A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate Pembrolizumab Versus Placebo as Adjuvant Therapy Following Surgery and Radiation in Participants With High-risk Locally Advanced Cutaneous Squamous Cell Carcinoma (LA cSCC) (KEYNOTE-630)
Phase: PHASE3
Conditions: Carcinoma, Squamous Cell
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase 3, Randomized, Double-blind, Placebo-controlled Study 
to Evaluate Pembrolizumab Versus Placebo as Adjuvant Therapy 
Following Surgery and Radiation in Participants with High-risk 
Locally Advanced Cutaneous Squamous Cell Carcinoma (LA 
cSCC) (KEYNOTE-630).
NCT03833167
12-DEC-2024

PRODUCT: MK-3475
1
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate 
Pembrolizumab Versus Placebo as Adjuvant Therapy Following Surgery and Radiation in 
Participants with High-risk Locally Advanced Cutaneous Squamous Cell Carcinoma 
(LA cSCC) (KEYNOTE-630)
Protocol Number: 630-10
Compound Number: MK-3475
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
03833167
EU CT
2022-500395-57-00
EudraCT
2018-001974-76
JAPIC-CT
Not applicable
WHO
Not applicable
UTN
Not applicable
IND
134760
Approval Date: 12 December 2024
08RB5W

PRODUCT: MK-3475
2
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
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
08RB5W

PRODUCT: MK-3475
3
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 10
12-DEC-2024
This amendment addresses a change in strategy to 
stop the study based on the recommendation of 
eDMC after review of the results from the 
prespecified efficacy IA (data cutoff 28-JUN-2024). 
At this IA, pembrolizumab did not cross the 
boundary for statistical significance in RFS by 
investigator assessment compared to placebo. OS
was not formally tested, but the HR point estimate 
did not favor pembrolizumab versus placebo. The 
risk/benefit profile did not support continuation of 
the study.
Amendment 9
02-NOV-2023
To update the statistical analysis strategy accounting 
for slower enrollment and faster RFS accumulation 
in the study
Amendment 8
28-JUN-2022
Include an iCRO to collect and hold images and add 
the collection of standard of care images during the 
Survival Follow-up Phase for participants who have 
not experienced a Recurrence-free Survival event
Amendment 7
09-AUG-2021
To correct inadvertent changes to contraception 
requirements table in Appendix 5 and make 
pregnancy testing required prior to every cycle to 
align with feedback from regulatory agencies
Amendment 6
10-JUN-2021
To harmonize the presentation of safety information 
across all Food and Drug Administration (FDA)-
approved programmed cell death 1/ ligand 1 
(PD-1/L1) antibody prescribing information; to roll 
country-specific requirements into the Country-
specific Requirements Appendix; for inclusion 
criteria clarification; removal of reference to a 
substudy for future biomedical research
Amendment 5/
Ireland-specific 
amendment
24-JAN-2020
Health authority request
Amendment 4/
Italy-specific 
amendment
04-NOV-2019
Health authority request
Amendment 3/
UK-specific 
amendment
25-JUL-2019
Change in eligibility for cross-over/retreatment 
participants
08RB5W

PRODUCT: MK-3475
4
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Document
Date of Issue
Overall Rationale
Amendment 2
25-JUL-2019
Change in eligibility for cross-over/retreatment 
participants
Amendment 1/
UK-specific 
amendment
30-JAN-2019
Clarify Screening exclusion, test requirements and 
dose modification guidelines for immune-related 
adverse events associated with pembrolizumab as 
required by the regulatory agency in the UK
Original 
Protocol
20-NOV-2018
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 10
Overall Rationale for the Amendment:
This amendment addresses a change in strategy to stop the study based on the 
recommendation of eDMC after review of the results from the prespecified efficacy IA 
(data cutoff 28-JUN-2024). At this IA, pembrolizumab did not cross the boundary for 
statistical significance in RFS by investigator assessment compared to placebo. OS was not 
formally tested, but the HR point estimate did not favor pembrolizumab versus placebo. The 
risk/benefit profile did not support continuation of the study.
Summary of Changes Table
Section 
Number and 
Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 1.1, 
Synopsis
Overall Design: Added a note (in alignment 
with the study-specific investigator letter 
dated 29-AUG-2024) to provide information 
regarding the results of the prespecified IA 
reviewed by eDMC and subsequent decision 
of the Sponsor to discontinue the study, and 
which analyses will or will not be conducted 
going forward. It also includes instructions for 
discontinuation of study intervention and a 
high-level summary of the modified protocol 
study procedures to be implemented as a 
result of the decision to discontinue the study.
To address a change in strategy to stop 
the study based on the results of the 
prespecified efficacy IA and incorporate 
instructions for discontinuation of study 
intervention, appropriate measures for 
follow-up of ongoing study participants, 
and the plan for end of study analysis 
going forward.
08RB5W

PRODUCT: MK-3475
5
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Section 1.1, 
Synopsis 
Duration of Participation: Added information on 
extension study giving ongoing study 
participants an option to transition into an 
extension study on study discontinuation.
To transition ongoing study 
participants into a pembrolizumab 
extension study, if available, prior to 
close out of this study.
Section 4.1, 
Overall Design
Added a note (in alignment with the study-
specific investigator letter dated 29-AUG-2024)
to provide information regarding the results of 
the prespecified IA reviewed by eDMC and 
subsequent decision of the Sponsor to 
discontinue the study, and which analyses will 
or will not be conducted going forward. It also 
includes instructions for discontinuation of study 
intervention and a high-level summary of the 
modified protocol study procedures to be 
implemented as a result of the decision to 
discontinue the study.
Refer to the rationale for primary 
reason for amendment.
Added information on extension study giving
ongoing study participants an option to 
transition into an extension study on study 
discontinuation.
To transition ongoing study 
participants into a pembrolizumab 
extension study, if available, prior to 
close out of this study.
Section 1.3, 
Schedule of 
Activities
Added a note to indicate the changes to the 
schedule of activities for participants who are 
still on the study. 
Refer to the rationale for primary 
reason for amendment.
Section 6.3.3, 
Blinding
Added text to indicate the study was unblinded 
after the efficacy IA.
Refer to the rationale for primary 
reason for amendment.
Section 8.2.1, 
Tumor Imaging 
and Assessment 
of Disease
Added text to indicate that scans will no longer 
be sent to the iCRO and digital photography of 
cutaneous lesions is no longer required.
Refer to the rationale for primary 
reason for amendment.
Section 8.2.1.7.2, 
iRECIST 
Assessment of 
Disease
Added text to indicate that scans will no longer 
be sent to the iCRO.
Refer to the rationale for primary 
reason for amendment.
Section 8.2.1.8, 
Photography for 
Cutaneous 
Lesions
Added text to indicate that digital photography 
of cutaneous lesions is no longer required.
Refer to the rationale for primary 
reason for amendment.
Section 8.2.2, 
Survival
Added text to indicate that scans will no longer 
be sent to the iCRO.
Refer to the rationale for primary 
reason for amendment.
Section 8.2.3, 
Patient Reported 
Outcomes
Added text to indicate that ePRO assessments 
will be discontinued.
Refer to the rationale for primary 
reason for amendment.
08RB5W

PRODUCT: MK-3475
6
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Section Number 
and Name
Description of Change
Brief Rationale
Section 8.11.4, 
Participants 
Discontinued 
From Study 
Intervention but 
Continuing to be 
Monitored in the 
Study
Added text to indicate the changes to the 
assessments/procedures for participants who are 
still on the study.
Refer to the rationale for primary 
reason for amendment.
Section 9, 
Statistical 
Analysis Plan
Added a note to provide information regarding 
the results of the prespecified IA reviewed by 
eDMC and subsequent decision of the Sponsor 
to discontinue the study and to clarify the scope 
of analyses to be performed subsequent to the 
decision to discontinue the study.
Refer to the rationale for primary 
reason for amendment.
Section 9.1, 
Statistical 
Analysis Plan 
Summary
Added text to clarify the scope of analyses to be 
performed subsequent to the decision to 
discontinue the study.
Refer to the rationale for primary 
reason for amendment.
Updated participant randomization status and 
added the final number of participants 
randomized in the study and the total sample 
size.
The study is being discontinued and 
no additional participants will be 
randomized.
Section 9.2, 
Responsibility 
for Analyses/In-
house Blinding
Added text to indicate the study was unblinded 
after efficacy IA.
Refer to the rationale for primary 
reason for amendment.
Section 9.6, 
Statistical 
Methods
Added a note to clarify the scope of analyses to 
be performed subsequent to the decision to 
discontinue the study.
Refer to the rationale for primary 
reason for amendment.
Section 9.7, 
Interim Analyses
Added a note to clarify that the prespecified 
final analysis described in the SAP will not be 
performed.
Refer to the rationale for primary 
reason for amendment.
Section 9.7.2, 
Safety Interim 
Analyses
Added text to clarify that safety monitoring will 
continue per protocol and safety analysis will be 
performed at the end of the study.
Refer to the rationale for primary 
reason for amendment.
Section 9.8, 
Multiplicity
Added a note to clarify that the prespecified 
final efficacy analysis involving hypothesis 
testing will not be performed and therefore, no 
multiplicity adjustment will be needed.
Refer to the rationale for primary 
reason for amendment.
Section 9.9, 
Sample Size and 
Power 
Calculations
Added final randomization numbers and noted 
that the power calculations are not applicable 
because no statistical testing will be performed.
Refer to the rationale for primary 
reason for amendment.
Throughout
Minor administrative, formatting, grammatical, 
and/or typographical changes were made 
throughout the document.
To ensure clarity and accurate 
interpretation of the intent of the 
protocol.
08RB5W

PRODUCT: MK-3475
7
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................23
1.3
Schedule of Activities...........................................................................................24
1.3.1
Adjuvant Treatment Phase...........................................................................24
1.3.2
Follow-up Phase...........................................................................................31
1.3.3
Cross-over / Retreatment .............................................................................35
2
INTRODUCTION..........................................................................................................40
2.1
Study Rationale....................................................................................................40
2.2
Background ..........................................................................................................40
2.2.1
Pharmaceutical and Therapeutic Background .............................................40
2.2.2
Preclinical and Clinical Studies ...................................................................45
2.2.3
Ongoing Clinical Studies.............................................................................46
2.3
Benefit/Risk Assessment......................................................................................46
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................47
4
STUDY DESIGN............................................................................................................49
4.1
Overall Design......................................................................................................49
4.2
Scientific Rationale for Study Design.................................................................51
4.2.1
Rationale for Endpoints ...............................................................................53
4.2.1.1
Efficacy Endpoints.............................................................................53
4.2.1.1.1
Recurrence-free Survival .........................................................53
4.2.1.1.2
Overall Survival.......................................................................53
4.2.1.2
Safety Endpoints................................................................................54
4.2.1.3
Patient-reported Outcomes.................................................................54
4.2.1.3.1
EORTC QLQ-C30 ...................................................................54
4.2.1.3.2
Skindex-16...............................................................................54
4.2.1.3.3
EuroQOL EQ-5D.....................................................................55
4.2.1.4
Planned Exploratory Biomarker Research.........................................55
4.2.1.5
Future Biomedical Research..............................................................56
4.3
Justification for Dose...........................................................................................57
4.4
Beginning and End-of-Study Definition ............................................................58
4.4.1
Clinical Criteria for Early Study Termination .............................................58
5
STUDY POPULATION ................................................................................................59
5.1
Inclusion Criteria.................................................................................................59
5.2
Exclusion Criteria................................................................................................63
08RB5W

PRODUCT: MK-3475
8
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
5.3
Lifestyle Considerations......................................................................................65
5.3.1
Meals and Dietary Restrictions....................................................................66
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................66
5.3.3
Activity Restrictions ....................................................................................66
5.3.4
Contraception...............................................................................................66
5.4
Screen Failures.....................................................................................................66
5.5
Participant Replacement Strategy......................................................................66
6
STUDY INTERVENTION............................................................................................67
6.1
Study Intervention(s) Administered...................................................................67
6.1.1
Treatment .....................................................................................................69
6.1.2
Medical Devices...........................................................................................69
6.2
Preparation/Handling/Storage/Accountability .................................................69
6.2.1
Dose Preparation..........................................................................................69
6.2.2
Handling, Storage, and Accountability........................................................69
6.3
Measures to Minimize Bias: Randomization and Blinding..............................70
6.3.1
Intervention Assignment..............................................................................70
6.3.2
Stratification.................................................................................................70
6.3.3
Blinding........................................................................................................70
6.4
Study Intervention Compliance..........................................................................71
6.5
Concomitant Therapy..........................................................................................71
6.5.1
Rescue Medications and Supportive Care ...................................................73
6.6
Dose Modification (Escalation/Titration/Other)...............................................73
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................73
6.6.2
Cross-over/Retreatment ...............................................................................78
6.7
Intervention After the End of the Study............................................................78
6.8
Clinical Supplies Disclosure................................................................................79
6.9
Standard Policies..................................................................................................79
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................80
7.1
Discontinuation of Study Intervention...............................................................80
7.2
Participant Withdrawal From the Study...........................................................81
7.3
Lost to Follow-up .................................................................................................81
8
STUDY ASSESSMENTS AND PROCEDURES........................................................82
8.1
Administrative and General Procedures ...........................................................82
8.1.1
Informed Consent.........................................................................................82
8.1.1.1
General Informed Consent.................................................................83
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................83
08RB5W

PRODUCT: MK-3475
9
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
8.1.2
Inclusion/Exclusion Criteria ........................................................................83
8.1.3
Participant Identification Card.....................................................................84
8.1.4
Medical History ...........................................................................................84
8.1.4.1
Disease Details...................................................................................84
8.1.5
Prior and Concomitant Medications Review...............................................84
8.1.5.1
Prior Medications...............................................................................84
8.1.5.2
Concomitant Medications..................................................................85
8.1.5.3
Post-study Anticancer Therapy Status...............................................85
8.1.6
Assignment of Screening Number...............................................................85
8.1.7
Assignment of Treatment/Randomization Number.....................................85
8.1.8
Study Intervention Administration ..............................................................85
8.1.8.1
Timing of Dose Administration.........................................................86
8.1.8.1.1
Adjuvant Treatment with Pembrolizumab/Placebo.................86
8.1.8.1.2
Cross-over/Retreatment with Pembrolizumab.........................86
8.1.9
Discontinuation and Withdrawal .................................................................88
8.1.9.1
Withdrawal From Future Biomedical Research ................................88
8.1.10
Participant Blinding/Unblinding..................................................................89
8.1.10.1
Emergency Unblinding......................................................................89
8.1.10.2
Unblinding by Investigator After First Disease Recurrence..............90
8.1.11
Domiciling ...................................................................................................90
8.1.12
Calibration of Equipment.............................................................................90
8.1.13
Tumor Tissue for Biomarker Status.............................................................91
8.2
Efficacy Assessments ...........................................................................................91
8.2.1
Tumor Imaging and Assessment of Disease................................................91
8.2.1.1
Initial Tumor Scans............................................................................92
8.2.1.2
Tumor Scans During the Study..........................................................92
8.2.1.3
End-of-treatment and Follow-up Tumor Scans .................................93
8.2.1.4
Cross-over/Retreatment Tumor Scans ...............................................93
8.2.1.5
Assessment of Disease Recurrence....................................................94
8.2.1.5.1
Criteria for Determination of Disease Recurrence...................94
8.2.1.5.2
Date of Recurrence ..................................................................95
8.2.1.6
Tumor Tissue Collection and Assessment of Disease Recurrence....96
8.2.1.7
Assessment of Disease Progression (Cross-over/Retreatment 
Phase Only)........................................................................................96
8.2.1.7.1
RECIST 1.1 Assessment of Disease........................................96
8.2.1.7.2
iRECIST Assessment of Disease.............................................96
8.2.1.8
Photography for Cutaneous Lesions..................................................99
8.2.2
Survival........................................................................................................99
08RB5W

PRODUCT: MK-3475
10
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
8.2.3
Patient-reported Outcomes.........................................................................100
8.3
Safety Assessments.............................................................................................100
8.3.1
Physical Examinations...............................................................................100
8.3.1.1
Full Physical Examination...............................................................100
8.3.1.2
Directed Physical Examination........................................................100
8.3.2
Vital Signs..................................................................................................101
8.3.3
Electrocardiograms ....................................................................................101
8.3.4
Clinical Safety Laboratory Assessments ...................................................101
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)........................................................................................101
8.3.4.2
Pregnancy Testing............................................................................102
8.3.4.3
HIV, HBV, and HCV Serology .......................................................102
8.3.5
Performance Assessments..........................................................................103
8.3.5.1
Eastern Cooperative Oncology Group Performance Status.............103
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................103
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................103
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....105
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.105
8.4.4
Regulatory Reporting Requirements for SAE ...........................................106
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................106
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................107
8.4.7
Events of Clinical Interest..........................................................................107
8.5
Treatment of Overdose......................................................................................108
8.6
Pharmacokinetics...............................................................................................108
8.7
Pharmacodynamics............................................................................................108
8.8
Biomarkers .........................................................................................................108
8.8.1
Planned Genetic Analysis Sample Collection............................................108
8.9
Future Biomedical Research Sample Collection.............................................109
8.10
Medical Resource Utilization and Health Economics.....................................109
8.11
Visit Requirements.............................................................................................109
8.11.1
Screening....................................................................................................109
8.11.2
Adjuvant Treatment Period Visits .............................................................110
8.11.3
Posttreatment Visit.....................................................................................110
8.11.3.1
End of Treatment Visit.....................................................................110
8.11.3.2
Safety Follow-up Visit.....................................................................111
8.11.3.3
Study Adjuvant Follow-up Visits ....................................................111
08RB5W

PRODUCT: MK-3475
11
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
8.11.3.4
Survival Follow-up Contacts ...........................................................111
8.11.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ..............................................................................112
8.11.5
Vital Status.................................................................................................112
9
STATISTICAL ANALYSIS PLAN ...........................................................................113
9.1
Statistical Analysis Plan Summary...................................................................113
9.2
Responsibility for Analyses/In-house Blinding ...............................................115
9.3
Hypotheses/Estimation ......................................................................................115
9.4
Analysis Endpoints.............................................................................................115
9.4.1
Efficacy Endpoints.....................................................................................115
9.4.2
Safety Endpoints........................................................................................116
9.4.3
PRO Endpoints...........................................................................................116
9.5
Analysis Populations..........................................................................................116
9.5.1
Efficacy Analysis Population.....................................................................116
9.5.2
Safety Analysis Population........................................................................116
9.5.3
PRO Analysis Population ..........................................................................116
9.6
Statistical Methods.............................................................................................117
9.6.1
Statistical Methods for Efficacy Analyses.................................................117
9.6.1.1
Recurrence-free Survival .................................................................117
9.6.1.2
Overall Survival...............................................................................118
9.6.1.3
Summary of Efficacy Analysis Methods.........................................119
9.6.2
Statistical Methods for Safety Analyses ....................................................119
9.6.3
Statistical Methods for PRO Analyses.......................................................121
9.6.4
Summaries of Baseline Characteristics and Demographics.......................121
9.7
................................................................................................122
9.7.1
..........................................................................122
9.7.2
.............................................................................123
9.8
.........................................................................................................123
9.8.1
...............................................123
9.8.2
...................................................125
9.9
Sample Size and Power Calculations ...............................................................125
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...................................................................................130
CCI
CCI
CCI
CCI
CCI
CCI
08RB5W

PRODUCT: MK-3475
12
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
10.1.3
Data Protection...........................................................................................130
10.1.3.1
Confidentiality of Data ....................................................................131
10.1.3.2
Confidentiality of Participant Records.............................................131
10.1.3.3
Confidentiality of IRB/IEC Information..........................................131
10.1.4
Committees Structure.................................................................................132
10.1.4.1
Scientific Advisory Committee (SAC)............................................132
10.1.4.2
Executive Oversight Committee......................................................132
10.1.4.3
External Data Monitoring Committee .............................................132
10.1.5
Publication Policy......................................................................................132
10.1.6
Compliance with Study Registration and Results Posting Requirements .133
10.1.7
Compliance with Law, Audit, and Debarment ..........................................133
10.1.8
Data Quality Assurance .............................................................................134
10.1.9
Source Documents .....................................................................................134
10.1.10
Study and Site Closure...............................................................................135
10.2
Appendix 2: Clinical Laboratory Tests............................................................136
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................138
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................138
10.3.2
Definition of AE ........................................................................................138
10.3.3
Definition of SAE ......................................................................................139
10.3.4
Additional Events Reported in the Same Manner as SAE.........................140
10.3.5
Recording AE and SAE .............................................................................141
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................144
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................146
10.5
Appendix 5: Contraceptive Guidance..............................................................147
10.5.1
Definitions..................................................................................................147
10.5.2
Contraceptive Requirements......................................................................148
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................149
10.7
Appendix 7: Country-specific Requirements..................................................153
10.7.1
France.........................................................................................................153
10.7.2
Germany.....................................................................................................155
10.7.3
Ireland ........................................................................................................156
10.7.4
Italy ............................................................................................................156
10.7.5
Norway.......................................................................................................158
10.7.6
United Kingdom.........................................................................................158
08RB5W

PRODUCT: MK-3475
13
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................161
10.9
Appendix 9: Abbreviations ...............................................................................165
11
REFERENCES.............................................................................................................170
08RB5W

PRODUCT: MK-3475
14
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values .............................................63
Table 2
Study Interventions......................................................................................68
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with Pembrolizumab Monotherapy, 
Coformulations, or IO Combinations ..........................................................74
Table 4
Pembrolizumab Monotherapy, Coformulations, or IO Combinations –
Infusion Reaction Dose Modification and Treatment Guidelines ...............77
Table 5
Required Scans.............................................................................................93
Table 6
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease.........................................................................................................98
Table 7
Reporting Time Periods and Time Frames for AEs and Other 
Reportable Safety Events...........................................................................105
Table 8
Censoring Rules for Primary and Sensitivity Analyses of RFS ................118
Table 9
Efficacy Analysis Methods for Primary and Secondary Efficacy 
Endpoints ...................................................................................................119
Table 10
Analysis Strategy for Safety Parameters....................................................121
Table 11
.................122
Table 12
.....................................123
Table 13
.............................124
Table 14
...............................125
Table 15
Protocol-required Safety Laboratory Assessments....................................136
CCI
CCI
CCI
CCI
08RB5W

PRODUCT: MK-3475
15
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
LIST OF FIGURES
Figure 1
Study Design................................................................................................23
Figure 2
Imaging and Treatment for Clinically Stable Participants Treated with 
Pembrolizumab after First Radiologic Evidence of PD Assessed by the 
Investigator ..................................................................................................99
Figure 3
...................................................................................124
CCI
08RB5W

PRODUCT: MK-3475
16
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate 
Pembrolizumab Versus Placebo as Adjuvant Therapy Following Surgery and Radiation in 
Participants with High-risk Locally Advanced Cutaneous Squamous Cell Carcinoma 
(LA cSCC) (KEYNOTE-630)
Short Title: Pembrolizumab as adjuvant therapy for resectable high-risk LA cSCC
Acronym: KEYNOTE-630
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
08RB5W

PRODUCT: MK-3475
17
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
In male/female participants aged 18 years or older with resectable high-risk LA cSCC after 
surgery and RT:
Primary Objective
Primary Endpoint
Objective: To compare the recurrence-free 
survival (RFS), as assessed by the 
investigator and confirmed by biopsy, in 
individuals who receive pembrolizumab 
with individuals who receive placebo as 
adjuvant therapy.
Hypothesis (H1): Pembrolizumab as 
adjuvant therapy is superior to placebo with 
respect to RFS as assessed by the 
investigator
-RFS: defined as the time from the date of 
randomization to the date of first record of 
the following events:
-Local or regional recurrence of the index 
lesion
-Distant metastasis
-Death due to any cause
Note: A new low risk primary cSCC is not 
considered as a RFS event
Secondary Objectives
Secondary Endpoints
Objective: To compare overall survival 
(OS) in individuals who receive 
pembrolizumab with individuals who 
receive placebo as adjuvant therapy.
Hypothesis (H2): Pembrolizumab as 
adjuvant therapy is superior to placebo with 
respect to OS.
OS: defined as time from randomization to 
death due to any cause
To compare mean change from baseline in 
health-related quality of life (HRQoL) 
scores from the European Organisation for 
Research and Treatment of Cancer 
(EORTC) QoL Questionnaire (QLQ) C30, 
in individuals who receive pembrolizumab 
with individuals who receive placebo as 
adjuvant therapy.
-EORTC QLQ-C30 global health 
status/QoL scales
-EORTC QLQ-C30 physical functioning 
scale
Objective: To determine the safety and 
tolerability of pembrolizumab as adjuvant 
therapy.
-Adverse events (AEs)
-Study drug discontinuations due to AEs
08RB5W

PRODUCT: MK-3475
18
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Squamous cell carcinoma of skin
Population
Participants with high-risk LA cSCC 
eligible for adjuvant treatment following 
surgery and RT with curative intent
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Placebo
Study Blinding
Double-blind
Blinding Roles
Investigator, Participant, Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 8 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.
NOTE: This study will be discontinued based on the results of the prespecified IA of efficacy 
and safety data (data cutoff 28-JUN-2024) reviewed by eDMC on 21-AUG-2024. At this IA, 
pembrolizumab did not cross the boundary for statistical significance in RFS by investigator 
assessment compared to placebo. Although not formally tested based on multiplicity strategy, 
the OS point estimate did not favor pembrolizumab versus placebo. The eDMC 
recommended that the study should be stopped for futility as the benefit/risk profile did not 
support continuing the study. The EOC reviewed the data and accepted the eDMC’s 
recommendation. Based on these data and the recommendation of the eDMC, the study was 
unblinded on 22-AUG-2024. The prespecified final efficacy analysis of the study described 
in the SAP will not be performed. Efficacy and safety analyses will be performed at the end 
of the study; there will be no further planned analyses for ePRO endpoints. 
In alignment with the study-specific investigator letter dated 29-AUG-2024, all participants 
should discontinue study treatment (pembrolizumab/placebo). On a case-by-case basis, the 
investigators may contact the Sponsor for the consideration of continuing pembrolizumab 
treatment if they assess a participant is deriving clinical benefit. All ongoing participants 
should undergo study procedures as specified in this amendment (Amendment 10).
As of Amendment 10, ePRO assessments are no longer required. Participants should 
continue tumor imaging and investigator assessment of the tumor scans per protocol; 
08RB5W

PRODUCT: MK-3475
19
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
however, scans no longer need to be submitted to the iCRO and digital photography of 
cutaneous lesions is not required.
Number of Participants:
Approximately 430 participants will be randomized in the study.
Intervention Groups and Duration:
Arm Name
Intervention Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment Period
Use
Pembrolizumab
Pembrolizumab
25 mg/mL
400 mg
IV Infusion
Q6W; Day 1 of 
each 42-day cycle 
for up to 9 cycles 
(approximately 
1 year)
Test 
Product
Placebo
Placebo
N/A
N/A
IV Infusion
Q6W; Day 1 of 
each 42-day cycle 
for up to 9 cycles 
(approximately 
1 year)
Placebo
IV=intravenous; N/A=not applicable; Q6W=every 6 weeks
Following surgical resection and RT, participants will be randomized to receive either:
•
Pembrolizumab (Pembrolizumab group) - 400 mg fixed dose, intravenously (IV) every 
6 weeks (Q6W) for up to 9 cycles, or
•
Placebo (Control group)
After first biopsy proven disease recurrence: if clinically indicated (and with Sponsor 
approval) participants may cross over to or receive retreatment with pembrolizumab 400 mg 
IV Q6W for up to 18 cycles; for participants that received pembrolizumab in the Adjuvant 
Treatment Phase, any retreatment will be a minimum of 6 months after completing all 
9 cycles in the Adjuvant Treatment Phase.
Other current or former names or aliases for study intervention are as follows: 
KEYTRUDA®, MK-3475.
08RB5W

