A Phase 3, Multicenter, Randomized, Double-Blind Study of MK-7684 With Pembrolizumab as a Coformulation (MK-7684A) Versus Pembrolizumab Monotherapy as First Line Treatment for Participants With PD-L1 Positive Metastatic Non-Small Cell Lung Cancer
Phase: PHASE3
Conditions: Lung Neoplasms, Non-Small-Cell Lung Carcinoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase 3, Multicenter, Randomized, Double-Blind 
Study of MK-7684 with Pembrolizumab as a 
Coformulation (MK-7684A) Versus Pembrolizumab 
Monotherapy as First Line Treatment for Participants 
With PD-L1 Positive Metastatic Non-Small Cell Lung 
Cancer (KEYVIBE-003)
NCT04738487
29-JAN-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 Phase 3, Multicenter, Randomized, Double-Blind Study of MK-7684 with 
Pembrolizumab as a Coformulation (MK-7684A) Versus Pembrolizumab Monotherapy as 
First Line Treatment for Participants With PD-L1 Positive Metastatic Non-Small Cell Lung 
Cancer (KEYVIBE-003)
Protocol Number: 003-06
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
NCT04738487
EU CT
2023-505362-28
EudraCT
2020-004049-35
JRCT
2021210025
WHO
NA
UTN
U1111-1291-5552
IND
147424
Approval Date: 29 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 06
29-JAN-2025
The Sponsor has decided to discontinue treatment 
with MK-7684A because the study did not meet 
the prespecified criteria for OS and based on lack 
of efficacy observed in other studies.
Amendment 05
11-OCT-2024
To update the primary endpoint to OS only and to 
change PFS to a powered secondary endpoint 
based on external study data.
Amendment 04
08-NOV-2022
Merck Sharp & Dohme Corp. underwent an 
entity name and address change to Merck Sharp 
& Dohme LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity name change 
and update to the address. Other minor updates 
were also made during this amendment.
Amendment 03
21-MAR-2022
To increase the sample size and revise the 
statistical analysis plan to include primary 
hypotheses testing for OS and PFS in participants 
with PD-L1 TPS ≥50%.
Amendment 02
16-APR-2021
This amendment is specific to Japan to address 
recommendations from Japan’s regulatory 
authority regarding inclusion and exclusion 
criteria.
Amendment 01
28-FEB-2021
The Dose Modification and Toxicity 
Management Guidelines for irAEs and table were 
updated to align with the USPI as requested by 
the FDA.
Original Protocol
19-OCT-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 06
Overall Rationale for the Amendment:
The Sponsor has decided to discontinue treatment with MK-7684A because the study did not 
meet the prespecified criteria for OS and 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 because the 
study did not meet the prespecified 
criteria for OS and 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
Added pembrolizumab row to the study interventions 
table for all participants.
Refer to rationale for Section 1 for the 
discontinuation of the MK7684A clinical 
program.
Section 4, Study 
Design
Section 6, Study 
Intervention
Section 7, 
Discontinuation 
of Study 
Intervention and 
Participant 
Withdrawal
Section 8, Study 
Assessments and 
Procedures
Section 9, Key 
Statistical 
Considerations
•
This study is closed to enrollment. This study has 
enrolled 1264 participants.
•
This study will be unblinded.
•
The estimated duration of study was updated 
from 6 years to 5 years.
•
Participants receiving MK-7684A will be 
transitioned to pembrolizumab.
•
Pembrolizumab can be sourced locally or 
centrally.
•
Participants with access to approved SOC (eg, 
immunotherapy, chemotherapy, targeted therapy, 
as monotherapy or in combination) should be 
considered for discontinuation from the study. 
Those benefiting from pembrolizumab with, but 
unable to access it as SOC outside the study, may 
continue on study and receive treatment with 
pembrolizumab until discontinuation criteria are 
met. The final required study visit will be the 
Safety Follow-up Visit.
Refer to rationale for Section 1 for the 
discontinuation of the MK7684A clinical 
program.
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Section Number 
and Name
Description of Change
Brief Rationale
•
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 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.
•
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.
•
The futility interim analysis (IA1) was 
conducted. The pre-specified efficacy interim 
analysis (IA2) and final analysis outlined in the 
SAP will not be conducted.
•
Selected analyses of safety and endpoints will be 
performed at the end of the study.
•
There will be no follow-up for survival status. 
Participants currently in imaging follow up 
should obtain imaging and further oncological 
care as per local standard of care. However, 
standard safety reporting should continue, as 
applicable.
•
Those participants remaining on study at the time 
of Amendment 06 should continue to be 
monitored in the study through the AE reporting 
period (Section 8.4).
•
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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Section Number 
and Name
Description of Change
Brief Rationale
-
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 4: added pembrolizumab row for all 
participants.
Refer to rationale for Section 1 for the 
discontinuation of the MK7684A clinical 
program.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................22
1.2.1
Initial Treatment Phase ................................................................................22
1.2.2
Second Treatment Course............................................................................23
1.3
Schedule of Activities...........................................................................................24
1.3.1
Initial Treatment Phase ................................................................................24
1.3.2
Second Course Treatment Phase..................................................................29
2
INTRODUCTION..........................................................................................................32
2.1
Study Rationale....................................................................................................32
2.2
Background ..........................................................................................................34
2.2.1
Pharmaceutical and Therapeutic Background .............................................34
2.2.1.1
MK-7684 Background .......................................................................34
2.2.1.2
Pembrolizumab Background..............................................................35
2.2.2
Preclinical and Clinical Studies ...................................................................35
2.2.2.1
MK-7684 Preclinical Studies.............................................................35
2.2.2.2
Pembrolizumab Preclinical and Clinical Trials .................................38
2.2.3
Ongoing Clinical Studies.............................................................................38
2.2.3.1
MK-7684 Ongoing Clinical Trials.....................................................38
2.2.3.2
Pembrolizumab Ongoing Clinical Trials ...........................................40
2.3
Benefit/Risk Assessment......................................................................................40
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................41
4
STUDY DESIGN............................................................................................................45
4.1
Overall Design......................................................................................................46
4.2
Scientific Rationale for Study Design.................................................................47
4.2.1
Rationale for Endpoints ...............................................................................47
4.2.1.1
Efficacy Endpoints.............................................................................47
4.2.1.2
Safety Endpoints................................................................................49
...................49
...................49
...................49
...................50
...................50
...................50
...................52
CCI
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4.3
Justification for Dose...........................................................................................52
4.3.1
MK-7684A...................................................................................................52
4.3.2
Pembrolizumab ............................................................................................53
4.3.3
Maximum Dose Exposure for This Study ...................................................53
4.4
Beginning and End-of-Study Definition ............................................................54
4.4.1
Clinical Criteria for Early Study Termination .............................................54
5
STUDY POPULATION ................................................................................................55
5.1
Inclusion Criteria.................................................................................................55
5.2
Exclusion Criteria................................................................................................58
5.3
Lifestyle Considerations......................................................................................60
5.3.1
Meals and Dietary Restrictions....................................................................60
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................60
5.3.3
Activity Restrictions ....................................................................................60
5.4
Screen Failures.....................................................................................................60
5.5
Participant Replacement Strategy......................................................................61
6
STUDY INTERVENTION............................................................................................62
6.1
Study Intervention(s) Administered...................................................................63
6.2
Preparation/Handling/Storage/Accountability .................................................65
6.2.1
Dose Preparation..........................................................................................65
6.2.2
Handling, Storage, and Accountability........................................................65
6.3
Measures to Minimize Bias: Randomization and Blinding..............................66
6.3.1
Intervention Assignment..............................................................................66
6.3.2
Stratification.................................................................................................66
6.3.3
Blinding........................................................................................................66
6.4
Study Intervention Compliance..........................................................................66
6.5
Concomitant Therapy..........................................................................................67
6.5.1
Rescue Medications and Supportive Care ...................................................68
6.6
Dose Modification (Escalation/Titration/Other)...............................................68
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................68
6.6.2
Initial Treatment or First Course..................................................................75
6.6.3
Second Course .............................................................................................76
6.7
Intervention After the End of the Study............................................................76
6.8
Clinical Supplies Disclosure................................................................................76
6.9
Standard Policies..................................................................................................76
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................77
7.1
Discontinuation of Study Intervention...............................................................78
7.2
Participant Withdrawal From the Study...........................................................79
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7.3
Lost to Follow-up .................................................................................................80
8
STUDY ASSESSMENTS AND PROCEDURES........................................................81
8.1
Administrative and General Procedures ...........................................................83
8.1.1
Informed Consent.........................................................................................83
8.1.1.1
General Informed Consent.................................................................83
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................84
8.1.2
Inclusion/Exclusion Criteria ........................................................................84
8.1.3
Participant Identification Card.....................................................................84
8.1.4
Medical History ...........................................................................................84
8.1.5
Prior and Concomitant Medications Review...............................................84
8.1.5.1
Prior Medications...............................................................................84
8.1.5.2
Concomitant Medications..................................................................85
8.1.6
Assignment of Screening Number...............................................................85
8.1.6.1
Treatment Eligibility Assessment Survey..........................................85
8.1.7
Assignment of Treatment/Randomization Number.....................................85
8.1.8
Study Intervention Administration ..............................................................86
8.1.8.1
Timing of Dose Administration.........................................................86
8.1.9
Discontinuation and Withdrawal .................................................................86
8.1.9.1
Withdrawal From Future Biomedical Research ................................86
8.1.10
Participant Blinding/Unblinding..................................................................87
8.1.11
Calibration of Equipment.............................................................................87
8.1.12
Tumor Tissue for Biomarker Status.............................................................88
8.2
Efficacy/Immunogenicity Assessments ..............................................................88
8.2.1
Tumor Imaging and Assessment of Disease................................................88
8.2.1.1
Initial Tumor Imaging........................................................................89
8.2.1.2
Tumor Imaging During the Study......................................................89
8.2.1.3
End-of-treatment and Follow-up Tumor Scans .................................90
8.2.1.4
Second Course (Retreatment) Tumor Imaging..................................90
8.2.1.5
RECIST 1.1 Assessment of Disease..................................................91
8.2.2
Quality-of-Life Assessments .......................................................................93
8.2.2.1
Patient-reported Outcomes.................................................................93
8.3
Safety Assessments...............................................................................................93
8.3.1
Physical Examinations.................................................................................94
8.3.1.1
Full Physical Examination.................................................................94
8.3.1.2
Directed Physical Examination..........................................................94
8.3.2
Vital Signs....................................................................................................94
8.3.3
Electrocardiograms ......................................................................................94
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8.3.4
Clinical Safety Laboratory Assessments .....................................................95
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)..........................................................................................95
8.3.5
Pregnancy Testing........................................................................................95
8.3.6
Eastern Cooperative Oncology Group Performance Status.........................96
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................96
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................96
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......99
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...99
8.4.4
Regulatory Reporting Requirements for SAE .............................................99
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................100
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................100
8.4.7
Events of Clinical Interest..........................................................................100
8.5
Treatment of Overdose......................................................................................101
8.6
Pharmacokinetics...............................................................................................101
8.6.1
Blood Collection for Serum MK-7684 and Pembrolizumab.....................101
8.6.1.1
Blood Collection for PK ..................................................................101
8.6.1.2
Blood Collection for Antidrug Antibodies ......................................101
8.7
Pharmacodynamics............................................................................................101
8.8
Biomarkers .........................................................................................................102
8.8.1
Planned Genetic Analysis Sample Collection............................................102
8.9
Future Biomedical Research Sample Collection.............................................102
8.10
Medical Resource Utilization and Health Economics.....................................102
8.11
Visit Requirements.............................................................................................103
8.11.1
Screening....................................................................................................103
8.11.2
Initial Treatment Period .............................................................................103
8.11.3
Second Course Treatment Phase................................................................103
8.11.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ..............................................................................104
8.11.5
Posttreatment Visit.....................................................................................104
8.11.5.1
Safety Follow-up Visit.....................................................................104
8.11.5.2
Efficacy Follow-up Visits................................................................104
8.11.5.3
Survival Follow-up Contacts ...........................................................104
8.11.6
Survival Status ...........................................................................................105
9
KEY STATISTICAL CONSIDERATIONS .............................................................106
9.1
Statistical Analysis Plan Summary...................................................................107
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9.2
Responsibility for Analyses/In-house Blinding ...............................................109
9.3
Hypotheses/Estimation ......................................................................................109
9.4
Analysis Endpoints.............................................................................................109
9.4.1
Efficacy Endpoints.....................................................................................110
9.4.2
Safety Endpoints........................................................................................110
9.4.3
PRO Endpoints...........................................................................................110
9.5
Analysis Populations..........................................................................................111
9.5.1
Efficacy Analysis Populations...................................................................111
9.5.2
Safety Analysis Populations ......................................................................111
9.5.3
Patient-reported Outcome Analysis Population.........................................111
9.6
Statistical Methods.............................................................................................111
9.6.1
Statistical Methods for Efficacy Analyses.................................................112
9.6.1.1
Overall Survival (OS) ......................................................................112
9.6.1.2
Progression-free Survival (PFS) ......................................................112
9.6.1.3
Objective Response Rate (ORR) .....................................................114
9.6.1.4
Duration of Response (DOR)...........................................................114
9.6.1.5
Analysis Strategy for Key Efficacy Variables.................................114
9.6.2
Statistical Methods for Safety Analyses ....................................................115
9.6.3
Statistical Methods for Patient-Reported Outcome Analyses....................116
9.6.4
Demographic and Baseline Characteristics ...............................................117
9.7
Interim Analyses ................................................................................................117
9.7.1
Efficacy Interim Analyses..........................................................................117
9.7.2
Safety Interim Analyses.............................................................................118
9.8
Multiplicity .........................................................................................................119
9.8.1
Overall Survival.........................................................................................119
9.8.2
Progression-free Survival...........................................................................123
9.8.3
Objective Response Rate ...........................................................................124
9.8.4
Safety Analyses..........................................................................................124
9.9
Sample Size and Power Calculations ...............................................................124
9.10
Subgroup Analyses.............................................................................................126
9.11
Compliance (Medication Adherence)...............................................................127
9.12
Extent of Exposure.............................................................................................127
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................128
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......128
10.1.1
Code of Conduct for Interventional Clinical Trials ...................................128
10.1.2
Financial Disclosure...................................................................................131
10.1.3
Data Protection...........................................................................................132
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10.1.3.1
Confidentiality of Data ....................................................................132
10.1.3.2
Confidentiality of Participant Records.............................................132
10.1.3.3
Confidentiality of IRB/IEC Information..........................................133
10.1.4
Committees Structure.................................................................................133
10.1.4.1
Scientific Advisory Committee........................................................133
10.1.4.2
Executive Oversight Committee......................................................133
10.1.4.3
External Data Monitoring Committee .............................................133
10.1.5
Publication Policy......................................................................................134
10.1.6
Compliance with Study Registration and Results Posting Requirements .134
10.1.7
Compliance with Law, Audit, and Debarment ..........................................134
10.1.8
Data Quality Assurance .............................................................................135
10.1.9
Source Documents .....................................................................................136
10.1.10
Study and Site Closure...............................................................................136
10.2
Appendix 2: Clinical Laboratory Tests............................................................137
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................139
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................139
10.3.2
Definition of AE ........................................................................................139
10.3.3
Definition of SAE ......................................................................................140
10.3.4
Additional Events Reported in the Same Manner as SAE.........................141
10.3.5
Recording AE and SAE .............................................................................141
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................145
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................147
10.5
Appendix 5: Contraceptive Guidance..............................................................148
10.5.1
Definitions..................................................................................................148
10.5.2
Contraceptive Requirements......................................................................149
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................150
10.7
Appendix 7: Country-specific Requirements..................................................154
10.7.1
South Africa-specific Requirements..........................................................154
10.7.2
Japan-specific Requirements .....................................................................154
10.7.3
Vietnam-specific Requirements.................................................................155
10.8
Appendix 8: Eastern Cooperative Oncology Group Performance Status....156
10.9
Appendix 9: Abbreviations ...............................................................................157
11
REFERENCES.............................................................................................................163
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LIST OF TABLES
Table 1
Study Schedule of Activities – Initial Treatment Phase ..............................24
Table 2
Study Schedule of Activities – Second Course Treatment Phase................29
Table 3
Adequate Organ Function Laboratory Values .............................................57
Table 4
Study Interventions......................................................................................64
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...........................................................................70
Table 6
MK-7684A or Pembrolizumab Infusion Reaction Dose Modification 
and Treatment Guidelines............................................................................................74
Table 7
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.............................................................................................98
Table 8
Censoring Rules for Primary and Sensitivity Analyses of PFS.................113
Table 9
Censoring Rules for DOR..........................................................................114
Table 10
Analysis Strategy for Key Efficacy Variables...........................................115
Table 11
Summarizes the Analysis Strategy for Safety Endpoints in this Study. ....116
Table 12
Summary of Interim and Final Analyses Strategy.....................................118
Table 13
Efficacy 
 Boundaries and Properties for OS Analyses in 
Participants with PD-L1 TPS ≥50% ..........................................................................120
Table 14
Efficacy Boundaries and Properties for OS Analyses in Participants 
with PD-L1 TPS ≥1%................................................................................................121
Table 15
Efficacy 
 Boundaries and Properties for OS Analyses in TPS 
1% to 49% Participants..............................................................................................121
Table 16
Efficacy Boundaries and Properties for PFS Analyses in Participants 
with PD-L1 TPS ≥50%..............................................................................................123
Table 17
Efficacy Boundaries and Properties for PFS Analyses in Participants 
with PD-L1 TPS ≥1%................................................................................................124
Table 18
Protocol-required Safety Laboratory Assessments....................................137
Table 19
Study Intervention Information for Vietnam .............................................155
CCI
CCI
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LIST OF FIGURES
Figure 1
Initial Treatment Schema.............................................................................22
Figure 2
Second Treatment Course Schema ..............................................................23
Figure 3
Results of a Dose-titration Study of Anti-TIGIT 18G10-IgG2a in the 
MC38 Colon Carcinoma Mouse Model.......................................................................36
Figure 4
Antitumor Efficacy of Anti-TIGIT 18G10-IgG2a as a Single Agent and 
in Combination With Anti-PD-1(muDX400) Therapy in the Murine Subcutaneous 
CT26 Colon Carcinoma-tumor Bearing Model. ..........................................................37
Figure 5
Decision Making Process When Progression Observed by Investigator.....93
Figure 6
Multiplicity Diagram for Type I Error Control..........................................119
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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.
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 is closed to enrollment. This study has enrolled 1264 participants.
•
This study will be unblinded.
•
The estimated duration of study was updated from 6 years to 5 years.
•
Participants receiving MK-7684A will be transitioned to pembrolizumab.
•
Pembrolizumab can be sourced locally or centrally.
•
Participants with access to approved SOC (eg, immunotherapy, chemotherapy, targeted 
therapy, as monotherapy or in combination) should be considered for discontinuation 
from the study. Those benefiting from pembrolizumab with, but unable to access it as 
SOC outside the study, may continue on study and receive treatment with pembrolizumab 
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 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.
•
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.
•
The futility interim analysis (IA1) was conducted. The pre-specified efficacy interim 
analysis (IA2) and final analysis outlined in the SAP will not be conducted.
CCI
CCI
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•
Selected analyses of safety and endpoints will be performed at the end of the study.
•
There will be no follow-up for survival status. Participants currently in imaging follow up 
should obtain imaging and further oncological care as per local standard of care. 
However, standard safety reporting should continue, as applicable.
•
Those participants remaining on study at the time of Amendment 06 should continue to 
be monitored in the study through the AE reporting period (Section 8.4).
•
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 Phase 3, Multicenter, Randomized, Double-Blind Study of MK-7684 with 
Pembrolizumab as a Coformulation (MK-7684A) Versus Pembrolizumab Monotherapy as 
First Line Treatment for Participants With PD-L1 Positive Metastatic Non-Small Cell Lung 
Cancer (KEYVIBE-003) 
Short Title: MK-7684 with Pembrolizumab as a Coformulation (MK-7684A) Versus 
Pembrolizumab Monotherapy for PD-L1 Positive Metastatic NSCLC (KEYVIBE-003)
Acronym: KEYVIBE-003
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
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In males and females with PD-L1 positive (TPS ≥1%) metastatic NSCLC who are 18 years 
of age or older and are treatment-naïve in the metastatic setting:
Primary Objective
Primary Endpoint
•
Objective: To compare MK-7684A to 
pembrolizumab alone with respect to 
OS
•
Hypothesis (H1): MK-7684A is superior 
to pembrolizumab alone with respect to 
OS in participants with PD-L1 TPS 
≥50%
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 to 
pembrolizumab alone with respect to 
OS
•
Hypothesis (H3): MK-7684A is superior 
to pembrolizumab alone with respect to 
OS in participants with PD-L1 TPS 
≥1%
•
Hypothesis (H5): MK-7684A is superior 
to pembrolizumab alone with respect to 
OS in participants with PD-L1 TPS 1% 
to 49%
•
OS
•
Objective: To compare MK-7684A to 
pembrolizumab alone with respect to 
PFS per RECIST 1.1 as assessed by 
BICR.
•
Hypothesis (H2): MK-7684A is superior 
to pembrolizumab alone with respect to 
PFS per RECIST 1.1 by BICR in 
participants with PD-L1 TPS ≥50%.
•
Hypothesis (H4): MK-7684A is superior 
to pembrolizumab alone with respect to 
PFS per RECIST 1.1 by BICR in 
participants with PD-L1 TPS ≥1%
•
PFS: The time from randomization to 
the first documented disease progression 
or death due to any cause, whichever 
occurs first.
•
Objective: To compare MK-7684A to 
pembrolizumab alone with respect to 
PFS per RECIST 1.1 as assessed by 
BICR in participants with PD-L1 TPS 
1% to 49%
•
PFS
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•
Objective: To compare MK-7684A to 
pembrolizumab alone with respect to 
ORR per RECIST 1.1 as assessed by 
BICR.
•
Hypothesis (H6): MK-7684A is superior 
to pembrolizumab alone with respect to 
ORR per RECIST 1.1 by BICR in 
participants with PD-L1 TPS ≥1%
•
OR: Defined as a confirmed CR or PR
•
Objective: To compare MK-7684A to 
pembrolizumab alone with respect to 
ORR per RECIST 1.1 as assessed by 
BICR in participants with PD-L1 TPS 
≥50% and in participants with PD-L1 
TPS 1% to 49% 
•
OR
•
Objective: To evaluate DOR per 
RECIST 1.1 as assessed by BICR for 
MK-7684A compared to 
pembrolizumab alone in participants 
with PD-L1 TPS ≥50%, in participants 
with PD-L1 TPS 1% to 49% and in 
participants with PD-L1 TPS ≥1%
•
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.
•
Objective: To evaluate the mean change 
from baseline (at randomization) in 
global health status/QoL, physical 
functioning, role functioning, dyspnea, 
cough, and chest pain for MK-7684A 
compared to pembrolizumab alone in 
participants with PD-L1 TPS ≥50%, in 
participants with PD-L1 TPS 1% to 
49% and in participants with PD-L1 
TPS ≥1%
•
Change from baseline 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 (European 
Organization for the Research and 
Treatment of Cancer Quality of Life 
Questionnaire-Core 30 items 6 and 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 TTD in 
global health status/QoL, physical 
functioning, role functioning, dyspnea, 
cough, and chest pain for MK-7684A 
compared to pembrolizumab alone in 
participants with PD-L1 TPS ≥50%, in 
participants with PD-L1 TPS 1% to 
49% and in participants with PD-L1 
TPS ≥1%
•
TTD: Defined as the time from baseline 
to the first onset of a >10-point decrease 
from baseline with confirmation by the 
subsequent visit of a >10-point 
deterioration from baseline. If the first 
deterioration is at the last patient-
reported outcomes assessment timepoint 
(in the current database lock), then no 
confirmation is required. 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 (European 
Organization for the Research and 
Treatment of Cancer Quality of Life 
Questionnaire-Core 30 items 6 and 7)
•
Dyspnea score (EORTC QLQ-C30 item 
8)
•
Cough (EORTC QLQ-LC13 item 31)
•
Chest pain (EORTC QLQ-LC13 item 
40)
•
To evaluate the safety and tolerability 
for MK-7684A compared to 
pembrolizumab alone
•
AEs
•
Discontinuations of study intervention 
due to an AE
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Non-small cell lung cancer
Population
Adult participants with metastatic NSCLC (TPS ≥1%) 
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
Participants or Subjects
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 6 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 1246 participants will be randomized in the study, as described in Section 9.
Intervention Groups and Duration:
Arm 
Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Arm 1
MK-7684A
MK-7684 200mg + 
pembrolizumab 
200mg/ 20 mL vial
200 mg/ 
200 mg
IV Infusion
q3w up to 35 cycles
Test 
Product
Arm 2
Pembrolizumab
25 mg/ml
200 mg
IV infusion
q3w up to 35 cycles
Comparator
All 
participants
Pembrolizumab
25 mg/ml
200 mg
IV infusion
q3w
Test 
Product
IV = Intravenous; Q3W = Every 3 weeks 
Other current or former name(s) or alias(es) for study intervention(s) are as follows: 
MK-7684A is a coformulation of vibostolimab and pembrolizumab.
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Total Number of 
Intervention Groups/Arms
2
Duration of Participation
Each participant will participate in the study for 
approximately 3 years from the time the participant provides 
documented informed consent through the final protocol-
specified contact. After a screening period of up to 28 days, 
each participant will be receiving assigned study intervention 
for approximately 2 years. After the end of treatment each
participant will be followed for 1 year.
After screening, 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, and 
participants who attain a complete response and stop study 
intervention may be eligible for up to 17 additional 
administrations of MK-7684A or pembrolizumab 
(approximately 1 year) upon experiencing disease 
progression.
Participants who discontinue for reasons other than 
radiographic disease progression will have posttreatment 
follow-up imaging for disease status until any of the 
conditions for discontinuation of imaging are met.
After the end of treatment, each participant will be followed 
for the occurrence of AEs, SAEs, and other reportable safety 
events. 
In addition, all participants will be followed for overall 
survival until death, withdrawal of consent, the end of the 
study, or enrollment into an extension study.
Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Steering Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations used in this document can be found in Appendix 9.
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1.2
Schema
1.2.1
Initial Treatment Phase
The Initial Treatment study design is depicted in Figure 1.
Figure 1
Initial Treatment Schema
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1.2.2
Second Treatment Course
The Second Treatment Course study design is depicted in Figure 2.
Figure 2
Second Treatment Course Schema
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1.3
Schedule of Activities
1.3.1
Initial Treatment Phase
Table 1
Study Schedule of Activities – Initial Treatment Phase
Post-treatment
Notes
Study Period
Screening
Treatment Cycle = 21 Days
EOT
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
All procedures are to be performed 
before study intervention 
administration unless otherwise 
indicated. Refer to Section 8.11 for visit 
details.
Visit Timing / Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At DC
30 Days post 
last dose
Every
12 weeks
Every
12 weeks
Cycle Day
1
1
1
1
1
1

Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
+14
±7
±14
Administrative Procedures
Informed consent
X
Documented informed consent must be 
obtained before any protocol-specific 
screening procedures are performed. 
Reconsent required to continue study 
intervention after PD.
Informed consent for FBR
X
This is optional for the participant.
Inclusion/exclusion criteria
X
Participant identification card
X
X
Update with randomization number at 
C1D1.
Demographic and medical 
history
X
Prior and concomitant 
medications review
X
X
X
X
X
X
X
X
X
Prior concomitant medications received 
within 30 days before the first dose of 
study intervention through 30 days after 
the last dose of study intervention (or 
90 days if used to treat an SAE) will be 
recorded.
Treatment randomization
X
Dose within 3 days of randomization.
Clinical Procedures/Assessments
Complete physical 
examination
X
X
To be performed within 7 days before 
start of study intervention.
Directed physical examination
X
X
X
X
X
X
X
Height
X
Vital signs, weight
X
X
X
X
X
X
X
X
X
Predose and as clinically indicated.
12-lead ECG
X
ECOG performance status
X
X
X
X
X
X
X
X
X
Performed within 7 days of beginning of 
C1 and prior to each treatment 
administration.
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Post-treatment
Notes
Study Period
Screening
Treatment Cycle = 21 Days
EOT
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
All procedures are to be performed 
before study intervention 
administration unless otherwise 
indicated. Refer to Section 8.11 for visit 
details.
Visit Timing / Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At DC
30 Days post 
last dose
Every
12 weeks
Every
12 weeks
Cycle Day
1
1
1
1
1
1

Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
+14
±7
±14
Study Intervention 
Administration
X
X
X
X
X
X
AE/SAE monitoring
X
X
X
X
X
X
X
X
X
X
Report AEs occurring within 30 days after 
the last dose of study intervention.
Report SAEs occurring within 90 days 
after the last dose of study intervention, or 
30 days after the last dose of study 
intervention if a new anticancer therapy is 
initiated, whichever is earlier.
Subsequent antineoplastic 
therapy status
X
X
X
X
All anticancer therapy will be recorded 
until time of death or termination of 
Survival Follow-up. If a clinic visit is not 
feasible, follow-up information may be 
obtained via documented contact.
Survival status
X
Refer to Sections 8.11.5.3 & 8.11.6. 
Updated survival status may be requested 
by the Sponsor at any time during the 
course of the study.
Imaging
Brain imaging
X
Required for all participants at screening. 
See Section 8.2.1.2 for other 
requirements. If MRI is contraindicated or 
cannot be performed, CT of the head with 
IV contrast is acceptable.
Bone imaging
X
Required at screening for participants with 
history of bone metastases. See Section 
8.2.1.2 for other requirements.
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Post-treatment
Notes
Study Period
Screening
Treatment Cycle = 21 Days
EOT
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
All procedures are to be performed 
before study intervention 
administration unless otherwise 
indicated. Refer to Section 8.11 for visit 
details.
Visit Timing / Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At DC
30 Days post 
last dose
Every
12 weeks
Every
12 weeks
Cycle Day
1
1
1
1
1
1

Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
+14
±7
±14
Tumor imaging and response 
assessment (chest, abdomen, 
and pelvis)
X
X
X
X
Schedule should be followed regardless of 
treatment delays.
Perform imaging at Screening, then Q9W 
(63 ±7 days) from randomization through 
Week 54, and Q12W (±7 days).thereafter 
until BICR confirmed PD or initiation of a 
new anticancer regimen.
If imaging was obtained within 4 weeks 
before treatment DC, scan at DC is not 
mandatory. Follow-up visits may be 
scheduled to coincide with the imaging 
schedule.
Note: On-study brain or bone imaging 
should be performed if clinically indicated 
or to confirm CR (if other lesions indicate 
CR and brain or bone lesions existed at 
baseline).
Laboratory Assessments
Pregnancy test for WOCBP 
X
X
X
X
X
X
X
X
X
WOCBP require negative serum test 
within 72 hours or negative urine test 
within 24 hours prior to each dose of 
study intervention.
Hepatitis B and C and HIV 
serology
X
Required at baseline if mandated by local 
health authority.
CBC with differential
X
X
X
X
X
X
X
X
Performed locally within 10 days before 
first dose.
After C1, collect within 3 days before 
dosing. Urinalysis should be performed 
every 4 cycles (C5, etc.).
Chemistry Panel
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
PT/INR and aPTT/PTT
X
Screening samples collected within 
10 days prior to first dose of study 
intervention. Additional testing to be 
conducted as clinically indicated for 
participants taking anticoagulant therapy.
Thyroid function 
(T3, T4, and TSH)
X
X
X
X
X
X
Should be performed at screening and Day 
1 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.
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Post-treatment
Notes
Study Period
Screening
Treatment Cycle = 21 Days
EOT
Safety 
Follow-up
Efficacy 
Follow-up
Survival 
Follow-up
All procedures are to be performed 
before study intervention 
administration unless otherwise 
indicated. Refer to Section 8.11 for visit 
details.
Visit Timing / Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At DC
30 Days post 
last dose
Every
12 weeks
Every
12 weeks
Cycle Day
1
1
1
1
1
1

Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
+14
±7
±14
Tumor Tissue Collection
Newly obtained/archival tissue 
sample for PD-L1 analysis and 
other biomarkers
X
May use archival tissue sample obtained 
before screening as part of the 
participant’s SOC. 
Patient-reported Outcomes
Perform every cycle through C17, then 
every other cycle through C35 (ie, C1-17, 
C19, C21, C23, C25, C27, C29, C31, C33, 
and C35). If the Treatment DC visit 
occurs 30 days from the last dose of study 
intervention, at the time of the mandatory 
Safety Follow-up Visit, ePROs do not 
need to be repeated.
Perform ePROs in the order listed in the 
SoA (
 first).
Pharmacokinetics
PK and ADA samples should be drawn 
within 24 hours prior to study intervention 
administration. Additional postdose (end-
of-infusion) PK only samples will be 
drawn within 10 minutes after end of 
infusion and the flushing time at C1 and 
C8.
Biomarkers
Collect before study intervention. May be 
performed either on C1D1 or on the next 
scheduled blood draw on C2D1, only one 
sample needs to be collected.
Collect at Screening, predose on Day 1 of 
C1, C2, C3, C4, C5, C7, C10, C13, C16, 
C19, then on Day 1 of every 4 cycles. 
Collect also at EOT and Efficacy Follow 
Up. During follow-up, if a clinic visit is 
not feasible, blood for ctDNA collection 
will not be collected.
CCI
CCI
CCI
CCI
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AE = adverse event; ADA = antidrug antibodies; aPTT = activated partial thromboplastin time; CBC = complete blood count CT = computed tomography; CXDY= Cycle X Day Y; 
DC = discontinuation; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC = European Organization for the Research and Treatment of Cancer; EOT = end of treatment; 
ePRO = electronic patient-reported outcome; FBR = future biomedical research; β-HCG = β human chorionic gonadotropin; HIV = human immunodeficiency virus; ICF = informed consent form; 
INR = international normalized ratio; IV = intravenous; MRI = magnetic resonance imaging; PD = progressive disease; PD-L1 = programmed cell death ligand 1; PK = pharmacokinetic(s); 
PT = prothrombin time; QXW = every X weeks; RNA = ribonucleic acid; SAE = serious adverse event; ; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women 
of childbearing potential; SoA = schedule of activities; SOC = standard of care.
a
CCI
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1.3.2
Second Course Treatment Phase
Table 2
Study Schedule of Activities – Second Course Treatment Phase
Study Period:
Treatment Cycle = 21 days
End of 
Treatment
Post-Treatment
Notes
Visit Timing / Cycle Number
1
2
3
4
5
6 to 17
At DC
Safety 
Follow-up
Efficacy 
Follow-up 
Survival 
Follow-up
Procedures within a given 
treatment visit should occur 
on Day 1 of each cycle unless 
otherwise noted.
30 days 
post last 
dose
Every 12 
weeks 
post-DC
Every 12 
weeks
Scheduling Window (Days):
±3
±3
±3
±3
±3
+14
±7
±14
Administrative Procedures
Eligibility Criteria
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
Concomitant medications 
received within 30 days before 
the first dose of study 
intervention in the Second 
Course through 30 days after 
the last dose of study 
intervention (or 90 days if used 
to treat an SAE) will be 
recorded.
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
Report AEs occurring within 
30 days after the last dose of 
study intervention.
Report SAEs occurring within 
90 days after the last dose of 
study intervention, or 30 days 
after the last dose of study 
intervention if a new anticancer 
therapy is initiated, whichever 
is earlier.
Complete Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
Predose and if clinically 
indicated. 
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Study Period:
Treatment Cycle = 21 days
End of 
Treatment
Post-Treatment
Notes
Visit Timing / Cycle Number
1
2
3
4
5
6 to 17
At DC
Safety 
Follow-up
Efficacy 
Follow-up 
Survival 
Follow-up
Procedures within a given 
treatment visit should occur 
on Day 1 of each cycle unless 
otherwise noted.
30 days 
post last 
dose
Every 12 
weeks 
post-DC
Every 12 
weeks
Scheduling Window (Days):
±3
±3
±3
±3
±3
+14
±7
±14
ECOG Performance Status
X
X
X
X
X
X
X
Performed within 7 days of 
beginning of C1 and prior to 
each treatment administration.
Study Intervention 
Administration
X
X
X
X
X
X
Poststudy Anticancer Therapy 
Status
X
X
X
X
Survival Status
X
Refer to Sections 8.11.5.3 & 
8.11.6. Updated survival status 
may be requested by the 
Sponsor at any time during the 
course of the study.
Laboratory Procedures/Assessments
Pregnancy Test for WOCBP
X
X
X
X
X
X
X
X
WOCBP require negative serum 
test within 72 hours or negative 
urine test within 24 hours prior 
to each dose of study 
intervention. 
PT/INR and aPTT/PTT
X
Required at C1. Additional 
testing as needed for 
participants on anticoagulation 
therapy.
CBC with Differential
X
X
X
X
X
X
X
X
Performed locally within 10 
days before first dose. After C1, 
collect within 3 days before 
dosing. Urinalysis should be 
performed every 4 cycles (C1, 
C5, etc.).
Chemistry Panel
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
Thyroid function 
(T3, T4, and TSH)
X
X
X
X
X
Should be performed at C1 and 
Day 1 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.
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Study Period:
Treatment Cycle = 21 days
End of 
Treatment
Post-Treatment
Notes
Visit Timing / Cycle Number
1
2
3
4
5
6 to 17
At DC
Safety 
Follow-up
Efficacy 
Follow-up 
Survival 
Follow-up
Procedures within a given 
treatment visit should occur 
on Day 1 of each cycle unless 
otherwise noted.
30 days 
post last 
dose
Every 12 
weeks 
post-DC
Every 12 
weeks
Scheduling Window (Days):
±3
±3
±3
±3
±3
+14
±7
±14
Imaging
Tumor Imaging
(Chest, Abdomen, and Pelvis)
Schedule should be followed 
regardless of treatment delays. 
Images are for investigator 
assessment of disease status 
only and should not be sent to 
the iCRO. If tumor image 
documenting PD is older than 
28 days prior to entry into 
Second Course, a new image
must be obtained and reviewed 
by the site prior to treatment. 
Perform Q9W through EOT and 
Q12W thereafter, until 
confirmed PD or initiation of a 
new anticancer regimen. The 
window for imaging is ±7 days. 
If imaging was obtained within 
4 weeks before DC, scan at DC 
is not mandatory. Follow-up 
visits may be scheduled to 
coincide with the imaging 
schedule.
Note: On-study brain or bone 
imaging should be performed if 
clinically indicated or to 
confirm CR (if other lesions 
indicate CR and brain or bone 
lesions existed at baseline).
AE = adverse event; aPTT = activated partial thromboplastin time; CXDY= Cycle X Day Y; CBC = complete blood count; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; 
EOT = end-of-treatment; FT4 = free thyroxine; MRI = magnetic resonance imaging; PT/INR = prothrombin time/international normalized ratio; SAE = serious adverse event; 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. 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 2.1 million cases in 2018, resulting in an estimated 
1.8 million deaths [International Agency for Research on Cancer 2018]. NSCLC represents 
approximately 85% of all lung cancers [National Cancer Institute 2020]. Of patients with 
NSCLC, tumor histology is approximately 46% adenocarcinoma, 16% squamous, and the 
remainder “not otherwise specified” [Sulpher, J. A., et al 2013], though histology varies 
somewhat by geographic region. At the time of diagnosis, approximately 80% of patients in 
the US with lung cancer have locally advanced or metastatic disease that is not amenable to 
surgical resection, and the 5-year relative survival for patients with metastatic lung cancer is 
only approximately 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 (in some countries) TPS ≥1%, 
respectively, with no EGFR or ALK genomic tumor aberrations [Brahmer, J. R., et al 2017] 
[Mok, T. S. K., et al 2019]. Likewise, 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] [Gandhi, L., et al 2018b] [Paz-Ares, L., et al 2018]. (See Section 2.2.3.2 for 
details on the results of these studies.)
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 [Smyth, M. J., et al 2016] 
[Kruger, S., et al 2019] [Martins, F., et al 2019]. 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; of particular interest to both patients and 
physicians is the development of chemotherapy-free options in biomarker selected patient 
population. 
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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 or have been approved recently. 
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 demonstrated that anti-mTIGIT 
antibodies on the mIgG2a backbone (with high affinity FcR binding) are more efficacious 
than anti-mTIGIT 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 for MK-7684-001, a Phase 1 study of MK-7684 as 
monotherapy or coformulated with pembrolizumab (known as MK-7684A) in advanced solid 
tumors demonstrates promising activity in PD-1 naïve and PD-1 refractory NSCLC (see 
Section 2.2.3.1).
Recent data from CITYSCAPE, a Phase 2 double-blind study of anti-TIGIT antibody 
tiragolumab plus atezolizumab versus placebo plus atezolizumab demonstrated a median PFS 
and OS of 5.6 months versus 3.9 months and 23.2 months versus 14.5 months, respectively in 
the ITT population after 2.5 years of median follow-up. The combination of tiragolumab plus 
atezolizumab reduced the risk of disease worsening or death (PFS) by 38% and improved 
overall response rates (38.8% vs. 20.6%) compared with atezolizumab alone. This 
improvement was driven predominantly in the participants with PD-L1 TPS ≥50% [F. 
Hoffmann-La Roche Ltd 2021] [Rodriguez-Abreu, D., et al 2020]. However, TIGIT and PD-
1 are co-expressed, and data demonstrate improvements in outcomes in all PD-L1 expression 
subgroups (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. The goal of this 
study is to enhance the approved anti-PD-1 immune stimulatory mechanism of 
pembrolizumab monotherapy in patients with TPS ≥1% NSCLC through combining it with a 
novel immune modulatory mechanism of action, blockade of TIGIT. This Phase 3 study is 
designed to assess the efficacy and safety of MK-7684A versus pembrolizumab monotherapy 
in participants with NSCLC who are treatment-naïve with a PD-L1 TPS ≥1% and PD-L1 
TPS ≥50%. This is an attractive scientific concept and by achieving the primary endpoint of 
this study, an improved chemotherapy-free clinical therapeutic approach would be created 
that would significantly enhance presently available options.
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2.2
Background
Refer to the MK-7684A IB and the pembrolizumab IB for detailed background information 
on MK-7684 and pembrolizumab, respectively.
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 TILs 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 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. TILs 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].
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, 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. 
TIGIT forms part of a co-stimulatory 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, Tregs, NK cells, and NKT cells [Dardalhon, V., et al 2005] [Stanietsky, N., et al 2013]. 
CD155/PVR (poliovirus receptor) and CD112/PVRL-2 (poliovirus receptor-related 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 co-expressed with PD-1 on both CD4+ and CD8+ TILs 
including Tregs, in mouse and human tumors, and has been reported to be co-expressed 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. We 
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hypothesize, therefore, that combining MK-7684 with pembrolizumab will offer substantially 
augmented antitumor efficacy.
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 safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated 
for the treatment of patients across a number of indications. For more details on specific 
indications refer to the IB.
2.2.2
Preclinical and Clinical Studies
2.2.2.1
MK-7684 Preclinical Studies
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2.2.2.2
Pembrolizumab Preclinical and Clinical Trials
Refer to the IB for preclinical and clinical study data for pembrolizumab.
2.2.3
Ongoing Clinical Studies
2.2.3.1
MK-7684 Ongoing Clinical Trials
Study MK-7684-001
MK-7684-001 is a safety, efficacy, and PK 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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A recent analysis (18-NOV-2021) of the data from this Phase 1 study also showed that MK-
7684 plus pembrolizumab was well tolerated and demonstrated antitumor activity in 
participants with advanced solid tumors, including in participants with advanced NSCLC 
[Niu, J., et al 2022]. Additional details regarding other ongoing studies of MK-7684 and 
specific benefits and risks for participants in the MK-7684 studies may be found in the IB.
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2.2.3.2
Pembrolizumab Ongoing Clinical Trials
Numerous interventional clinical studies involving pembrolizumab are currently ongoing in a 
number of advanced solid tumor indications, as well as in hematological malignancies. 
In the NSCLC development program, pembrolizumab monotherapy for PD-L1 positive 
NSCLC was approved in the first-line setting based on KEYNOTE-024 and KEYNOTE-042 
and approved in the second-line setting based on KEYNOTE-001 and KEYNOTE-010. 
KEYNOTE-189 and KEYNOTE-407 led to the approval of pembrolizumab in combination 
with chemotherapy for first-line treatment of metastatic NSCLC irrespective of PD-L1 status, 
while KEYNOTE-021 established the benefits of the combination. For further details, refer 
to the 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 compared with SOC platinum-doublet chemotherapy in KEYNOTE-042 in 
participants with metastatic TPS ≥1% NSCLC, an unmet medical need remains for safe and 
efficacious treatments offering added benefit for this patient population. 
 
