblinded to the treatment-level results in order to act on these recommendations. The 
extent to which individuals are unblinded with respect to results of interim analyses will be 
documented by the unblinded team. Additional logistic details will be provided in the eDMC 
Charter.
Treatment-level results of the interim analyses will be provided by the unblinded statistician 
to the eDMC. Prior to final study unblinding, the unblinded statistician will not be involved 
in any discussions regarding modifications to the protocol or statistical methods, 
identification of protocol deviations, or data validation efforts after the interim analyses.
9.7.1
Efficacy Interim Analyses
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9.7.2
Safety Interim Analyses
The eDMC will conduct regular safety monitoring. The timing of the safety monitoring will 
be specified in the eDMC charter.
 
 
9.8
Multiplicity
The study uses the graphical method of Maurer and Bretz [Maurer, W., et al 2011] to provide 
strong multiplicity control for multiple hypotheses as well as interim analyses. According to 
this approach, study hypotheses may be tested more than once, and when a particular null 
hypothesis is rejected, the α allocated to that hypothesis can be reallocated to other 
hypothesis tests.
 
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9.8.1
Progression-free Survival
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9.8.2
Overall Survival
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9.8.3
Safety Analyses
The DMC has responsibility for assessment of overall risk/benefit. When prompted by safety 
concerns, the DMC can request corresponding efficacy data. DMC review of efficacy data to 
assess the overall risk/benefit to study participants will not require a multiplicity adjustment 
typically associated with a planned efficacy interim analysis. However, to account for any 
multiplicity concerns raised by the DMC review of unplanned efficacy data prompted by 
safety concerns, a sensitivity analysis for ORR, PFS, and OS adopting a conservative 
multiplicity adjustment will be prespecified in the sSAP.
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9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
Extent of exposure for a participant is defined as the number of cycles in which the 
participant receives the study intervention. Summary statistics will be provided on the extent 
of exposure for the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, conducting, analyzing, 
and reporting these trials in compliance with the highest ethical and scientific 
standards. Protection of participants in clinical trials is the overriding concern in the 
design and conduct of clinical trials. In all cases, MSD clinical trials will be 
conducted in compliance with MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), Regulation 
(EU) 536/2014, the International Council for Harmonisation Good Clinical Practice 
(ICH GCP) E6 and ICH General Considerations for Clinical Studies E8, and in 
accordance with the ethical principles that have their origin in the Declaration of 
Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (e.g., contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy, and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial and shall respect the data 
protection rights of all participants, trial site staff and, where applicable, third 
parties. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
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healthcare providers to ensure operational feasibility. Trial design also includes 
proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. All trial protocols are and will be assessed for the 
need and capability to enroll underrepresented groups. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the 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.
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MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III.Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations and ICH Guidelines. Changes to the protocol that are required 
urgently to eliminate an immediate hazard and to protect participant safety may be 
enacted in anticipation of ethics committee approval. MSD will inform regulatory 
authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. Participants may 
withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on medical record review and medical evaluation 
to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the 
trial protocol, and in signing the protocol, agree to support these ethical and scientific 
standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
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financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that their 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 their 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.
The Sponsor has EU-approved Binding Corporate Rules since 2017, covering all aspects of 
its Global Privacy Program (Corporate Policy 20), and is self-certified pursuant to the EU-US 
Data Privacy Framework.
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 
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process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules, 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7) and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.4.2
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
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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 ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, https://euclinicaltrials.eu, or other local registries. MSD, as 
Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. MSD entries are not limited to FDAAA or the EMA clinical trials 
Regulation 536/2014 mandated trials. Information posted will allow participants to identify 
potentially appropriate studies for their disease conditions and pursue participation by calling 
a central contact number for further information on appropriate study locations and study-site 
contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials Regulation 536/2014, or other locally mandated registries 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
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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.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol, which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
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study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period 
(eg, EU CTR: 25 years after the end of the study). No records may be destroyed during the
retention period without the written approval of the Sponsor. No records may be transferred 
to another location or party without written notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 22 will be performed by the local laboratory.
•
All on-treatment samples will be collected before administration of study intervention.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and 5.2, respectively.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 22
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCVa
MCHa
Reticulocytesa
WBC count with 
Differentialb:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUNc
Potassium
AST/SGOT
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
above the ULN)
Albumin
Bicarbonatea
Chloride
Phosphorousa
Creatinine or 
creatinine 
clearanced
Sodium
ALT/SGPT
Total Protein
Glucose 
(nonfasting)
Calcium
Alkaline 
phosphatase
TSHe
Free thyroxine 
(FT4)e
Lactate 
dehydrogenase 
(LDH)
Amylase
Lipase
Triiodothyronine 
(Total T3)e
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterasef
by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
FSH (as needed in women of nonchildbearing potential only)
Serum or urine β-hCG pregnancy test (as needed for WOCBP)
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody) as required by local health authority or institutional regulations.