PRODUCT: MK-3475
20
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Total Number of Intervention Groups/Arms
2
Duration of Participation
Each participant will participate in the study 
from the time that the participant provides 
documented informed consent through the 
final protocol-specified contact.
After a screening phase of up to 28 days, 
each participant will be assigned to receive 
study adjuvant treatment until new high-risk 
primary cSCC or biopsy proven* disease 
recurrence, start of new anticancer 
treatment, unacceptable AE(s) toxicity, 
intercurrent illness that prevents further 
administration of treatment, investigator’s 
decision to discontinue the participant, 
participant withdrawal of consent, 
pregnancy of the participant, administrative 
reasons requiring cessation of treatment, or 
until the participant has received 9 
administrations of pembrolizumab 
(approximately 1 year). Upon first biopsy 
proven* disease recurrence, treatment will 
be unblinded. If clinically indicated (and 
with Sponsor approval), participants may 
cross over to or receive open-label 
retreatment with pembrolizumab until 
disease progression as assessed by the 
investigator per Response Evaluation 
Criteria in Solid Tumors 1.1 (RECIST 
1.1)/modified RECIST 1.1 for 
immune-based therapeutics (iRECIST), start 
of new systemic anticancer therapy, 
unacceptable AE(s) toxicity, intercurrent 
illness that prevents further administration 
of treatment, investigator’s decision to 
discontinue the participant, noncompliance 
with study treatment or procedure 
requirements, participant withdrawal of 
consent, pregnancy of the participant, 
administrative reasons requiring cessation 
of treatment, or until the participant has 
received 18 administrations of 
pembrolizumab (approximately 2 years); for 
participants that received pembrolizumab in 
the Adjuvant Treatment Phase, any 
retreatment will be a minimum of 6 months 
08RB5W

PRODUCT: MK-3475
21
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
after completing all 9 cycles (approximately 
1 year) in the Adjuvant Treatment Phase. 
The decision to retreat will be at the 
discretion of the investigator (after approval 
from the Sponsor) if they meet the criteria 
for cross-over/retreatment and the study is 
ongoing.
After the end of treatment, each participant 
will be followed for the occurrence of AEs 
and spontaneously reported pregnancy as 
described under Section 8.4. 
Participants who discontinue study adjuvant 
treatment for reasons other than a new 
high-risk primary cSCC or disease 
recurrence will have Study Adjuvant 
follow-up for disease status monitoring until 
a new high-risk primary cSCC or biopsy 
proven* disease recurrence, withdrawal of 
consent, pregnancy, death, or lost to 
followup. Participants who discontinue 
study treatment in cross-over/retreatment 
for reasons other than disease progression 
will have Safety and Survival Follow-up. 
All participants will be followed by 
telephone for OS until death, withdrawal of 
consent, or the end of the study.
* Tissue biopsy is required for the 
confirmation of disease recurrence. Only if 
a biopsy cannot be performed due to 
feasibility, such as location of recurrence 
(ie, bone lesion), and upon Sponsor 
consultation, can radiographic imaging be 
used to confirm disease recurrence.
On study discontinuation, all ongoing 
participants will be discontinued and may 
be enrolled in an extension study, if 
available. In the extension study, 
participants who experience disease 
recurrence per SOC clinical assessment may 
be considered eligible for 
cross-over/retreatment upon consultation 
with the Sponsor.
08RB5W

PRODUCT: MK-3475
22
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Scientific Advisory Committee
Yes
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 9.
08RB5W

PRODUCT: MK-3475
23
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
* Upon biopsy proven disease recurrence, and with Sponsor approval, treatment will be unblinded; if clinically 
indicated, participants may cross over to (within 12 weeks of biopsy proven recurrence) or receive retreatment 
(if biopsy proven disease recurrence occurs more than 6 months after completing 1 year of study adjuvant 
therapy) with open-label pembrolizumab 400 mg IV Q6W. 
FU=follow-up; IV=intravenous; Q6W=every 6 weeks
08RB5W

PRODUCT: MK-3475
24
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
1.3
Schedule of Activities
Details of each procedure outlined in the Schedule of Activities are provided in Section 8. Refer to Appendix 7 for country-specific 
requirements.
NOTE: As of Amendment 10, participants who are still on the study will no longer require ePRO assessments to be performed. For all 
ongoing participants, tumor imaging and investigator assessments of tumor scans should continue per protocol. Digital photography of 
cutaneous lesions is not required and tumor scans no longer need to be submitted to the iCRO.
The full SoA tables below are retained for reference.
1.3.1
Adjuvant Treatment Phase
Trial Period
Screening
Treatment Cycle
EOT
Notes:
Cycles will be repeated up to 9 infusions or until 
protocol-specific criteria to discontinue treatment is met.
Participants that complete or discontinue study treatment 
for reasons other than a new high-risk primary cSCC or 
disease recurrence will have a Safety FU and then proceed 
to Adjuvant FU (Section 1.3.2).
Participants that discontinue study treatment due to a new 
high-risk primary cSCC or disease recurrence will have a 
Safety FU and then proceed directly to Survival FU 
(Section 1.3.2) or cross-over, if eligible (Section 1.3.3).
Treatment Cycle/Title
1
2
3
4 to 9
Discon
Scheduled Window (days)
-28 to -1
+3
±3
±3
±3
±3
±3
At time of 
treatment discon
Day of visit
D1
D22
D1
D22
D1
D1
Administrative Procedures
Informed Consent
X
Additional consent is required at disease recurrence.
Informed Consent for Future 
Biomedical Research 
X
Optional, the participant may participate in the study 
without participating in FBR.
Inclusion/ Exclusion Criteria
X
Participant Identification Card
X
X
Add the allocation or randomization number at the time of 
allocation or randomization.
Demographics and Medical History
X
08RB5W

PRODUCT: MK-3475
25
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Trial Period
Screening
Treatment Cycle
EOT
Notes:
Cycles will be repeated up to 9 infusions or until 
protocol-specific criteria to discontinue treatment is met.
Participants that complete or discontinue study treatment 
for reasons other than a new high-risk primary cSCC or 
disease recurrence will have a Safety FU and then proceed 
to Adjuvant FU (Section 1.3.2).
Participants that discontinue study treatment due to a new 
high-risk primary cSCC or disease recurrence will have a 
Safety FU and then proceed directly to Survival FU 
(Section 1.3.2) or cross-over, if eligible (Section 1.3.3).
Treatment Cycle/Title
1
2
3
4 to 9
Discon
Scheduled Window (days)
-28 to -1
+3
±3
±3
±3
±3
±3
At time of 
treatment discon
Day of visit
D1
D22
D1
D22
D1
D1
Prior/Concomitant Medication Review
X
X
X
X
X
X
X
X
Prior medications – Record all medications taken within 
28 days of first dose. 
Concomitant medications – Enter new medications started 
during the study through the Safety Follow-up visit.
Post-study Anticancer Therapy Status
X
Treatment Randomization via IRT
X
Site personnel will access the IRT after screening and 
determine if the participant is eligible for randomization.
Study Intervention Administration 
X
X
X
X
Treatment 1, Cycle 1 must be given within 3 days after 
treatment randomization via IRT. Study drug to be 
administered on D1 of each cycle after all procedures/ 
assessments have been completed.
Unblinding - for Participants with 
Disease Recurrence Only
X*
*Upon biopsy-confirmed disease recurrence participants 
will be unblinded (see Section 8.1.10); if clinically 
indicated (and with Sponsor approval) participants may 
cross over to or receive retreatment with pembrolizumab 
(see Section 8.1.8). Participants that complete study 
treatment or discontinue for reasons other than disease 
recurrence will not be unblinded.
Vital Status
Upon Sponsor request, participants may be contacted for 
survival status at any time during the study.
08RB5W

PRODUCT: MK-3475
26
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Trial Period
Screening
Treatment Cycle
EOT
Notes:
Cycles will be repeated up to 9 infusions or until 
protocol-specific criteria to discontinue treatment is met.
Participants that complete or discontinue study treatment 
for reasons other than a new high-risk primary cSCC or 
disease recurrence will have a Safety FU and then proceed 
to Adjuvant FU (Section 1.3.2).
Participants that discontinue study treatment due to a new 
high-risk primary cSCC or disease recurrence will have a 
Safety FU and then proceed directly to Survival FU 
(Section 1.3.2) or cross-over, if eligible (Section 1.3.3).
Treatment Cycle/Title
1
2
3
4 to 9
Discon
Scheduled Window (days)
-28 to -1
+3
±3
±3
±3
±3
±3
At time of 
treatment discon
Day of visit
D1
D22
D1
D22
D1
D1
Efficacy Procedures
Tumor Imaging - CT/MRI - Head and 
Neck, Chest, Abdomen, Pelvis and 
Extremities (if indicated)
X
--If clinically indicated‡--
X‡
Q12W
X*
Baseline imaging will be performed within 28 days prior 
to the date of randomization. 
‡ The first on-study imaging assessment should be 
performed at 12 weeks (±7 days) from the date of 
randomization; subsequent tumor imaging (to include 
disease involved areas and associated draining lymph node 
regions) every 12 weeks (84 days ±7days) until end of 
Year 2, or more frequently if clinically indicated. For all 
imaging, the clock will start from the date of treatment 
allocation. 
* In participants who discontinue study therapy, imaging 
should be performed at the time of treatment 
discontinuation (ie, date of discontinuation ±4 weeks). If 
previous scan/ was obtained within 4 weeks prior to the 
date of discontinuation, then a scan at treatment 
discontinuation does not need to be performed.
Continuation of imaging/biopsies is required for 
participants who have not yet experienced a new high-risk 
primary cSCC or disease recurrence. 
Digital Photography: Cutaneous 
Lesions
------If Clinically Indicated------
At time of disease recurrence (see Section 8.2.1.8).
Biopsy
------If Clinically Indicated------
Details of any biopsy-confirmed disease recurrence to be 
inserted into the eCRF. Sponsor consultation is required if 
a biopsy cannot be performed due to feasibility.
08RB5W

PRODUCT: MK-3475
27
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Trial Period
Screening
Treatment Cycle
EOT
Notes:
Cycles will be repeated up to 9 infusions or until 
protocol-specific criteria to discontinue treatment is met.
Participants that complete or discontinue study treatment 
for reasons other than a new high-risk primary cSCC or 
disease recurrence will have a Safety FU and then proceed 
to Adjuvant FU (Section 1.3.2).
Participants that discontinue study treatment due to a new 
high-risk primary cSCC or disease recurrence will have a 
Safety FU and then proceed directly to Survival FU 
(Section 1.3.2) or cross-over, if eligible (Section 1.3.3).
Treatment Cycle/Title
1
2
3
4 to 9
Discon
Scheduled Window (days)
-28 to -1
+3
±3
±3
±3
±3
±3
At time of 
treatment discon
Day of visit
D1
D22
D1
D22
D1
D1
EORTC QLQ-C30
X
X
X
X‡
Q12W
X*
PROs are to be administered by trained site personnel on 
D1 of C1, C2, C3 and then every 2 cycles (ie, every 
12 weeks)‡ until end of Year 2. It is strongly 
recommended that PROs are completed by participants 
prior to all procedures/assessments, and in the following 
order: EORTC QLQ-C30, Skindex-16, and then EQ-5D.
If the participant does not complete the PROs for any 
reason, the Miss Mode form must be completed to capture 
the reason the assessment was not performed.
*In participants who discontinue study therapy, PROs 
should be administered at the time of treatment 
discontinuation (ie, date of discontinuation ±4 weeks). If 
previous PROs were obtained within 4 weeks prior to the 
date of discontinuation, then administration of PROs at 
treatment discontinuation does not need to be performed.
Skindex-16
X
X
X
X‡
Q12W
X*
EuroQol EQ-5D
X
X
X
X‡
Q12W
X*
Safety Procedures
Full Physical Examination and Height*
X
X
To be performed by the investigator or medically qualified 
designee. 
Follow NCCN cSCC 2018 guidelines: To include a history 
and physical exam that includes a complete skin and 
lymph node exam. *Height will be measured at Screening 
only.
08RB5W

PRODUCT: MK-3475
28
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Trial Period
Screening
Treatment Cycle
EOT
Notes:
Cycles will be repeated up to 9 infusions or until 
protocol-specific criteria to discontinue treatment is met.
Participants that complete or discontinue study treatment 
for reasons other than a new high-risk primary cSCC or 
disease recurrence will have a Safety FU and then proceed 
to Adjuvant FU (Section 1.3.2).
Participants that discontinue study treatment due to a new 
high-risk primary cSCC or disease recurrence will have a 
Safety FU and then proceed directly to Survival FU 
(Section 1.3.2) or cross-over, if eligible (Section 1.3.3).
Treatment Cycle/Title
1
2
3
4 to 9
Discon
Scheduled Window (days)
-28 to -1
+3
±3
±3
±3
±3
±3
At time of 
treatment discon
Day of visit
D1
D22
D1
D22
D1
D1
Directed Physical Examination 
X
X
X
X
X
X
To be performed by the investigator or medically qualified 
designee. Follow NCCN cSCC 2018 guidelines: To 
include a history and physical exam that includes a 
complete skin and lymph node exam.
Weight and Vital Signs
X
X
X
X
X
X
X
X
Vital signs to be collected include: temperature, resting 
pulse, resting respiratory rate, blood pressure. 
12-lead ECG (local)
X
Urine or Serum β-hCG Pregnancy Test 
(POCBP only) – as per local SOP
X
X
X
X
X
The protocol requires pregnancy testing within 72 hours 
prior to administration of each dose of study treatment. 
Refer to Appendix 7 for country-specific requirements for 
Germany, Ireland, Italy, Norway, and the UK.
HIV, Hepatitis B and C Screen (testing 
optional per site SOP)
X
Testing is required where mandated by the local health 
authority. For Germany-and UK-specific requirements see 
Appendix 7.
Coagulation Tests (PT/INR and 
aPTT/PTT)
X
--If Clinically Indicated-
Screening - within 10 days prior to the start of study 
treatment. Samples to be taken prior to study drug 
administration. 
Any participant receiving anticoagulant therapy should 
have coagulation tests monitored closely throughout the 
study. PTT may be performed if the local laboratory is 
unable to perform aPTT. 
08RB5W

PRODUCT: MK-3475
29
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Trial Period
Screening
Treatment Cycle
EOT
Notes:
Cycles will be repeated up to 9 infusions or until 
protocol-specific criteria to discontinue treatment is met.
Participants that complete or discontinue study treatment 
for reasons other than a new high-risk primary cSCC or 
disease recurrence will have a Safety FU and then proceed 
to Adjuvant FU (Section 1.3.2).
Participants that discontinue study treatment due to a new 
high-risk primary cSCC or disease recurrence will have a 
Safety FU and then proceed directly to Survival FU 
(Section 1.3.2) or cross-over, if eligible (Section 1.3.3).
Treatment Cycle/Title
1
2
3
4 to 9
Discon
Scheduled Window (days)
-28 to -1
+3
±3
±3
±3
±3
±3
At time of 
treatment discon
Day of visit
D1
D22
D1
D22
D1
D1
CBC With Differential
X
X§
X
X
X
X
X
X
Screening - within 10 days prior to the start of study 
treatment. Samples to be taken prior to study drug 
administration. After Cycle 1, samples can be collected up 
to 72 hours prior to the scheduled time point.
§Optional - CBC and Chemistry labs are not required at 
C1D1 if they were collected during screening and within 
10 days of first dose.
* In case of elevated TSH add free T3 and free T4.
‡ To be repeated every 2 cycles.
Unresolved abnormal labs that are drug-related AEs 
should be followed until resolution. Labs do not need to be 
repeated after the EOT if labs are within normal range.
Chemistry Panel
X
X§
X
X
X
X
X
X
Urinalysis
X
Thyroid Function (TSH)*, T3, FT4
X
X
X‡
X
ECOG Performance Status
X
X
X
X
X
X
X
X
Screening - ECOG is to be performed within 10 days prior 
to the first dose of study therapy. Must be performed prior 
to each dose of study treatment where ECOG is collected.
AE/SAE Review
X
-------------Continuous Reporting-------------
Record all AEs and ECIs occurring within 30 days after 
EOT and SAEs for 90 days after the EOT or 30 days after 
EOT if the participant initiates new anticancer therapy 
(whichever is earlier). Report treatment-related SAEs 
regardless of when they occur.
Pharmacodynamics/ Biomarkers
Blood for Genetic Analysis
X
See Section 8.8 for details
Blood for RNA Analyses
X
X
X
X*
X
* Cycle 5 only
Blood for Plasma Biomarker Analysis
X
X
X
X*
X
* Cycle 5 only
08RB5W

PRODUCT: MK-3475
30
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Trial Period
Screening
Treatment Cycle
EOT
Notes:
Cycles will be repeated up to 9 infusions or until 
protocol-specific criteria to discontinue treatment is met.
Participants that complete or discontinue study treatment 
for reasons other than a new high-risk primary cSCC or 
disease recurrence will have a Safety FU and then proceed 
to Adjuvant FU (Section 1.3.2).
Participants that discontinue study treatment due to a new 
high-risk primary cSCC or disease recurrence will have a 
Safety FU and then proceed directly to Survival FU 
(Section 1.3.2) or cross-over, if eligible (Section 1.3.3).
Treatment Cycle/Title
1
2
3
4 to 9
Discon
Scheduled Window (days)
-28 to -1
+3
±3
±3
±3
±3
±3
At time of 
treatment discon
Day of visit
D1
D22
D1
D22
D1
D1
Blood for Serum Biomarker Analyses
X
X
X
X*
X
* Cycle 5 only
Blood for ctDNA
X
X*
*Collected at end of treatment or disease recurrence
(whichever comes first).
Tumor Tissue Sample Collection
Tissue Collection for Biomarker 
Analysis (tested centrally)
X
(x)
Baseline tumor tissue for biomarker analysis from a newly 
obtained core or excisional biopsy (FNA not adequate) or 
prior archival tissue specimen must be provided to the 
central vendor for PD-L1 biomarker testing. 
(x) Optional - biopsy may be collected at recurrence if 
participant consents.
AE=adverse event; aPTT=activated partial thromboplastin time; β-hCG=β-human chorionic gonadotropin; C=cycle; CBC=complete blood count; cSCC=cutaneous squamous cell 
carcinoma; ctDNA=circulating tumor DNA; CT=computed tomography; D=day; ECG=electrocardiogram; ECI=event of clinical interest; ECOG=Eastern Cooperative Oncology 
Group; eCRF=electronic case report form; EORTC=European Organisation for Research and Treatment of Cancer; EOT=End of Treatment; EQ-5D=EuroQol-5 Dimensions; 
FBR=Future Biomedical Research; FNA=fine needle aspirate; FT4=free thyroxine; FU=follow-up; HIV=human immunodeficiency virus; INR=international normalized ratio; 
IRT=Interactive Response Technology; MRI=magnetic resonance imaging; NCCN=National Comprehensive Cancer Network; PD L1=Programmed Death Ligand 1; 
POCBP=participants of childbearing potential; PRO=patient-reported outcome; PT=prothrombin time; PTT=partial thromboplastin time; Q12W=every 12 weeks; QLQ-
C30=Quality of Life Questionnaire-C30; RNA=ribonucleic acid; SAE=serious adverse event; SOP=standard operating procedure; T3=triiodothyronine; TSH=thyroid-stimulating 
hormone; UK=United Kingdom.
08RB5W

PRODUCT: MK-3475
31
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
1.3.2
Follow-up Phase
Trial Period
Follow-up Phase
Notes:
A participant may discontinue from study treatment for any reason other than 
a new high-risk primary cSCC or disease recurrence but will remain in the 
study for Study Adjuvant follow-up for disease recurrence (Section 8.11.3.3) 
unless consent is withdrawn.
Participants that discontinue study treatment due to a new high-risk primary 
cSCC or disease recurrence will have Safety FU then proceed directly to 
Survival FU or cross-over/retreatment if eligible (Section 1.3.3).
Participants that complete adjuvant treatment or discontinue study treatment 
for reasons other than a new high-risk primary cSCC or disease recurrence 
will enter Safety FU then proceed to Adjuvant FU. 
*For participants that discontinue before Year 1. 
‡ More frequent FU is permitted based on risk and per treating physician 
discretion. When clinically indicated additional diagnostic evaluation, 
including imaging, can be performed by treating physician discretion.
Visit Number/Title
Safety 
FU
Study Adjuvant FU‡
Survival 
FU
Treatment Cycle/Day
Up to 
Year 1*
Years 1-
2
Years 
3-5
Scheduling Window Days 
(unless noted)
30 days 
from 
last 
dose 
±14 
Q12W
±7
Q12W
±7
Q6M 
±14
Q12W 
±14
Administrative 
Procedures
Prior/Concomitant 
Medication Review 
X
Unblinding- for participants 
with disease recurrence 
only.
Upon biopsy-confirmed disease recurrence participants will be unblinded 
(see Section 8.1.10); if clinically indicated (and with Sponsor approval) 
participants may cross over to or receive retreatment with pembrolizumab 
(see Section 8.1.8). Participants that discontinue FU for reasons other than 
disease recurrence will not be unblinded.
Post-study Anticancer 
Therapy Status
X
Vital Status
X
By telephone contact in Survival FU.
The Sponsor may request survival status to be assessed at additional time 
points during the study.
08RB5W

PRODUCT: MK-3475
32
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Trial Period
Follow-up Phase
Notes:
A participant may discontinue from study treatment for any reason other than 
a new high-risk primary cSCC or disease recurrence but will remain in the 
study for Study Adjuvant follow-up for disease recurrence (Section 8.11.3.3) 
unless consent is withdrawn.
Participants that discontinue study treatment due to a new high-risk primary 
cSCC or disease recurrence will have Safety FU then proceed directly to 
Survival FU or cross-over/retreatment if eligible (Section 1.3.3).
Participants that complete adjuvant treatment or discontinue study treatment 
for reasons other than a new high-risk primary cSCC or disease recurrence 
will enter Safety FU then proceed to Adjuvant FU. 
*For participants that discontinue before Year 1. 
‡ More frequent FU is permitted based on risk and per treating physician 
discretion. When clinically indicated additional diagnostic evaluation, 
including imaging, can be performed by treating physician discretion.
Visit Number/Title
Safety 
FU
Study Adjuvant FU‡
Survival 
FU
Treatment Cycle/Day
Up to 
Year 1*
Years 1-
2
Years 
3-5
Scheduling Window Days 
(unless noted)
30 days 
from 
last 
dose 
±14 
Q12W
±7
Q12W
±7
Q6M 
±14
Q12W 
±14
Efficacy Procedures
Tumor Imaging 
X
X
X
For all imaging, the clock will start from the date of treatment allocation. 
Follow-up tumor imaging (to include disease involved areas and associated 
draining lymph node regions) will be performed every 12 weeks (±7 days) 
until end of Year 2, then every 6 months (±14 days) until end of Year 5, or 
more frequently if clinically indicated. Imaging timing should follow 
calendar days and should not be recalculated based on the date of previous 
scans. In participants who discontinue study therapy without documented 
disease recurrence, every effort should be made to continue monitoring their 
disease status by radiologic imaging as outlined in Section 8.2.1.3.
Continuation of imaging/biopsies is required for participants who have not 
yet experienced an RFS event. Additionally, imaging assessment/biopsies 
performed as part of standard of care to evaluate disease status for 
participants in Survival FU who have not yet experienced a new high-risk 
primary cSCC or disease recurrence should be collected during Survival FU. 
All available images should be submitted to the iCRO and recorded in the 
applicable eCRF (see Section 8.2.2).
Digital Photography: 
Cutaneous Lesions
---If Clinically Indicated----
At time of disease recurrence (see Section 8.2.1.8).
Biopsy
-If Clinically Indicated-
Details of any biopsy-confirmed disease recurrence to be inserted into the 
eCRF. Sponsor consultation is required if a biopsy cannot be performed due 
to feasibility.
08RB5W

PRODUCT: MK-3475
33
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Trial Period
Follow-up Phase
Notes:
A participant may discontinue from study treatment for any reason other than 
a new high-risk primary cSCC or disease recurrence but will remain in the 
study for Study Adjuvant follow-up for disease recurrence (Section 8.11.3.3) 
unless consent is withdrawn.
Participants that discontinue study treatment due to a new high-risk primary 
cSCC or disease recurrence will have Safety FU then proceed directly to 
Survival FU or cross-over/retreatment if eligible (Section 1.3.3).
Participants that complete adjuvant treatment or discontinue study treatment 
for reasons other than a new high-risk primary cSCC or disease recurrence 
will enter Safety FU then proceed to Adjuvant FU. 
*For participants that discontinue before Year 1. 
‡ More frequent FU is permitted based on risk and per treating physician 
discretion. When clinically indicated additional diagnostic evaluation, 
including imaging, can be performed by treating physician discretion.
Visit Number/Title
Safety 
FU
Study Adjuvant FU‡
Survival 
FU
Treatment Cycle/Day
Up to 
Year 1*
Years 1-
2
Years 
3-5
Scheduling Window Days 
(unless noted)
30 days 
from 
last 
dose 
±14 
Q12W
±7
Q12W
±7
Q6M 
±14
Q12W 
±14
EORTC QLQ-C30
X
X
X
X
To be administered at safety FU, and every 12 weeks (±7 days) until end of 
Year 2, then every 6 months (±14 days) until end of Year 5. PROs are to be 
administered by trained site personnel. It is strongly recommended that 
PROs are completed by participants prior to all procedures/assessments, and 
in the following order: EORTC QLQ-C30, Skindex-16, and then EQ-5D. 
If the participant does not complete the PROs for any reason, the Miss Mode 
form must be completed to capture the reason the assessment was not 
performed.
Skindex-16
X
X
X
X
EuroQol EQ-5D
X
X
X
X
Safety Procedures
Directed Physical 
Examination
X
X
X
X
Follow NCCN cSCC 2018 guidelines for FU: include a history and physical 
exam that includes a complete skin and lymph node exam every 12 weeks 
until Year 2, every 6 months until Year 5.
Weight and Vital Signs 
X
----If Clinically Indicated------
Vital signs to be collected include temperature, resting pulse, resting 
respiratory rate, blood pressure.
Urine or Serum β-hCG 
Pregnancy Test (POCBP 
only) 
X
Pregnancy testing should be performed approximately 120 days after last 
dose of pembrolizumab.
CBC With Differential
X
----If Clinically Indicated------
Chemistry Panel
X
----If Clinically Indicated------
Coagulation Tests (PT/INR 
and aPTT/PTT)
X
----If Clinically Indicated------
PTT may be performed if the local laboratory is unable to perform aPTT.
08RB5W

PRODUCT: MK-3475
34
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Trial Period
Follow-up Phase
Notes:
A participant may discontinue from study treatment for any reason other than 
a new high-risk primary cSCC or disease recurrence but will remain in the 
study for Study Adjuvant follow-up for disease recurrence (Section 8.11.3.3) 
unless consent is withdrawn.
Participants that discontinue study treatment due to a new high-risk primary 
cSCC or disease recurrence will have Safety FU then proceed directly to 
Survival FU or cross-over/retreatment if eligible (Section 1.3.3).
Participants that complete adjuvant treatment or discontinue study treatment 
for reasons other than a new high-risk primary cSCC or disease recurrence 
will enter Safety FU then proceed to Adjuvant FU. 
*For participants that discontinue before Year 1. 
‡ More frequent FU is permitted based on risk and per treating physician 
discretion. When clinically indicated additional diagnostic evaluation, 
including imaging, can be performed by treating physician discretion.
Visit Number/Title
Safety 
FU
Study Adjuvant FU‡
Survival 
FU
Treatment Cycle/Day
Up to 
Year 1*
Years 1-
2
Years 
3-5
Scheduling Window Days 
(unless noted)
30 days 
from 
last 
dose 
±14 
Q12W
±7
Q12W
±7
Q6M 
±14
Q12W 
±14
Thyroid Function (TSH) 
X
----If Clinically Indicated------
TSH; in case of elevated TSH add free T3 and free T4.
ECOG Performance Status
X
X
X
X
AE/SAE Review
X
--Continuous Reporting--
All AEs occurring up until 30 days following EOT and SAEs occurring up 
until 90 days following EOT or 30 days if the participant initiates new 
anticancer therapy, whichever is earlier should be reported. Treatment-
related toxicity may be collected for up to 5 years.
AE=adverse event; aPTT=activated partial thromboplastin time; β-hCG=β-human chorionic gonadotropin; C=cycle; cSCC=cutaneous squamous cell carcinoma; D=day; 
ECOG=Eastern Cooperative Oncology Group; eCRF=electronic case report form; EORTC=European Organisation for Research and Treatment of Cancer; EOT=End of 
Treatment; EQ-5D=EuroQol-5 Dimensions; FT4=free thyroxine; FU=follow-up; iCRO = Imaging Contract Research Organization; INR=international normalized ratio; 
NCCN=National Comprehensive Cancer Network; POCBP=participants of childbearing potential; PRO=patient-reported outcome; PT=prothrombin time; PTT=partial 
thromboplastin time; Q6M=every 6 months; Q12M=every 12 months; Q12W=every 12 weeks; Q8W=every 8 weeks; QLQ-C30=Quality of Life Questionnaire-C30; RFS = 
Recurrence-free Survival; SAE=serious adverse event; SoC=standard of care; SOP=standard operating procedure; T3=triiodothyronine; TSH=thyroid-stimulating hormone.
08RB5W