 
 
 
 
 
 
 
 
Additional details regarding specific benefits and risks for participants in this clinical study 
may be found in the accompanying IBs 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 PD-L1 positive (TPS ≥1%) metastatic NSCLC who are 18 years 
of age or older and are treatment-naïve in the metastatic setting:
Primary Objective
Primary Endpoint
•
Objective: To compare MK-7684A to 
pembrolizumab alone with respect to 
OS
•
Hypothesis (H1): MK-7684A is superior 
to pembrolizumab alone with respect to 
OS in participants with PD-L1 TPS 
≥50%
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 to 
pembrolizumab alone with respect to 
OS
•
Hypothesis (H3): MK-7684A is superior 
to pembrolizumab alone with respect to 
OS in participants with PD-L1 TPS 
≥1%
•
Hypothesis (H5): MK-7684A is superior 
to pembrolizumab alone with respect to 
OS in participants with PD-L1 TPS 1% 
to 49%
•
OS
•
Objective: To compare MK-7684A to 
pembrolizumab alone with respect to 
PFS per RECIST 1.1 as assessed by 
BICR.
•
Hypothesis (H2): MK-7684A is superior 
to pembrolizumab alone with respect to 
PFS per RECIST 1.1 by BICR in 
participants with PD-L1 TPS ≥50%.
•
Hypothesis (H4): MK-7684A is superior 
to pembrolizumab alone with respect to 
PFS per RECIST 1.1 by BICR in 
participants with PD-L1 TPS ≥1%
•
PFS: 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 compare MK-7684A to 
pembrolizumab alone with respect to 
PFS per RECIST 1.1 as assessed by 
BICR in participants with PD-L1 TPS 
1% to 49%
•
PFS
•
Objective: To compare MK-7684A to 
pembrolizumab alone with respect to 
ORR per RECIST 1.1 as assessed by 
BICR.
•
Hypothesis (H6): MK-7684A is superior 
to pembrolizumab alone with respect to 
ORR per RECIST 1.1 by BICR in 
participants with PD-L1 TPS ≥1%
•
OR: Defined as a confirmed CR or PR
•
Objective: To compare MK-7684A to 
pembrolizumab alone with respect to 
ORR per RECIST 1.1 as assessed by 
BICR in participants with PD-L1 TPS 
≥50% and in participants with PD-L1 
TPS 1% to 49% 
•
OR
•
Objective: To evaluate DOR per 
RECIST 1.1 as assessed by BICR for 
MK-7684A compared to 
pembrolizumab alone in participants 
with PD-L1 TPS ≥50%, in participants 
with PD-L1 TPS 1% to 49% and in 
participants with PD-L1 TPS ≥1%
•
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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•
Objective: To evaluate the mean change 
from baseline (at randomization) in 
global health status/QoL, physical 
functioning, role functioning, dyspnea, 
cough, and chest pain for MK-7684A 
compared to pembrolizumab alone in 
participants with PD-L1 TPS ≥50%, in 
participants with PD-L1 TPS 1% to 
49% and in participants with PD-L1 
TPS ≥1%
•
Change from baseline 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 (European 
Organization for the Research and 
Treatment of Cancer Quality of Life 
Questionnaire-Core 30 items 6 and 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 TTD in 
global health status/QoL, physical 
functioning, role functioning, dyspnea, 
cough, and chest pain for MK-7684A 
compared to pembrolizumab alone in 
participants with PD-L1 TPS ≥50%, in 
participants with PD-L1 TPS 1% to 
49% and in participants with PD-L1 
TPS ≥1%
•
TTD: Defined as the time from baseline 
to the first onset of a >10-point decrease 
from baseline with confirmation by the 
subsequent visit of a >10-point 
deterioration from baseline. If the first 
deterioration is at the last patient-
reported outcomes assessment timepoint 
(in the current database lock), then no 
confirmation is required. 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 (European 
Organization for the Research and 
Treatment of Cancer Quality of Life 
Questionnaire-Core 30 items 6 and 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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•
To evaluate the safety and tolerability 
for MK-7684A compared to 
pembrolizumab alone
•
AEs
•
Discontinuations of study intervention 
due to an AE
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
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4
STUDY DESIGN
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 is closed to enrollment. This study has enrolled 1264 participants.
•
This study will be unblinded.
•
The estimated duration of study was updated from 6 years to 5 years.
•
Participants receiving MK-7684A will be transitioned to pembrolizumab.
•
Pembrolizumab can be sourced locally or centrally.
•
Participants with access to approved SOC (eg, immunotherapy, chemotherapy, targeted 
therapy, as monotherapy or in combination) should be considered for discontinuation 
from the study. Those benefiting from pembrolizumab with, but unable to access it as 
SOC outside the study, may continue on study and receive treatment with pembrolizumab 
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 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.
•
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.
•
The futility interim analysis (IA1) was conducted. The pre-specified efficacy interim 
analysis (IA2) and final analysis outlined in the SAP will not be conducted.
•
Selected analyses of safety and endpoints will be performed at the end of the study.
•
There will be no follow-up for survival status. Participants currently in imaging follow up 
should obtain imaging and further oncological care as per local standard of care. 
However, standard safety reporting should continue, as applicable.
•
Those participants remaining on study at the time of Amendment 06 should continue to 
be monitored in the study through the AE reporting period (Section 8.4).
•
Participants may enroll in an extension study, if available.
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-
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.
4.1
Overall Design
This is a Phase 3, randomized, active-controlled, parallel-group, multisite, double-blind study 
of MK-7684A versus pembrolizumab. Participants with metastatic Stage IV NSCLC with no 
previous treatment for Stage IV disease and PD-L1 positive tumors (TPS ≥1%) will be 
enrolled in the study. This study will be conducted in participants with measurable disease in 
whom EGFR-, ALK-, or ROS1-targeted therapy is not indicated.
Participants will be stratified by:

ECOG performance status (0 versus 1)

PD-L1 TPS (1% to 49% versus ≥50%)

Geographic Region: East Asia versus Non-East Asia
Initial Treatment Phase
Overall, approximately 1246 participants will be randomized 1:1 to:

MK-7684A (Arm 1) 

Pembrolizumab (Arm 2)
No treatment crossover is planned for the study. The study design is shown in Figure 1
(Initial Treatment) and Figure 2 (Second Course). 
Participants will be evaluated with radiographic imaging to assess response to study 
intervention every 9 weeks from randomization through 54 weeks, then every 12 weeks until
confirmed PD or initiation of a new anticancer regimen. All imaging 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, OR, and DOR. Tumor
imaging showing site-assessed PD should be submitted immediately for verification by BICR 
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before study intervention discontinuation. Once disease progression is verified centrally, 
subsequent imaging (if acquired) should not 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.
Survival follow-up will continue after PD, discontinuation of study intervention, and the start 
of new anticancer treatment. In addition, upon Sponsor request, participants may be 
contacted for survival status at any time during the study.
AE monitoring will be ongoing throughout the study. AEs will be graded in severity 
according to the guidelines outlined in the NCI CTCAE, version 5.0.
Treatment with MK-7684A or pembrolizumab will continue for up to 35 treatment cycles, or 
until a discontinuation criterion is met (see Section 7.1). Treatment may be discontinued for 
participants with a confirmed CR (see Section 6.6.2).
for this 
study. Details regarding interim analyses are provided in Section 9.7.
Second Course Treatment Phase
Participants who stop MK-7684A or pembrolizumab after receiving 35 treatment cycles of 
MK-7684A or pembrolizumab or participants who stop study intervention after attaining a 
confirmed CR may be eligible for the Second Course. See Section 6.6.3 for details.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study is being conducted to compare the efficacy and safety of MK-7684A to 
pembrolizumab monotherapy in participants with metastatic NSCLC in a randomized, 
double-blinded fashion.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
This study has OS as the primary endpoint. PFS, OR and DOR will be secondary efficacy 
endpoints.
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OS has been recognized as the gold standard for demonstration of superiority of a new 
antineoplastic therapy in randomized clinical studies.
PFS and OR are secondary endpoints and acceptable measures 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 benefit/risk profile. The use 
of BICR and RECIST 1.1 to assess PFS and OR is considered acceptable by regulatory 
authorities. Images will be submitted to an iCRO and read by an independent central review 
blinded to study intervention assignment to minimize bias in 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.
As of Amendment 5, OS in the PD-L1 TPS ≥50% population is the only primary endpoint. 
PFS and OS in the TPS ≥1% population were moved to secondary endpoints. 
PFS was moved from a primary to a secondary endpoint based on external data from 
SKYSCRAPER-01, a Phase 3 study evaluating patients with newly diagnosed metastatic 
NSCLC and PD-L1 TPS ≥50% and treated with atezolizumab + placebo compared to 
atezolizumab + tiragolumab (TIGIT mAb). Recent data from the study demonstrated that the 
PFS endpoint was not met at the final prespecified analysis and delayed survival benefit was 
observed though not statistically significant (HR=0.81, 95% CI: 0.63, 1.03) [F. Hoffmann-La 
Roche Ltd. 2023].
OS in the PD-L1 TPS ≥50% population was selected based on these NSCLC results from 
SKYSCRAPER-01 and data from the Phase 2 study KEYVIBE-005 in participants with 
advanced solid tumors treated with vibostolimab and pembrolizumab. The KV-005 study 
demonstrates potential benefit in the most IO sensitive tumor populations, such as dMMR 
endometrial cancer [Toullec, C., et al 2024] and in tumors with higher PD-L1, including in 
the HNSCC and cervical cancer cohorts [Leary, A., et al 2024] [Toullec, C., et al 2024]. 
In participants with HNSCC and PD-L1 CPS ≥20, the ORR by investigator review was 41% 
(7/17 participants; 95% CI: 18, 67) compared to 21% (5/24 participants; 95% CI: 7, 42) in 
the PD-L1 CPS ≥1 to 19 population [Toullec, C., et al 2024]. 
 