Coagulation factors (PT or INR, and aPTT/PTT). Additional testing to be conducted as 
clinically indicated for participants taking anticoagulation therapy.
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Laboratory 
Assessments
Parameters
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-stimulating 
hormone; GFR=glomerular filtration rate; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; 
MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; SGOT=serum glutamic 
oxaloacetic transaminase; SGPT=serum glutamic pyruvic transaminase; SOC=standard of care; ULN=upper limit of 
normal; WBC=white blood count; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing 
potential
Notes:
a.
Performed only if considered local SOC.
b. Absolute or % acceptable per institutional standard.
c.
If BUN is not available, urea may be tested.
d. GFR (measured or calculated) or creatinine clearance can be used in place of creatinine.
e.
Participants may be dosed in subsequent cycles after C1D1 while thyroid function tests are pending. Free T3 and 
free T4 are acceptable.
f.
Leukocyte esterase testing is optional if it is not the local SOC
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Refer to Appendix 7 for country-specific requirements.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
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•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
Any new cancer (that is not a condition of the study). Progression of the cancer under study 
is not a reportable event. Refer to Section 8.4.6 for additional details.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
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d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
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 the cancer under study) as noted in Section 8.4.1.
•
Is associated with an overdose.
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
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•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
- Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
- Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
- Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
- Grade 4: Life-threatening consequences; urgent intervention indicated.
- Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
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•
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 
(diary, etc.), seroconversion or identification of vaccine virus 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?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Dechallenge: was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
-
(Note: This criterion is not applicable if: (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of the 
Sponsor’s product; (3) the study is a single-dose drug study; or (4) Sponsor’s 
product(s) is/are only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the 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, 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 their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a 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.)
The investigator must review and provide an assessment of causality for each AE/SAE and 
document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
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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.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with 2 FSH 
measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb
•
IUSc
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner 
of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c
IUS is a progestin releasing IUD.
See Appendix 7 for country-specific requirements.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Argentina-specific Requirements
Section 1.3 Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
Pregnancy testing must be performed at each cycle during treatment as well as at the end of 
study intervention.
CCI
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10.7.3
France-specific Requirements
Section 1.3.1 Screening and Intervention Phase
Audiogram to be completed at screening and at the beginning of each cycle for participants 
taking cisplatin.
Monthly and end-of-treatment pregnancy testing must be conducted as per local regulations.
Section 1.3.3 End-of-intervention and Long-term Follow-up
Monthly and end-of-treatment pregnancy testing must be conducted as per local regulations.
Section 5.2 Exclusion Criteria
•
Participants who have a known history of HIV infection. HIV testing is required for 
participants.
•
Participants who have a known history of hepatitis B or C infection. Hepatitis B and C 
testing is required for participants.
Carboplatin / Paclitaxel only:
a.
Participants who experience hemorrhage from tumor
b. Participants who use phenytoin or fosphenytoin
Cisplatin / Pemetrexed only:
a.
Participants with a hearing impairment
b. Participants with pathologies that are a contraindication to hyperhydration before 
chemotherapy administration
c.
Participants who are unable to tolerate use of phenytoin
Section 6.5 Concomitant Therapy
Investigators must refer to the up-to-date SmPC of registered products used in this study, 
regarding forbidden medications or medications to be used with precaution.
Section 6.6.1 Immune-Related Events and Dose Modification (Withhold, Treat, Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab Monotherapy, Coformulations (MK-7684A) or IO Combinations
CCI
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Participants are to be discontinued from study intervention if any of the following AEs occur:
•
Grade 4 skin rash
•
Stevens-Johnson syndrome
•
Toxic epidermal necrolysis
Section 8.3.5 Pregnancy Testing
•
Monthly and end-of-treatment pregnancy testing must be conducted as per local 
regulations.
Section 10.5 Appendix 5: Contraceptive Guidance
Monthly and end-of-treatment pregnancy testing must be conducted as per local regulations.
10.7.4
Germany-specific Requirements
Section 1.3 Schedule of Activities
Monthly urine pregnancy testing is required during study intervention as well as at the end of 
study intervention.