PRODUCT: MK-3475
35
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
1.3.3
Cross-over / Retreatment
Only applicable for participants that have confirmation of disease recurrence and qualify for cross-over to or retreatment with up to 
18 cycles of pembrolizumab (Section 8.1.8.1.2).
For participants eligible for cross-over only, tests performed at the Adjuvant Treatment Phase EOT/Safety FU visits do not need to be 
repeated at screening if performed within the screening window.
Trial Period
Screening
Treatment Cycle
EOT
Safety 
FU
Survival 
FU
Notes: 
Cycles will be repeated up to 18 infusions or until 
protocol-specific criteria to discontinue treatment is met.
Participants that complete cross-over/retreatment or 
discontinue study treatment for any reason will have 
Safety FU then proceed directly to Survival FU.
Treatment 
Cycle/Title
1
2
3
4 to 
18
Discon
Scheduled Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
At time of 
treatment 
discontinuatio
30 days 
from 
last 
dose 
±14 
days
Q12W 
±14
Day of visit
D1
D22
D1
D22
D1
D1
Administrative 
Procedures
Informed Consent
X
Separate consent required for cross-over/retreatment
Additional consent is required at disease progression.
Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
Concomitant medications – Enter new medications 
started since Adjuvant treatment EOT visit through the 
cross-over/retreatment Safety FU.
Post-study Anticancer 
Therapy Status
X
X
X
X
X
X
X
X
X
X
Enter anticancer therapy started since Adjuvant 
treatment EOT visit through cross-over/retreatment 
survival FU. 
By telephone contact in Survival FU.
Vital Status
X
Survival FU begins after end of cross-over/retreatment 
for whatever reason. 
In addition, upon Sponsor request, participants may be 
contacted for survival status at any time during the 
course of the study.
08RB5W

PRODUCT: MK-3475
36
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Trial Period
Screening
Treatment Cycle
EOT
Safety 
FU
Survival 
FU
Notes: 
Cycles will be repeated up to 18 infusions or until 
protocol-specific criteria to discontinue treatment is met.
Participants that complete cross-over/retreatment or 
discontinue study treatment for any reason will have 
Safety FU then proceed directly to Survival FU.
Treatment 
Cycle/Title
1
2
3
4 to 
18
Discon
Scheduled Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
At time of 
treatment 
discontinuatio
30 days 
from 
last 
dose 
±14 
days
Q12W 
±14
Day of visit
D1
D22
D1
D22
D1
D1
Pembrolizumab 
Administration 
X
X
X
X
For Cross-over (participants originally assigned to 
placebo) - Treatment 1, Cycle 1 must be given within 
12 weeks after confirmed disease recurrence.
Pembrolizumab to be administered on D1 of each cycle 
after all procedures/ assessments have been completed.
Efficacy Procedures
Tumor Imaging and 
RECIST 
1.1/iRECIST 
assessment
X
X
X‡ 
Q12W
X*
Baseline imaging/digital photography should be 
performed within 28 days before starting study 
treatment with pembrolizumab. If the recurrence scan 
falls outside of this window, a new scan is required at 
baseline.
The first on-treatment imaging assessment should be 
performed at 12 weeks (±7 days) from the date of the 
first dose of pembrolizumab in cross-over/retreatment.
‡Subsequent tumor imaging should be performed every 
12 weeks (84 days ±7 days) until Year 2, or more 
frequently if clinically indicated. The visit window for 
imaging/photography is ±7 days.
* In participants who discontinue study therapy, 
imaging/digital photography should be performed at the 
time of treatment discontinuation (ie, date of 
discontinuation ±4 weeks). If previous scan/digital 
photograph was obtained within 4 weeks prior to the 
date of discontinuation, then a scan/digital photograph 
at treatment discontinuation does not need to be 
performed.
Digital Photography: 
Cutaneous Lesions
X
X
X‡ 
Q12W
X*
08RB5W

PRODUCT: MK-3475
37
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Trial Period
Screening
Treatment Cycle
EOT
Safety 
FU
Survival 
FU
Notes: 
Cycles will be repeated up to 18 infusions or until 
protocol-specific criteria to discontinue treatment is met.
Participants that complete cross-over/retreatment or 
discontinue study treatment for any reason will have 
Safety FU then proceed directly to Survival FU.
Treatment 
Cycle/Title
1
2
3
4 to 
18
Discon
Scheduled Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
At time of 
treatment 
discontinuatio
30 days 
from 
last 
dose 
±14 
days
Q12W 
±14
Day of visit
D1
D22
D1
D22
D1
D1
EORTC QLQ-C30
X
X
X
X‡
Q12W
X*
X
PROs are to be administered by trained site personnel 
on D1 of C1, C2, C3 and then every 2 cycles (ie, every 
12 weeks)‡ until Year 2. It is strongly recommended that 
PROs are completed by participants prior to all 
procedures/assessments, and in the following order: 
QLQ-C30, Skindex-16, and then EQ-5D EORTC.
If the participant does not complete the PROs for any 
reason, the Miss Mode form must be completed to 
capture the reason the assessment was not performed.
*In participants who discontinue study therapy, PROs 
should be administered at the time of treatment 
discontinuation (ie, date of discontinuation ± 4 weeks). 
If previous PROs were obtained within 4 weeks prior to 
the date of discontinuation, then administration of PROs 
at treatment discontinuation does not need to be 
performed.
Skindex-16
X
X
X
X‡
Q12W
X*
X
EuroQol EQ-5D
X
X
X
X‡
Q12W
X*
X
Safety Procedures
Full Physical 
Examination
X
X
To be performed by the investigator or medically 
qualified designee. 
Directed Physical 
Examination
X
X
X
X
X
X
X
Weight and Vital 
Signs
X
X
X
X
X
X
X
X
X
Vital signs to be collected include: temperature, resting 
pulse, resting respiratory rate, blood pressure. 
08RB5W

PRODUCT: MK-3475
38
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Trial Period
Screening
Treatment Cycle
EOT
Safety 
FU
Survival 
FU
Notes: 
Cycles will be repeated up to 18 infusions or until 
protocol-specific criteria to discontinue treatment is met.
Participants that complete cross-over/retreatment or 
discontinue study treatment for any reason will have 
Safety FU then proceed directly to Survival FU.
Treatment 
Cycle/Title
1
2
3
4 to 
18
Discon
Scheduled Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
At time of 
treatment 
discontinuatio
30 days 
from 
last 
dose 
±14 
days
Q12W 
±14
Day of visit
D1
D22
D1
D22
D1
D1
Urine or Serum β-
hCG Pregnancy Test 
(POCBP only) – as 
per local SOP
X
X
X
X
X
X
The protocol requires pregnancy testing within 72 hours 
prior to administration of each dose of pembrolizumab. 
Refer to Appendix 7 for country-specific requirements 
for Germany, Ireland, Italy, Norway, and the UK.
Coagulation Tests 
(PT/INR and 
aPTT/PTT)
X
----If Clinically Indicated----
Screening - within 10 days prior to the start of study 
treatment. Samples to be taken prior to pembrolizumab 
administration. Any participant receiving anticoagulant 
therapy should have coagulation tests monitored closely 
throughout the study. PTT may be performed if the local 
laboratory is unable to perform aPTT.
CBC With 
Differential
X
X§
X
X
X
X
X
X
X
Screening - within 10 days prior to the start of study 
treatment. Samples to be taken prior to study drug 
administration. After Cycle 1, samples can be collected 
up to 72 hours prior to the scheduled time point.
§ Optional - CBC and Chemistry labs are not required at 
C1D1 if they were collected during screening and 
within 10 days of first dose.
* In case of elevated TSH add free T3 and free T4.
‡ To be repeated every 2 cycles.
Chemistry Panel
X
X§
X
X
X
X
X
X
X
Urinalysis
X
Thyroid Function 
(TSH)*, T3, FT4
X
X
X‡
X
X
ECOG Performance 
Status
X
X
X
X
X
X
X
X
X
Screening - ECOG is to be performed within 10 days 
prior to the first dose of pembrolizumab. Must be 
performed prior to each dose of pembrolizumab where 
ECOG is collected.
08RB5W

PRODUCT: MK-3475
39
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Trial Period
Screening
Treatment Cycle
EOT
Safety 
FU
Survival 
FU
Notes: 
Cycles will be repeated up to 18 infusions or until 
protocol-specific criteria to discontinue treatment is met.
Participants that complete cross-over/retreatment or 
discontinue study treatment for any reason will have 
Safety FU then proceed directly to Survival FU.
Treatment 
Cycle/Title
1
2
3
4 to 
18
Discon
Scheduled Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
At time of 
treatment 
discontinuatio
30 days 
from 
last 
dose 
±14 
days
Q12W 
±14
Day of visit
D1
D22
D1
D22
D1
D1
AE/SAE Review
X
-------------Continuous Reporting-------------
Record all AEs and ECIs occurring within 30 days after 
last dose of study treatment and SAEs for 90 days after 
the EOT or 30 days after EOT if the participant initiates 
new anticancer therapy (whichever is earlier). Report 
treatment-related SAEs regardless of when they occur.
AE=adverse event; aPTT=activated partial thromboplastin time; β-hCG=β-human chorionic gonadotropin; C=cycle; CBC=complete blood count; D=day; ECI=event of clinical 
interest; ECOG=Eastern Cooperative Oncology Group; EORTC=European Organisation for Research and Treatment of Cancer; EOT=End of Treatment; EQ-5D=EuroQol-5 
Dimensions; FT4=free thyroxine; FU=follow-up; INR=international normalized ratio; POCBP=participants of childbearing potential; PRO=patient-reported outcome; 
PT=prothrombin time; PTT=partial thromboplastin time; Q12W=every 12 weeks; QLQ-C30=Quality of Life Questionnaire-C30; SAE=serious adverse event; SOP=standard 
operating procedure; T3=triiodothyronine; TSH=thyroid-stimulating hormone; UK=United Kingdom.
08RB5W

PRODUCT: MK-3475
40
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
2
INTRODUCTION
This study will assess the safety and efficacy of pembrolizumab adjuvant therapy in 
participants with resectable high-risk LA cSCC following surgical resection with curative 
intent and RT.
2.1
Study Rationale
Pembrolizumab has demonstrated durable clinical activity in participants with R/M HNSCC 
and is currently approved in the US and in several global locations for the treatment of R/M 
HNSCC with disease progression on or after platinum-containing chemotherapy. 
Approximately 80% of cSCC involves the head and neck region. Although, HNSCC and 
cSCC are biologically different cancers, they clinically behave very similarly. Therefore, it is 
proposed that treatment with pembrolizumab will also work for cSCC.
Cutaneous squamous cell carcinoma is the second most frequent skin cancer. Most patients 
with cSCC are successfully treated with surgical treatment of the primary site. However, a 
minority of patients are at risk for local recurrence and regional metastasis [Burton, K. A., et 
al 2016]. With the incidence of cSCC continuing to rise, and because R/M cSCC has a 
potentially devastating impact on patients, the development of adjuvant treatment strategies 
to eradicate early micrometastatic disease following SoC (detailed in Section 2.2.1) and thus 
decrease the rate of recurrence without compromising the QoL [Kang, S. Y. 2016] for 
patients identified as at high-risk of recurrence and/or metastasis would have an important 
clinical significance. We propose to evaluate the efficacy and safety of pembrolizumab as 
adjuvant therapy in a randomized, double-blind, placebo-controlled, Phase 3 study for 
resectable high-risk LA cSCC.
2.2
Background
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated 
for the treatment of patients across several indications. For more details on specific 
indications refer to the IB.
2.2.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
08RB5W

PRODUCT: MK-3475
41
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling on engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an IgV–type domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. After T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and 
SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70, 
which are involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, 
J. M., et al 2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which 
PD-1 down-modulates T-cell responses is similar to, but distinct from, that of CTLA-4, 
because both molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 
2005] [Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an 
attractive target for therapeutic intervention in patients with solid tumors.
The Association Between Ultraviolet Light and cSCC
Exposure to solar ionizing UV rays is the major risk factor for cSCC. The head and neck 
region is one of the most common anatomical regions for cSCCs to develop because of its 
daily exposure to solar ionizing UV rays. Development of cSCC involves multi-step 
carcinogenic events that accumulate over time with UV exposure [World Health 
Organization 1992] [International Agency for Research on Cancer 2007]. A pattern of UV-B 
induced mutations (typically cytosine [C]>thymine [T] and/or CC>TT transitions) occur 
commonly within the p53 gene and are thought to be an early event in the carcinogenic 
process [Lawrence, M. S., et al 2013] [Davoli, T., et al 2013] [Boukamp, P. 2005]. 
Ultraviolet-A rays that directly induce DNA damage by inducing double-strand DNA breaks 
and generating genomic instability occur throughout the initiation and development of cSCC. 
Therefore, while UV-B dependent mutational inactivation of p53 may be an early 
carcinogenic event resulting in loss of protection of chromosomal integrity, with continued 
sun exposure, repetitive UV-A exposure propagates genomic and karyotypic instability by 
inducing DNA damage that is not efficiently repaired. The accumulation of these karyotypic 
and chromosomal aberrations ultimately results in a cumulative high mutational burden 
within cSCC.
08RB5W

PRODUCT: MK-3475
42
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
The Role of Human Papillomavirus Infection and cSCC
HPV, which replicate exclusively in keratinocytes [Cardoso, J. C. 2011] [Aldabagh, B., et al 
2013] [Doorbar, J. 2005], have been implicated in the pathogenesis of cSCC by facilitating 
the accumulation of UV mediated DNA damage. There is evidence of a dose-response 
relationship between HPV and cSCC; the risk of development of cSCC increases with 
increasing numbers of infection with HPV genus β-species [Farzan, S. F., et al 2013]. 
Although there seems to be consensus for a role for β-HPVs in the initiation of cSCC, the 
role in the maintenance and propagation of the disease is less clear as a greater number of 
HPV types are present in premalignant lesions, and the number and frequency of HPV types 
decrease in advanced/metastatic lesions [Hampras, S. S., et al 2016] [Toll, A., et al 2014] 
[Aldabagh, B., et al 2013]. Although there is no consensus regarding the specific HPV 
species involved in cSCC, HPV local infection can vary depending on anatomic location; 
HPV DNA from topical skin infection was higher from sun exposed areas compared to non-
sun exposed areas [Aldabagh, B., et al 2013]. Ultraviolet light and HPV can interact to alter 
the body’s local immunity at sun exposed or sunburned sites [Halprin, K. M., et al 1981] 
[Cestari, T. F., et al 1995]. Although the immune response to HPV infection is both antibody-
and cell-mediated, a functional T-cell response is the major mechanism of immunity against 
HPV [Aldabagh, B., et al 2013]. Thus, UV light exposure is hypothesized to promote 
localized HPV infection through localized cutaneous immunosuppression. 
In other malignancies, high mutation burden has been associated with clinical benefit from 
pembrolizumab therapy [Le, D. T., et al 2017]. Highly mutated tumors are more likely to 
express immunogenic tumor neoantigens that attract effector T-cells, which can be unleashed 
by blockade of the PD-1 immune checkpoint. Furthermore, immunosuppression, usually 
associated with organ transplantation, elevates the risk of developing cSCC by over 100-fold 
[Pickering, C. R., et al 2014], suggesting the important of the adaptive cellular immune 
system in the surveillance and eradication of cSCC. 
Evidence for Efficacy of PD-l Immune Checkpoint Inhibitors in cSCC
Initial evidence of a role for checkpoint inhibitor therapy in cSCC comes from early studies 
of pembrolizumab that included participants with MCC. 
Similar to cSCC, the rare neuroendocrine MCC is an aggressive skin cancer linked to UV 
light exposure, resulting in distinctive UV associated mutations with the distinctive signature 
(C>T, CC>TT) similar to cSCC, associated with increased genomic instability, and MCPyV 
infection [Cassler, N. M., et al 2016]. Approximately 80% of MCC can be directly linked to 
the clonal integration of the MCPyV into the host genome. While ubiquitous in the general 
population from early childhood, and usually clinically asymptomatic [Chang, Y. 2012], in 
the elderly and immunosuppressed, where mechanisms of immune surveillance are 
decreased, MCPyV disease progression has been correlated with increasing detectable 
viremia [Chang, Y. 2012] [Pastrana, D. V., et al 2009] [Tolstov, Y. L., et al 2009], [Touze, 
A., et al 2011].
In a Phase 2, multicenter uncontrolled study, treatment naïve participants with advanced 
MCC not amenable to curative therapy, received pembrolizumab 2 mg/kg of body weight 
08RB5W

PRODUCT: MK-3475
43
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
every 3 weeks (Q3W) for up to 2 years. Of the 26 evaluable participants with Stage IIIB or 
IV MCC, 14 had a confirmed response (4 with CR and 10 with PR) for an ORR of 56% (95% 
CI: 35 to 76). With a median follow-up of 33 weeks (range, 7 to 53 weeks), the DOR ranged 
from at least 2.2 months to at least 9.7 months. Clinically relevant responses were reported in 
both MCPyV positive and negative participants with response rates of 62% and 44%, 
respectively. PD-L1 expression (defined as at least 1% staining by immunohistochemistry 
[IHC] on tumor cells) was more frequent in virus positive tumors than virus negative tumors 
(71% versus 25%, p=0.049), but as not required for clinical activity of pembrolizumab 
[Nghiem, P. T., et al 2016]. 
Clinical Efficacy of Pembrolizumab in HNSCC
Evidence of both clinical efficacy and safety of pembrolizumab has been reported in studies 
evaluating pembrolizumab in HNSCC, as detailed in the IB. 
In KN012, a Phase 1b global, multi-cohort study, participants with incurable R/M HNSCC, 
whose tumor tissues contained at least 1% of tumor cells or stroma that were PD-L1 positive 
by IHC, were treated with IV pembrolizumab 10 mg/kg Q2W. Of 60 participants enrolled, 
approximately 38% (23/60) were HPV-positive. Approximately 63% (38/60) of participants 
had been treated with both platinum and cetuximab based therapies prior to enrolling on 
study, and 70% (42/60) had at least 2 or more prior lines of treatment for R/M disease prior 
to study entry. In this heavily pretreated population, the proportion of participants with an 
overall response by central imaging review was 18% (8/45 evaluable for response; 95% CI: 
8% to 32%) with similar clinical efficacy in HPV-positive or negative disease (25% ORR, 
range 7-52, and 14% ORR, range 4-32, respectively). The median DOR was 53 weeks (95% 
CI: 13 weeks to not reached) and median PFS and OS were 2 (95% CI: 2 to 4 months) and 13 
(95% CI: 5 months to not reached) months, respectively [Seiwert, T. Y., et al 2016]. 
In the KN012 expansion cohort, 132 participants with incurably R/M HNSCC, irrespective of 
PD-L1 or HPV status, received a fixed dose of pembrolizumab at 200 mg Q3W. PD-L1 
positive disease was reported in 125 participants, 28 (21%) were HPV positive, and 
approximately 57% of participants had been treated with at least 2 or more lines of therapy 
for R/M HNSCC. After a median follow-up duration of 9 months, ORR was 18% (95% CI: 
12 % to 26%) by BICR, with a median time to response of 2 months (range, 2 to 11 months), 
and a median DOR that was not reached (range, >2 to >11 months). PFS and OS were 
2 months (95% CI: 2.0 to 2.2 months) and 8 months (95% CI: 6 to 10 months), respectively. 
For participants whose tumors expressed at least 1% of PD-L1 positivity, ORR was further 
confirmed at 22%. Irrespective of PD-L1 status, response rates were 32% and 14% in 
participants that were HPV-positive and HPV-negative, respectively [Chow, L. Q., et al 
2016]. Thus, similar to MCC, evidence of broad clinical activity was seen regardless of viral 
etiology. Of note, the consistent ORR of 14% observed in participants with HPV-negative 
disease in both KN012 HNSCC cohorts, suggests that patients with non–HPV-associated 
R/M cSCC may also benefit from pembrolizumab. The safety profile of pembrolizumab 
remained consistent utilizing the fixed dose of 200 mg Q3W [Chow, L. Q., et al 2016].
08RB5W

PRODUCT: MK-3475
44
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Cutaneous Squamous Cell Carcinoma
Cutaneous squamous cell carcinoma is the second most frequent non-melanoma skin cancer, 
representing approximately 20% of all non-melanoma skin cancers and 20% of all skin 
cancer deaths. cSCC is diagnosed at a rate of 100-150 per 100,000 persons in the United 
States [Vandergriff, T., et al 2010] and is expected to increase as much as 2% to 4% per year 
[Burton, K. A., et al 2016]. The age-adjusted incidence rates of cSCC in Europe is generally 
lower, with Northern European countries, such as Norway, Finland, and Denmark, reporting 
rates 10 per 100,000 person-years, and the UK, Ireland and Germany reporting 20-30 cSCC 
cases per 100,000 person-years [Lomas, A., et al 2012] [Vandergriff, T., et al 2010] 
[Eisemann, N., et al 2014]. It is estimated that over 3.3 million persons with non-melanoma 
skin cancers or keratinocyte carcinoma were treated in the US in 2012, with ~38% of those 
cases being invasive cSCCs [Rogers, H. W., et al 2015]. Due to its ability to metastasize to 
distant regions, when not cured by local therapy, cSCC ultimately results in death with 
mortality rates that exceed 70% [Burton, K. A., et al 2016]. The rate of local recurrence and 
regional metastasis may be as high as 20% in tertiary care centers [Moore, B. A., et al 2005]. 
Patients with regional metastasis have 3-year disease-free survival (DFS) rate of 56%. While 
5-year OS ranges from 25% to 35%, 10-year OS appears to be less than 20% [Johnson, T. 
M., et al 1992] [Kraus, D. H., et al 1998] [Kwa, R. E., et al 1992]. cSCC carries a low but 
significant risk of metastasis and death. A US study of 974 cSCC patients at Brigham and 
Women’s Hospital reported a risk of nodal metastasis of 3.4% [Karia, P. S., et al 2014], and 
approximately 3,000 deaths are attributed to LA/high-risk cSCC annually [Jennings, L. 2010] 
[Brantsch, K. D., et al 2008].
Locally advanced high-risk cSCC is defined as a cSCC that has high-risk features, including 
regional nodal disease, and has no distant metastasis. High-risk features of cSCC defined per 
NCCN eSCC guidelines [National Comprehensive Cancer Network 2017] and include depth 
of invasion, histologic features, anatomical location, horizontal size, perineural involvement, 
tumor recurrence, incomplete excision, multiple tumors, patient characteristics, and 
genetic/molecular markers [Burton, K. A., et al 2016] [National Comprehensive Cancer 
Network 2017]. Clinically, the initial lesions of a cSCC tumor can be present as a painless 
plaque-like or verrucous tumor that can ultimately progress to being large, necrotic, and 
infected. Tumors can also present with paresthesia or lymphadenopathy depending on the 
location involved. 
The majority of patients with cSCC are successfully treated with surgical treatment of the 
primary site. Some patients are at risk for local recurrence and regional metastasis and these 
patients have signiﬁcantly worse outcomes compared to those cured by initial surgery. 
Current Therapies for Resectable High-Risk LA cSCC
The current SoC for resectable high-risk LA cSCC, as recommended by NCCN cSCC 2018 
guidelines (evidence category 2A - low-level evidence) [National Comprehensive Cancer 
Network 2017], consists of surgical resection of the primary tumor and the involved lymph 
nodes, followed by adjuvant RT based on the presence of involved lymph nodes and/or high-
risk features for recurrent/metastatic disease [Porceddu, S. V., et al 2015] [Porceddu, S. V. 
2015a]. While the majority of patients are cured with local surgical excision, approximately 
08RB5W

PRODUCT: MK-3475
45
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
20% of patients develop local recurrence and regional metastasis [Moore, B. A., et al 2005]. 
The majority of recurrences tend to occur within 2 years of the initial primary diagnosis 
[Porceddu, S. V. 2015a]. The presence of primary disease with high-risk features increases 
the risk for regional nodal metastatic disease and predicts for inferior survival. 
Results from the first Phase 3, randomized study (Trans Tasman Radiation Oncology Group 
05.01), comparing adjuvant RT (60 to 70 Gy) to concurrent chemoradiotherapy in 310 
patients with high-risk cSCC, showed freedom from locoregional relapse was high following 
surgery and post-operative RT (83% [95% CI: 77 to 90%]) and the addition of concurrent 
chemotherapy (carboplatin) did not improve freedom from locoregional relapse. The 5-year 
DFS and OS was similar between the treatment arms (67% [95% CI: 60% to 76%] and 76% 
[95% CI: 69% to 84%], respectively, for RT alone; 73% [95% CI: 66% to 81%] and 79% 
[95 % CI: 72% to 86%], respectively, for RT plus carboplatin) [Porceddu, S. V., et al 2017].
Similar to MCC, where 2 distinct causes of carcinogenesis have been identified, UV light and 
viral infection, cSCC has also been long considered to be an immunogenic cancer. UV light 
associated with a high mutation burden, karyotypic and chromosomal instability, and 
increased neoantigens, as well as chronic HPV infection with T-cell dysfunction, make cSCC 
a likely candidate to benefit from checkpoint inhibitor therapy. In malignancies with 
dichotomous etiologies such as MCC and HNSCC, pembrolizumab therapy has provided 
similar benefit for each dichotomous subpopulation and has proven to be an important 
clinical treatment advance for diseases with limited treatment options. Therefore, we propose 
to test the clinical activity of pembrolizumab as adjuvant therapy in resectable high-risk LA 
cSCC following SoC surgery and RT.
Recent data on cemiplimab (REGN2810), a human anti-PD-1 mAb, provides evidence that 
PD 1 inhibitors, could provide a well-tolerated, effective, and durable response in patients 
with LA or metastatic cSCC. In a Phase 1 open-labeled study (NCT02383212), populations 
of patients with unresectable LA or metastatic cSCC were treated for up to 48 weeks with 
cemiplimab (3 mg/kg Q2W). Final results from 26 patients were represented by Owonikoko 
et al [Owonikoko, T. K., et al 2018] at the ASCO 2018. The ORR, based on RECIST 1.1 by 
independent central review, for the LA population (n=16) was 43.8% (95% CI: 19.8 to 70.1 
[CR, n=0; PR, n=7]) and the durable DCR was 56.3% (11/16, 95% CI: 29.9 to 80.2). In the 
preliminary results, 81% (17/21) of evaluated tumors were positive (≥1%) for tumor 
expression of PD-L1 by IHC and there was no apparent association between PD L1 IHC 
results and objective response [Papadopoulos, K., et al 2017].
2.2.2
Preclinical and Clinical Studies
Details of preclinical and clinical studies are provided in the IB. Two clinical studies (KN012 
and KN055) formed the basis of approval for pembrolizumab in the treatment of R/M 
HNSCC.
Clinical studies with pembrolizumab have demonstrated efficacy in participants with 
advanced melanoma, non–small cell lung cancer, gastric cancer, HNC, bladder cancer, 
Hodgkin’s lymphoma, and MSI high cancers.
08RB5W