 
 
 
Altogether, the NSCLC Phase 3 data and advanced solid tumor Phase 2 data indicate 
potential greater benefit with anti-TIGIT antibodies in tumors with higher PD-L1 and provide 
the rationale for the primary endpoint change to OS in the PD-L1 TPS ≥50% population.
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The secondary efficacy endpoint of DOR based on RECIST 1.1 and assessed by BICR is 
accepted by regulatory authorities and the oncology community.
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures. 
Although original RECIST 1.1 publication recommends a maximum of 5 target lesions in 
total and 2 per organ, this protocol has implemented an adjustment to RECIST 1.1 to allow a 
maximum of 10 target lesions in total and 5 per organ, if a larger number of target lesions is 
needed to adequately represent the tumor burden. Refer to Section 8.2.1.5 for additional 
detail.
4.2.1.2
Safety Endpoints
Safety parameters frequently used for evaluating investigational-systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs, and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version 5.0.
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4.3
Justification for Dose
4.3.1
MK-7684A
Based on the totality of available data, including preliminary 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. 
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4.3.2
Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the pembrolizumab development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab for adults across all indications. As outlined below, this dose is 
justified by:

Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 10 
mg/kg Q2W representing an approximate 5- to 7.5-fold exposure range (refer to IB, 
Section 5.2.2)

Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W

Clinical data showing meaningful improvement in benefit-risk including OS 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.
For more information, please refer to the pembrolizumab IB.
4.3.3
Maximum Dose Exposure for This Study
The maximum dose/exposure of MK-7684A allowed in this study is 200 mg MK-7684/ 
200 mg pembrolizumab for up to 2 years (35 treatment cycles) of initial treatment (Section 
6.6.2) and an additional 1 year (17 cycles) for Second Course (Section 6.6.3). 
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The maximum dose/exposure of pembrolizumab allowed in this study is 200 mg IV Q3W for 
up to 2 years (35 treatment cycles) of initial treatment (Section 6.6.2) and an additional 
1 year (17 cycles) for Second Course (Section 6.6.3).
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 6 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
Recruitment in the study or at (a) particular study site(s) may be stopped due to insufficient 
compliance with the protocol, GCP and/or other applicable regulatory requirements, 
procedure-related problems or the number of discontinuations for administrative reasons is 
too high.
Early study termination will be the result of the criteria specified below:
1. Incidence or severity of emerging effects/clinical endpoints is such that the risk/benefit 
ratio for the study population as a whole is unacceptable.
2. Plans to modify or discontinue the development of the study drug
Ample notification will be provided in the event of Sponsor’s 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 (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
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 NSCLC (Stage IV: M1a, 
M1b, M1c, AJCC Staging Manual, version 8).
Note: Mixed tumors will be characterized by the predominant cell type; if small cell 
elements are present, the participant is ineligible.
2. Has measurable disease based on RECIST 1.1, as determined by the local site 
assessment.
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.
3. 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).
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.
4. Has provided tumor tissue that demonstrates PD-L1 expression in ≥1% of tumor cells 
(TPS ≥1%) as assessed by IHC at a central laboratory.
Note: Assessment of PD-L1 expression must be made from provided archival tumor 
tissue sample or newly obtained core or excisional biopsy of a tumor lesion not 
previously irradiated. 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.
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Demographics
5. Is male or female, ≥ 18 years of age at the time of providing documented informed 
consent. 
6. Has an ECOG PS of 0 or 1 assessed within 7 days prior to randomization.
7. Has a life expectancy of at least 3 months.
Female Participants
8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
◦
Is not a WOCBP
OR
◦
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent 
basis), as described in Appendix 5 during the intervention period and for at least 120 days 
after the last dose of study intervention. The investigator should evaluate the potential for 
contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the 
first dose of study intervention.
-
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum 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 
located in Section 8.3.5.
-
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
-
Contraceptive use by females 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 drugs is more 
stringent than the requirements above, the local label requirements should be 
followed. 
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Informed Consent
9. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide consent for future biomedical 
research. However, the participant may participate in the main study without participating 
in future biomedical research.
Additional Categories
10. Has adequate organ function as defined in Table 3. Specimens must be collected within 
10 days before the start of study intervention.
Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematologic
Absolute neutrophil count 
≥1500/µL
Platelets
≥100,000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine OR
Measured or calculatedb CrCl 
(GFR can be used in place of creatinine or CrCl)
≤1.5 × ULN OR
≥30 mL/min for participants with creatinine 
levels >1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 × ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases)
Coagulation
INR or PT
aPTT/PTT
≤1.5 × ULN unless the participant is receiving 
anticoagulants, as long as PT or aPTT is within 
the therapeutic range for intended use of 
anticoagulants
ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); aPTT = activated partial 
thromboplastin time; AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); CrCl = 
creatinine clearance; GFR = glomerular filtration rate; INR = international normalized ratio; PT = prothrombin time; 
ULN = upper limit of normal.
a This criterion must be met without erythropoietin dependency and without packed red blood cell transfusion within the 
last 2 weeks.
b CrCl should be calculated per the institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements 
should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.
See Appendix 7 for country specific requirements.
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5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. Has a known history of an additional malignancy, except if the participant has undergone
potentially curative therapy with no evidence of that disease recurrence for at least 3 
years since initiation of that therapy.
Note: The time requirement for no evidence of disease for at least 3 years does not apply 
to the NSCLC for which a participant is enrolled in the study. The time requirement also 
does not apply to participants who underwent successful definitive resection of basal cell 
carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in 
situ cervical cancer, or other in situ cancers.
Prior/Concomitant Therapy
2. Has received prior systemic chemotherapy or other targeted or biological antineoplastic 
therapy for their metastatic NSCLC.
Note: Prior treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant 
or chemoradiation therapy for nonmetastatic NSCLC is allowed as long as therapy was 
completed at least 6 months before the diagnosis of metastatic NSCLC.
Note: Participants must have recovered from all AEs due to previous therapies to Grade 
≤1 or baseline. Participants with Grade ≤2 neuropathy may be eligible. Participants with 
endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be 
eligible.
3. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-
40, CD137).
4. Has received previous treatment with another agent targeting the TIGIT receptor 
pathway. 
5. Has received radiotherapy within 2 weeks of start of study intervention. Participants must 
have recovered from all radiation-related toxicities, not require corticosteroids, and not 
have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation 
(≤2 weeks of radiotherapy) to non-CNS disease.
6. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of 
study intervention. Administration of killed vaccines is allowed. Refer to Section 6.5 for 
information on COVID-19 vaccines.
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Prior/Concurrent Clinical Study Experience
7. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
intervention.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
8. Has known active or untreated CNS metastases and/or carcinomatous meningitis. 
Participants with previously treated brain metastases may participate provided they are 
radiologically stable (ie, without evidence of progression) for at least 4 weeks by repeat 
imaging (note: repeat imaging should be performed during study screening), clinically 
stable, and without requirement of steroid treatment for at least 14 days prior to first dose 
of study intervention.
9. Has severe hypersensitivity (≥Grade 3) to MK-7684A or pembrolizumab and/or any of its 
excipients. 
10. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed.
11. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study intervention.
12. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis. 
13. Has a known history of interstitial lung disease. Lymphangitic spread of the NSCLC is 
not exclusionary.
14. Has an active infection requiring systemic therapy.
15. Has a known history of HIV infection. No HIV testing is required unless mandated by 
local health authority. See Section 10.7.1 for South Africa-specific requirements.
16. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active 
Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. 
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority. 
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17. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that prevents the participant from receiving platinum-doublet chemotherapy for first line 
NSCLC, or that might confound the results of the study, interfere with the participant's 
participation for the full duration of the study, or is not in the best interest of the 
participant to participate, in the opinion of the treating investigator.
18. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
Other Exclusions
19. If the participant had major surgery, the participant must have recovered adequately from 
the procedure and/or any complications from the surgery prior to starting study 
intervention.
20. Has had an allogenic tissue/solid organ transplant. 
See Appendix 7 for country-specific requirements.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an
AE such as diarrhea, nausea, or vomiting.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
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 for eligibility after consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
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5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws consent from the 
study will not be replaced.
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6
STUDY INTERVENTION
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 is closed to enrollment. This study has enrolled 1264 participants.
•
This study will be unblinded.
•
The estimated duration of study was updated from 6 years to 5 years.
•
Participants receiving MK-7684A will be transitioned to pembrolizumab.
•
Pembrolizumab can be sourced locally or centrally
•
Participants with access to approved SOC (eg, immunotherapy, chemotherapy, targeted 
therapy, as monotherapy or in combination) should be considered for discontinuation 
from the study. Those benefiting from pembrolizumab with, but unable to access it as 
SOC outside the study, may continue on study and receive treatment with pembrolizumab 
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 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.
•
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.
•
The futility interim analysis (IA1) was conducted. The pre-specified efficacy interim 
analysis (IA2) and final analysis outlined in the SAP will not be conducted.
•
Selected analyses of safety and endpoints will be performed at the end of the study.
•
There will be no follow-up for survival status. Participants currently in imaging follow up 
should obtain imaging and further oncological care as per local standard of care. 
However, standard safety reporting should continue, as applicable.
•
Those participants remaining on study at the time of Amendment 06 should continue to 
be monitored in the study through the AE reporting period (Section 8.4).
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•
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.
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 (MK-7684A and pembrolizumab) 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) are in Table 4.
Country-specific requirements are noted in Appendix 7.
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Table 4
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulatio
n
Unit Dose 
Strength(s)
Dosage 
Level(s
)
Route of 
Administratio
n
Regimen/
Treatment 
Period/
Vaccinatio
n Regimen
Use
IMP 
or 
NIMP
/
AxMP
Sourcin
g
Arm 1
Experimenta
l
MK-7684A
Biological/Vaccin
e
Solution
MK-7684 
200mg + 
pembrolizuma
b 200mg/ 20 
mL vial
200 mg/ 
200 mg
IV Infusion
q3w up to 35 
cycles
Test 
Product
IMP
Central
Arm 2
Active 
comparator
Pembrolizuma
b
Biological/vaccin
e
Solution
25 mg/ml
200 mg
IV infusion
q3w up to 35 
cycles
Comparato
r
IMP
Central
All 
participant
s
Experimenta
l
Pembrolizuma
b
Biological/vaccin
e
Solution
25 mg/ml
200 mg
IV infusion
q3w 
Test 
Product 
IMP
Central
IMP = investigational medicinal product; MK-7684A = Coformulated as 200 mg MK-7684 and 200 mg pembrolizumab; NIMP/AxMP = noninvestigational/auxiliary medicinal 
product.
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 European Economic Area (EEA). 
Country differences with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All study interventions will be administered on an outpatient basis. 
All products indicated in Table 4 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary, or designee, depending on local country operational or regulatory 
requirements. 
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor. 
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of MK-7684A and pembrolizumab are provided in 
the Pharmacy Manual.
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.
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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 or 
pembrolizumab alone, respectively.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. ECOG performance score (0 versus 1)
2. PD-L1 TPS (1% to 49% versus ≥50%)
3. Geographic Region: East Asia versus Non-East Asia
6.3.3
Blinding
A double-blinding technique with in-house blinding 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 so that the blind is maintained. 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.
Access to the randomization schedule and unblinded results for presentation of summaries 
and analyses to the eDMC will be restricted to an unblinded statistician and as needed, an 
unblinded scientific programmer performing the analysis, who will have no other 
responsibilities associated with the study. Participant level PD-L1 results will be masked to 
the site.
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, the details of and reason for any 
interruption of study intervention will be documented in the participant’s medical record.
Refer to Section 6.6.1 for dose modification and toxicity management for irAEs associated 
with MK-7684A or pembrolizumab and for other allowed dose interruptions of MK-7684A 
or pembrolizumab.
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When participants will be 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 site should ensure and confirm that the study intervention is administered at the correct 
dose to the assigned study participant.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the treatment period. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study therapy or vaccination may be required. 
The investigator should discuss any questions regarding this with the Sponsor's Clinical 
Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
Participants are prohibited from receiving the following therapies during the screening and 
treatment periods of this study:
•
Antineoplastic systemic chemotherapy or biological therapy.
•
Immunotherapy not specified in this protocol.
•
Chemotherapy not specified in this protocol.
•
Investigational agents other than pembrolizumab or MK-7684A.
•
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.
•
Live or live-attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study, and for after the last dose of study intervention. 
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.
-
As needed for the prevention of emesis.
-
Premedication for IV contrast allergies.
-
Short-term oral or IV use in doses >10 mg/day prednisone equivalent for COPD 
exacerbations.
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-
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent.
•
In addition, the following glucocorticoid use is allowed:
-
For topical use or ocular use
-
Intraarticular joint use
-
For inhalation in the management of asthma or COPD
If the investigator determines that a participant requires any of the aforementioned treatments 
for any reason, study intervention must be discontinued:
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, OTC products, herbal supplements, and IV medications, and fluids. If changes 
occur during the study period, documentation of drug dosage, frequency, route, and date 
should also be included on the eCRF.
All concomitant medications received within 30 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.
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 6.6.1.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab 
or MK-7684A, the investigator does not need to follow the treatment guidance. Refer to 
Table 4 in Section 6.6.1 for guidelines regarding dose modification and supportive care.
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
AEs associated with pembrolizumab monotherapy, coformulation, or IO combination 
exposure may represent an immune-related response. These irAEs may occur shortly after 
the first dose or several months after the last dose of pembrolizumab monotherapy, 
coformulation, or IO combination treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
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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 5.
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Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the irAEs are not 
controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not 
≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after corticosteroid 
taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Add prophylactic antibiotics 
for opportunistic infections
Monitor participants for signs and symptoms 
of pneumonitis
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
Recurrent Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
Diarrhea/
Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation (ie, 
peritoneal signs and ileus)
Participants with ≥Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion
Recurrent Grade 3 or 
Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST or ALT 
Elevation or 
Increased 
Bilirubin
Grade 2 a
Withhold
Administer corticosteroids 
(initial dose of 0.5 to 
1 mg/kg prednisone or 
equivalent) followed by 
taper
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable)
Grade 3 b or 4 c
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM or 
Grade 3 or 4 
hyperglycemia associated 
with evidence of -cell 
failure
Withhold d
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer 
antihyperglycemic in 
participants with 
hyperglycemia
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
Administer corticosteroids 
and initiate hormonal
replacements as clinically 
indicated
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hyperthyroidism
Grade 2
Continue
Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hypothyroidism
Grade 2, 3 or 4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
Monitor for signs and symptoms of thyroid 
disorders
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Nephritis:
grading according 
to increased 
creatinine or acute 
kidney injury
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by 
taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Neurological 
Toxicities
Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Asymptomatic cardiac 
enzyme elevation with 
clinical suspicion of 
myocarditis (which was 
previously myocarditis 
Grade 1 using CTCAE 
v4.0)
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, TEN, or 
DRESS
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm 
etiology or exclude other causes
Confirmed SJS, TEN, or 
DRESS
Permanently 
discontinue
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
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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
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 MK-
7684A or Pembrolizumab
MK-7684A or pembrolizumab may cause severe or life-threatening infusion-reactions 
including severe hypersensitivity or anaphylaxis. Signs and symptoms usually develop 
during or shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. Dose modification and toxicity management guidelines on 
MK-7684A or pembrolizumab associated infusion reaction are provided Table 6.
Table 6
MK-7684A or Pembrolizumab Infusion Reaction Dose Modification and 
Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital 
signs as medically indicated until 
the participant is deemed 
medically stable in the opinion 
of the investigator
None
Grade 2
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion
Additional appropriate medical 
therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital 
signs as medically indicated until 
the participant is deemed 
medically stable in the opinion 
of the investigator.
If symptoms resolve within 1 
hour of stopping drug infusion, 
the infusion may be restarted at 
50% of the original infusion rate 
(eg, from 100 mL/hr to 50 
mL/hr). Otherwise dosing will be 
held until symptoms resolve and 
the participant should be 
premedicated for the next 
scheduled dose.
Participants who develop Grade 
2 toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study drug intervention.
Participant may be premedicated 1.5 h (±30 
minutes) prior to infusion of study intervention
with:
Diphenhydramine 50 mg PO (or equivalent 
dose of antihistamine).
Acetaminophen 500-1000 mg PO (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical 
therapy may include but is not 
limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital 
signs as medically indicated until 
the participant is deemed 
medically stable in the opinion 
of the investigator.
Hospitalization may be 
indicated.
**In cases of anaphylaxis, 
epinephrine should be used 
immediately.
Participant is permanently 
discontinued from further study 
drug intervention.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 
(CTCAE) at http://ctep.cancer.gov
Other Allowed Dose Interruption for MK-7684A or Pembrolizumab
MK-7684A or pembrolizumab may be interrupted for situations other than treatment-related 
AEs such as medical or surgical events and/or unforeseen circumstances not related to study 
intervention. However, study intervention is to be restarted within 3 weeks of the originally 
scheduled dose and within 6 weeks 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
Initial Treatment or First Course
The initial treatment or first course of MK-7684A Q3W or pembrolizumab Q3W consists of 
35 treatments (approximately 2 years). Note: The number of treatments is calculated starting 
with the first dose.
For participants who have attained a confirmed CR and have received at least 8 doses of 
MK-7684A or pembrolizumab, including at least 2 doses of MK-7684A or pembrolizumab 
beyond the initial CR confirmation date, treatment may be stopped.
These participants may be eligible for Second Course, as described in Section 6.6.3.
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6.6.3
Second Course 
All participants who have SD, PR, or CR may be eligible for up to an additional 17 cycles of 
MK-7684A or pembrolizumab treatment based on original randomization assignment if there 
is BICR verification of radiographic disease progression by RECIST 1.1 after initial 
treatment or first course has been completed or stopped for confirmed CR, as specified in 
Section 6.6.2. This retreatment is the Second Course of this study.
Participants may enter the Second Course if all of the following criteria are met:
1. No new anticancer treatment was administered after the last dose of study intervention
2. The participant meets all of the inclusion criteria and none of the exclusion criteria
3. The study is ongoing
An objective response or disease progression that occurs during the Second Course will not 
be counted as an event for the primary analysis of either endpoint in this study.
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
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). In the 
event that 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
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 is closed to enrollment. This study has enrolled 1264 participants.
•
This study will be unblinded.
•
The estimated duration of study was updated from 6 years to 5 years.
•
Participants receiving MK-7684A will be transitioned to pembrolizumab.
•
Pembrolizumab can be sourced locally or centrally.
•
Participants with access to approved SOC (eg, immunotherapy, chemotherapy, targeted 
therapy, as monotherapy or in combination) should be considered for discontinuation 
from the study. Those benefiting from pembrolizumab with, but unable to access it as 
SOC outside the study, may continue on study and receive treatment with pembrolizumab 
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 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.
•
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.
•
The futility interim analysis (IA1) was conducted. The pre-specified efficacy interim 
analysis (IA2) and final analysis outlined in the SAP will not be conducted.
•
Selected analyses of safety and endpoints will be performed at the end of the study.
•
There will be no follow-up for survival status. Participants currently in imaging follow up 
should obtain imaging and further oncological care as per local standard of care. 
However, standard safety reporting should continue, as applicable.
•
Those participants remaining on study at the time of Amendment 06 should continue to 
be monitored in the study through the AE reporting period (Section 8.4).
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•
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.
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period will still continue to be monitored in the study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.11.4 unless the participant has 
withdrawn from the study (see 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.
•
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. 
•
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 iCRO-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 6.6.1.
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
If a participant fails to return for scheduled visits and/or if the study site is unable to contact 
the participant after multiple attempts (ie, is lost to follow-up), the procedures to be 
performed are outlined in Section 7.3.
If a participant decides not to continue receiving study intervention, the participant is to be 
encouraged to continue visits in the study for follow-up, imaging, and vital status assessment.
Participants who withdraw consent during the study.
If the participant or participant’s legally acceptable representative withdraws consent from 
the study, the participant must be withdrawn from the study.
Section 8.1.9 delineates the specific procedures performed at the time of withdrawal and 
withdrawal from future biomedical research. Any AEs that are present at the time of 
withdrawal should be followed in accordance with the safety requirements outlined in 
Section 8.4.
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7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
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 is closed to enrollment. This study has enrolled 1264 participants.
•
This study will be unblinded.
•
The estimated duration of study was updated from 6 years to 5 years.
•
Participants receiving MK-7684A will be transitioned to pembrolizumab.
•
Pembrolizumab can be sourced locally or centrally
•
Participants with access to approved SOC (eg, immunotherapy, chemotherapy, targeted 
therapy, as monotherapy or in combination) should be considered for discontinuation 
from the study. Those benefiting from pembrolizumab with, but unable to access it as 
SOC outside the study, may continue on study and receive treatment with pembrolizumab 
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 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.
•
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.
•
The futility interim analysis (IA1) was conducted. The pre-specified efficacy interim 
analysis (IA2) and final analysis outlined in the SAP will not be conducted.
•
Selected analyses of safety and endpoints will be performed at the end of the study.
•
There will be no follow-up for survival status. Participants currently in imaging follow up 
should obtain imaging and further oncological care as per local standard of care. 
However, standard safety reporting should continue, as applicable.
•
Those participants remaining on study at the time of Amendment 06 should continue to 
be monitored in the study through the AE reporting period (Section 8.4).
•
Participants may enroll in an extension study, if available.
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-
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.
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF 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
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements. The 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.
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 their legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated ICF should be given to the participant (or their legally 
acceptable representative) before participation in the study.
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) and assent, when applicable, prior to participating in this clinical 
study. If there are changes to the participant’s status during the study (eg, age of majority 
requirements or health), the investigator or medically qualified designee must ensure the 
appropriate documented informed consent from the participant (or their legally acceptable 
representative) 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.
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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 future biomedical research 
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 future biomedical research. A copy of the informed consent will be given to the 
participant before performing any procedure related to future biomedical research.
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.
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 
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within 30 days before starting the study. Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit. (30 days after the last dose of study 
intervention or 90 days if used to treat an SAE). Any new anticancer therapy started after the 
participant’s discontinuation from initial treatment will be recorded separately. Additional 
information collected on this treatment will include, but is not limited to, best response and 
date of progression. 
In addition, medications taken within 30 days of the first dose of Second Course treatment 
through the Second Course Safety Follow-up Visit (30 days after the last dose of study 
intervention or 90 days if used to treat an SAE) should 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.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.11.1.
8.1.6.1
Treatment Eligibility Assessment Survey
A Treatment Eligibility Assessment survey will be included in this study to document the 
rationale for the investigator’s choice for each individual participant to participate in the 
study rather than receive other licensed therapies. These data may be required to support 
reimbursement efforts for MK-7684A.
The survey will be administered using a survey software platform after participant enrollment 
is completed, with one survey sent to the investigator per participant enrolled in the trial. 
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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8.1.8
Study Intervention Administration
Study interventions will be administered by the investigator and/or study staff according to 
the specifications within the Pharmacy manual.
Study intervention should begin within 3 days of randomization.
8.1.8.1
Timing of Dose Administration
MK-7684A or pembrolizumab will be administered using 30-minute IV infusion every 
3 weeks. The Pharmacy Manual contains specific instructions for MK-7684A and 
pembrolizumab reconstitution, preparation of the infusion fluid, and administration.
All study treatment will be dosed on Day 1 of each 21-day cycle. After Cycle 1 Day 1, study 
medication may be administered up to 3 days before or after the scheduled Day 1 of each 
subsequent cycle for administrative reasons.
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 (Table 1 and Table 2) 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. Prior to 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 chart. If it is not possible to record this assessment in the chart 
prior to the unblinding, the unblinding should not be delayed.
In the event that 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 or a nonemergency unblinding that is part of the study design 
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. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that 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 tissue sample for each participant is required and is to be:
◦
A newly obtained core or incisional biopsy of a tumor lesion, which was not previously 
irradiated 
Or
◦
An archival tumor tissue sample if a new biopsy is unavailable (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 kit except it is labeled IUO.
8.2
Efficacy/Immunogenicity 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 scans to evaluate changes in tumor 
burden over time, until the participant is discontinued from the study or enters the survival 
follow-up. The process for scan collection and transmission to the iCRO can be found in the 
Site Imaging Manual. 
Chest, abdomen, and pelvis scans are required for all participants. CT scans are preferred 
over other tumor imaging methods. For the abdomen and pelvis, contrast-enhanced MRI may 
be used when CT with iodinated contrast is contraindicated, or when mandated by local 
practice. The same type of scan should be used in a participant throughout the study to 
optimize the reproducibility of the assessment of existing and new tumor burden and improve 
the accuracy of the response assessment. Note: for the purposes of assessing tumor scans, the 
term “investigator” refers to the local investigator at the site and/or the radiological reviewer 
at the site or at an offsite facility.
If brain scans are performed, MRI is preferred; however, CT scans are 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.
Additional imaging (including via other modalities, such as PET-CT, X-ray) that are obtained 
at an unscheduled time point to determine disease progression, and scans obtained for other 
reasons that capture radiologic progression based on investigator assessment, should be 
submitted to the iCRO. Other types of scans (eg, ultrasound) should not be submitted to the 
iCRO and will not be included in response assessment.
Participant eligibility will be determined using local assessment (investigator assessment) 
based on RECIST 1.1. When the investigator identifies radiographic progression per RECIST 
1.1, the iCRO will perform expedited verification of radiologic disease progression and 
communicate the results to the study site and Sponsor via email. In clinically stable 
participants, imaging should continue until disease progression has been verified by BICR (if 
initial site-assessed disease progression was not verified by BICR, each subsequent scan 
must be submitted to iCRO with verification of disease progression request until disease 
progression has been verified by BICR). Once disease progression is verified centrally, 
subsequent imaging (if acquired) should not be submitted to the iCRO.
8.2.1.1
Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 28 days prior to the date of 
randomization. Tumor imaging performed as part of routine clinical management is 
acceptable for use as screening tumor imaging if it is of diagnostic quality and performed 
within 28 days prior to randomization. The screening images must be submitted to the iCRO 
for retrospective review.
Brain imaging is required for all participants at Screening. Bone imaging is required at 
Screening for participants with a history of bone metastases and/or for those participants with 
clinical indication, such as bone pain or elevated alkaline phosphatase.
8.2.1.2
Tumor Imaging During the Study
The first on-study imaging assessment should be performed at 9 weeks (63 days ±7 days) 
from the date of randomization. Subsequent tumor imaging should be performed every 
9 weeks (63 days ±7 days), or more frequently if clinically indicated. After 54 weeks 
(378 days ±7 days), imaging should be performed every 12 weeks (84 days ±7 days). 
Imaging timing should follow calendar days and should not be adjusted for delays in cycle 
starts. Imaging should continue to be performed until disease progression is identified by the 
investigator and verified by BICR, the start of new anticancer treatment, withdrawal of 
consent, or death, whichever occurs first. All supplemental imaging must be submitted to the 
iCRO.
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting with 
the next scheduled imaging time point. Participants who receive additional imaging for 
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confirmation do not need to undergo the next scheduled tumor imaging if it is less than 4 
weeks later; tumor imaging may resume at the subsequent scheduled imaging time point. 
Note: Response does not typically need to be verified in real time by BICR.
On-study brain or bone imaging should be performed if clinically indicated or to confirm CR 
(if other lesions indicate CR and brain or bone lesions existed at baseline).
Treatment beyond BICR-verified PD per RECIST 1.1 may be permitted at the discretion of 
the investigator after consulting with the Sponsor and after the participant provides a new 
documented informed consent (see Figure 5). Participants who continue treatment beyond 
BICR-verified PD must continue tumor imaging assessments as described in the SoA 
(Section 1.3.1). Investigator assessments are to be documented on the eCRF, but scans are 
not to be submitted to the iCRO. Further progression and discontinuation of study 
intervention are to be determined by the investigator.
For participants who have unconfirmed disease progression (investigator assessment of 
disease progression, but BICR assessment of disease progression per RECIST 1.1 = “No”), 
treatment can continue at the investigator’s discretion for clinically stable participants (see 
Section 8.2.1.5). Imaging should continue to be performed as per imaging schedule and must 
be submitted to the iCRO along with a VOP request until central confirmation of progression 
is received.
8.2.1.3
End-of-treatment and Follow-up Tumor Scans
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (±4-week window). If previous imaging was obtained 
within 4 weeks before the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study intervention due to documented 
disease progression, this is the final required tumor imaging.
For participants who complete all 35 cycles of initial treatment or discontinue study 
intervention without documented disease progression, every effort should be made to 
continue monitoring disease status by tumor imaging using the same imaging schedule used 
while on treatment, calculated from the date of randomization (see Section 8.2.1.2) until the 
start of a new anticancer treatment, disease progression, pregnancy, death, withdrawal of 
consent, or the end of the study, whichever occurs first.
8.2.1.4
Second Course (Retreatment) Tumor Imaging
Before a participant may enter the Second Course Phase, BICR verification of radiographic 
disease progression must have occurred. Tumor imaging must be performed within 28 days 
prior to restarting treatment with MK-7684A or pembrolizumab in the Second Course. The 
disease progression imaging may also be used as the Second Course baseline imaging if it is 
within 28 days before restarting treatment and otherwise meets the baseline standards 
outlined in the Site Imaging Manual. 
Response assessments and progressive disease in the Second Course are determined by site 
assessment only. No imaging from the Second Course Phase should be provided to the 
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central vendor, except for the Second Course Phase baseline scan if this scan is also the final 
imaging for the Initial Treatment Phase.
The first on-study imaging assessment should be performed at 9 weeks (63 days ±7 days) 
after the restart of treatment. Subsequent tumor imaging should be performed every 9 weeks 
(63 days ±7 days) through the end of treatment and every 12 weeks (84 days ±7 days) 
thereafter, or more frequently if clinically indicated. Imaging should continue to be 
performed until disease progression, the start of a new anticancer treatment, withdrawal of 
consent, death, or notification by the Sponsor, whichever occurs first. The schedule should be 
followed regardless of treatment delays.
For participants who discontinue Second Course study intervention, tumor imaging should be 
performed at the time of intervention discontinuation (±4-week window). If previous imaging 
was obtained within 4 weeks prior to the date of discontinuation, then imaging at intervention 
discontinuation is not mandatory. For participants who discontinue study intervention due to 
documented disease progression, this is the final required tumor imaging.
For participants who complete all 17 cycles of Second Course treatment or discontinue 
Second Course treatment without documented disease progression, every effort should be 
made to continue monitoring their disease status by radiologic imaging every 12 weeks 
(84 days ±7 days) until the start of a new anticancer treatment, disease progression, death, or 
the end of the study, whichever occurs first.
8.2.1.5
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study intervention). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant, to enable a broader sampling of tumor burden. 
Upon investigator-assessed disease progression, the indicative scan(s) 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 
o
Resume imaging per protocol schedule (≥4 weeks to next scan)
o
Send scans to iCRO 
o
Continue local assessment 
o
Do not change investigator assessment of progression
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o
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 
Note: the reconsent addendum may be signed any time after investigator-assessed 
progression is identified, but must be signed prior to starting study intervention after 
verification of disease progression is provided by the iCRO 