Section 5.2 Exclusion Criteria
Exclusion Criterion: Participant has a known history of human immunodeficiency virus 
(HIV) infection. HIV testing is required for participants.
Exclusion Criterion: hepatitis B and C testing is required for participants.
Section 6.5.1 Rescue Medications and Supportive Care
Live vaccines must not be administered for 90 days after the last dose of study intervention.
Legally Acceptable Representative Protocol Sections
In order for a participant to be eligible to participate in Germany, they must be capable of 
providing documented informed consent; therefore, all references to a participant’s “legally 
acceptable representative” in the protocol are not applicable for participants in Germany.
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10.7.5
Japan-specific Requirements
Section 1.3 Schedule of Activities
For the assistance to early diagnosis of pneumonitis/interstitial lung disease in study 
participants, the following items, such as SpO2, CRP, KL-6, and SP-D, will be measured in 
this study. These items should be measured as follows:
•
SpO2 at the timing of vital sign assessment.
•
CRP, KL-6, and SP-D at screening*, predose on Day 1 of every cycle, EOT, and the 
Safety Follow-up Visit (30 days after last dose).
*Should be measured at the timing of clinical laboratory tests (such as 
hematology/chemistry).
If pneumonitis/ILD occurs, regardless of causality with study intervention, an independent 
ILD evaluation committee will conduct adjudication of cases of the pneumonitis/ILD. For 
this purpose, relevant data, such as chest imaging (from the baseline to the recovery of 
pneumonitis/ILD) will be submitted to MSD K.K.
Section 6.1 Study Intervention(s) Administered
Table 5 Study Interventions
Pembrolizumab used in this study is categorized as “product(s) used in the clinical trial other 
than test product(s)” in Japan local regulation.
10.7.6
Spain-specific Requirements
Section 1.3.1 Screening and Intervention Phase
Monthly and end-of-treatment pregnancy testing must be conducted as per local regulations.
HBV, HCV, and HIV testing at screening is mandatory.
Tuberculosis (TB; Bacillus tuberculosis) testing at screening is a required evaluation for 
study entry and needs to be performed to evaluate eligibility. This testing can be performed at 
any time during the screening period.
Section 1.3.3 End-of-intervention and Long-term Follow-up
Monthly and end-of-treatment pregnancy testing must be conducted as per local regulations.
Section 5.2 Exclusion Criteria
Has a known history of HIV infection. HIV testing is required at screening as mandated by 
local regulation.
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Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) 
or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. 
Testing for Hepatitis B and Hepatitis C is required at screening.
Has known active tuberculosis (TB; Bacillus tuberculosis). Testing for tuberculosis is 
required at screening.
Section 6.5 Concomitant Therapy
Investigators must refer to the up-to-date SmPC of registered products used in this study, 
regarding forbidden medications or medications to be used with precaution.
Live vaccines must not be administered for 90 days after the last dose of study intervention.
Section 8.3.5 Pregnancy Testing
Monthly and end-of-treatment pregnancy testing must be conducted as per local regulations.
Section 10.2 Appendix 2: Clinical Laboratory Tests
Other screening tests: serology (HIV-RNA, hepatitis B surface antigen, hepatitis C virus 
antibody, and tuberculosis), amylase, lipase.
Section 10.5 Appendix 5: Contraceptive Guidance
Monthly and end-of-treatment pregnancy testing must be conducted as per local regulations.
10.7.7
United Kingdom-specific Requirements
Section 5.1 Inclusion Criteria – Demographics
Males are to be advised to seek counseling on sperm storage before starting treatment with 
pemetrexed, taxane (paclitaxel/nab-paclitaxel), and/or platinum-based therapy as per 
respective SmPCs.
If male, agrees to the following during the intervention period and for at least the time 
required to continue contraception for each study intervention is as follows:
•
Chemotherapy: at least 6 months from the last dose
•
Refrain from donating sperm
PLUS:
•
Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on 
a long-term and persistent basis) and agrees to remain abstinent
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Section 6.5 Concomitant Therapy
Listed below are specific concomitant therapies or vaccinations that are prohibited during the 
study (exceptions noted):
•
Live vaccines must not be administered for 90 days after the last dose of study 
intervention. Refer to Section 6.5 for information on COVID-19 vaccines.
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10.8
Appendix 8: ECOG Performance Status
Grade
Performance Status
0
Normal activity. Fully active, able to carry on all predisease performance without 
restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (eg, light housework, office 
work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry 
out any work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair.