PRODUCT: MK-3475
46
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
2.2.3
Ongoing Clinical Studies
There is an expansive ongoing research program of clinical studies evaluating 
pembrolizumab in patients with a number of hematological and solid malignancies, including 
HNC. For study details please refer to the IB. 
KEYNOTE-629 (KN629)
KN629 is an ongoing Phase 2, open-label, single arm study of pembrolizumab in participants 
with R/M cSCC or LA unresectable cSCC. Approximately 150 participants with cSCC not 
amenable to surgery and/or radiation and/or systemic therapies are planned to be enrolled to 
examine the efficacy and safety of pembrolizumab 200 mg Q3W for up to 35 cycles. The 
primary endpoint of the study is the ORR per RECIST 1.1 as assessed by BICR; secondary 
endpoints include DOR, DCR, PFS per RECIST 1.1 as assessed by BICR, OS and safety. 
Enrollment has started and is ongoing.
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.
In this clinical study, participants who have received SoC become eligible for the study and 
will be randomized to receive either pembrolizumab or placebo control. The benefit of 
pembrolizumab as adjuvant therapy in this specific patient population is unknown.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
08RB5W

PRODUCT: MK-3475
47
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In male/female participants aged 18 years or older with resectable high-risk LA cSCC after 
surgery and RT:
Primary Objective
Primary Endpoint
Objective: To compare the recurrence-free 
survival (RFS), as assessed by the 
investigator and confirmed by biopsy, in 
individuals who receive pembrolizumab 
with individuals who receive placebo as 
adjuvant therapy.
Hypothesis (H1): Pembrolizumab as 
adjuvant therapy is superior to placebo with 
respect to RFS as assessed by the 
investigator
-RFS: defined as the time from the date of 
randomization to the date of first record of 
the following events:
-Local or regional recurrence of the index 
lesion
-Distant metastasis
-Death due to any cause
Note: A new low risk primary cSCC is not 
considered as a RFS event
Secondary Objectives
Secondary Endpoints
Objective: To compare overall survival 
(OS) in individuals who receive 
pembrolizumab with individuals who 
receive placebo as adjuvant therapy.
Hypothesis (H2): Pembrolizumab as 
adjuvant therapy is superior to placebo with 
respect to OS.
OS: defined as time from randomization to 
death due to any cause
To compare mean change from baseline in 
health-related quality of life (HRQoL) 
scores from the European Organisation for 
Research and Treatment of Cancer 
(EORTC) QoL Questionnaire (QLQ) C30, 
in individuals who receive pembrolizumab 
with individuals who receive placebo as 
adjuvant therapy.
-EORTC QLQ-C30 global health 
status/QoL scales
-EORTC QLQ-C30 physical functioning 
scale
Objective: To determine the safety and 
tolerability of pembrolizumab as adjuvant 
therapy.
-Adverse events (AEs)
-Study drug discontinuations due to AEs
08RB5W

PRODUCT: MK-3475
48
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
The study is considered to have met its primary objective if pembrolizumab is superior to 
placebo as adjuvant therapy with respect to RFS 
 
.
CCI
CCI
08RB5W

PRODUCT: MK-3475
49
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
4
STUDY DESIGN
4.1
Overall Design
NOTE: This study will be discontinued based on the results of the prespecified IA of efficacy 
and safety data (data cutoff 28-JUN-2024) reviewed by eDMC on 21-AUG-2024. At this IA, 
pembrolizumab did not cross the boundary for statistical significance in RFS by investigator 
assessment compared to placebo. Although not formally tested based on the prespecified 
multiplicity strategy, the OS point estimate did not favor pembrolizumab versus placebo. The 
eDMC recommended that the study should be stopped for futility as the benefit/risk profile 
did not support continuing the study. The EOC reviewed the data and accepted the eDMC’s 
recommendation. Based on these data and the recommendation of the eDMC, the study was 
unblinded on 22-AUG-2024. The prespecified final efficacy analysis of the study described 
in the SAP will not be performed. Efficacy and safety analyses will be performed at the end 
of the study; there will be no further planned analyses for ePRO endpoints. 
In alignment with the study-specific investigator letter dated 29-AUG-2024, all participants 
should discontinue study treatment (pembrolizumab/placebo). On a case-by-case basis, the 
investigators may contact the Sponsor for the consideration of continuing pembrolizumab 
treatment if they assess a participant is deriving clinical benefit. All ongoing participants 
should undergo study procedures as specified in this amendment (Amendment 10).
As of Amendment 10, ePRO assessments are no longer required. All ongoing participants 
should continue tumor imaging and investigator assessment of the tumor scans per protocol; 
however, scans no longer need to be submitted to the iCRO and digital photography of 
cutaneous lesions is not required.
On study discontinuation, all ongoing participants will be discontinued and may be enrolled 
in an extension study, if available. In the extension study, participants who experience 
disease recurrence per SOC clinical assessment may be considered eligible for 
cross-over/retreatment upon consultation with the Sponsor.
Original protocol text included below in this section has been retained for reference.
This is a Phase 3, randomized, double-blind, placebo-controlled, multisite study to evaluate 
the efficacy and safety of pembrolizumab as adjuvant therapy in participants with high-risk 
LA cSCC. The study will be conducted in conformance with GCP.
Participants with high-risk LA cSCC (as defined in the inclusion criteria) that have 
undergone surgery with curative intent and adjuvant RT (last dose of RT ≥4 weeks and 
≤16 weeks from randomization) may be screened and randomized for this study. Participants 
must be tumor-free as assessed by the investigator via radiological imaging of the head, neck, 
chest, abdomen, pelvis, and extremities (if disease involvement). All participants must 
provide a tissue specimen from either the resected tumor or archival FFPE tumor biopsy 
assessed as adequate for PD-L1 determination by IHC by a central laboratory.
Approximately 430 participants will be randomized in a 1:1 ratio to receive either 
pembrolizumab 400 mg Q6W (up to 9 cycles) or placebo (see Figure 1). Study 
08RB5W

PRODUCT: MK-3475
50
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
randomization will start at a minimum of 4 weeks and maximum of 16 weeks after the last 
dose of RT and when participants have recovered adequately from the morbidity and/or 
complications from RT. Participants will be stratified by 
 
 (see 
Section 6.3.2).
Participants will have baseline imaging performed at screening and subsequently every 
12 weeks (± 7 days) until Year 2, then every 6 months (± 14 days) until the end of Year 5 
from the date of treatment allocation, or more frequently if clinically indicated, until a 
documented new high-risk primary cSCC tumor occurs or disease recurrence, death, 
pregnancy, or the end of the study, whichever occurs first. The primary efficacy endpoint 
will be evaluated by RFS as assessed by the investigator and confirmed by biopsy. Secondary 
objectives include evaluation of OS of the study participants, HRQoL, and safety. 
In the Adjuvant Treatment Phase, participants will continue study treatment until: a new 
high-risk primary cSCC tumor occurs or biopsy proven disease recurrence, the start of any 
new anticancer treatment, unacceptable AE(s) toxicity, intercurrent illness that prevents 
further administration of treatment, investigator’s decision to discontinue treatment, 
participant withdrawal of consent, pregnancy of the participant, administrative reasons 
requiring cessation of treatment, or the participant completes 9 administrations of study drug 
(approximately 1 year of treatment). Participants discontinued from treatment will continue 
to be monitored in the study except when the participant withdraws consent resulting in 
discontinuation from the study. Participants who withdraw consent will be treated thereafter 
at the discretion of the physician.
Upon first biopsy proven disease recurrence (Sections 8.2.1.5 and 8.2.1.6), and with Sponsor 
approval, study treatment will be unblinded (Section 8.1.10). Tissue biopsy is required for 
the confirmation of disease recurrence; only if a biopsy cannot be performed due to 
feasibility, such as location of recurrence (ie, bone lesion), and upon Sponsor consultation, 
can radiographic imaging be used to confirm disease recurrence. 
Following documented disease recurrence, if the participant is not eligible for surgical 
resection, the participant may cross-over to or receive retreatment with open-label 
pembrolizumab 400 mg IV Q6W for up to 18 cycles (approximately 2 years). Participants 
assigned to placebo who experience biopsy proven disease recurrence before the end of 
Year 5, and who wish to continue study treatment after discussion with the investigator, must 
start cross-over treatment within 12 weeks of biopsy proven recurrence; participants assigned 
to pembrolizumab are eligible for retreatment if biopsy proven disease recurrence occurs 
before the end of Year 5 and more than 6 months after completing 9 cycles (approximately 
1 year) of study adjuvant therapy, if clinically indicated and after approval from the Sponsor. 
Section 8.1.8.1.2 provides cross-over/retreatment criteria and guidance. Participants in the 
Cross-over/Retreatment Phase will continue study cross-over/retreatment until: documented 
disease progression as assessed by the investigator per response evaluation criteria in solid 
tumors (RECIST 1.1)/ modified RECIST 1.1 for immune-based therapeutics (iRECIST), the 
start of a new systemic anticancer treatment, unacceptable AE(s) toxicity, intercurrent illness 
that prevents further administration of treatment, investigator’s decision to discontinue 
treatment, participant withdrawal of consent, pregnancy of the participant, noncompliance 
CCI
08RB5W

PRODUCT: MK-3475
51
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
with study treatment or procedure requirements, administrative reasons requiring cessation of 
treatment, or the participant completes 18 administrations of study drug (approximately 
2 years of treatment), or cessation due to administrative reasons. Participants that discontinue 
study treatment in the Cross-over/Retreatment Phase will have Safety FU and enter Survival 
Follow-up and be treated thereafter at the discretion of the physician.
Participants will be monitored carefully for the development of AEs and for clinical and/or 
radiographic evidence of disease recurrence (or progression for participants receiving cross-
over/retreatment) as assessed by the investigator and confirmed by biopsy. AEs will be 
monitored throughout the study and graded in severity according to the guidelines outlined in 
the NCI CTCAE Version 4.0. 
A safety follow-up visit will be conducted at 30 days (± 14 days) after the last dose of study 
treatment (see Section 8.11.3.2 and Section 8.4) for participants who receive study treatment 
and for those with Early Discontinuations. All participants will be followed by telephone 
contact every 12 weeks for OS until death, withdrawal of consent, lost to follow-up, or the 
end of the study, whichever occurs first. The Sponsor may request survival status to be 
assessed at additional time points during the study. For example, survival status may be 
requested prior to the final analysis. All participants who are in the Survival Follow-up Phase 
and not known to have died prior to the request for these additional survival status time 
points will be contacted at that time.
This study will use an independent, eDMC and an EOC to monitor safety and efficacy 
(Appendix 1). There will be 1 formal IA for efficacy (see Section 9.7).
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
Cutaneous squamous cell carcinoma has long been considered to be an immunogenic cancer. 
Immune checkpoints that regulate the immune response have led to the development of 
strategies that can be positively exploited to impact T-cell activity and generate clinically 
relevant antitumor activity.
Until 2017, there was no prospective data for anti-PD1 therapy in the cSCC LA setting. Data 
from ASCO 2017 and ASCO-Society for Immunotherapy of Cancer 2018 on cemiplimab 
(REGN2810), a human anti-PD-1 mAb, provides evidence that PD-1 inhibitors could provide 
a well-tolerated, effective, and durable response in patients with LA or metastatic cSCC (see 
Section 2.2.1 for more details). In a Phase 1 open-labeled study (NCT02383212) patients 
with unresectable locally and/or regionally advanced cSCC were treated for up to 48 weeks 
with cemiplimab (REGN2810). Final results revealed an ORR of 43.8% (95% CI: 19.8 to 
70.1) and DCR of 56.3% (95% CI: 29.9 to 80.2) in the LA population [Owonikoko, T. K., et 
al 2018]. 
08RB5W

PRODUCT: MK-3475
52
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
In a recent press release, Regeneron announced positive results from an ongoing pivotal 
Phase 2 study of cemiplimab (REGN2810) in 82 patients with advanced cSCC [Regeneron 
Pharmaceuticals, Inc. 2017]. Data from the primary analysis presented at ASCO 2018 from 
the metastatic population (n=59) reported ORR of 47.5% (95% CI: 34.3 to 60.9) and DCR of 
61.0% (95% CI: 47.4 to 73.5), as determined by independent review; the median DOR had 
not yet been reached at the data cutoff point [Rischin, D., et al 2018]. Results for the LA 
population are yet to be published. Further Phase 2 data for pembrolizumab in the LA setting 
will be provided in KN629 (see Section 2.2.3); the Sponsor plans to include a cohort with LA 
cSCC whose disease is not eligible for surgery.
This Phase 3 study will evaluate the efficacious advantage of pembrolizumab adjuvant 
therapy in participants with resectable high-risk LA cSCC (as defined in Section 5.1 –
Inclusion Criteria). Upon study entry, all participants will have undergone surgical resection 
with curative intent and RT. The specific treatment must comply with ASTRO and RCR 
guidelines for adjuvant RT of high-risk LA cSCC [Likhacheva, A., et al 2020] [The Royal 
College of Radiologists 2019]. The study is a randomized, double-blind, placebo-controlled 
design, which will provide controlled data in this population for which limited data are 
available. The placebo control is necessary to ensure double blinding since the 
presence/absence of extra infusions would identify treatment assignment. The placebo 
control also allows statistical isolation of the true effect associated with pembrolizumab 
therapy from the placebo effect.
Participants will be stratified by extracapsular extension (yes vs. no), cortical bone invasion 
(yes vs. no), and prior systemic therapy (yes vs. no) (see Section 6.3.2); extracapsular 
extension and cortical bone invasion are poor prognostic factors for cSCC and the effect of 
prior systemic therapy on the adjuvant setting for cSCC is unknown; stratification will allow 
the latter to be explored.
The primary objective of the study is to compare RFS of pembrolizumab versus placebo, 
while ensuring access to pembrolizumab for all participants entering the study by allowing 
cross-over after first recurrence. Upon disease recurrence, participants will move from 
having LA disease to R/M disease for which treatment options are limited and mortality rates 
exceed 70% [Burton, K. A., et al 2016]. Upon biopsy proven disease recurrence, and with 
Sponsor approval, study treatment will be unblinded (see Section 8.1.10.2). If the participant 
is not eligible for surgical resection participants may cross over to or receive retreatment with 
pembrolizumab 400 mg IV Q6W for up to 18 cycles. Participants randomized to placebo 
must start cross-over treatment within 12 weeks of disease recurrence. Participants assigned 
to pembrolizumab are eligible for retreatment if biopsy proven disease recurrence occurs 
before Year 5 and more than 6 months after completing 9 cycles (1 year) of study adjuvant 
therapy; participants that experience recurrence earlier than this could indicate 
pembrolizumab refractory disease and would not be eligible for retreatment. A treatment 
duration of up to 18 cycles is consistent with the total dosage in Phase 2 KN629 study in 
participants with R/M cSCC.
Immunosuppression has long been associated with increased risk of cSCC. Participants with 
prior allogeneic transplantation or chronic immunosuppression have been found to be up to 
65 times as likely to develop the risk of developing an invasive cSCC compared to 
08RB5W

PRODUCT: MK-3475
53
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
age-matched controls. However, several case reports of allograft rejection following anti-PD-
1 therapy have recently been described [Spain, L., et al 2016]. Although there is evidence of 
robust clinical response in allograft organ recipients, including PR and CR, the potential risk 
for allograft rejection may not justify the potential therapeutic benefit. Therefore, participants 
with a history of prior solid organ or allogeneic bone marrow transplant will be excluded in 
this study.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
4.2.1.1.1
Recurrence-free Survival
This study will use RFS, as assessed by the investigator, as the primary endpoint. RFS is 
considered an appropriate clinical endpoint for adjuvant studies that will evaluate the study 
treatment’s impact on disease recurrence and is a common clinical surrogate endpoint to in 
adjuvant settings in which patients are expected to experience cancer symptoms upon 
recurrence (eg, adjuvant breast cancer hormonal therapy, adjuvant colon cancer, and adjuvant 
cytotoxic breast cancer therapy). Additionally, given the morbidity and mortality associated 
with recurrent high-risk LA cSCC, RFS of the baseline index lesion represents a clinically 
significant endpoint for patients with this disease. See Section 9.4 for the primary and 
secondary endpoint definitions. Images will be assessed by local site investigator; the final 
determination of radiologic recurrence will be confirmed by biopsy. 
Note: A new high-risk primary cSCC is considered an RFS event; however, a new low risk 
primary cSCC is not considered as an RFS event (see Section 8.2.1.5). The occurrence of a 
new low risk primary cSCC that can be surgically removed without the need for additional 
radiotherapy and/or systemic therapy would not threaten OS and would not be expected to 
require a clinical need for pembrolizumab. The use of pembrolizumab will be focused to 
prevent debilitating morbidity and recurrence of life-threatening disease, which would be the 
case for recurrence of high-risk LA cSCC.
4.2.1.1.2
Overall Survival
OS has been recognized as the gold standard for the demonstration of superiority of a new 
antineoplastic therapy in randomized clinical studies. In this study, OS will be measured as a 
secondary endpoint. The OS endpoint may be potentially confounded by subsequent therapy, 
thus limiting its utility as a primary endpoint. In this study, participants randomized to 
placebo can cross over and receive pembrolizumab upon disease recurrence. The OS 
endpoint for this disease can be heterogeneous given the variability of salvage procedures, 
which is highly center and expertise dependent, and this variability may have an impact on 
the OS endpoint. Further complicating the OS endpoint is that patients who survive more 
than 3 years have an OS impact mainly driven by participant comorbidities and second 
primaries, rather than by disease recurrence. For all the reasons stated above, RFS is the 
primary endpoint and OS will be a secondary endpoint.
08RB5W

PRODUCT: MK-3475
54
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
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 [4.0]. The severity (as CTCAE grade), 
attribution to drug, time-of-onset, duration, resolution, and any concomitant medications 
administered will be recorded.
4.2.1.3
Patient-reported Outcomes
The study will incorporate HRQoL measures as secondary and exploratory endpoints. 
Participants will provide information regarding their HRQoL using the EORTC QLQ-C30 
and Skindex-16 PRO instruments. Health utilities will be evaluated using the EQ-5D PRO 
instrument. The EORTC QLQ-C30, Skindex-16, and EQ-5D PROs are not pure efficacy or 
safety endpoints because they are affected by both disease recurrence and treatment 
tolerability.
4.2.1.3.1
EORTC QLQ-C30
The EORTC QLQ-C30 is the most widely used cancer specific HRQoL instrument, which 
contains 30 items and measures 5 functioning dimensions (physical, role, emotional, 
cognitive, and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 6 single items 
(dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a 
global health and QoL scale [Aaronson, N. K., et al 1993]. The EORTC QLQ C30 is a 
psychometrically and clinically validated instrument appropriate for assessing HRQoL in 
oncology studies [Aaronson, N. K., et al 1993] and has been psychometrically validated in 
the NMSC population (N=172) [Muller, K., et al 2017].
4.2.1.3.2
Skindex-16
Skindex-16 is a 16-item instrument that is broadly used for dermatology skin conditions to 
measure the extent that patients are bothered by their skin condition, in terms of skin 
symptoms, feelings, and effects on function. Scores vary from 0 (best QoL) to 100 (worst 
QoL), and responses are analyzed into 3 domains, including symptoms (4 items: itching, 
burning/stinging, hurting, irritated), emotions (7 items: persistence/recurrence, worry, 
appearance, frustration, embarrassment, being annoyed, feeling depressed), and functioning 
(5 items: interaction with others, desire to be with people, affection, daily activities, ability to 
work) [Chren, M. M. 2012]. The original Skindex-61 instrument was developed in a cohort 
of N=201 dermatology patients inclusive of N=35 NMSC patients; the reduced Skindex-29 
instrument was developed in a cohort of N=685 dermatology patients including N=136 
NMSC patients [Chren, M. M., et al 1997], and the subsequent refinement into the Skindex-
16 was psychometrically validated in a cohort of N=386 dermatology patients including 
N=84 NMSC patients [Chren, M. M., et al 2001]. The Skindex-16 has been used to assess 
disease-related HRQoL in NMSC patients including patients with cSCC, where it was able to 
detect changes in disease-related HRQoL following surgical treatment [Chren, M. M., et al 
2007] [Chen, T., et al 2007]. The instrument has also been incorporated in a study of 
08RB5W

PRODUCT: MK-3475
55
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
systemic therapy for the treatment of unresectable LA basal cell carcinoma [Grob, J. J., et al 
2016].
4.2.1.3.3
EuroQOL EQ-5D
The EQ-5D is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. and de 
Charro, F. 2001]. The 5 health state dimensions in the EQ-5D include the following: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension 
is rated on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems). The EQ 
5D also includes a graded (0 to 100) vertical visual analog scale on which the participant 
rates their general state of health at the time of the assessment. This instrument has been used 
extensively in cancer studies and published results from these studies support its validity and 
reliability [Pickard, A. S., et al 2007].
4.2.1.4
Planned Exploratory Biomarker Research
The mechanism of action of many antitumor agents is not completely understood and much 
remains to be learned regarding how best to leverage new drugs in treating patients. Thus, to 
aid future patients, it is important to investigate the determinants of response or resistance to 
cancer treatments. These efforts may identify novel predictive/pharmacodynamic biomarkers 
and generate information that may better guide single-agent and combination therapy with 
antineoplastic drugs. To identify novel biomarkers, biospecimens (eg, blood components, 
tumor material, etc) will be collected to support analyses of cellular components (eg, protein, 
DNA, RNA, metabolites) and other circulating molecules. Investigations may include, but
are not limited to the following:
Germline genetic analyses (eg, SNP analyses, whole exome sequencing, whole genome 
sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy, the data might inform optimal use of therapies in the patient population. 
Furthermore, it is important to evaluate germline DNA variation across the genome to 
interpret tumor-specific DNA mutations. Finally, MSI may be evaluated as this is an 
important biomarker for some cancers (ie, colorectal cancer).
Genetic (DNA) tumor analyses 
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify important tumor-specific DNA changes (eg, mutations, 
methylation status, microsatellite instability, etc). Key molecular changes of interest to 
oncology drug development may also include the mutational burden of tumors and the 
clonality of T-cells in the tumor microenvironment. Microsatellite instability may also be 
evaluated as this is an important biomarker for some cancers (eg, colorectal cancer). 
Genome-wide approaches may be used for this effort. Note that to understand tumor-specific 
mutations, it is necessary to compare the tumor genome with the germline genome. 
Circulating tumor DNA may also be evaluated from biospecimens (eg, blood, urine, etc).
08RB5W

PRODUCT: MK-3475
56
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Tumor and/or blood RNA analyses
Both genome-wide and targeted mRNA expression profiling and sequencing in tumor tissue 
and/or in blood may be performed to define gene signatures that might correlate to clinical 
response to treatment with antitumor therapies. Specific gene sets (eg, those capturing 
interferon-gamma transcriptional pathways) may be evaluated and new signatures may be 
identified. Expression of individual genes may also be evaluated. MicroRNA profiling may 
also be pursued as well as exosomal profiling. Circulating tumor RNA may also be evaluated 
from biospecimens (eg, blood, urine, etc).
Immunohistochemical (IHC) and/or proteomic analyses using tumor
Tumor samples from this study may undergo histopathological (eg, PD-L1 IHC), proteomic, 
and/or immunological analyses. These approaches could identify novel protein biomarkers 
that could aid in patient selection for antitumor therapy.
Other biomarkers
In addition to expression on the tumor tissue, tumor-derived proteins can be shed from tumor 
and released into the blood. Assays such as ELISA may be used to measure such proteins in 
serum and/or plasma. Correlation of expression with response to therapy may identify new 
approaches for predictive biomarkers in blood, representing a major advance from today’s 
reliance on assessing tumor biomarkers.
Other molecular changes of interest may include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated. Furthermore, when applicable, cell populations may be also separated by either 
flow cytometry or mass cytometry-based sorting. These approaches may be used to quantify 
cell- and/or tissue-based analytes to further elucidate mechanism of action and/or assess 
disease-related parameters.
4.2.1.5
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in 
Appendix 6.
08RB5W

PRODUCT: MK-3475
57
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
4.3
Justification for Dose
Maximum Dose/Exposure for This Study
In the Adjuvant Treatment Phase, participants may receive pembrolizumab 400 mg Q6W for 
up to 9 cycles in total. A 400 mg Q6W dosing regimen of pembrolizumab is expected to have 
a similar benefit-risk profile as 200 mg Q3W, in all treatment settings in which 200 mg Q3W 
pembrolizumab is currently appropriate [Lala, M., et al 2020]. Specifically, the dosing 
regimen of 400 mg Q6W for pembrolizumab is considered adequate based on modeling and 
simulation analyses, given the following rationale:
•
PK simulations demonstrating that in terms of pembrolizumab exposures:

Cav (or AUC) at 400 mg Q6W is similar to the approved 200 mg Q3W dose, thus 
bridging efficacy between dosing regimens.

Cmin at 400 mg Q6W are generally within the range of those achieved with 2 mg/kg 
or 200 mg Q3W in the majority (>99%) of patients.

Cmax at 400 mg Q6W are well below the Cmax for the highest clinically tested dose of 
10 mg/kg Q2W, supporting that the safety profile for 400 mg Q6W should be 
comparable to the established safety profile of pembrolizumab.
•
E-R for pembrolizumab has been shown to be flat across indications, and OS predictions 
in melanoma and NSCLC show that efficacy at 400 mg Q6W is expected to be similar to 
200 mg or 2 mg/kg Q3W, given the similar exposures; thus, 400 mg Q6W is expected to 
be efficacious across indications.
The safety, efficacy, and PK profile of the pembrolizumab 400 mg Q6W dose regimen are 
objectives of the ongoing KEYNOTE-555 study.
The optimal duration of treatment with immune checkpoint inhibitors has yet to be defined; 
only Phase 1 data is available for anti-PD-1 or anti-PD-L1 immune checkpoints inhibitors in 
LA cSCC. For breast cancer, treatment modalities such as human epidermal growth factor 
receptor 2 directed therapy (trastuzumab) the optimal treatment duration is 1 year; increasing 
treatment duration to 2 years was not associated with additional benefit for trastuzumab in 
this indication, even though patients with advanced disease might receive treatment for a 
longer time [Piccart-Gebhart, M. J., et al 2005]. Based on this experience and in the absence 
of additional data for immune checkpoint inhibitors, this study will evaluate pembrolizumab 
adjuvant therapy for up to 1 year (9 cycles); the same duration therapy was used in a study of 
pembrolizumab adjuvant therapy in resected Stage III melanoma [Eggermont, A. M. M., et al 
2018].
After first documented disease recurrence, if clinically indicated and with Sponsor approval, 
participants may cross over to or receive retreatment with pembrolizumab 400 mg IV Q6W 
for up to 18 cycles; for participants that received pembrolizumab in the Adjuvant Treatment 
Phase, any retreatment will be a minimum of 6 months after the last dose in the Adjuvant 
Treatment Phase. A treatment duration of up to 18 cycles is consistent with the total dosage 
in Phase 2 KN629 study of R/M cSCC.
08RB5W

PRODUCT: MK-3475
58
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
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.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects is such that the risk/benefit ratio to the study population as a whole is 
unacceptable. In addition, further recruitment in the study or at (a) particular study site(s) 
may be stopped as described in Appendix 1.10.
08RB5W

PRODUCT: MK-3475
59
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
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. Participant must have histologically confirmed cSCC as the primary site of malignancy 
(metastatic skin involvement from another type of primary cancer or from an unknown 
primary cancer is not permitted). 
Note: Participants for whom the primary site of squamous cell carcinoma was anogenital 
area (penis, scrotum, vulva, perianal region) are not eligible. Participants with tumors 
arising on cutaneous non-glabrous (hair-bearing) lip with extension onto vermillion 
(dry red lip) may be eligible after communication and approval from the clinical director. 
Participants for whom the primary site is the nose may be eligible after communication 
and approval from the clinical director if the primary site is skin, not nasal mucosa with 
outward extension to skin.
2. Participant must have undergone complete macroscopic resection of all known cSCC 
disease with or without microscopic positive margins. For those participants with residual 
microscopic positive margin involvement, confirmation that additional re-excision is not 
possible must be provided. Surgery may consist of 1 or a combination of the following:
a.
Resection of the primary lesion (Note: If a primary lesion is present, it must be 
completely resected as above)
b. Any type of neck dissection(s)
c.
Any type of parotidectomy (superficial, total, partial)
3. Participant must have histologically confirmed LA cSCC with a high-risk feature(s) as 
the primary site of malignancy (metastatic skin involvement from another primary cancer 
or from an unknown primary cancer is not permitted) [National Comprehensive Cancer 
Network 2017]. High-risk features include at least 1 of the following: 
a.
Histologically involved nodal disease with the following features:
◦
Extracapsular extension with either at least 1 lymph node >2 cm in greatest 
diameter or ≥2 lymph nodes involved.
08RB5W

PRODUCT: MK-3475
60
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
b. Any index tumor with ≥2 of the following high-risk features: 
◦
Tumor ≥4 cm with a depth >6 mm or invasion beyond subcutaneous fat 
◦
Multifocal perineural invasion for nerves of <0.1 mm diameter (3 or more foci) or 
any involved nerve ≥0.1 mm diameter
◦
Poor differentiation and/or sarcomatoid and/or spindle cell histology
◦
Recurrent disease (any cSCC that recurs within 3 years in the previously 
surgically or topically treated area)
◦
Satellite lesions (satellitosis) and/or in-transit metastases
◦
Lymphatic or vascular involvement
c.
Any gross cortical bone invasion or skull base invasion and/or skull base foramen 
invasion.
4. Participant must have completed adjuvant RT for LA cSCC with last dose of RT ≥4 
weeks and ≤16 weeks from randomization.
5. Participants who received an adequate post op dose of RT (either hypofractionated or 
conventional) are eligible. This includes all participants with a BED EQD2 >48 Gy. 
Examples of commonly used acceptable regimens include doses of 30-35Gy in 5fx; 
40Gy/10 fx; 40-45Gy/15fx; 50-55Gy/20fx; 45-50Gy/25fx; 50.4Gy/28fx; 54Gy/30fx; 60-
66Gy/30-33fx; the specific treatment must comply with ASTRO and RCR guidelines for 
adjuvant RT of high-risk LA cSCC [Likhacheva, A., et al 2020] [The Royal College of 
Radiologists 2019].
6. Participant is disease-free as assessed by the investigator with complete radiographic 
staging assessment ≤28 days from randomization.
Demographics
7. Participant is male or female and at least 18 years of age at the time of signing the 
informed consent.
08RB5W

PRODUCT: MK-3475
61
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Female Participants
8. Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
•
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 POCBP 

OR

Is a POCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year) 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 POCBP must have a negative highly sensitive pregnancy test (as required by local 
regulations) within 72 hours 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 Appendix 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.