Obtain scans locally per original protocol schedule

Do not send scans to iCRO
Figure 5 illustrates the 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 5
Decision Making Process When Progression Observed by Investigator
iCRO = imaging CRO; RECIST = Response Evaluation Criteria in Solid Tumors.
8.2.2
Quality-of-Life Assessments
8.2.2.1
Patient-reported Outcomes
The 
, and 
 questionnaires will be 
administered by trained site personnel and completed electronically by participants in the 
following order: 
 and lastly 
. The 
questionnaires should be administered prior to dosing every cycle through Cycle 17, then 
every other cycle through Cycle 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 MISS_MODE form 
must be completed to capture the reason the assessment was not performed.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided in the Central Laboratory Manual.
Planned time points for all safety assessments are provided in the SoA.
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8.3.1
Physical Examinations
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
•
Temperature (oral, tympanic, rectal, axillary, skin, or temporal artery); pulse rate; 
respiratory rate; and BP will be assessed.
•
Weight will also be measured and recorded.
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 PR, QRS, and QT 
intervals.
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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 study 
Procedures Manual. Refer to the SoA (Section 1.3) for the timing of laboratory assessments.
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2 and 
the schedule is provided in the SoA (Section 1.3).
8.3.5
Pregnancy Testing
Pregnancy testing requirements for study inclusion are described in Section 5.1.
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 
120 days after the last dose of MK-7684A or pembrolizumab.
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.
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8.3.6
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG PS at screening, prior to the 
administration of each dose of study intervention and during the follow-up period as 
specified in the SoA (Section 1.3). See Appendix 8 for details.
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.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention randomization, must be reported by 
the investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event cause the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
•
All AEs from the time of intervention randomization through 30 days after cessation of 
study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation/randomization 
through 90 days after cessation of study intervention or 30 days after cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator.
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•
All pregnancies and exposure during breastfeeding, from the time of intervention 
randomization through the time required to eliminate systemic exposure after cessation of 
study intervention as described in Sections 5.1 and 8.3.5, or 30 days after cessation of 
study intervention if the participant initiates new anticancer therapy must be reported by 
the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside the 
time specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 7.
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 7
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
NSAE
Report if:
- due to protocol-
specified
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE including 
Cancer and 
Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation Exposure
Report if:
-participant has 
been exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout 
or run-in treatment 
including placebo 
run-in)
Exception: A 
positive pregnancy 
test at the time of 
initial screening is 
not a reportable 
event unless the 
participant has 
received study 
intervention.
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
ECI (do not require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
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.
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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) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE. 
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
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 
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:
-
An overdose of Sponsor's product, as defined in Section 8.5.
-
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
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than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The 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 the purpose of 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. 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.
8.6
Pharmacokinetics
8.6.1
Blood Collection for Serum MK-7684 and Pembrolizumab
 
8.6.1.1
Blood Collection for PK
 
 
8.6.1.2
Blood Collection for Antidrug Antibodies
 
 
 
8.7
Pharmacodynamics
.
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8.8
Biomarkers
8.8.1
Planned Genetic Analysis Sample Collection
8.9
Future Biomedical Research Sample Collection
8.10
Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency room visits must be reported in the eCRF, from the 
time of treatment allocation/randomization through 90 days after cessation of study 
intervention, or 30 days after cessation of study intervention, if the participant initiates new 
anticancer therapy, whichever is earlier.
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8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Written consent must be obtained prior to performing any protocol-specific procedure. 
Results of a test performed prior to the participant signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose of 
study intervention except for the following:
•
Laboratory tests are to be performed within 10 days prior to the first dose of study 
intervention. An exception is hepatitis testing which may be done up to 28 days prior to 
the first dose of study intervention.
•
Evaluation of ECOG is to be performed within 7 days prior to the first dose of study 
intervention.
•
For WOCBP, a serum pregnancy test will be performed within 72 hours or a urine 
pregnancy test within 24 hours prior to the first dose of study intervention. If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required (performed by the local study site laboratory). Additional pregnancy testing can 
be conducted if required by local regulations or clinically indicated.
•
Archival tumor sample collection is not required to be obtained within 28 days before the 
first dose of study intervention. Newly obtained tumor tissue may be obtained according 
to the Procedures Manual.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
8.11.2
Initial Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
8.11.3
Second Course Treatment Phase
See Section 6.6.3 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 treatment due to disease recurrence 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 Discontinuation Visit should 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 should be performed.
8.11.5
Posttreatment Visit
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 pembrolizumab or MK-7684A 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 disease progression will begin Efficacy 
Follow-up and should be assessed every 12 weeks to monitor disease status. Every effort 
should be made to collect information regarding disease status until the start of new 
anticancer therapy, disease progression, death, end of study. Information regarding poststudy 
anticancer treatment will be collected if new treatment is initiated. Participants who 
completed all efficacy assessments and/or will not have further efficacy assessments must 
enter Survival Follow-up.
Participants who are eligible to receive retreatment with pembrolizumab or MK-7684A 
according to the criteria in Section 6.6.3 will move from the Efficacy Follow-up Phase to the 
Second Course Phase when they experience disease progression. Details are provided in the 
SoA (Section 1.3) for retreatment with 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.
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The first survival follow-up assessment should be scheduled as described below:
•
For participants who discontinue treatment intervention and who will not enter Efficacy 
Follow-up, the first survival follow-up contact will be scheduled 12 weeks after the 
Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).
•
For participants who completed assessments in Efficacy Follow-up, the first survival 
follow-up contact will be scheduled 12 weeks after the last efficacy assessment follow-up 
visit has been performed.
8.11.6
Survival Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an eDMC review, 
interim and/or final analysis. Upon Sponsor notification, all participants who do not/will not 
have a scheduled study visit or study contact during the Sponsor-defined period will be 
contacted for their vital status.
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9
KEY STATISTICAL CONSIDERATIONS
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 is closed to enrollment. This study has enrolled 1264 participants.
•
This study will be unblinded.
•
The estimated duration of study was updated from 6 years to 5 years.
•
Participants receiving MK-7684A will be transitioned to pembrolizumab.
•
Pembrolizumab can be sourced locally or centrally.
•
Participants with access to approved SOC (eg, immunotherapy, chemotherapy, targeted 
therapy, as monotherapy or in combination) should be considered for discontinuation 
from the study. Those benefiting from pembrolizumab with, but unable to access it as 
SOC outside the study, may continue on study and receive treatment with pembrolizumab 
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 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.
•
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.
•
The futility interim analysis (IA1) was conducted. The pre-specified efficacy interim 
analysis (IA2) and final analysis outlined in the SAP will not be conducted.
•
Selected analyses of safety and endpoints will be performed at the end of the study.
•
There will be no follow-up for survival status. Participants currently in imaging follow up 
should obtain imaging and further oncological care as per local standard of care. 
However, standard safety reporting should continue, as applicable.
•
Those participants remaining on study at the time of Amendment 06 should continue to 
be monitored in the study through the AE reporting period (Section 8.4).
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•
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.
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding/final database lock, changes are made to 
primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses, then the protocol will be amended (consistent with ICH Guideline E-9). Changes 
to exploratory or other nonconfirmatory analyses made after the protocol has been finalized, 
but prior to unblinding/final database lock, will be documented in a supplemental SAP 
(sSAP) and referenced in the Clinical Study Report (CSR) for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR. Separate analysis plans (ie, separate 
documents from the sSAP) will be developed to detail PK and biomarker analyses. The 
ePRO analysis plan will be included in the sSAP.
9.1
Statistical Analysis Plan Summary 
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 to 9.12.
Study Design 
Overview
A Phase 3, multicenter, randomized, double-blind study of MK-7684 with 
pembrolizumab as a coformulation (MK-7684A) versus pembrolizumab 
monotherapy as first line treatment for participants with PD-L1 positive (TPS ≥1%) 
metastatic NSCLC (KEYVIBE-003)
Treatment 
Assignment
Approximately 1246 participants will be randomized in a 1:1 ratio between 
treatment groups: (1) MK-7684A (2) pembrolizumab. 
Stratification factors are: 

ECOG PS (0 versus 1)

PD-L1 TPS (1% to 49% versus ≥50%)

Region: East Asia vs Non-East Asia
Analysis 
Populations
Efficacy: ITT
Safety: APaT
PRO: PRO FAS
Primary Endpoints

OS in participants with PD-L1 TPS ≥50%
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Secondary 
Endpoints

OS in participants with PD-L1 TPS ≥1% and PD-L1 TPS 1% to 49%

PFS per RECIST 1.1 as assessed by BICR in participants with PD-L1 TPS 
≥50%, PD-L1 TPS ≥1% and PD-L1 TPS 1% to 49%

OR per RECIST 1.1 as assessed by BICR in participants with PD-L1 TPS 
≥50%, PD-L1 TPS ≥1% and PD-L1 TPS 1% to 49%

DOR per RECIST 1.1 as assessed by BICR in participants with PD-L1 TPS 
≥50%, PD-L1 TPS ≥1% and PD-L1 TPS 1% to 49%

ePROs: global health status/QoL score, physical functioning score, role 
functioning score, and dyspnea score using EORTC QLQ C30 and cough and
chest pain scores using EORTC QLQ-LC13 in participants with PD-L1 TPS 
≥50%, PD-L1 TPS ≥1% and PD-L1 TPS 1% to 49%

Safety and tolerability
Statistical Methods
for Key Efficacy
Analyses
The primary hypotheses testing for OS and the secondary hypotheses testing for 
PFS and OS will be evaluated by comparing the MK-7684A group to the 
pembrolizumab group using 
. The HR will be estimated 
using a 
 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
 
Interim Analyses
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Multiplicity
Sample Size and
Power
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. Randomization will be implemented in an IRT.
Key aspects of blinding during interim analyses are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected 
endpoints.
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9.4.1
Efficacy Endpoints
Primary

Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause.
Secondary

Progression-free survival (PFS) 
PFS is defined as the time from randomization to the first documented disease 
progression per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. 

Objective Response (OR)
OR is defined as a confirmed CR or PR per RECIST 1.1 based on BICR.

Duration of Response (DOR)
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
Key safety endpoints are AEs and study treatment discontinuations due to AEs. In addition, 
safety parameters commonly used for evaluating investigational systemic anticancer 
treatments, including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes, 
will be evaluated by clinical review. AEs will be assessed as defined by NCI CTCAE, 
Version 5.0. A description of safety measures is provided in Section 8.3.
9.4.3
PRO Endpoints
Key PRO endpoints include the following:
•
Change from baseline in EORTC QLQ-C30 global health status/QoL score, physical 
functioning score, role functioning score, dyspnea score, and EORTC QLQ-LC13 cough 
and chest pain scores.
•
TTD as measured by EORTC QLQ-C30 global health status/QoL score, physical 
functioning score, role functioning score, dyspnea score, and EORTC QLQ-LC13 cough 
and chest pain scores.
Based on prior literature [Bjordal, K., et al 2000] [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 first onset of 10 or more (of 100) deterioration 
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from baseline in a given scale/subscale/item and confirmed by a second adjacent 10 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.
 
 
Details regarding PRO endpoints will be provided in the sSAP.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The analyses of the efficacy endpoints are based on the ITT population. All randomized 
participants will be included in this population. Participants will be analyzed in the treatment 
group to which they are randomized. Details on the approach to handling missing data are 
provided in Section 9.6.1.5.
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 analyzed in the treatment group corresponding to the study 
treatment they actually received. 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. 
At least one laboratory 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
Statistical testing and inference for safety analyses are described in Section 9.6.2. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 9.8. Nominal p-values may be computed for 
other efficacy analyses, but should be interpreted with caution due to potential issues of 
multiplicity, sample size, etc.
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Participants will be categorized into PD-L1 TPS groups based on stratification level at 
randomization.
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
The stratification factors used for randomization (see Section 6.3.2) will be applied to all 
stratified analyses, in particular,
 
In the 
event that there are small strata, for the purpose of analysis, strata will be combined to ensure 
sufficient number of participants, responses and events in each stratum. Details regarding the 
pooling strategy will be prespecified in the sSAP prior to the database lock for the first 
efficacy interim analysis, and decisions regarding the pooling will be based on a blinded 
review of response and event counts by stratum.
The efficacy analyses for PFS, OR, and DOR will include documented progression events 
and responses that occur prior to Second Course treatment.
9.6.1.1
Overall Survival (OS)
The nonparametric Kaplan-Meier method will be used to estimate the overall survival curves 
in each treatment group.
 