5
Dead 
[ECOG ACRIN Cancer Research Group 2016]
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
5-HT3
5-hydroxytryptamine type 3
ADA
antidrug antibodies
AE
adverse event 
AEOSI
adverse event of special interest
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the curve
BICR
blinded independent central review
BID
twice daily
CD
cluster of differentiation
CI
confidence interval
Cmax
maximum plasma concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease 2019
CR
complete response
CrCl
creatinine clearance
CRF
Case Report Form 
CSF
colony-stimulating factor
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor deoxyribonucleic acid
CTFG
Clinical Trial Facilitation Group 
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Abbreviation
Expanded Term
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
Ctrough
minimum concentration
CYP
cytochrome P450
DCR
disease control rate
DL
dose level
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DILI
drug-induced liver injury
DOR
duration of response
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
EEA
European Economic Area
EGFR
endothelial growth factor receptor
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EORTC
European Organisation for Research and Treatment of Cancer
EORTC 
QLQ-C30
European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire C30
EORTC 
QLQ-LC13
European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire Lung Cancer 13
EOT
end of treatment
ePROs
electronic patient-reported outcomes
EU CTR
European Union Clinical Trial Regulation
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
FA
final analysis
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Abbreviation
Expanded Term
FAS
Full Analysis Set
FBR
future biomedical research
FcR
Fc gamma receptor
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed, paraffin embedded
FoxP3
forkhead box P3
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice 
H
hypothesis
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HGRAC
Human Genetic resources Administration of China
HIV
human immunodeficiency virus
HR
hazard ratio
HRQoL
health-related quality of life
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
ICSR
individual Case Safety Report
iCRO
imaging Clinical Research Organization
ID
identification
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG
immunoglobulin G
IHC
immunohistochemistry
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Abbreviation
Expanded Term
ILD
interstitial lung disease
IM
intramuscular
IMP
investigational medicinal product
IND
Investigational New Drug 
IO
immune-oncology
irAEs
immune-related AEs
IRB
Institutional Review Board
IRT
intervention randomization system
ITT
Intent-to-Treat
IUD
intrauterine device
IUO
Investigational Use Only
IUS
intrauterine hormone-releasing system
IV
intravenous
JAPIC-CT
Japan Pharmaceutical Information Center – Clinical Trials
KRAS
Kirsten rat sarcoma viral oncogene homolog
LAM
lactational amenorrhea method
LS
least squares
mAb
monoclonal antibody
MASCC
Multinational Association of Supportive Care in Cancer
M&N
Miettinen and Nurminen
MM
multiple myeloma
mPD-1
murine programmed cell death 1 protein
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose 
NCI
National Cancer Institute
NE
not evaluable
NHL
non-Hodgkin lymphoma
NK
natural killer
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Abbreviation
Expanded Term
NKT
natural killer T
N/n
number
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non–small cell lung cancer
NSCLC-SAQ
Non-small Cell Lung Cancer Symptom Assessment Questionnaire
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PBPK
physiologically-based PK
PD
progressive disease
PD-1
programmed cell death 1 protein
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PFS
progression-free survival
PMDA
Pharmaceuticals and Medical Device Agency
PK
pharmacokinetic
PO
orally
PR
partial response
PRO
patient-reported outcome
PS
performance status
PT
prothrombin time
PTT
partial thromboplastin time
PVR
poliovirus receptor
PVRIG
poliovirus receptor-related immunoglobulin
PVRL-2
poliovirus receptor-related 2
Q2W
every 2 weeks
Q3W
every 3 weeks
QLQ
quality of life questionnaire
QoL
quality of life
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Abbreviation
Expanded Term
RBC
red blood cell
RECIST
Response Evaluation Criteria In Solid Tumors
RMST
restricted mean survival time
RNA
ribonucleic acid
ROS1
c-ros oncogene 1
RP2D
recommended Phase 2 dose
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SCLC
small cell lung cancer
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SIM
Site Imaging Manual
SLAB
supplemental laboratory test(s)
SmPC
Summary of Product Characteristics
SNP
single nucleotide polymorphism
SoA
schedule of activities
SOC
standard of care
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
TB
Tuberculosis
TIGIT
T-cell immunoreceptor with Ig and ITIM domains
TIL
tumor-infiltrating lymphocyte(s)
Tim-3
T-cell immunoglobulin and mucin domain-containing-3
TPS
tumor proportion score
T-regs
regulatory T cells
TTD
time to deterioration
ULN
upper limit of normal
US
United States
VAS
Visual Analog Scale
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Abbreviation
Expanded Term
vs
versus
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of nonchildbearing potential
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11
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