Abstains from breastfeeding during the study intervention period and for at least 120 
days after study intervention.

If the contraception requirements in the local label for any of the study interventions 
is more stringent than the requirements above, the local label requirements are to be 
followed.
Refer to Appendix 7 for country-specific requirements.
Informed Consent
9. Participant (or legally acceptable representative, if applicable) provides 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. 
Note: Eligible participants must provide additional informed consent for participation in 
post-study cross-over/retreatment.
08RB5W

PRODUCT: MK-3475
62
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Additional Categories
10. Participant provides a tumor tissue sample adequate for PD-L1 testing as determined by 
central laboratory testing. This tissue sample may be obtained from either the surgical 
resection, or a prior archival tissue specimen not previously irradiated. FFPE tissue 
blocks are preferred to slides.
Note: Participants from whom PD-L1 testing cannot be performed due to infeasibility of 
testing of the tissue sample will not be eligible. Participants will not be excluded if tissue 
was initially thought to be adequate but a PD-L1 result was unable to be reported for 
whatever reason.
Note: Central pathological review for PD-L1 will not be performed before 
randomization.
11. Participant has a life expectancy of greater than 3 months.
12. Participant has an ECOG performance status of 0 or 1 performed within 10 days prior to 
treatment initiation.
13. Participant has adequate organ function as defined in the following table (Table 1). 
Specimens must be collected within 10 days prior to the start of study treatment.
08RB5W

PRODUCT: MK-3475
63
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL without granulocyte colony-stimulating 
factor (G-CSF) support within 2 weeks prior to the 
first dose of study treatment
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La Participants are eligible 
if levels are reached after blood transfusion.
Renal
Creatinine OR
Measured or calculatedb creatinine clearance (CrCl; 
glomerular filtration rate [GFR] can also be used in 
place of creatinine or CrCl)
≤1.5 × ULN OR
≥30 mL/min for participant with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN 
Coagulation
International normalized ratio (INR) OR prothrombin 
time (PT)
Activated partial thromboplastin time (aPTT)c
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic-pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic-oxaloacetic transaminase); CrCl=creatinine clearance; GFR=glomerular filtration rate; 
ULN=upper limit of normal.
a
Criteria must be met without erythropoietin dependency.
b
Cockcroft Gault calculation of CrCl preferred, but CrCl can be calculated per institutional standard.
c
PTT may be performed if the local laboratory is unable to perform aPTT. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements 
should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Has macroscopic residual cSCC after surgery and/or recurrence with active cSCC disease 
before randomization.
2. Has any other histologic type of skin cancer other than invasive cSCC, eg, basal cell 
carcinoma that has not been definitively treated with surgery or radiation, Bowen’s 
disease, MCC, melanoma.
08RB5W

PRODUCT: MK-3475
64
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
3. A POCBP who has a positive urine pregnancy test within 72 hours before the first dose of 
study treatment (see Appendix 5). If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive.
Note: If 72 hours have elapsed between the screening pregnancy test and the first dose of 
study treatment, another pregnancy test (urine or serum) must be performed and must be 
negative in order for participant to start receiving study treatment.
Refer to Appendix 7 for country-specific requirements.
Prior/Concomitant Therapy
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another costimulatory or coinhibitory T-cell receptor (eg, CTLA-4, 
OX-40, CD137).
5. Has received prior systemic anticancer therapy including investigational agents for cSCC 
within 4 weeks before the start of study intervention.
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.
Note: If participant received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting study treatment.
6. Participant must have recovered from all radiation-related toxicities and not have had 
radiation pneumonitis. 
7. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of 
study treatment. Administration of killed vaccines are allowed.
Refer to Section 6.5 for information on COVID-19 vaccines.
Prior/Concurrent Clinical Study Experience
8. Has received an investigational agent or has used an investigational device within 4 
weeks prior to the first dose of study treatment.
Diagnostic Assessments
9. 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 drug.
10. Known additional malignancy that is progressing or has required active treatment within 
the past 2 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin or carcinoma in situ, excluding carcinoma in situ of the bladder, that have 
undergone potentially curative therapy are not excluded. Other exceptions may be 
considered with Sponsor consultation.
08RB5W

PRODUCT: MK-3475
65
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Note: Participants with low risk early-stage prostate cancer defined as below are not 
excluded: Stage T1c or T2a with a Gleason score ≤6 and a prostate-specific antigen (≤10 
ng/ml) either treated with definitive intent or untreated in active surveillance that has 
been stable for the past year prior to study allocation. Early stage asymptomatic CLL 
without prior treatment and without any of the risk features (unmutated IGHV, 
lymphocytes >15,000µL, palpable lymph nodes) will be eligible for the study [Condoluci, 
A., et al 2020].
11. Has known active central nervous system metastases and/or carcinomatous meningitis. 
12. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients 
(refer to the Investigator’s Brochure for a list of excipients).
Refer to Appendix 7 for UK-specific requirements.
13. Has an active autoimmune disease that has required systemic treatment in past 2 years 
except replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid).
14. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
15. Has an active infection requiring systemic therapy.
16. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing 
is required unless mandated by local health authority.
Refer to Appendix 7 for Germany and UK-specific requirements. 
17. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] 
reactive) or known active hepatitis C virus (HCV; 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. 
Refer to Appendix 7 for Germany and UK-specific requirements.
18. Has a history or current evidence of any condition, therapy, or laboratory abnormality, or 
other circumstances that might confound the results of the study, interfere with the 
participant's participation for the full duration of the study such that it is not in the best 
interest of the participant to participate, in the opinion of the treating investigator.
19. 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
20. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days after 
the last dose of study treatment. 
21. Has had an allogeneic tissue/solid organ transplant.
5.3
Lifestyle Considerations
There are no lifestyle restrictions.
08RB5W

PRODUCT: MK-3475
66
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
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
There are no activity restrictions during participation in this study. As part of SoC, 
participants will receive repetitive education throughout the study regarding sun avoidance 
and protection.
5.3.4
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Refer to Appendix 5 for 
approved methods of contraception.
Participants should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study, participants of childbearing potential must adhere to the contraception 
requirement (Appendix 5) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of study medication. If there is any question that a participant of 
childbearing potential will not reliably comply with the requirements for contraception, that 
participant should not be entered into the study.
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.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention or withdraws from the study will not 
be replaced.
08RB5W

PRODUCT: MK-3475
67
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study intervention(s) provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 2.
08RB5W

PRODUCT: MK-3475
68
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Table 2
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
Use
IMP or 
NIMP/AxM
P
Sourcin
g
Pembrolizuma
b
Experiment
al
Pembrolizuma
b
Biological/Vaccin
e
Solution
25 mg/mL
400 mg
IV Infusion
Q6W; Day 1 
of each 42-
day cycle for 
up to 9 cycles 
(approximatel
y 1 year)
Test 
Produc
t
IMP
Provided 
centrally 
by the 
Sponsor
Placebo
Placebo 
Comparator
Placebo
Drug
Solution
N/A
N/A
IV Infusion
Q6W; Day 1 
of each 42-
day cycle for 
up to 9 cycles 
(approximatel
y 1 year)
Placeb
o
IMP
Locally 
by the 
site
AxMP=auxiliary medical product; IMP=investigational medicinal product; IV=intravenous; N/A=not applicable; NIMP=noninvestigational medicinal product; 
pembro=pembrolizumab; Q6W=every 6 weeks.
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. 
Country differences with respect to the definition/classification of IMP or NIMP/AxMP may exist. In these circumstances, local legislation is followed.
08RB5W

PRODUCT: MK-3475
69
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
All study interventions will be administered on an outpatient basis.
All products indicated in Table 2 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary, or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Treatment
Following surgical resection and RT, participants will be randomized to receive either:
•
Pembrolizumab (Pembrolizumab group) - 400 mg fixed dose, IV Q6W for up to 9 cycles, 
or 
•
Placebo (Control group)
After first biopsy proven disease recurrence: if clinically indicated (and with Sponsor 
approval) participants may cross over to or receive retreatment with pembrolizumab 400 mg 
IV Q6W for up to 18 cycles; for participants that received pembrolizumab in the Adjuvant 
Treatment Phase, any retreatment will be a minimum of 6 months after completing all 
9 cycles in the Adjuvant Treatment Phase.
6.1.2
Medical Devices
Not applicable.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab and placebo 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.
08RB5W

PRODUCT: MK-3475
70
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation/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 
pembrolizumab (pembrolizumab group) and placebo (control group), respectively.
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:
•
Extracapsular extension (yes vs. no)
•
Cortical bone invasion (yes vs. no)
•
Prior systemic therapy (yes vs. no) 
6.3.3
Blinding
In this study a double-blinding technique will be used. Pembrolizumab will be provided as 
open-label supplies. Therefore, an unblinded pharmacist or medically qualified study 
personnel will be used for blinding supplies. Pembrolizumab and placebo will be prepared 
and/or dispensed in a blinded fashion by an unblinded pharmacist or qualified study-site 
08RB5W

PRODUCT: MK-3475
71
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
personnel. The participant, the investigator, and Sponsor personnel or delegate(s) who are 
involved in the study intervention administration or clinical evaluation of the participants are 
unaware of the intervention assignments.
Upon disease recurrence, the investigator will request authorization via an SCF for official 
unblinding and consideration to proceed to cross-over/retreatment. Cross-over/retreatment is 
open-label; therefore, the Sponsor, site personnel, study staff, investigator, participant, and 
study teams associated with the conduct of the study will know the treatment administered. 
See Section 8.1.10 for details of the method for unblinding a participant.
After efficacy IA, the study was unblinded on 22-AUG-2024. Original protocol text in this 
section has been retained for reference.
6.4
Study Intervention Compliance
Administration of study medication(s) will be witnessed by the investigator and/or study 
staff. The total volume of study medication infused will be compared with the total volume 
prepared to determine compliance with each dose administered.
Interruptions from the protocol-specified treatment plan for more than 12 weeks between 
pembrolizumab doses for nondrug-related or administrative reasons require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption or infusion/injection cessation of study 
intervention will be documented in the participant’s medical record.
Refer to Section 6.6.1 for Dose Modification and Toxicity Management Guidelines for irAEs 
associated with pembrolizumab monotherapy, coformulations, or IO combinations and for 
other allowed dose interruptions.
6.5
Concomitant Therapy
If there is a clinical indication for any medications or vaccinations prohibited, the 
investigator must discuss any questions regarding this with the Sponsor’s Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator and the Sponsor.
The following medications and vaccinations are prohibited during the study:
•
Surgical intervention to skin lesions.
Note: Surgical intervention to skin lesion(s), without consultation with the Sponsor, is not 
permitted during the Adjuvant Treatment Phase. 
08RB5W

PRODUCT: MK-3475
72
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
•
Live or live-attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study.
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.
•
Systemic glucocorticoids except when used for the following purposes:

To modulate symptoms of an AE that is suspected to have an immunologic etiology

For the prevention of emesis

To premedicate for IV contrast allergies

To treat asthma or COPD exacerbations (only short-term oral or IV use in doses 
>10 mg/day prednisone equivalent)

For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent
•
Other glucocorticoid use except when used for the following purposes:

For topical use or ocular use

Intraarticular joint use

For inhalation in the management of asthma or COPD
If the investigator determines that a participant requires any of the following prohibited 
medications and vaccinations for any reason during the study, study intervention must be 
discontinued:
•
Systemic antineoplastic chemotherapy, immunotherapy, or biological therapy not 
specified in this protocol
•
Investigational agents other than those specified in this protocol
•
Radiation therapy 
Note: RT is not permitted during the Adjuvant Treatment Phase. After determination of 
eligibility for cross-over/retreatment, participants may undergo sequential RT after 
consultation with the Sponsor.
•
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medications will be recorded on the eCRF including all 
prescriptions, OTC products, herbal supplements, and IV medications, and fluids. If changes 
occur during the study period, documentation of drug dosage, frequency, route, and date 
should also be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
08RB5W

PRODUCT: MK-3475
73
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
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.
Where appropriate, these guidelines include the use of oral or IV treatment with 
corticosteroids, as well as additional anti-inflammatory agents if symptoms do not improve 
with administration of corticosteroids. Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
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
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids, and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation.
Dose Modification and Toxicity Management Guidelines for irAEs Associated With 
Pembrolizumab Monotherapy, Coformulations, or IO Combinations are provided in Table 3.
08RB5W

PRODUCT: MK-3475
74
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related AEs 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 Version 
4.0)
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 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
· Monitor participants for signs and symptoms 
of pneumonitis
· Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
· Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 or 
Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
· Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
· Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs and 
ileus)
· Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
· Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids. 
If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion.
Recurrent Grade 3 or 
Grade 4
Permanently 
discontinue
08RB5W

PRODUCT: MK-3475
75
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
irAEs
Toxicity Grade 
(CTCAE Version 
4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations, or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST / ALT 
Elevation or 
Increased Bilirubin
Grade 2
Withhold
· Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper
· Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
· Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withholda
· Initiate insulin replacement 
therapy for participants with 
T1DM
· Administer anti-
hyperglycemic in participants 
with hyperglycemia
· Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
· Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
· Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinuea
Hyperthyroidism 
Grade 2
Continue
· Treat with non-selective 
beta-blockers (eg, propranolol) 
or thionamides as appropriate
· Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinuea
08RB5W

PRODUCT: MK-3475
76
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
irAEs
Toxicity Grade 
(CTCAE Version 
4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations, or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue
· Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
· Monitor for signs and symptoms of thyroid 
disorders
Nephritis and renal 
dysfunction
Grade 2
Withhold
· Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper
· Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
· Based on severity of AE 
administer corticosteroids
· Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold
· Based on severity of AE 
administer corticosteroids
· Ensure adequate evaluation to confirm etiology 
or exclude other causes
Grade 3
Withhold or 
discontinueb
Recurrent Grade 3 or 
Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune-related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 
diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
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.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically 
important irAEs (eg, vasculitis and sclerosing cholangitis).
08RB5W

PRODUCT: MK-3475
77
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab Monotherapy, Coformulations, or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations may cause severe or life-
threatening infusion reactions including severe hypersensitivity or anaphylaxis. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Dose modification and toxicity 
management guidelines on pembrolizumab monotherapy, coformulations, or IO 
combinations associated infusion reactions are provided in Table 4.
Table 4
Pembrolizumab Monotherapy, Coformulations, or IO Combinations –
Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 h
Stop Infusion
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(eg, from 100 mL/h to 50 mL/h). Otherwise, 
dosing will be held until symptoms resolve 
and the participant should be premedicated 
for the next scheduled dose.
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
study intervention.
Participant may be premedicated 1.5 h 
(±30 min) prior to infusion of study 
intervention with:
Diphenhydramine 50 mg po (or equivalent 
dose of antihistamine).
Acetaminophen 500 to 1000 mg po (or 
equivalent dose of analgesic).
08RB5W

PRODUCT: MK-3475
78
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
after initial improvement; 
hospitalization indicated 
for other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine 
should be used immediately.
Participant is permanently discontinued 
from further study intervention.
No subsequent dosing
CTCAE=Common Terminology Criteria for Adverse Events; h=hour; IV=intravenous; NCI=National Cancer Institute; 
NSAIDs=nonsteroidal anti-inflammatory drugs.
Note: Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration.
For further information, please refer to the CTCAE v4.0 at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab Monotherapy, Coformulations, 
or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations may be interrupted for 
situations other than treatment-related AEs such as medical or surgical events and/or 
unforeseen circumstances not related to study intervention. Participants should be placed 
back on study therapy within 3 weeks of the scheduled interruption, 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
Cross-over/Retreatment
Upon biopsy proven disease recurrence, participants may be eligible for up to an additional 
18 cycles (approximately 2 years) of pembrolizumab treatment. Cross-over/retreatment is 
optional, at the discretion of the investigator after approval from the Sponsor, and is only 
available if the study remains open and the participant meets conditions detailed in 
Section 8.1.8.1.2.
6.7
Intervention After the End of the Study
The study is complete upon consent of the last active treatment participant for an extension 
study using pembrolizumab monotherapy, if available.
08RB5W

PRODUCT: MK-3475
79
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
All study-related procedures and data collection as defined per protocol will be terminated at 
study completion. In addition, survival follow-up will be stopped upon study completion as 
defined in Section 4.4.
6.8
Clinical Supplies Disclosure
The adjuvant treatment phase of the study is blinded but supplies are provided open-label; 
therefore, an unblinded pharmacist or qualified study site personnel will be used to blind 
supplies. Study treatment identity (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity for study adjuvant 
treatment. The emergency unblinding call center should only be used in cases of emergency 
(see Section 8.1.10.1). If the emergency unblinding call center is not available for a given site 
in this study, the central electronic intervention allocation/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.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
6.9
Standard Policies
Not applicable.
08RB5W

PRODUCT: MK-3475
80
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
periods will still continue to be monitored in this study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.11.4 unless the participant has 
withdrawn from the study as outlined in 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.
•
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 urine or serum pregnancy test.
•
Biopsy-confirmed disease recurrence as outlined in Section 8.2.1.6 (exception if the 
participant moves into Cross-over/Retreatment). 
•
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.
•
Recurrent Grade 2 pneumonitis.
08RB5W

PRODUCT: MK-3475
81
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
•
Use of prohibited concomitant medication (see Section 6.5).
•
Completion of 9 cycles of study treatment (approximately 1 year).
Note: The number of treatments is calculated starting with the first dose.
Participants may be allowed to begin study treatment again if deemed medically appropriate 
(see Section 8.1.8.1.2).
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in 
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
08RB5W

PRODUCT: MK-3475
82
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before providing documented informed consent may be used for 
screening or baseline purposes provided the procedures meet the protocol-specified 
criteria and were performed within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, are detailed in the Vendor 
Manual.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
08RB5W

PRODUCT: MK-3475
83
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
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.
The investigator must ensure that eligibility criteria are met for all participants that 
experience disease recurrence and enter cross-over/retreatment before the start of 
pembrolizumab treatment. Cross-over/retreatment eligibility criteria are detailed in 
Section 8.1.8.1.2.
08RB5W

PRODUCT: MK-3475
84
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
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 
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant’s ID card will be updated if they enter cross-over/retreatment.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout, or run-in treatment including placebo run-in).
8.1.4.1
Disease Details
Details regarding participants cSCC status at baseline must be thoroughly evaluated by the 
investigator or qualified designee and recorded in the appropriate eCRF including: date of 
initial diagnosis, stage at diagnosis, tumor grade, primary tumor location and type (ie, single 
lesion, multifocal), tumor, node, and metastasis staging at baseline. Prior to entry in the 
study, all participants will have undergone surgical resection; details regarding date of 
surgery, type of surgery, etc. will be recorded in the appropriate eCRF. Refer to Sections 5.1 
and 5.2 to ensure participant’s disease status meets the relevant inclusion and exclusion 
criteria for study entry.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the study. Treatment for the disease for which the participant 
08RB5W

PRODUCT: MK-3475
85
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
has enrolled in this study will be recorded separately and not listed as a prior medication. 
Prior treatment for other cancers will be recorded 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. All medications related to reportable 
AEs, SAEs, and ECIs should be recorded as defined in Appendix 3.
8.1.5.3
Post-study Anticancer Therapy Status
The investigator or qualified designee will record anticancer therapy medication, if any, 
taken by the participant after discontinuing from study adjuvant treatment and through study 
follow up. For participants that enter cross-over/retreatment, the investigator or qualified 
designee will record anticancer therapy (including RT and surgical intervention) if any, 
received by the participant, from the study adjuvant phase End of Treatment visit and 
through Survival Follow-up.
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 individual 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. 
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
randomization. Once a randomization number is assigned to a participant, it can never be 
reassigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or an appropriately 
qualified designee according to the specifications within the pharmacy manual.
Interruptions from the protocol-specified treatment plan for greater than 12 weeks between 
pembrolizumab/placebo doses require consultation between the investigator and the Sponsor 
and written documentation of the collaborative decision on participant management.
08RB5W

PRODUCT: MK-3475
86
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Study intervention should begin within 3 days of randomization. Thereafter, study treatment 
may be administered up to 3 days before or after the scheduled Day 1 of each cycle (eg, due 
to administrative reasons) after Cycle 1.
8.1.8.1
Timing of Dose Administration
The dose and schedule modifications of pembrolizumab are provided in Section 6.6 – Dose 
Modification (Escalation/Titration/Other).
8.1.8.1.1
Adjuvant Treatment with Pembrolizumab/Placebo
Study treatment will be administered on Day 1 of each 6-week dosing cycle after all 
procedures and assessments are completed according to the SoA (Section 1.3). Each cycle is 
42 days.
Participants will be administered pembrolizumab 400 mg or placebo using a 30-minute IV 
infusion. Sites should make every effort to target infusion timing to be as close to 30 minutes 
as possible. However, given the variability of infusion pumps from site to site, a window 
between −5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes −5 min / 
+10 min).
Participants can receive study treatment at a minimum of 4 weeks (± 3 days) and a maximum 
of 16 weeks (± 3 days) after the last dose of RT and once they have recovered adequately 
from the morbidity and/or complications from RT, as determined by the investigator.
Participants may receive up to 9 cycles of study treatment in total. If an interruption occurs, 
the participant should restart study treatment as soon as medically appropriate with the 
subsequent cycle and should not skip cycles. The participant, after an interruption, may 
restart treatment cycles without delay from the original 6-week interval schedule, but all 
future doses should be recalculated in 6-week intervals. Participants should be administered 
all planned 9 cycles, which could extend beyond the 1-year timeframe of the study.
The Pharmacy Manual contains specific instructions for the pharmacist for the preparation of 
the pembrolizumab and placebo infusions and administration of infusion solutions.
8.1.8.1.2
Cross-over/Retreatment with Pembrolizumab
Upon documented disease recurrence, adjuvant treatment will be unblinded as per 
Section 8.1.10. The primary objective of the study is to compare RFS of pembrolizumab 
versus placebo, while ensuring access to pembrolizumab for all patients entering the study. 
08RB5W

PRODUCT: MK-3475
87
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Next Line of Treatment – Cross-over 
Participants assigned to placebo in the Adjuvant Treatment Phase who experience biopsy 
proven disease recurrence may be eligible for up to 18 cycles (approximately 2 years) of 
pembrolizumab 400 mg Q6W treatment. Cross-over is optional, at the discretion of the 
investigator after approval from the Sponsor, and is only available if the study remains open 
and the participant meets the following conditions:
•
Stopped study treatment after attaining an investigator-determined disease recurrence 
confirmed by histology. 
AND
•
The participant is not eligible for surgical resection, and
•
Upon unblinding at the time of verified disease recurrence, is found to have received 
placebo, and
•
No new systemic anticancer treatment was administered after the last dose of study 
treatment, and
•
Biopsy proven recurrence occurred before the end of Year 5 and ≤12 weeks before the 
start of Cross-over Treatment, and
•
The participant meets all of the safety parameters listed in the inclusion criteria 
(criteria 11 to 13) and none of the safety parameters listed in the exclusion criteria 
(criteria 3, 7, and 9 to 21), and
•
The study is ongoing.
A disease progression that occurs during the Cross-over Phase for a participant will not be 
counted as an event for the primary analysis of endpoints in this study.
Next Line of Treatment – Pembrolizumab Retreatment
Participants may be considered for retreatment with pembrolizumab after biopsy proven 
disease recurrence >6 months after completing 1 year of adjuvant pembrolizumab treatment. 
Participants may be retreated with up to an additional 18 cycles (approximately 2 years) of 
pembrolizumab 400 mg IV Q6W. Retreatment is optional and at the discretion of the 
investigator after approval from the Sponsor. This retreatment is only available if the study 
remains open and the participant meets the following conditions:
•
Attaining an investigator-determined disease recurrence confirmation by histology before 
the end of Year 5 and >6 months after last dose of treatment in the Adjuvant Treatment 
Phase, and 
•
The participant is not eligible for surgical resection, and
•
Completion of 9 cycles of adjuvant treatment before disease recurrence, and
08RB5W

PRODUCT: MK-3475
88
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
•
Upon unblinding at the time of verified disease recurrence, is found to have received 
pembrolizumab, and
•
No new systemic anticancer treatment was administered after the last dose of study 
treatment, and
•
The participant meets all of the safety parameters listed in the inclusion criteria (criteria 
11 to 13) and none of the safety parameters listed in the exclusion criteria (criteria 3, 7, 
and 9 to 21), and
•
The study is ongoing.
For both cross-over and retreatment pembrolizumab will be administered at a dose of 400 mg 
using a 30-minute IV infusion. Sites should make every effort to target infusion timing to be 
as close to 30 minutes as possible. However, given the variability of infusion pumps from 
site to site, a window between −5 minutes and +10 minutes is permitted (ie, infusion time is 
30 minutes −5 min / +10 min). 
Participants may receive up to 18 cycles of pembrolizumab in total. If an interruption occurs, 
the participant should restart pembrolizumab as soon as medically appropriate with the 
subsequent cycle and should not skip cycles. The participant, after an interruption, may 
restart pembrolizumab cycles without delay from the original 6-week interval schedule, but 
all future doses should be recalculated in 6-week intervals. Participants should be 
administered all planned 18 cycles, which could extend beyond the 2-year treatment 
timeframe of the study.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the study Adjuvant 
Treatment period should be encouraged to continue to be followed for all remaining study 
visits.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the End of Treatment 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 
08RB5W

PRODUCT: MK-3475
89
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
8.1.10.1
Emergency Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity/toxicity grade of the AEs observed, the relation to study intervention, the reason 
thereof, etc, in the medical record. If it is not possible to record this assessment in the 
medical record before the unblinding, the unblinding should not be delayed.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician may be allowed to continue study 
intervention and should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
If unblinding has occurred, in response to events other than biopsy-proved disease recurrence 
(See Section 8.1.10.2), 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. Only the principal investigator or delegate and the respective 
participant’s code should be unblinded. Other study site personnel and Sponsor personnel 
directly associated with the conduct of the study should not be unblinded.
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
08RB5W