 
The stratification factors used for randomization 
(see Section 6.3.2) will be applied to both the stratified log-rank test and the stratified Cox 
model. Participants without documented death at the time of analysis will be censored at the 
date the participant was last known to be alive. Additional supportive unstratified analyses 
may also be provided.
9.6.1.2
Progression-free Survival (PFS)
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. 
 
 
 
 
 
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. The true date of disease progression will be approximated by the earlier of the 
date of the first assessment at which PD is objectively documented per RECIST 1.1 by BICR 
and the date of death. Death is always considered a PD event.
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9.6.1.3
Objective Response Rate (ORR)
The stratified Miettinen and Nurminen’s method will be used for the comparison of ORR 
between 2 treatment groups. The difference in ORR and its 95% CI from the 
 
 will be reported. The 
stratification factors used for randomization (see Section 6.3.2) will be applied to the 
analysis. The point estimate of ORR will be provided by treatment group, together with 95% 
CI using
 
9.6.1.4
Duration of Response (DOR)
If sample size permits, DOR will be summarized descriptively using Kaplan-Meier medians 
and quartiles. Only the subset of participants who show a confirmed CR or PR will be 
included in this analysis. 
 
9.6.1.5
Analysis Strategy for Key Efficacy Variables
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 10. 
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Table 10
Analysis Strategy for Key Efficacy Variables 
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses
OS
ITT 
(participants 
with PD-L1 
TPS ≥50%)
Censored at the date 
participant last known to be 
alive
Key Secondary Analyses
OS
Censored at the date 
participant last known to be 
alive
PFS per RECIST 1.1 
by BICR
Censored according to rules 
in Table 8
ORR per RECIST 1.1 
by BICR
Participants with missing 
data are considered 
nonresponders
BICR = blinded independent central review; ITT = intent-to-treat; ORR = objective response rate; OS = overall survival; PFS = 
progression-free survival; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors.
9.6.2
Statistical Methods for Safety Analyses
The primary safety analyses will include only events that occur prior to Second Course 
Treatment.
The overall safety evaluation will include a summary by treatment group of the number and 
percentage of participants with at least one AE, drug-related AE, serious AE, serious 
drug-related AE, Grade 3-5 AE, discontinuation from study intervention due to an AE, and 
an AE resulting in death. Only point estimates by treatment group are provided.
 
 
 
 
 
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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 (Table 11).
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 global health 
status/QoL, physical functioning, role functioning, dyspnea, cough, chest pain, and, EQ-5D-
5L VAS outcome 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 
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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 (TTD)
The Kaplan-Meier method will be used to estimate the TTD curve for each treatment group. 
The estimate of median TTD and its 95% confidence interval 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.
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 analyses 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. eDMC monitoring for safety will be conducted at a 
minimum every 6 months until such time that the eDMC determines that monitoring at a 
different frequency is appropriate.
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9.8
Multiplicity
9.8.1
Overall Survival
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9.8.2
Progression-free Survival
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9.8.3
Objective Response Rate
No initial alpha is allocated to test ORR. If superiority for all PFS and OS hypotheses (H1, 
H2, H3, H4 and H5) are declared, 
 
 
9.8.4
Safety Analyses
The eDMC has responsibility for assessment of overall risk/benefit. When prompted by 
safety concerns, the eDMC can request corresponding efficacy data. 
 
 
 
 
 
9.9
Sample Size and Power Calculations
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9.10
Subgroup Analyses
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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 Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, conducting, analyzing, 
and reporting these trials in compliance with the highest ethical and scientific 
standards. Protection of participants in clinical trials is the overriding concern in the 
design and conduct of clinical trials. In all cases, MSD clinical trials will be 
conducted in compliance with MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), 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 pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
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MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III.Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations and ICH Guidelines. Changes to the protocol that are required 
urgently to eliminate an immediate hazard and to protect participant safety may be 
enacted in anticipation of ethics committee approval. MSD will inform regulatory 
authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. Participants may 
withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on medical record review and medical evaluation 
to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the 
trial protocol, and in signing the protocol, agree to support these ethical and scientific 
standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
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financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
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By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules, 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee
This study was developed in consultation with a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide scientific and strategic guidance on 
various aspects of the clinical trial and/or development, which may include study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
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.
10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 Interim 
Analysis) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
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10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with 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 trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study-site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, 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.
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The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
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.
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Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
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 18 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 18
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
Blood Urea 
Nitrogen (BUN)c
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Bicarbonatea
Chloride
Phosphorousa
Creatinined
Sodium
Alanine 
Aminotransferase 
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose 
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 
esterase] by dipstick
• Microscopic examination (if blood or protein is abnormal)
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Laboratory 
Assessments
Parameters
Other Screening 
Tests
• PT/INR and aPTT/PTTf
• Serology (HIV antibody, HBsAg, and hepatitis C virus antibody) NOTE: certain ex-
US sites require testing for HIV and hepatitis B and C during screening. Consult with 
regional health authorities and institutional standards to confirm if such testing is 
applicable.
• Follicle-stimulating hormone (as needed in women of nonchildbearing potential only)
• TB Testing (South Africa only)
• Highly sensitive serum or urine human chorionic gonadotropin (hCG) pregnancy test 
(as needed for WOCBP).
FT4 = free thyroxine; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; INR = international 
normalized ratio; MCH = mean corpuscular hemoglobin; MCV, mean corpuscular volume; PT = prothrombin time; PTT 
= partial thromboplastin time; RBC = red blood cells; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating 
hormone; WBC = white blood cell; WOCBP = women of childbearing potential.
a.
Performed only if considered local standard of care.
b.
Absolute or % acceptable per institutional standard.
c.
Urea is acceptable if BUN is not available as per institutional standard.
d.
Glomerular filtration rate (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.
Performed as part of the screening assessment and as clinically indicated for participants taking anticoagulants.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
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 a condition of the study).
•
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.
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•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI 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 (pill 
count, diary, etc), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with IMP)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
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MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
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•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
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SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure 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 two FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only subdermal contraceptive implantc,d

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. 
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.

Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable

Progestogen-only hormonal contraceptionc,d
-
Oral
-
Injectable
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
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c
If locally required, in accordance with CTFG guidelines, acceptable hormonal contraceptives are limited to 
those which inhibit ovulation.
d IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
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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
South Africa-specific Requirements

Section 5.2 Exclusion Criteria
Exclusion Criterion: HIV testing is required for participants.
Exclusion Criterion: TB testing is required for participants.
10.7.2
Japan-specific Requirements

1.3 Schedule of Activities
Note: 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 the Sponsor. 

Section 1.3, Section 5.2, Section 8.11.1, and Section 10.2 Appendix 2
Hepatitis B testing (HBsAg, HBsAb, HBcAb) and Hepatitis C testing (HCV RNA 
[qualitative]) at screening is mandatory in Japan.

5.1 Inclusion Criteria
-
In addition to inclusion criterion 8, to be eligible for enrollment into this study, 
participants in Japan must also satisfy the following requirement: 
o
Female participants who stop breastfeeding at the start of the study but wish to 
resume breastfeeding thereafter are not eligible for enrollment in the study.
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
5.2 Exclusion Criteria
-
For participants in Japan, exclusion criterion 16 is as follows: 
o
Has an active hepatitis B infection (HBsAg positive) or known history of hepatitis 
B infection (defined as HBsAg is negative, and HBsAb and/or HBcAb is positive) 
or known active hepatitis C virus infection (defined as HCV RNA [qualitative] is 
detected). Note: Patients who are hepatitis B surface antibody (anti-HBs) positive 
by vaccine are eligible.
10.7.3
Vietnam-specific Requirements
Table 19
Study Intervention Information for Vietnam
No.
Study Drug Details
Arm 1
Arm 2
1
Drug name, Dosage form, Packaging
Drug name: MK-7684A 
(MK-3475 and MK-
7684)
Dosage form: Sterile 
solution for IV infusion.
Packaging: Each box
contains one vial of 20 
mL.
Drug name: MK-3475
Dosage form: Sterile 
solution for IV infusion.
Packaging: Each box 
contains 2 vials; each 
vial contains 4 mL.
2
Active Ingredient, Unit dose 
strength(s)/Concentration
MK-7684A at 10/10 
mg/mL (MK-3475 10 
mg/mL and MK-7684 10 
mg/mL).
MK-3475 at 100 mg/mL 
(25 mg/mL)
1 vial of 4 mL.
3
Unit
Box
Box
4
Amount
2496
2496
5
Shelf life
36 months
24 months
6
Specification
Manufacturer’s 
specification.
Manufacturer’s 
specification.
7
Indication
For the treatment of 
patients with PD-L1 
positive metastatic 
NSCLC.
For the treatment of 
patients with PD-L1 
positive metastatic 
NSCLC.
8
Manufacturer and manufactured country
MSD international 
GmbH t/a MSD Ireland 
(Carlow), Ireland
Or:
Patheon biologics LLC, 
US
Or:
Boehringer Ingelheim 
pharma GmbH & 
Co.KG, Germany.
MSD international 
GmbH t/a MSD Ireland 
(Carlow), Ireland
OR:
Patheon biologics LLC, 
US
Or:
Boehringer Ingelheim 
pharma GmbH & 
Co.KG, Germany.
9
Company owned marketed license on 
certification of pharmaceutical products
Not applicable as the drugs are in clinical trials in 
Vietnam.
IV= intravenous; PD-L1=programmed cell death ligand 1; NSCLC= non-small cell lung cancer; US=United States. 
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10.8
Appendix 8: Eastern Cooperative Oncology Group Performance Status
Grade
Performance Status
0
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair.
5
Dead 
[ECOG ACRIN Cancer Research Group 2016]
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
1L
first line
ACCP
American College of Chest Physicians
ADA
antidrug antibodies
AE
adverse event 
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
AST
aspartate aminotransferase
β-hCG
β-human chorionic gonadotropin
BICR
blinded independent central review
BP
blood pressure
CAC
Clinical Adjudication Committee
CD
cluster of differentiation
CI
confidence interval
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CL
clearance
COPD
chronic obstructive pulmonary disease
CPS
combined positive score
CrCl
creatinine clearance
CR
complete response
CRF
Case Report Form 
CRU
clinical research unit
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
ctDNA
circulating tumor DNA
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Abbreviation
Expanded Term
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DC
discontinuation
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
dMMR
defective DNA mismatch repair
DNA
deoxyribonucleic acid 
DOR
duration of response
DRESS
drug reaction with eosinophilia and systemic symptoms
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection 
eDMC
Data Monitoring Committee 
EGFR
epidermal growth factor receptor
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EORTC
European Organization for the Research and Treatment of Cancer
EOT
end-of-treatment
ePROs
electronic patient-reported outcomes
EQ-5D
EuroQoL-5D
ES-SCLC
Extensive stage small-cell lung cancer
FA
final analysis
FAS
Full Analysis Set
FBR
future biomedical research
FcR
Fc gamma receptor
FDA (AA)
Food and Drug Administration (Amendments Act)
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Abbreviation
Expanded Term
FFPE
Formalin-fixed, paraffin-embedded
FSH
follicle stimulating hormone 
FSR
first subject randomized
GCP
Good Clinical Practice 
G-CSF
Granulocyte Colony-Stimulating Factor
GERD
gastroesophageal reflux disease
GI
Gastrointestinal
GM-CSF
Granulocyte Macrophage Colony-Stimulating Factor
HBcAb
Hepatitis B core antibody
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCG
human chorionic gonadotropin
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HRQoL
health-related quality of life
IA
interim analysis
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iCRO
imaging Clinical Research Organization
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IgG
immunoglobulin G
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IND
Investigational New Drug 
IO
Immune-oncology
irAEs
immune-related AEs
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Abbreviation
Expanded Term
IRB
Institutional Review Board
iRECIST
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics
IRT
interactive response technology
ITT
intention to treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
Intravenous
IVD
in vitro diagnostic
LAM
lactational amenorrhea method
LS
least square 
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose 
NCI
National Cancer Institute
NK
natural killer
NKT
natural killer T
NSCLC
non-small cell lung cancer
NDA
New Drug Application 
NSAID
nonsteroidal anti-inflammatory drug
OR
objective response
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PBPK
physiologically based PK
PD
progressive disease
PD-1
programmed cell-death 1
PD-L1
programmed cell death ligand 1
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Abbreviation
Expanded Term
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PFS
progression-free survival
PK
Pharmacokinetic
PO
Orally
PR
partial response
PRO
patient-reported outcome
PS
performance status
PT
prothrombin time
PTT
partial thromboplastin time
PVRL-2
poliovirus receptor-related 2
QXW
every X week(s)
QoL
quality of life
QP2
department of quantitative pharmacology and pharmacometrics
RECIST
Response Evaluation Criteria in Solid Tumors
RFS
Recurrence-free survival
RNA
ribonucleic acid
ROS
c-ROS oncogene 1
RP2D
recommended Phase 2 dose
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SD
stable disease
siDMC
standing internal Data Monitoring Committee
SIM
Site Imaging Manual
SJS
Stevens-Johnson Syndrome
SNP
single nucleotide polymorphism
SoA
schedule of activities
SOC
standard of care
sSAP
supplemental Statistical Analysis Plan
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Abbreviation
Expanded Term
SUSAR
suspected unexpected serious adverse reaction
T3
triiodothyronine 
T4
thyroxine
Teff
effector T cell
TEN
toxic epidermal necrolysis
TIGIT
T cell immunoreceptor with Ig and ITIM domains
Tim-3
T cell immunoglobulin and mucin domain containing-3  
Treg
regulatory T cell
TSH
thyroid-stimulating hormone
TPS
tumor proportion score
TRAE
Treatment-related adverse events
TTD
time to deterioration
Vc
(central) volume of distribution
VAS
Visual Analog Scale
VOP
verification of progression
VS
vital sign
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
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11
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