PRODUCT: MK-3475
90
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
8.1.10.2
Unblinding by Investigator After First Disease Recurrence
Upon biopsy/confirmed disease recurrence, the investigator will request authorization for 
official non-emergency unblinding. If the participant is determined to be ineligible for 
surgical resection, a request for consideration to proceed to cross-over or retreatment will 
also be submitted. Non-emergency unblinding may occur on an individual basis and only 
after consultation with and approval of Sponsor Clinical Director via an SCF. Every effort 
should be made not to unblind the participant unless necessary.
The emergency unblinding methods described in Section 8.1.10.1 should not be used in this 
process. 
Upon biopsy-confirmed disease recurrence, every effort will be made to have all pending 
data entered into the eCRFs within 1 business day or before the site is unblinded to the 
participant’s treatment assignment.
The site should ensure data for disease recurrence is entered in the database prior to 
unblinding. Additionally, any AEs and/or SAEs should be reported and causality attributed in 
the database prior to unblinding. 
After unblinding is complete, the site will assess participant eligibility for Cross-
over/Retreatment by reviewing all qualifications per protocol Sections 8.1.8.1.2, 5.1, and 5.2. 
If a participant fulfills the eligibility criteria, the site will access the recurrence phase module 
in IRT and request treatment assignment in Cross-over or Retreatment. 
After biopsy proven disease recurrence, the study participant, investigator, site personnel, 
Sponsor personnel, study teams associated with the conduct of the study will become 
unblinded in order to continue monitoring each participant in the study.
8.1.11
Domiciling
At the discretion of the investigator, participants will report to the CRU the evening before 
the scheduled day of study intervention administration for each treatment period and remain 
in the unit until 24 hours postdose. At the discretion of the investigator, participants may be 
requested to remain in the CRU longer.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
08RB5W

PRODUCT: MK-3475
91
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
8.1.13
Tumor Tissue for Biomarker Status
Details regarding time points for collection of tumor tissue are outlined in the SoA 
(Section 1.3). Include a copy of the local pathology report with the tissue for biomarker 
analysis.
In accordance with the study inclusion criteria, participants are required to provide baseline 
tumor tissue from new or archived FFPE tissue specimens for PD-L1 assessment. 
Tissue biopsy is required for confirmation of disease recurrence (Section 8.2.1.6); Sponsor 
consultation is required if a biopsy cannot be performed due to feasibility, such as location of 
recurrence (ie, bone lesion). If the participant provides documented informed consent for 
Future Biomedical Research, any leftover tissue that would ordinarily be discarded at the end 
of the main study will be retained for Future Biomedical Research. 
Detailed instructions for tissue collection, processing, and shipment are provided in the 
Vendor Manual.
PD-L1 testing
Archived tumor specimens will be tested centrally for characterization of PD-L1 status and 
translational research. The tissue sample must be assessed as adequate for PD-L1 testing as 
determined by central laboratory testing before randomization but central review of PD-L1 
does not need to be completed before randomization.
This specimen may be the diagnostic sample for participants with a new diagnosis of LA 
cSCC or the surgical excised sample.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
Throughout this section, the term ‘scan’ refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, or other methods as specified in this protocol.
The process for scan acquisition can be found in the SIM. At screening, tumor scans (head, 
neck, chest, abdomen, and pelvis; scans of the affected extremities are required for those 
participants with disease in the extremities at baseline) are strongly preferred to be acquired 
by CT. For the head, neck, abdomen, pelvis, and extremities, contrast-enhanced MRI may be 
used when CT with iodinated contrast is contraindicated, or when mandated by local 
practice. On-study scans should cover affected site of the disease under study, along with 
associated draining lymph nodes (see Section 8.2.1.5). The same scan technique should be 
used in a participant throughout the study to optimize the reproducibility of the assessment of 
disease recurrence based on scans (See SIM). Note: for the purposes of assessing tumor 
scans, the term “investigator” refers to the local investigator at the site and/or the radiological 
reviewer located at the site or at an offsite facility. 
08RB5W

PRODUCT: MK-3475
92
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Brain scans are required for all participants at Screening. MRI is preferred; however, CT 
scans will be acceptable, if MRI is medically contraindicated.
All scheduled scans for all randomized study participants will be submitted to the iCRO. 
Also, additional scans (CT, MRI, or FDG-PET) that are obtained at an unscheduled time 
point for any reason should be submitted to the iCRO if they show disease progression.
Note: As of Amendment 10, all ongoing participants should continue tumor imaging and 
investigator assessment of the scans per protocol; however, scans no longer need to be 
submitted to the iCRO and digital photography of cutaneous lesions is not required.
8.2.1.1
Initial Tumor Scans
Initial tumor scans at Screening must be performed within 28 days prior to the date of 
randomization and should include the anatomical sites detailed in Section 8.2.1. During 
screening, tumor scans of the site of the disease after surgical resection and RT will be 
considered as baseline scans.
Tumor scans performed as part of routine clinical management is acceptable for use as 
screening tumor scans if it is of diagnostic quality and performed within 28 days prior to the 
date of randomization. 
Brain scans are required to rule out radiographically detectable brain metastases. MRI is 
preferred; however, CT scans will be acceptable, if MRI is medically contraindicated or CT 
is mandated by local practice.
8.2.1.2
Tumor Scans During the Study
The first on-study scans (to include disease involved areas and associated draining lymph 
node regions, see Table 5) should be performed at 12 weeks (± 7 days) from the date of 
randomization. Subsequent tumor scans should be performed every 12 weeks 
(84 days ± 7 days) or more frequently if clinically indicated, during treatment. Scan timing 
should follow calendar days and should not be adjusted for delays in cycle starts. Scans are to 
be performed until disease recurrence is identified by the investigator/site radiologist, 
pregnancy, withdrawal of consent, or death, whichever occurs first.
08RB5W

PRODUCT: MK-3475
93
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Table 5
Required Scans
Affected disease site
Scans Required to cover Affected Sites and Associated 
Draining Lymph Nodes
Skin of the Head and Neck (including 
scalp)
Head and Neck (occipital, parotid, cervical, perifacial, and 
supraclavicular), Chest 
Skin of the Back/Torso/Upper Chest
Neck, Chest (axillary, supraclavicular, and posterior cervical) 
Skin of the Lower 
Abdomen/Buttock/Groin
Chest Abdomen, Pelvis (inguino-femoral, internal iliac, and 
external iliac) 
Pelvis
Chest, Abdomen, Pelvis (inguino-femoral, internal iliac, and 
external iliac) 
Skin of the Upper Extremities 
Involved Extremity and Chest (axillary, supraclavicular, and 
posterior cervical) 
Skin of the Lower Extremities 
Involved Extremity, Chest, Abdomen, Pelvis (inguino-femoral, 
internal iliac, and external iliac) 
8.2.1.3
End-of-treatment and Follow-up Tumor Scans
For participants who complete or discontinue study treatment, tumor scans should be 
performed at the time of treatment discontinuation (±4-week window). If previous scans 
were obtained within 4 weeks prior to the date of discontinuation, then scans at treatment 
discontinuation is not mandatory. Tumor scans (to include disease involved areas and 
associated draining lymph node regions, see Table 5) should be performed at end of 
treatment (±4 weeks). For participants who discontinue study treatment due to biopsy proven 
disease recurrence, these are the final required tumor scans.
For participants who complete or discontinue study treatment without documented disease 
progression, every effort should be made to continue monitoring disease status by tumor 
scans every 12 weeks (±7 days) until Year 2, then every 6 months (±14 days) until the end of 
Year 5, until new high risk primary cSCC/biopsy proven disease recurrence, pregnancy, 
death, withdrawal of consent, or the end of the study, whichever occurs first.
8.2.1.4
Cross-over/Retreatment Tumor Scans
Tumor scans must be performed within 28 days prior to starting study treatment with 
pembrolizumab. If the recurrence scan falls outside of this window, a new scan is required at 
baseline.
The first on-study scans should be performed at 12 weeks (84 days ±7 days) after the restart 
of pembrolizumab treatment. Subsequent tumor scans should be performed every 12 weeks 
(84 days ±7 days) until end of year 2, or more frequently, if clinically indicated from the date 
of the first dose of pembrolizumab in cross-over/retreatment.
Per iRECIST (Section 8.2.1.7.2), if tumor scans show initial PD per RECIST 1.1, tumor 
assessment should be repeated 4 to 8 weeks later to confirm PD with the option of continuing 
treatment while awaiting radiologic confirmation of progression in clinically stable 
participants. Participants who obtain confirmatory scans do not need to undergo scheduled 
tumor scans if it is less than 4 weeks later and may wait until the next scheduled scan time 
point, if clinically stable.
08RB5W

PRODUCT: MK-3475
94
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Scans should continue to be performed until disease progression, the start of a new systemic 
anticancer treatment, withdrawal of consent, pregnancy, death, or notification by the 
Sponsor, whichever occurs first. In clinically stable participants, disease progression may be 
confirmed by the investigator using iRECIST 4 to 8 weeks after the first tumor scans 
indicating PD.
For participants who discontinue cross-over/retreatment study therapy, tumor scans should be 
performed at the time of treatment discontinuation (± 4-week window). If a previous scan 
was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment 
discontinuation is not mandatory. These are the final required tumor scans.
8.2.1.5
Assessment of Disease Recurrence
8.2.1.5.1
Criteria for Determination of Disease Recurrence
Recurrence is defined as cancer that has recurred (come back), usually after a period of time 
during which the cancer could not be detected. The cancer may come back to the same place 
as the original (primary) tumor or to another place in the body 
(https://www.cancer.gov/publications/dictionaries/cancer-terms/def/recurrence).
Local cutaneous recurrence: Recurrence that has recurred at or near the same place as the 
original (primary) tumor, usually after a period of time during which the cancer could not be 
detected (https://www.cancer.gov/publications/dictionaries/cancer-terms/def/locally-
recurrent-cancer). Its neoplastic nature must be confirmed either by histology/cytology.
Regional lymphatic and nodal recurrences: The neoplastic nature of the regional 
recurrences should be confirmed by histology/cytology.
•
In-Transit Metastases: The American Joint Committee on Cancer defines in-transit 
metastases as any skin or subcutaneous metastases that are more than 2 cm from the 
primary lesion but are not beyond the regional nodal basin. 
•
Regional Nodal Recurrences: Regional nodal failure in a previously dissected basin is 
usually found at the periphery of the prior surgical procedure.
Distant metastases: cancer that has spread from the original (primary) tumor to distant 
organs or distant lymph nodes (https://www.cancer.gov/publications/dictionaries/cancer-
terms/def/distant-cancer). 
Note: A new high risk primary cSCC is considered an RFS event; however, a new low risk 
primary cSCC is not considered as an RFS event. A new low risk primary cSCC should be in 
an anatomically separate site to the original (Index) cSCC site. A new lesion(s) in close 
proximity (≤5 cm from the index lesion) to the index cSCC lesion site should be considered a 
recurrence unless the lesion originates from the epidermis and is completely contained within 
the dermis with epidermal connection and contains no “high risk” features (outlined below). 
Discussion with the Sponsor Clinical Director is required where there is uncertainty of new 
primary cSCC lesion versus recurrence of a lesion. If the new lesion does not originate from 
the epidermis and is confined to the dermis without epidermal connection or invading 
08RB5W

PRODUCT: MK-3475
95
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
subcutaneous fat tissue, the lesion will be considered as “in-transit metastasis” and will be 
deemed as an event. 
For a lesion to be considered “low risk” per NCCN cSCC Guidelines [National 
Comprehensive Cancer Network 2017], the histopathology report needs to confirm the 
following: well or moderately differentiated lesion, no adenoid, adenosquamous, 
desmoplastic or metaplastic subtypes, <2 mm in thickness, and no perineural, lymphatic or 
vascular involvement. 
Discussion with the Sponsor Clinical Director is required if these criteria are not met, and the 
investigator assesses the new lesion as consistent with a new primary cSCC.
In the Adjuvant Treatment Phase, tumor scans (to include disease involved areas and 
associated draining lymph node regions, see Table 5) will be performed with assessments 
based on disease recurrence. If indicated, biopsy confirmation of recurrent lesion/s will be 
performed (see Section 8.2.1.6). Confirmation of radiographic disease recurrence by 
cytology/histology is mandatory; only if a biopsy cannot be performed due to feasibility, 
such as location of recurrence (ie, bone lesion), and upon Sponsor consultation, can 
radiographic imaging be used alone to confirm disease recurrence.
If scans are performed after screening and disease recurrence is assessed, this will be an RFS 
event. However, the participant may be allowed to stay on study until a biopsy recurrence, if 
clinically stable upon consultation with Sponsor. 
Clinical stability is defined as the following: 
•
Absence of symptoms and signs indicating clinically significant recurrence/progression 
of disease
•
No decline in ECOG performance status 
•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic/histologic evidence of recurrence.
8.2.1.5.2
Date of Recurrence
The first date when recurrence was observed is taken into account, regardless of the method 
of assessment. Therefore, recurrence will be declared for any lesion when:
•
Only pathology was performed, and recurrence confirmed (in solitary or in doubtful 
lesions, cutaneous, subcutaneous, or lymph node lesions).
•
Both pathology and imaging were done, and recurrence confirmed. In this case, whatever 
examination came first; its date is considered to be the date of recurrence.
•
Only imaging was performed, and disease recurrence confirmed.
08RB5W

PRODUCT: MK-3475
96
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Note: Sponsor consultation is required if a biopsy cannot be obtained.
8.2.1.6
Tumor Tissue Collection and Assessment of Disease Recurrence
A core biopsy or punch biopsy (fine needle aspirate is not acceptable) will be collected at the 
time of suspected disease recurrence. Communication from surgeon to local pathologist 
should follow local practice and institutional guidelines. Pathology results will be entered to 
eCRF.
Representative specimens of tumor tissue collected will be submitted to the central laboratory 
for translational research, for participants who agree to participate, as specified in 
Section 4.2.1.4 – Planned Exploratory Biomarker Research. Any leftover tissue will be 
archived for FBR if the participant has signed the optional informed consent for FBR as 
specified in Section 4.2.1.5 – Future Biomedical Research.
Detailed instructions for tissue collection, processing, and shipment are provided in the 
Vendor Manual.
8.2.1.7
Assessment of Disease Progression (Cross-over/Retreatment Phase Only)
8.2.1.7.1
RECIST 1.1 Assessment of Disease
For participants that start cross-over/retreatment, RECIST 1.1 will be used by investigators 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 
treatment). Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per 
organ, this protocol allows a maximum of 10 target lesions in total and 5 per organ, if 
clinically relevant to enable a broader sampling of tumor burden.
8.2.1.7.2
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression and make treatment decisions. When clinically stable, participants 
should not be discontinued until progression is confirmed by the investigator, working with 
local radiology, according to the rules outlined in Appendix 8. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some 
participants can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. This data will be captured 
in the clinical database.
Clinical stability is defined as the following:

Absence of symptoms and signs indicating clinically significant progression of 
disease

No decline in ECOG performance status 
08RB5W

PRODUCT: MK-3475
97
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD and is not required to have repeat tumor imaging 
for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Scans must be sent to the iCRO. 
Note: As of Amendment 10, scans are no longer required to be submitted to the iCRO.
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 8, 
study treatment should be discontinued; however, if the participant is achieving a clinically 
meaningful benefit, an exception to continue study treatment may be considered following 
consultation with the Sponsor. In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in Section 1.3. 
A description of the adaptations and iRECIST process is provided in Appendix 8, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 6 and illustrated in Figure 2.
08RB5W

PRODUCT: MK-3475
98
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Table 6
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 per 
investigator 
assessment
Repeat imaging 
at 4 to 8 weeks to 
confirm PD
May continue study 
treatment at the 
assessment of the 
investigator and after 
the participant’s 
consent
Repeat imaging 
at 4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue treatment
Repeat tumor 
imaging confirms 
PD (iCPD) by 
iRECIST per 
investigator 
assessment
No additional 
imaging 
required.
Discontinue 
treatment (exception 
is possible upon 
consultation with 
Sponsor).
No additional 
imaging 
required.
Not applicable
Repeat tumor 
imaging shows 
iUPD by 
iRECIST per 
investigator 
assessment
Repeat imaging 
at 4 to 8 weeks to 
confirm PD. May 
occur at next 
regularly 
scheduled 
imaging visit.
Continue study 
treatment at the 
investigator’s 
discretion.
Repeat imaging 
at 4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue treatment
Repeat tumor 
imaging shows 
iSD, iPR, or iCR 
by iRECIST per 
investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments.
Continue study 
treatment at the 
investigator’s 
discretion.
Continue 
regularly 
scheduled 
imaging 
assessments.
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
investigator’s 
discretion. Next 
tumor imaging should 
occur according to the 
regular imaging 
schedule.
iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iRECIST=modified Response 
Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD=iRECIST stable disease; iUPD=iRECIST 
unconfirmed progressive disease; PD=progressive disease; RECIST 1.1=Response Evaluation Criteria in Solid Tumors 
1.1.
08RB5W

PRODUCT: MK-3475
99
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Figure 2
Imaging and Treatment for Clinically Stable Participants Treated with 
Pembrolizumab after First Radiologic Evidence of PD Assessed by the Investigator
iCR=iRECIST complete response; iRECIST=modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; iSD=iRECIST stable disease; iUPD=iRECIST unconfirmed progressive disease; PD=progressive disease; 
RECIST 1.1=Response Evaluation Criteria in Solid Tumors 1.1.
8.2.1.8
Photography for Cutaneous Lesions
Initial digital photography is required at the time of disease recurrence. Digital color 
photography should include the initial site of tumor prior to surgery and RT target areas. Any 
recurrent skin lesion must be followed using color photography, which includes a ruler to 
estimate lesion size. Specific guidance on how to acquire digital photographs of skin lesions 
will be provided in the SIM. The timing for capturing cutaneous lesion photographs must 
follow the same schedule as the imaging scans. All photography is required to be sent to the 
iCRO. 
As of Amendment 10, digital photography for cutaneous lesions is no longer required.
8.2.2
Survival
RFS and OS data will be collected from the time of randomization throughout the study. 
Definitions of the survival endpoints are provided in Section 9.4 and censoring rules are 
presented in Section 9.6.1.
At the time of obtaining survival status, evidence of a new high risk primary cSCC or disease 
recurrence confirmed by biopsy and/or surgery (eg, biopsy and surgery pathology reports) 
will also be collected for participants in Survival Follow-up who have not yet experienced a 
new high risk primary cSCC or disease recurrence, if available, and maintained in source 
documentation and recorded in the database, as appropriate. Additionally, imaging 
08RB5W

PRODUCT: MK-3475
100
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
assessment performed as a part of standard of care to evaluate for disease status for 
participants in Survival Follow-up who have not yet experienced a new high risk primary 
cSCC or disease recurrence, should be collected during Survival Follow-up. All available 
images must be submitted to the iCRO and recorded in the database.
Note: As of Amendment 10, scans are no longer required to be submitted to the iCRO.
8.2.3
Patient-reported Outcomes
The EQ-5D-5L and EORTC QLQ-C30 questionnaires will be administered by trained site 
personnel and completed electronically by participants in the following order: EORTC 
QLQ-C30 first, 
. Details regarding time points for 
administering the questionnaires are outlined in the SoA (Section 1.3).
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.
Note: As of Amendment 10, ePRO assessments will be discontinued. 
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below.
Planned time points for all safety assessments are provided in the SoA.
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; height will be 
measure at Screening only. After the first dose of study intervention, new clinically 
significant abnormal findings should be recorded as AEs.
8.3.1.2
Directed Physical Examination
For visits that do not require a full physical examination as defined in Section 1.3, the 
investigator or medically qualified designee (consistent with local requirements) will perform 
a directed physical examination to include a complete skin and lymph node examination as 
per NCCN cSCC 2018 guidelines [National Comprehensive Cancer Network 2017] prior to 
the administration of study treatment. New clinically significant abnormal findings should be 
recorded as AEs.
CCI
08RB5W

PRODUCT: MK-3475
101
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
The investigator or qualified designee will take weight and vital signs at Screening and as 
specified in the SoA (Section 1.3). Vital signs will be measured after 5 minutes of rest and 
will include temperature, systolic and diastolic blood pressure, respiratory rate, and pulse. 
Vital signs should be measured prior to administration of each dose of study treatment.
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 once at 
Screening. Clinically significant abnormal findings should be recorded as medical history. 
Additional time points may be performed as clinically necessary.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation In the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
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 Vendor 
Manual. Refer to the SoA (Section 1.3) for the timing of laboratory assessments.
08RB5W

PRODUCT: MK-3475
102
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Laboratory tests for screening should be performed within 10 days prior to the first dose of 
study medication. (If the screening labs are collected outside 10 days from treatment 
allocation, then the Day 1 screening labs will be collected and reviewed before the start of 
study treatment). After Cycle 1, lab samples can be collected up to 72 hours prior to the 
scheduled time point. Participants eligible for cross-over treatment should have imaging 
performed within 28 days and laboratory tests performed within 10 days prior to the first 
dose of study treatment in the Cross-over Phase.
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each dose of study treatment. Unresolved 
abnormal laboratory values that are drug-related AEs should be followed until resolution. 
Laboratory tests do not need to be repeated after the end of treatment if laboratory results are 
within the normal range.
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.4.2
Pregnancy Testing
•
Pregnancy testing:

Pregnancy testing requirements for study inclusion are described in Section 5.1.

Pregnancy testing (urine and/or serum) should be conducted as per SoA at every 
protocol cycle.

Pregnancy testing (urine and/or serum) should be conducted at the end of relevant 
systemic exposure. The length of time required to continue pregnancy testing for each 
study intervention is:
◦
MK-3475: 120 days

Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
Refer to Appendix 7 for country-specific requirements.
8.3.4.3
HIV, HBV, and HCV Serology
Screening tests are only required if mandated by local regulations. Refer to Appendix 7 for 
country-specific requirements. HIV, HBV, and HCV serology will be conducted on 
participants per local regulations and site standard operating procedures. Active hepatitis B is 
defined as a known positive HBsAg result. Active hepatitis C is defined by a known positive 
hepatitis C Ab antibody result and known quantitative HCV RNA results greater than the 
lower limits of detection of the assay.
08RB5W

PRODUCT: MK-3475
103
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
8.3.5
Performance Assessments
8.3.5.1
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG status (see http://ecog-
acrin.org/resources/ecog-performance-status) at screening, before the administration of each 
dose of study intervention and during the follow-up period as specified in the SoA 
(Section 1.3).
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. Recurrence of the cancer under study is not considered an AE as described 
in Section 8.4.6 and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
Adverse events will not be collected for participants during the prescreening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention. If the participant requires a blood draw, fresh 
tumor biopsy, etc, the participant is first required to provide consent to the main study, and 
AEs will be captured according to guidelines for standard AE reporting.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation/randomization, must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event cause the participant to be excluded from the study, or is the result of a 
08RB5W

PRODUCT: MK-3475
104
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
protocol-specified intervention, including, but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
•
All AEs from the time of intervention allocation/randomization through 30 days 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.
•
All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation/randomization through the time required to eliminate systemic exposure after 
cessation of study intervention as described in Sections 5.1 and 8.3.4.2, 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.
08RB5W

PRODUCT: MK-3475
105
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Table 7
Reporting Time Periods and Time Frames for AEs and Other Reportable 
Safety Events
Type of Event
Time Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor
Consent to 
Randomization/
Allocation
Randomization/
Allocation Through 
Protocol-specified 
Follow-up Period
After the 
Protocol-
specified 
Follow-up 
Period
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
– drug/vaccine 
related.
(Follow 
ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously 
reported –
Follow to 
completion/
termination; 
report outcome
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
– potential DILI
– require regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
– non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 
5 calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
08RB5W

PRODUCT: MK-3475
106
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
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.
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 (spontaneously reported to the 
investigator or their designee) that occurs in a participant 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.
08RB5W

PRODUCT: MK-3475
107
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
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 
recurrence of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
Any suspected endpoint that upon review is not recurrence of the cancer under study will be 
forwarded to Global Pharmacovigilance as an SAE within 24 hours of determination that the 
event is not recurrence of the cancer under study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
•
An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
•
An elevated AST or ALT laboratory value that is greater than or equal to 3× the ULN and 
an elevated total bilirubin laboratory value that is greater than or equal to 2× the ULN 
and, at the same time, an alkaline phosphatase laboratory value that is less than 2× the 
ULN, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in 
the setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and 
alkaline phosphatase that do not meet the criteria noted above. In these cases, the decision 
to proceed with additional evaluation will be made through consultation between the 
study investigators and the Sponsor Clinical Director. However, abnormalities of liver 
blood tests that do not meet the criteria noted above are not ECIs for this study.
08RB5W

PRODUCT: MK-3475
108
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
8.5
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater.
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
8.8.1
Planned Genetic Analysis Sample Collection
 
 
 
CCI
CCI
08RB5W

PRODUCT: MK-3475
109
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
 
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
Biomarker samples listed in Section 8.8.
8.10
Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency department visits must be reported in the eCRF 
from the time of treatment allocation/randomization through 90 days after cessation of study 
intervention or 30 days after cessation of study intervention if the participant initiates new 
anticancer therapy, whichever is earlier.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Documented informed consent must be provided before performing any protocol-specific 
procedure. Results of a test performed before the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame.
Screening procedures are to be completed within 28 days before the first dose of study 
intervention. Except for the following:
•
Laboratory tests are to be performed within 10 days prior to the first dose of study 
intervention. An exception is hepatitis testing, which may be done up to 28 days prior to 
the first dose of study intervention.
•
Evaluation of ECOG is to be performed within 10 days prior to the first dose of study 
treatment.
•
For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 72 hours prior to the first dose of study treatment. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required (performed by 
the local study site laboratory).
CCI
08RB5W

PRODUCT: MK-3475
110
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Refer to Appendix 7 for Germany and UK-specific requirements.
•
Archival tumor sample collection is not required to be obtained within 28 days prior to 
the first dose of study treatment. The tumor sample must be collected within the past 
5 years prior to randomization.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria 
upon agreement with the Sponsor. 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
Adjuvant Treatment Period Visits
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
The Adjuvant Treatment Phase is expected to start at a range of 4 to 16 weeks after the last 
dose of RT. If performed outside of this window, Sponsor consultation will be required. At 
the start of the study, participants will be advised by the investigator regarding the use of sun 
protection and self-examination of skin and lymph nodes, as per NCCN cSCC 2018 
guidelines [National Comprehensive Cancer Network 2017].
8.11.3
Posttreatment Visit
Post-treatment visit requirements are outlined in the SoA (Section 1.3.2).
8.11.3.1
End of Treatment Visit
The End of Treatment visit should occur at the time study treatment is completed or 
discontinued for any reason. Participants who are eligible for cross-over/retreatment with 
pembrolizumab may have 2 End of Treatment visits, 1 after the initial Adjuvant Treatment 
Period and 1 after cross-over/retreatment. 
Participants who discontinue study treatment for a reason other than a new high risk primary 
cSCC or disease recurrence will still be considered on study and should continue with 
regularly scheduled assessments (see Section 8.11.4), including collecting participant 
information on the start of new anticancer therapy, a new high risk primary cSCC or disease 
recurrence, and death. If the End of Treatment visit occurs 30 days from the last dose of 
study treatment, at the same time as the mandatory 30-Day Safety Follow-up visit, the End of 
Treatment visit procedures and any additional Safety Follow-up procedures can be combined 
into a single visit.
Participants who discontinue study treatment due to disease recurrence will be unblinded. 
Participants in the placebo group will be offered to cross over and receive pembrolizumab, if 
cross-over eligibility criteria are met (Section 8.1.8.1.2).
08RB5W

PRODUCT: MK-3475
111
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
8.11.3.2
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 cross-over/retreatment with pembrolizumab may have 
2 Safety Follow-up visits, 1 after the initial Adjuvant Treatment Period and 1 after cross 
over/retreatment.
8.11.3.3
Study Adjuvant Follow-up Visits 
Participants who complete study adjuvant treatment or discontinue study adjuvant treatment 
for a reason other than a new high risk primary cSCC or disease recurrence will move into 
the Study Adjuvant Follow-up Phase and should be assessed in office every 12 weeks 
(±7 days) until end of Year 2 (measured from time of randomization), then every 6 months 
until the end of Year 5, to monitor disease status. After Year 5, participants will move into 
Survival Follow-up. Any additional tests/investigations or imaging assessments for recurrent 
disease or safety will be at the discretion of participant’s treating physician per local SoC. 
Every effort should be made to collect information regarding disease status until a new high 
risk primary cSCC or disease recurrence, death, or end of study. Information regarding post-
study anticancer treatment will be collected if new treatment is initiated. 
Participants who discontinue Study Adjuvant Follow-up Phase early, have entered Survival 
Follow-up, and have not experienced a new high risk primary cSCC or disease recurrence, 
will be requested to have standard of care imaging assessments/biopsy performed to evaluate 
disease status. All imaging assessments must be uploaded to the iCRO.
Details are provided in the SoA (Section 1.3.3) for cross-over/retreatment with 
pembrolizumab.
For a participant who dies during the Follow-up period, date and cause of death should be 
recorded in the appropriate eCRF.
Participants in Study Adjuvant Follow-up will be followed for treatment-related toxicities for 
up to Year 5 and should be recorded.
8.11.3.4
Survival Follow-up Contacts
Participant survival follow-up status will be assessed approximately every 12 weeks to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
The first survival follow-up assessment should be scheduled as described below:
•
For participants who discontinue treatment intervention and who will not enter Adjuvant 
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).
08RB5W

PRODUCT: MK-3475
112
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
•
For participants who completed assessments in Adjuvant Follow-up, the first survival 
follow-up contact will be scheduled 12 weeks after the last Adjuvant Follow-up 
assessment follow-up visit has been performed.
8.11.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Participants who discontinue study treatment for reasons other than a new high risk primary 
cSCC or disease recurrence will enter Safety and Study Adjuvant Follow-up and undergo all 
assessments at the scheduled time points per the SoA (Section 1.3) as described in 
Sections 8.11.3.2, 8.11.3.3, and 8.11.3.4.
As of Amendment 10, ePRO assessments will no longer be required. Digital photography of 
cutaneous lesions is not required and tumor scans no longer need to be submitted to the 
iCRO.
Participants that discontinue study treatment due to a new high risk primary cSCC or disease 
recurrence will have Safety Follow-up and then proceed directly to Survival Follow-up as 
described in Section 8.11.3.4. Participants who discontinue study treatment because of the 
start of new anticancer treatment will enter Safety Follow-up and then proceed directly to 
Adjuvant Follow-up as described in Section 8.11.3.3.
8.11.5
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an eDMC review, 
. 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.
CCI
08RB5W

PRODUCT: MK-3475
113
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
9
STATISTICAL ANALYSIS PLAN
As of Amendment 10, the SAP is amended as follows: 
NOTE: Based on the data from the interim efficacy and safety analysis for KN630 (data 
cutoff 28-JUN-2024) reviewed by eDMC on 21-AUG-2024, the study will be discontinued. 
Pembrolizumab did not cross the boundary for statistical significance in RFS by investigator 
assessment compared to placebo. OS point estimate did not favor pembrolizumab versus 
placebo, although not formally tested based on the prespecified multiplicity strategy. The 
eDMC recommended that the study should be stopped for futility as the risk/benefit profile 
did not support continuing the trial. Based upon these data and the recommendation of the 
eDMC, the study was unblinded on 22-AUG-2024. The prespecified final efficacy analysis 
of the study described in the SAP will not be performed. Efficacy and safety analyses will be 
performed at the end of the study; there will be no further planned analyses for ePRO 
endpoints.
This section outlines the statistical analysis strategy and procedures for the study. The study 
has been unblinded as of 22-AUG-2024. Changes made to primary and/or key secondary 
hypotheses, or the statistical methods related to those hypotheses that occurred prior to 
Amendment 10 were documented in previous protocol amendments (consistent with ICH 
Guideline E-9). Changes to exploratory or other non-confirmatory analyses made after the 
protocol has been finalized, but prior to the conduct of any analysis, will be documented in 
an sSAP and referenced in the CSR for the study. The PRO analysis plan will also 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 through 9.12. As of Amendment 10, the prespecified final 
efficacy analysis of the study described in the SAP will not be performed. Efficacy and safety 
analyses will be performed at the end of the study; there will be no further planned analyses 
of ePRO endpoints. The SAP summary has been updated accordingly.
Study Design Overview
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
Pembrolizumab versus Placebo as Adjuvant Therapy Following Surgery and 
Radiation of High-Risk Locally Advanced Cutaneous Squamous Cell 
Carcinoma (LA cSCC).
Treatment Assignment
As of Amendment 10, 450 participants have been randomized 1:1 into 
pembrolizumab group and control group and no additional participants will 
be randomized.
Pembrolizumab Group: Pembrolizumab 400 mg Q6W
Control Group: placebo
This study will be conducted as a double-blind study.
Stratification factors are as follows:
Extracapsular extension (yes vs. no)
Cortical bone invasion (yes vs. no)
Prior systemic therapy (yes vs. no)
CCI
08RB5W

PRODUCT: MK-3475
114
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Analysis Populations
Efficacy: Intention-to-Treat (ITT) 
Safety: All Participants as Treated (APaT)
PRO: Full Analysis Set (FAS) 
Primary Endpoint(s)
Recurrence-free Survival (RFS) 
Key Secondary Endpoints
Overall Survival (OS)
Statistical Methods for 
Key Efficacy Analyses
The primary hypothesis for RFS will be evaluated by comparing 
pembrolizumab to placebo using a stratified log-rank test. Estimation of the 
hazard ratio (HR) will be done using a stratified Cox regression model. Event 
rates over time will be estimated within each treatment group using the 
Kaplan-Meier method.
The same method for the analysis of RFS will be applied to the key 
secondary hypothesis for OS.
Statistical Methods for 
Key Safety Analyses
For specific AEs that meet predefined threshold rules, point estimates and 
95% CIs for the differences between treatment groups in the percentages of 
participants with events will be provided using the Miettinen and Nurminen 
(M&N) method [Miettinen, O. and Nurminen, M. 1985].
Interim Analyses
Multiplicity
Sample Size and Power 
CCI
08RB5W

PRODUCT: MK-3475
115
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
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.
After efficacy IA, the study was unblinded on 22-AUG-2024.
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 investigator will request authorization for official unblinding upon disease 
recurrence and consideration to proceed to cross-over to or receive retreatment with 
pembrolizumab.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented in an IRT.
The investigator will be blinded to participant-level biomarker results.
9.3
Hypotheses/Estimation 
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints 
Primary and secondary efficacy, safety and PRO endpoints that will be evaluated for within-
and/or between-treatment differences are listed below. 
 
9.4.1
Efficacy Endpoints
Primary
Recurrence-free survival (RFS): the time from the date of randomization to the date of first 
of the following events:
-
Local or regional recurrence of the index lesion
-
Distant metastasis
-
Death due to any cause
For disease recurrence, the assessment will be based on investigator assessment with biopsy 
confirmation. Only if a biopsy cannot be performed due to feasibility, disease recurrence will 
be based on radiographic imaging only. In addition, a second new low risk primary cSCC is 
not considered as an RFS event. However, a new high risk primary cSCC is considered an 
RFS event.
CCI
CCI
08RB5W

PRODUCT: MK-3475
116
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Secondary
Overall survival (OS): the time from randomization to death due to any cause.
9.4.2
Safety Endpoints
Safety measurements are described in Section 4.2.1.2 and Section 8.
9.4.3
PRO Endpoints
The following main PRO endpoint will be evaluated as described in Section 4.2.1.3:

Global health status/ QoL scales from EORTC QLQ-C30. 

Physical function scale from EORTC QLQ-C30.
 
9.5
Analysis Populations 
9.5.1
Efficacy Analysis Population
 
 
9.5.2
Safety Analysis Population
 
 
 
 
 
 
9.5.3
PRO Analysis Population
 
CCI
CCI
CCI
CCI
08RB5W

PRODUCT: MK-3475
117
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
9.6
Statistical Methods
NOTE: As of Amendment 10, the prespecified final efficacy analysis of the study described 
in the SAP will not be performed. Efficacy and safety analyses will be performed at the end 
of the study; there will be no further planned analyses of ePRO endpoints. Original protocol 
text that is contained in this section has been retained for reference. For the efficacy analyses 
to be performed at the end of study, there will be no formal comparisons between treatment 
arms. Nominal p-values will be provided.
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. 
 
 
9.6.1.1
Recurrence-free Survival
The non-parametric Kaplan-Meier method will be used to estimate the RFS curve in each 
treatment group. The treatment difference in RFS will be assessed by the stratified log-rank 
test. A stratified Cox PH model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (ie, HR) between the treatment group and placebo 
group. The HR and its 95% CI from the Cox model with Efron's method of tie handling and 
with a single treatment covariate will be reported. The stratification factors used for 
randomization (see Section 6.3.2) will be applied to both the stratified log-rank test and the 
stratified Cox model. In the event that there are small number of events in one or more strata, 
for the purpose of analysis, strata will be combined to ensure sufficient number of events in 
each stratum.
 
Since disease recurrence is assessed periodically, recurrence can occur any time in the time 
interval between the last assessment where recurrence was not documented and the 
assessment when recurrence is first documented. The true date of recurrence will be 
approximated by the date of the first assessment at which recurrence is objectively 
documented. Death is always considered as an event. Participants who do not experience a
recurrence event will be censored at the last disease assessment. 
 
 
CCI
CCI
CCI
CCI
08RB5W

PRODUCT: MK-3475
118
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
 
Table 8
Censoring Rules for Primary and Sensitivity Analyses of RFS
9.6.1.2
Overall Survival
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test. A stratified 
Cox PH model with Efron's method of tie handling will be used to assess the magnitude of 
the treatment difference (ie, the HR). The HR and its 95% CI from the Cox model with a 
single treatment covariate will be reported. The stratification factors used for randomization 
(see Section 6.3.2) will be applied to both the stratified log-rank test and the stratified Cox 
model.
 
 
CCI
CCI
CCI
CCI
08RB5W

PRODUCT: MK-3475
119
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
 
 
9.6.1.3
Summary of Efficacy Analysis Methods
A summary of the primary analysis strategy for the primary and secondary efficacy endpoints 
is provided in Table 9.
Table 9
Efficacy Analysis Methods for Primary and Secondary Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Analyses:
RFS (investigator assessment 
with biopsy confirmation)
Testing: stratified Log-rank 
test
Estimation: stratified Cox 
model with Efron's tie 
handling method 
ITT
Censored according to 
rules in Table 8.
Secondary Analyses:
OS
Testing: stratified Log-rank 
test
Estimation: stratified Cox 
model with Efron's tie 
handling method
ITT
Censored at last date 
when participant was 
known to be alive 
RFS=recurrence-free survival; ITT=intent-to-treat; OS=overall survival
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs.
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, drug-related Grade 3-5 AE, discontinuation from study 
intervention due to an AE, and an AE resulting in death. 
The number and percentage of participants with specific AEs will also be provided. Point 
estimate and 95% CIs for the difference between treatment groups in the percentage of 
participants with specific AEs will be provided for AEs that occur in at least 
of 
participants in any treatment group. The threshold of at least 
of participants was chosen 
because the population enrolled in this study is in critical condition and usually experiences 
various AEs of similar types regardless of treatment; events reported less frequently than 
of participants would obscure the assessment of the overall safety profile and add little 
to the interpretation of potentially meaningful treatment differences. In addition, difference in 
the percentage of participants with specific Grade 3-5 AEs 
 
 and SAEs 
 will also be 
CCI
CCI
CCI
CCI
CCI
CCI
08RB5W

PRODUCT: MK-3475
120
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
summarized by point estimate and 95% CI. Rainfall plots with point estimates and 95% CIs 
will be displayed for specific AEs, specific Grade 3-5 AEs, and specific SAEs that meet the 
corresponding predefined threshold rules.
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 helpful descriptive measures for 
the review of the safety profile and not as a formal method for assessing the statistical 
significance of the between-group differences. 
The number and percentage of participants with laboratory toxicity grade increased from 
baseline will be summarized by the post-baseline maximum toxicity grade per CTCAE 
Version 4.0 for each gradable laboratory test.
For continuous safety measures, such as change from baseline in laboratory and vital signs, 
summary statistics for baseline, on-treatment, and change from baseline values will be 
provided.
Assessment of Safety Topics of Special Interest 
AEs that are immune-mediated or potentially immune-mediated are considered safety topics 
of special interest (AEOSI) in this study. These events have been characterized consistently 
throughout the pembrolizumab clinical development program. Point estimates and 95% CIs 
for between-group difference is not expected to add value to the safety evaluation, and hence 
only number and percentage of participants with such pembrolizumab AEOSI will be 
provided, as well as the number and percentage of participants with corticosteroids 
administration to treat an AEOSI. Summary statistics will be provided for the analysis of 
time from first dose to the onset of an AEOSI. Table 10 summarizes the analysis strategy for 
safety endpoints in this study.
08RB5W

PRODUCT: MK-3475
121
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Table 10
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
Descriptive 
Statistics
95% between-
group CI 
(Graphical 
display)
Overall Safety 
Assessment
Specific AEs 
 
X
X
Specific Grade 3-5 AE 
 
X
X
Specific serious AE 
 
X
X
Any AE
X
Any Grade 3-5 AE
X
Any serious AE 
X
Any drug-related AE
X
Any serious and drug-related AE
X
Any Grade 3-5 and drug-related AE
X
Discontinuation of study treatment due to AE
X
Interruption of study treatment due to AE
X
AE that resulted in death
X
Laboratory toxicity grade increase from baseline
X
Change from baseline results (vital signs)
X
Assessment of 
safety topics of 
special interest
Pembrolizumab AEOSI
X
AE=adverse event; AEOSI=adverse event of special interest; CI=confidence interval 
9.6.3
Statistical Methods for PRO Analyses
To assess the treatment effects on the PRO score changes from baseline in the global health 
status/QoL and physical function outcomes, a constrained longitudinal data analysis model 
will be applied, with the PRO score as the response variable, and treatment, time, 
stratification factors, the treatment by time interaction as covariates. The differences in the 
least square mean change from baseline will be evaluated. The long-term treatment effect on 
PRO score change from baseline will be primarily evaluated and compared in both treatment 
arms at 1 year adjuvant follow-up, and each year during the study adjuvant follow-up phase.
9.6.4
Summaries of Baseline Characteristics and Demographics
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 reason for screening failure and discontinuation 
will be displayed. Demographic variables (eg, age, race, etc), baseline characteristics, and 
prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
CCI
CCI
CCI
08RB5W

PRODUCT: MK-3475
122
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
9.7
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.7.1
CCI
CCI
CCI
CCI
08RB5W

PRODUCT: MK-3475
123
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
9.7.2
9.8
 
 
9.8.1
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
08RB5W

PRODUCT: MK-3475
124
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
CCI
08RB5W

PRODUCT: MK-3475
125
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
9.9
Sample Size and Power Calculations 
This study is well-powered for the primary efficacy endpoint for comparisons. Enrollment of 
430 participants is assumed to occur over 58 months.
NOTE: As of Amendment 10, the study randomized 450 participants in a 1:1 ratio into the 
pembrolizumab and placebo arms. Because no statistical testing will be performed, the power 
calculations are not applicable.
Recurrence-free Survival
The RFS hypothesis testing strategy was designed fo
 
 
CCI
CCI
08RB5W

PRODUCT: MK-3475
126
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
 
 
 
Overall Survival
At α = 0.025 (one-sided), the final OS hypothesis test yields 
power to detect a HR of 
. The duration of OS in the placebo group is assumed to follow 
 
 
 
Power and 
 for RFS and OS were performed using the 
.
9.10
Subgroup Analyses 
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for RFS and OS will 
be estimated and plotted within each category of the following classification variables:
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above. In addition, a Forest plot will be 
produced, which provides the estimated point estimates and CIs for the treatment effect 
across the categories of subgroups listed above. If the number of participants in a category of 
a subgroup variable is less than 10%, the subgroup analysis will not be performed for this 
category of the subgroup variable, and this subgroup variable will not be displayed in the 
forest plot. The subgroup analyses will be conducted using the unstratified analysis based on 
the corresponding analysis method for RFS and OS.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
08RB5W

PRODUCT: MK-3475
127
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
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 number of cycles in which the participant 
receives the study treatment infusion. Summary statistics will be provided on Extent of 
Exposure for APaT population.
08RB5W

PRODUCT: MK-3475
128
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
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 and Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. 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 to assess the ability to successfully conduct 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.
08RB5W

PRODUCT: MK-3475
129
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
08RB5W

PRODUCT: MK-3475
130
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, 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.
08RB5W

PRODUCT: MK-3475
131
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
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.
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.
08RB5W

PRODUCT: MK-3475
132
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee (SAC)
This study was developed in collaboration with an SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide input with respect to 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 eDMC or Steering Committee 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 
 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. 
 
 
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the external collaborating organization 
protocol team; meeting facilitation; the study governance structure; and requirements for and 
proper documentation of DMC reports, minutes, and recommendations will be described in 
the DMC charter that is reviewed and approved by all the DMC members.
10.1.5
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.
CCI
CCI
08RB5W

PRODUCT: MK-3475
133
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, https://euclinicaltrials.eu, or other local registries. MSD, as 
Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. MSD entries are not limited to FDAAA or the EMA clinical trials 
Regulation 536/2014 mandated trials. Information posted will allow participants to identify 
potentially appropriate studies for their disease conditions and pursue participation by calling 
a central contact number for further information on appropriate study locations and study-site 
contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials Regulation 536/2014, or other locally mandated registries 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries. 
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
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.
08RB5W

PRODUCT: MK-3475
134
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
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.
08RB5W

PRODUCT: MK-3475
135
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
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).
08RB5W

PRODUCT: MK-3475
136
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 15 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2 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 15
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN)a
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)
Creatinine
A measure of CO2
or bicarbonateb
Chloride
Phosphorous
Creatinine 
clearance (CrCl)c or 
GFR
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose (fasting or 
nonfasting, as per 
local SOP)
Calciumd
Alkaline phosphatase
Magnesium
Albumin
Coagulation tests 
(Screening)e
Prothrombin (PT) or International 
normalized ratio (INR)
Activated partial thromboplastin time 
(aPTT)f
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick
Microscopic examination (if blood or protein is abnormal)
08RB5W

PRODUCT: MK-3475
137
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Laboratory 
Assessments
Parameters
Other Screening 
Tests
Follicle-stimulating hormone and estradiol (as needed in POCBP only)
Serum or urine β-human chorionic gonadotropin (β-hCG) pregnancy test (as needed 
for POCBP. Refer to Section 8.3.4.2) 
Note: Refer to Appendix 7 for country-specific requirements
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody) is not required unless mandated by local health authority. 
Note: For countries that mandate testing at screening see Appendix 7 – Country-
specific Requirements. If required, testing will be conducted per local regulations and 
site SOPs. 
Total free triiodothyronine (T3)g
Free thyroxine (FT4)g
Thyroid-stimulating hormone (TSH)
NOTES:
BUN=blood urea nitrogen; CrCl=creatinine clearance; GFR=glomerular filtration rate; HIV=human immunodeficiency 
virus; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; ULN=upper limit of 
normal; WBC=white blood cell
a.
BUN is preferred; if not available, urea may be tested.
b.
Performed if available as SoC in your region. The carbon dioxide may be either a measurement of CO2 or 
bicarbonate as an electrolyte.
c.
CrCl should be calculated per institutional standard. 
d
Corrected calcium should be checked for participants with hypoalbuminemia.
e.
Any participant receiving anticoagulant therapy should have coagulation tests monitored closely throughout the 
study.
f.
PTT may be performed if the local lab is unable to perform aPTT.
g.
In case of elevated TSH, add free T3 and free T4. Free T3 if available as SoC in your region. If not available locally, 
thyroid function testing can be performed by the central laboratory
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
08RB5W

PRODUCT: MK-3475
138
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
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.
08RB5W

PRODUCT: MK-3475
139
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not a reportable event. Refer to Section 8.4.6 for additional details.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening

The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
08RB5W

PRODUCT: MK-3475
140
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect

In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported 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.
08RB5W

PRODUCT: MK-3475
141
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 4.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.

Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.

Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.

Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.

Grade 4: Life-threatening consequences; urgent intervention indicated.

Grade 5: Death related to AE.
08RB5W

PRODUCT: MK-3475
142
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:

Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen?

Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with IMP)?

Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.

Dechallenge: Was the study intervention discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)

Rechallenge: Was the participant reexposed to the study intervention in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose drug study; or (3) study 
intervention (s) is/are used only 1 time.)
08RB5W

PRODUCT: MK-3475
143
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).

Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.

No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
08RB5W

PRODUCT: MK-3475
144
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.

Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.

Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
08RB5W

PRODUCT: MK-3475
145
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
08RB5W

PRODUCT: MK-3475
146
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not Applicable
08RB5W

PRODUCT: MK-3475
147
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Participants of Childbearing Potential (POCBP)
A participant assigned female sex at birth is considered fertile following menarche and 
capable of becoming pregnant until becoming postmenopausal unless permanently sterile 
(see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, not considered POCBP:
•
Premenarchal
•
Premenopausal with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in participants assigned female sex at birth who are not 
using hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range 
is required.

Participants assigned female sex at birth who are on HRT and whose menopausal 
status is in doubt will be required to use one of the 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.
08RB5W

PRODUCT: MK-3475
148
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
10.5.2
Contraceptive Requirements
Contraceptives allowed during the study include:
Highly Effective Contraceptive Methods That Have Low User Dependencya
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only subdermal contraceptive implantb
IUSc
Nonhormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause) –
All sexual partner(s) of the POCBP must be azoospermic. The participant must provide verbal 
confirmation of partner azoospermia during Medical History. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraception b
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraception b
- Oral
- Injectable
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from penile-
vaginal intercourse with a partner capable of producing sperm, during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
a
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptives are limited to those which inhibit 
ovulation.  
c
IUS is a progestin-releasing IUD.
Note:
Tubal occlusion includes tubal ligation
08RB5W

PRODUCT: MK-3475
149
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
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.
08RB5W

PRODUCT: MK-3475
150
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
08RB5W

PRODUCT: MK-3475
151
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
08RB5W

PRODUCT: MK-3475
152
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
08RB5W

PRODUCT: MK-3475
153
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
10.7
Appendix 7: Country-specific Requirements
10.7.1
France
Patients should be permanently discontinued from study treatment if any of the following 
AEs occur:
•
Steven-Johnson Syndrome
•
Toxic-epidermal necrolysis
•
Recurrent Grade 3 Colitis
08RB5W

PRODUCT: MK-3475
154
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Table 3
Dose modification and toxicity management guidelines for immune-related 
AEs associated with pembrolizumab
General instructions:
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks.
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab must be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to 
≤10 mg prednisone or equivalent per day within 12 weeks. 
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-
related AEs
Toxicity grade or 
conditions 
(CTCAE Version 
4.0)
Action taken to 
pembrolizumab
irAE 
management with 
corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Diarrhea / 
Colitis 
Grade 4 or 
recurrent Grade 3
Permanently 
discontinue
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper
Monitor participants for 
signs and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 
bowel perforation 
(ie, peritoneal signs and 
ileus).
Participants with 
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.
Skin 
Reactions
Grade 3 or 
suspected Stevens-
Johnson Syndrome 
or Toxic-epidermal 
necrolysis
Withhold
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper
Grade 4 or 
confirmed Stevens-
Johnson Syndrome 
or Toxic-epidermal 
necrolysis
Permanently 
discontinue
08RB5W

PRODUCT: MK-3475
155
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Relates to section:
6.6.1 Dose Modification
10.7.2
Germany
1. Monthly pregnancy testing is required throughout study treatment and at end of treatment 
for women of childbearing potential.
Urine β-hCG or serum pregnancy test (as needed for POCBP)
Relates to sections:
1.3 Schedule of Activities (1.3.1, 1.3.2, and 1.3.3)
8.3.4.2 Pregnancy testing
Appendix 2: Clinical Laboratory Tests
Appendix 5: Contraceptive Guidance and Pregnancy Testing
2. Has a known history of HIV infection. HIV testing is required at Screening for participants 
enrolled from German sites.
Relates to sections:
1.3 Schedule of Activities (1.3.1)
5.2 Exclusion Criterion #16
8.3.4.3
HIV, HBV, and HCV Serology
Appendix 2: Clinical Laboratory Tests
3. Has a known history of hepatitis B (defined as HBsAg reactive) or known active HCV 
(defined as HCV RNA [qualitative] is detected) infection. Testing is required at Screening 
for participants enrolled from German sites.
Relates to sections:
1.3 Schedule of Activities (1.3.1)
5.2 Exclusion Criterion #17
8.3.4.3
HIV, HBV, and HCV Serology
Appendix 2: Clinical Laboratory Tests
Throughout
Persons of legal age, who are incapable of comprehending the nature, significance, and 
implications of the clinical study and of determining their will, are excluded from the study at 
German sites; therefore, all references to a participant’s “legally acceptable representative” in 
the protocol are not applicable for participants in Germany.
08RB5W

PRODUCT: MK-3475
156
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
10.7.3
Ireland
Monthly pregnancy testing throughout study treatment and at end of treatment is required for 
women of childbearing potential.
Relates to sections:
1.3 Schedule of Activities
8.3.4.2 Pregnancy testing
Appendix 2: Clinical Laboratory Tests
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.7.4
Italy
1. Monthly pregnancy testing throughout study treatment and at end of treatment is required 
for women of childbearing potential.
Relates to sections:
1.3 Schedule of Activities
8.3.4.2 Pregnancy testing
Appendix 2: Clinical Laboratory Tests
Appendix 5: Contraceptive Guidance and Pregnancy Testing
2. Patients should be permanently discontinued from study treatment if any of the following 
AEs occur:
•
Steven-Johnson Syndrome
•
Toxic-epidermal necrolysis
•
Recurrent Grade 3 Colitis
08RB5W

PRODUCT: MK-3475
157
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Table 3
Dose modification and toxicity management guidelines for immune-related 
AEs associated with pembrolizumab.
General instructions:
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks.
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab must be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to 
≤10 mg prednisone or equivalent per day within 12 weeks. 
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-
related AEs
Toxicity grade or 
conditions 
(CTCAE Version 
4.0)
Action taken to 
pembrolizumab
irAE 
management 
with 
corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Diarrhea / 
Colitis 
Grade 4 or 
recurrent Grade 3
Permanently 
discontinue
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper
Monitor participants for 
signs and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 
bowel perforation 
(ie, peritoneal signs and 
ileus).
Participants with 
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.
Skin 
Reactions
Grade 3 or 
suspected Stevens-
Johnson Syndrome 
or Toxic-epidermal 
necrolysis
Withhold
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper
Grade 4 or 
confirmed Stevens-
Johnson Syndrome 
or Toxic-epidermal 
necrolysis
Permanently 
discontinue
08RB5W

PRODUCT: MK-3475
158
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Relates to section:
•
6.6.1 Dose Modification
10.7.5
Norway
Monthly pregnancy testing throughout study treatment and until 4 months after the last 
administration of study treatment is required for women of childbearing potential.
Relates to sections:
1.3 Schedule of Activities
8.3.4.2 Pregnancy testing
Appendix 2: Clinical Laboratory Tests
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.7.6
United Kingdom
1. Monthly pregnancy testing throughout study treatment and at end of treatment is required 
for women of childbearing potential.
Relates to sections:
1.3 Schedule of Activities (1.3.1 and 1.3.3)
8.3.4.2 Pregnancy testing
Appendix 2: Clinical Laboratory Tests
Appendix 5: Contraceptive Guidance and Pregnancy Testing
2. Serum pregnancy testing is required at Screening for women of childbearing potential.
Relates to sections:
1.3 Schedule of Activities (1.3.1, 1.3.3)
5.2 Exclusion Criterion #3
8.3.4.2 Pregnancy Testing
8.11.1 Screening
Appendix 2: Clinical Laboratory Tests
Appendix 5: Contraceptive Guidance and Pregnancy Testing
08RB5W

PRODUCT: MK-3475
159
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
3. Has a known history of HIV infection. HIV testing is required at Screening for participants 
enrolled from UK sites.
Relates to sections:
1.3 Schedule of Activities (1.3.1)
5.2 Exclusion Criterion #16
8.3.4.3 HIV, HBV, and HCV Serology
Appendix 2: Clinical Laboratory Tests
4. Has a known history of hepatitis B (defined as HBsAg reactive) or known active HCV 
(defined as HCV RNA [qualitative] is detected) infection. Testing is required at Screening 
for participants enrolled from UK sites.
Relates to sections:
1.3 Schedule of Activities (1.3.1)
5.2 Exclusion Criterion #17
8.3.4.3 HIV, HBV, and HCV Serology
Appendix 2: Clinical Laboratory Tests
5. Participants enrolled from UK sites are excluded from the study if they have had 
hypersensitivity to pembrolizumab and/or any of its excipients.
Relates to sections:
5.2 Exclusion Criterion #12
6. Patients should be permanently discontinued from study treatment if any of the following 
AEs occur:
•
Steven-Johnson Syndrome
•
Toxic-epidermal necrolysis
•
Recurrent Grade 3 Colitis
08RB5W

PRODUCT: MK-3475
160
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Table 3
Dose modification and toxicity management guidelines for immune-related 
AEs associated with pembrolizumab
General instructions:
1.Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at 
least 4 weeks.
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab must be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to 
≤10 mg prednisone or equivalent per day within 12 weeks. 
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Relates to section:
6.6.1 Dose Modification
Immune-
related AEs
Toxicity grade or 
conditions 
(CTCAE Version 
4.0)
Action taken to 
pembrolizumab
irAE 
management 
with 
corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Diarrhea / 
Colitis 
Grade 4 or 
recurrent Grade 3
Permanently 
discontinue
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper
Monitor participants for 
signs and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 
bowel perforation 
(ie, peritoneal signs and 
ileus).
Participants with 
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.
Skin 
Reactions
Grade 3 or 
suspected Stevens-
Johnson Syndrome 
or Toxic-epidermal 
necrolysis
Withhold
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper
Grade 4 or 
confirmed Stevens-
Johnson Syndrome 
or Toxic-epidermal 
necrolysis
Permanently 
discontinue
08RB5W

PRODUCT: MK-3475
161
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1, as determined by the 
investigator, the investigator will decide whether to continue a participant on study treatment 
until repeat imaging 4 to 8 weeks later is obtained using iRECIST for participant 
management (see Table 6 and Figure 2). This decision by the investigator should be based on 
the participant’s overall clinical condition.
Clinical stability is defined as the following: 
•
Absence of symptoms and signs indicating clinically significant progression of disease
•
No decline in ECOG performance status 
•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD and is not required to have repeat tumor imaging 
for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:
•
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and ≥
5 mm from nadir

Note: the iRECIST publication uses the terminology “sum of measurements,” but 
“sum of diameters” will be used in this protocol, consistent with the original RECIST 
1.1 terminology.
•
Unequivocal progression of non-target lesion(s) identified at baseline
•
Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
08RB5W

PRODUCT: MK-3475
162
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
•
Any of the factors that were the basis for the iUPD at the previous visit show worsening

For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point

For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1

For new lesions, worsening is any of these:
◦
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time 
point 
◦
Visible growth of new non-target lesions 
◦
The appearance of additional new lesions
•
Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
•
None of the progression-confirming factors identified above occurs AND
•
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
08RB5W

PRODUCT: MK-3475
163
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
•
None of the progression-confirming factors identified above occurs, AND
•
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset.” This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered following consultation with the Sponsor. In this case, if study 
treatment is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 1.3.
Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:
•
Target lesions

Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression. The nadir 
is always the smallest sum of diameters seen during the entire trial, either before or
after an instance of pseudo-progression.
•
Non-target lesions
08RB5W

PRODUCT: MK-3475
164
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024

If non-target lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD.

If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole.
•
New lesions

New lesions appear for the first time

Additional new lesions appear

Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum

Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to 
iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
08RB5W

PRODUCT: MK-3475
165
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
ADL
activities of daily living 
AE
adverse event 
ALT
alanine aminotransferase
APaT
all participants as treated
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
aspartame aminotransferase
ASTRO
American Society for Radiation Oncology
AUC
area under the curve
BCG
Bacillus Calmette–Guérin
BICR
blinded independent central review
C
cytosine
Cav
average concentration over the dosing interval
CD
cluster of differentiation
CI
confidence interval
CLL
chronic lymphocytic leukemia
Cmin
trough concentration
Cmax
peak concentration
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
CPS
combined positive score
CR
complete response
CRF
case report form 
CSR
clinical study report
cSSC
cutaneous squamous cell carcinoma
CT
computed tomography
CTCAE
common terminology criteria for adverse events
ctDNA
circulating tumor DNA
CTFG
Clinical Trial Facilitation Group 
08RB5W

PRODUCT: MK-3475
166
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Abbreviation
Expanded Term
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DCR
disease control rate
DFS
disease-free survival
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
duration of response
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
EEA
European Economic Area
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EORTC
European Organisation for Research and Treatment of Cancer
ePRO
electronic patient-reported outcome
EQ-5D
EuroQol-5 Dimensions
E-R
exposure-response
EU CT
European Union Clinical Trial
FA
final analysis
FAS
full analysis set
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDG-PET
fluorodeoxyglucose positive emission tomography
FFPE
formalin-fixed paraffin-embedded
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice 
08RB5W

PRODUCT: MK-3475
167
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Abbreviation
Expanded Term
H1/H2
hypothesis 1/2
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HNC
head and neck cancer
HNSCC
head and neck squamous cell carcinoma
HPV
human papillomavirus
HR
hazard ratio
HRQoL
health-related quality of life
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator’s Brochure
ICF
informed consent form 
ICH
International Conference on Harmonisation
iCPD
confirmed progressive disease
iCRO
Imaging Contract Research Organization
IEC
Independent Ethics Committee
Ig
immunoglobulin
IGHV
immunoglobulin heavy chain
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug 
IO
immuno-oncology
irAE
immune-related adverse event
IRB
Institutional Review Board 
iRECIST
modified RECIST 1.1 for immune-based therapeutics
IRT
interactive response technology
ITT
intent-to treat
IUD
intrauterine device
iUPD
unconfirmed progressive disease
08RB5W

PRODUCT: MK-3475
168
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Abbreviation
Expanded Term
IUS
intrauterine hormone-releasing system
IV
intravenous(ly)
KN012/KN069
KEYNOTE-012/KEYNOTE-069
LA
locally advanced
mAb
monoclonal antibody
MCC
Merkel cell carcinoma
MCPyV
Merkel cell polyomavirus
MRI
magnetic resonance imaging
MSI
microsatellite instability
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NMSC
non-melanoma skin cancer
NSCLC
non–small cell lung cancer
ORR
objective response rate
OS
overall survival
PD
progressive disease / pharmacodynamic
PD-1
programmed cell death 1
PD-L1
programmed death ligand 1
PD-L2
programmed death ligand 2
PFS
progression-free survival
PH
proportional hazard
PK
pharmacokinetic
po
per os (orally)
POCBP
participants of childbearing potential
PR
partial response
PRO
patient-reported outcome
Q2W
every 2 weeks
Q3W
every 3 weeks
Q6W
every 6 weeks
QLQ-C30
quality of life questionnaire-C30
08RB5W

PRODUCT: MK-3475
169
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
Abbreviation
Expanded Term
QoL
quality of life
R/M
recurrent/metastatic
RCR
Royal College of Radiologists
RECIST
response evaluation criteria in solid tumors
RFS
recurrence-free survival
RNA
ribonucleic acid
RT
radiotherapy
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SCF
sponsor consultation form
SHP
src homology region 2 domain-containing
SIM
site imaging manual
SoA
schedule of activities
SoC
standard of care
sSAP
supplemental statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
T
thymine
T-regs
regulatory T cells
UK
United Kingdom
ULN
upper limit of normal
US
United States
UV
ultraviolet
β-hCG
β-human chorionic gonadotropin
08RB5W

PRODUCT: MK-3475
170
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
11
REFERENCES
[Aaronson, N. K., et al 1993]
Aaronson NK, Ahmedzai S, Bergman B, 
Bullinger M, Cull A, Duez NJ, et al. The 
European Organization for Research and 
Treatment of Cancer QLQ-C30: a 
quality-of-life instrument for use in 
international clinical trials in oncology. J 
Natl Cancer Inst 1993;85(5):365-76.
[03Q3QL]
[Aldabagh, B., et al 2013]
Aldabagh B, Angeles JG, Cardones AR, 
Arron ST. Cutaneous squamous cell 
carcinoma and human papillomavirus: is 
there an association? Dermatol Surg. 
2013 Jan;39(1 Pt 1):1-23.
[04N4PC]
[Boukamp, P. 2005]
Boukamp P. Non-melanoma skin cancer: 
what drives tumor development and 
progression? Carcinogenesis. 2005 
Oct;26(10):1657-67.
[04N459]
[Brantsch, K. D., et al 2008]
Brantsch KD, Meisner C, Schonfisch B, 
Trilling B, Wehner-Caroli J, Rocken M, 
et al. Analysis of risk factors determining 
prognosis of cutaneous squamous-cell 
carcinoma: a prospective study. Lancet 
Oncol. 2008 Aug;9:713-20.
[04VRT2]
[Burton, K. A., et al 2016]
Burton KA, Ashack KA, Khachemoune 
A. Cutaneous Squamous Cell Carcinoma: 
A Review of High-Risk and Metastatic 
Disease. Am J Clin Dermatol. 2016 
Oct;17(5):491-508.
[04L4BK]
[Cardoso, J. C. 2011]
Cardoso JC, Calonje E. Cutaneous 
manifestations of human 
papillomaviruses: a review. Acta 
Dermatovenerol Alp Pannonica Adriat. 
2011 Sep;20(3):145-54.
[04N468]
[Cassler, N. M., et al 2016]
Cassler NM, Merrill D, Bichakjian CK, 
Brownell I. Merkel Cell Carcinoma 
Therapeutic Update. Curr Treat Options 
Oncol. 2016 Jul;17(7):36.
[04N4PK]
08RB5W

PRODUCT: MK-3475
171
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
[Cestari, T. F., et al 1995]
Cestari TF, Kripke ML, Baptista PL, 
Bakos L, Bucana CD. Ultraviolet 
radiation decreases the granulomatous 
response to lepromin in humans. J Invest 
Dermatol. 1995 Jul;105(1):8-13.
[04N46L]
[Chang, Y. 2012]
Chang Y, Moore PS. Merkel cell 
carcinoma: a virus-induced human 
cancer. Annu Rev Pathol. 2012;7:123-44.
[04N4PJ]
[Chemnitz, J. M., et al 2004]
Chemnitz JM, Parry RV, Nichols KE, 
June CH, Riley JL. SHP-1 and SHP-2 
associate with immunoreceptor tyrosine-
based switch motif of programmed death 
1 upon primary human T cell stimulation, 
but only receptor ligation prevents T cell 
activation. J Immunol 2004;173:945-54.
[00VMPN]
[Chen, T., et al 2007]
Chen T, Bertenthal D, Sahay A, Sen S, 
Chren MM. Predictors of skin-related 
quality of life after treatment of 
cutaneous basal cell carcinoma and 
squamous cell carcinoma. Arch 
Dermatol. 2007 Nov;143(11):1386-92.
[04W9J5]
[Chow, L. Q., et al 2016]
Chow LQ, Haddad R, Gupta S, Mahipal 
A, Mehra R, Tahara M, et al. Antitumor 
Activity of Pembrolizumab in Biomarker-
Unselected Patients With Recurrent 
and/or Metastatic Head and Neck 
Squamous Cell Carcinoma: Results From 
the Phase Ib KEYNOTE-012 Expansion 
Cohort. J Clin Oncol. 2016 Nov 
10;34(32):3838-45.
[04M4TX]
[Chren, M. M. 2012]
Chren MM. Skindex (Skindex-29; 
Skindex-16): scaling and scoring; version 
2.0. Lyon (France): MAPI Research 
Trust; 2012 Feb. 11 p.
[04ZD3D]
08RB5W

PRODUCT: MK-3475
172
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
[Chren, M. M., et al 1997]
Chren MM, Lasek RJ, Flocke SA, 
Zyzanski SJ. Improved discriminative 
and evaluative capability of a refined 
version of Skindex, a quality-of-life 
instrument for patients with skin diseases. 
Arch Dermatol. 1997 Nov;133:1433-40.
[04W9J8]
[Chren, M. M., et al 2001]
Chren MM, Lasek RJ, Sahay AP, Sands 
LP. Measurement properties of Skindex-
16: a brief quality-of-life measure for 
patients with skin diseases. J Cutan Med 
Surg. 2001 Mar;5(2):105-10.
[04W96G]
[Chren, M. M., et al 2007]
Chren MM, Sahay AP, Bertenthal DS, 
Sen S, Landefeld CS. Quality-of-life 
outcomes of treatments for cutaneous 
basal cell carcinoma and squamous cell 
carcinoma. J Invest Dermatol. 
2007;127:1351-7.
[04W96K]
[Condoluci, A., et al 2020]
Condoluci A, Terzi di Bergamo L, 
Langerbeins P, Hoechstetter MA, Herling 
CD, De Paoli L, et al. International 
prognostic score for asymptomatic early-
stage chronic lymphocytic leukemia. 
Blood. 2020 May 21;135(21):1859-69.
[0825VL]
[Davoli, T., et al 2013]
Davoli T, Xu AW, Mengwasser KE, Sack 
LM, Yoon JC, Park PJ, et al. Cumulative 
haploinsufficiency and triplosensitivity 
drive aneuploidy patterns and shape the 
cancer genome. Cell. 2013 Nov 
7;155(4):948-62.
[04N477]
[Disis, M. L. 2010]
Disis ML. Immune regulation of cancer. J 
Clin Oncol 2010;28(29):4531-8.
[058SQL]
[Doorbar, J. 2005]
Doorbar J. The papillomavirus life cycle. 
J Clin Virol. 2005 Mar;32 Suppl 1:S7-15.
[04N4Q0]
08RB5W

PRODUCT: MK-3475
173
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
[Dudley, M. E., et al 2005]
Dudley ME, Wunderlich JR, Yang JC, 
Sherry RM, Topalian SL, Restifo NP, et 
al. Adoptive cell transfer therapy 
following non-myeloablative but 
lymphodepleting chemotherapy for the 
treatment of patients with refractory 
metastatic melanoma. J Clin Oncol 
2005;23(10):2346-57.
[00VMPR]
[Eggermont, A. M. M., et al 
2018]
Eggermont AMM, Blank CU, Mandala 
M, Long GV, Atkinson V, Dalle S, et al. 
Adjuvant pembrolizumab versus placebo 
in resected stage III melanoma. N Engl J 
Med. 2018 May 10;378(19):1789-801.
[04ZK6C]
[Eisemann, N., et al 2014]
Eisemann N, Waldmann A, Geller AC, 
Weinstock MA, Volkmer B, Greinert R, 
et al. Non-melanoma skin cancer 
incidence and impact of skin cancer 
screening on incidence. J Invest 
Dermatol. 2014;134:43-50.
[04XZXK]
[Farzan, S. F., et al 2013]
Farzan SF, Waterboer T, Gui J, Nelson 
HH, Li Z, Michael KM, et al. Cutaneous 
alpha, beta and gamma human 
papillomaviruses in relation to squamous 
cell carcinoma of the skin: a population-
based study. Int J Cancer. 2013 Oct 
1;133(7):1713-20.
[04N4Q3]
[Francisco, L. M., et al 2010]
Francisco LM, Sage PT, Sharpe AH. The 
PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 
2010;236:219-42.
[058SQP]
[Greenwald, R. J., et al 2005]
Greenwald RJ, Freeman GJ, Sharpe AH. 
The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48.
[00VMQL]
08RB5W

PRODUCT: MK-3475
174
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
[Grob, J. J., et al 2016]
Grob JJ, Bartley K, Kuntsfeld R, Dreno 
B, Mortier L, Ascierto PA, et al. 
Assessment of quality of life (QoL) using 
Skindex-16 in patients (pts) with locally 
advanced basal cell carcinoma (laBCC) 
treated with vismodegib (VISMO) in the 
STEVIE study [abstract]. J Am Acad 
Dermatol. 2016 May;74(5 suppl 
1):AB193. Abstract no. 3140.
[04WC6F]
[Halprin, K. M., et al 1981]
Halprin KM, Comerford M, Presser SE, 
Taylor JR. Ultraviolet light treatment 
delays contact sensitization to nitrogen 
mustard. Br J Dermatol. 1981 
Jul;105(1):71-6.
[04N4Q4]
[Hampras, S. S., et al 2016]
Hampras SS, Reed RA, Bezalel S, 
Cameron M, Cherpelis B, Fenske N, et al. 
Cutaneous human papillomavirus 
infection and development of subsequent 
squamous cell carcinoma of the skin. J 
Skin Cancer. 2016;2016:1368103.
[04L4WQ]
[Hunder, N. N., et al 2008]
Hunder NN, Wallen H, Cao J, Hendricks 
DW, Reilly JZ, Rodmyre R, et al. 
Treatment of metastatic melanoma with 
autologous CD4+ T cells against NY-
ESO-1. N Engl J Med 
2008;358(25):2698-703.
[00VMPX]
[International Agency for 
Research on Cancer 2007]
International Agency for Research on 
Cancer Working Group on artificial 
ultraviolet (UV) light and skin cancer.. 
The association of use of sunbeds with 
cutaneous malignant melanoma and other 
skin cancers: A systematic review. Int J 
Cancer. 2007 Mar 1;120(5):1116-22. 
Erratum in: Int J Cancer. 2007 Jun 
1;120(11):2526.
[04N4Q7]
[Jennings, L. 2010]
Jennings L, Schmults CD. Management 
of high-risk cutaneous squamous cell 
carcinoma. J Clin Aesthet Dermatol. 
2010 Apr;3(4):39-48.
[04VRT3]
08RB5W

PRODUCT: MK-3475
175
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
[Johnson, T. M., et al 1992]
Johnson TM, Rowe DE, Nelson BR, 
Swanson NA. Squamous cell carcinoma 
of the skin (excluding lip and oral 
mucosa). J Am Acad Dermatol. 1992 
Mar;26(3):467-84
[04VRT8]
[Kang, S. Y. 2016]
Kang SY, Toland AE. High risk 
cutaneous squamous cell carcinoma of 
the head and neck. World J 
Otorhinolaryngol Head Neck Surg. 2016 
Aug 1;2:136-40.
[04VRTD]
[Karia, P. S., et al 2014]
Karia PS, Jambusaria-Pahlajani A, 
Harrington DP, Murphy GF, Qureshi AA, 
Schmults CD. Evaluation of American 
Joint Committee on Cancer, International 
Union Against Cancer, and Brigham and 
Women's Hospital tumor staging for 
cutaneous squamous cell carcinoma. J 
Clin Oncol. 2014 Feb 1;32(4):327-34.
[04XZY6]
[Kraus, D. H., et al 1998]
Kraus DH, Carew JF, Harrison LB. 
Regional lymph node metastasis from 
cutaneous squamous cell carcinoma. 
Arch Otolaryngol Head Neck Surg. 1998 
May;124:582-7.
[04VRVG]
[Kwa, R. E., et al 1992]
Kwa RE, Campana K, Moy RL. Biology 
of cutaneous squamous cell carcinoma. J 
Am  Acad Dermatol. 1992 Jan;26(1):1-
26.
[04VRTH]
[Lala, M., et al 2020]
Lala M, Li TR, de Alwis DP, Sinha V, 
Mayawala K, Yamamoto N, et al. A six-
weekly dosing schedule for 
pembrolizumab in patients with cancer 
based on evaluation using modelling and 
simulation. Eur J Cancer. 2020;131:68-
75.
[05GNZM]
08RB5W

PRODUCT: MK-3475
176
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
[Lawrence, M. S., et al 2013]
Lawrence MS, Stojanov P, Polak P, 
Kryukov GV, Cibulskis K, Sivachenko 
A, et al. Mutational heterogeneity in 
cancer and the search for new cancer-
associated genes. Nature. 2013 Jul 
11;499(7457):214-8.
[04N4PG]
[Le, D. T., et al 2017]
Le DT, Durham JN, Smith KN, Wang H, 
Bartlett BR, Aulakh LK, et al. Mismatch 
repair deficiency predicts response of 
solid tumors to PD-1 blockade. Science. 
2017 Jul;357(6349):409-13.
[04SRJK]
[Likhacheva, A., et al 2020]
Likhacheva A, Awan M, Barker CA, 
Bhatnagar A, Bradfield L, Brady MS, et 
al. Definitive and postoperative radiation 
therapy for basal and squamous cell 
cancers of the skin: executive summary 
of an American Society for Radiation 
Oncology clinical practice guideline. 
Pract Radiat Oncol. 2020 Jan-Feb;10:8-
20.
[06CKSR]
[Lomas, A., et al 2012]
Lomas A, Leonardi-Bee J, Bath-Hextall 
F. A systematic review of worldwide 
incidence of nonmelanoma skin cancer. 
Br J Dermatol. 2012;166:1069-80.
[04XZYJ]
[Miettinen, O. and Nurminen, 
M. 1985]
Miettinen O and Nurminen M. 
Comparative Analysis of Two Rates. Stat 
Med 1985;4:213-26.
[03QCDT]
[Moore, B. A., et al 2005]
Moore BA, Weber RS, Prieto V, El-
Naggar A, Holsinger FC, Zhou X, et al. 
Lymph node metastases from cutaneous 
squamous cell carcinoma of the head and 
neck. Laryngoscope. 2005 Sep;115:1561-
7.
[04VRTM]
08RB5W

PRODUCT: MK-3475
177
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
[Muller, K., et al 2017]
Muller K, Karrer S, Szeimies RM, 
Steinbauer J, Kohl E, Steinbauer D, et al. 
Quality of life assessment in patients with 
nonmelanoma skin cancer - psychometric 
validation of the EORTC QLQ-C30 
questionnaire. J Dtsch Dermatol Ges. 
2017;15(11):1090-100.
[04XJQX]
[National Comprehensive 
Cancer Network 2017]
National Comprehensive Cancer 
Network. NCCN clinical practice 
guidelines in oncology: squamous cell 
skin cancer; version 2.2018. Fort 
Washington (PA): National 
Comprehensive Cancer Network 
(NCCN); 2017. 85 p.
[04XKZY]
[Nghiem, P. T., et al 2016]
Nghiem PT, Bhatia S, Lipson EJ, 
Kudchadkar RR, Miller NJ, Annamalai L, 
et al. PD-1 blockade with pembrolizumab 
in advanced merkel-cell carcinoma. N 
Engl J Med. 2016 Jun 30;374(26):2542-
52.
[04GWXL]
[Okazaki, T., et al 2001]
Okazaki T, Maeda A, Nishimura H, 
Kurosaki T, Honjo T. PD-1 
immunoreceptor inhibits B cell receptor-
mediated signaling by recruiting src 
homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. Proc 
Natl Acad Sci U S A 2001;98(24):13866-
71.
[00VMQ6]
[Owonikoko, T. K., et al 
2018]
Owonikoko TK, Papadopoulos KP, 
Johnson ML, Gil-Martin M, Moreno V, 
Salama AK, et al. Phase 1 study of 
cemiplimab, a human monoclonal anti-
PD-1, in patients with unresectable 
locally advanced or metastatic cutaneous 
squamous cell carcinoma (CSCC): final 
efficacy and safety data. Poster session 
presented at: 2018 American Society of 
Clinical Oncology (ASCO) Annual 
Meeting; 2018 Jun 1-5; Chicago, IL. 
Abstract no. 9557.
[04YHB6]
08RB5W

PRODUCT: MK-3475
178
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
[Papadopoulos, K., et al 
2017]
Papadopoulos K, Owonikoko T, Johnson 
M, Brana I, Martin MG, Perez R, et al. 
REGN2810, a human anti-PD-1 
monoclonal antibody, for patients with 
unresectable locally advanced or 
metastatic cutaneous squamous cell 
carcinoma (CSCC): initial safety and 
efficacy. ASCO Annual Meeting; 2017 
Jun 2-6; Chicago, IL.
[04SWFJ]
[Parry, R. V., et al 2005]
Parry RV, Chemnitz JM, Frauwirth KA, 
Lanfranco AR, Braunstein I, Kobayashi 
SV, et al. CTLA-4 and PD-1 receptors 
inhibit T-cell activation by distinct 
mechanisms. Mol Cell Biol 
2005;25(21):9543-53.
[00VMQ7]
[Pastrana, D. V., et al 2009]
Pastrana DV, Tolstov YL, Becker JC, 
Moore PS, Chang Y, Buck CB. 
Quantitation of human 
seroresponsiveness to Merkel cell 
polyomavirus. PLoS Pathog. 2009 
Sep;5(9):e1000578.
[04N4PN]
[Piccart-Gebhart, M. J., et al 
2005]
Piccart-Gebhart MJ, Procter M, Leyland-
Jones B, Goldhirsch A, Untch M, Smith 
I, et al. Trastuzumab after adjuvant 
chemotherapy in HER2-positive breast 
cancer. N Engl J Med. 2005 Oct 
20;353(16):1659-72.
[04X60L]
[Pickard, A. S., et al 2007]
Pickard AS, Wilke CT, Lin H-W, Lloyd 
A. Health utilities using the EQ-5D in 
studies of cancer. Pharmacoeconomics 
2007;25(5):365-84.
[03RLHG]
[Pickering, C. R., et al 2014]
Pickering CR, Zhou JH, Lee JJ, 
Drummond JA, Peng SA, Saade RE, et 
al. Mutational landscape of aggressive 
cutaneous squamous cell carcinoma. Clin 
Cancer Res. 2014 Dec 15;20(24):6582-
92.
[04N46X]
08RB5W

PRODUCT: MK-3475
179
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
[Porceddu, S. V. 2015a]
Porceddu SV. Prognostic factors and the 
role of adjuvant radiation therapy in non-
melanoma skin cancer of the head and 
neck. Am Soc Clin Oncol Educ Book. 
2015:e513-8.
[04VQKV]
[Porceddu, S. V., et al 2015]
Porceddu SV, Veness MJ, Guminski A. 
Nonmelanoma cutaneous head and neck 
cancer and Merkel cell carcinoma: 
current concepts, advances, and 
controversies. J Clin Oncol. 2015 Oct 
10;33(29):3338-45.
[04VQKW]
[Porceddu, S. V., et al 2017]
Porceddu SV, Poulsen M, Bressel M, 
Stoneley A, Veness M, Kenny L, et al. 
Post-operative concurrent chemo-
radiotherapy versus post-operative 
radiotherapy in high-risk cutaneous 
squamous cell carcinoma of the head and 
neck (cSCCHN): a randomized phase III 
trial. Presented at: 2017 ASCO Annual 
Meeting; 2017 Jun 2-6; Chicago, IL.
[04VR7N]
[Rabin, R. and de Charro, F. 
2001]
Rabin R and de Charro F. EQ-5D: a 
measure of health status from the 
EuroQol group. Ann Med 2001;33:337-
43.
[03QM46]
[Regeneron Pharmaceuticals, 
Inc. 2017]
Regeneron Pharmaceuticals, Inc 
[Internet]. Tarrytown (NY): Regeneron 
Pharmaceuticals, Inc. Regeneron and 
Sanofi announce positive topline pivotal 
results for PD-1 antibody cemiplimab in 
advanced cutaneous squamous cell 
carcinoma [press release]. 2017 Dec 13 
[cited 2018 Apr 30]; 3 p. Available from:  
https://files.shareholder.com/downloads/
REGN/0x0x966618/7AEDA08B-6093-
48ED-8483-
744E18D1AB5D/REGN_News_2017_12
_13_General_Releases.pdf.
[04X6BK]
[Riley, J. L. 2009]
Riley JL. PD-1 signaling in primary T 
cells. Immunol Rev 2009;229:114-25.
[00VMQ9]
08RB5W

PRODUCT: MK-3475
180
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
[Rischin, D., et al 2018]
Rischin D, Migden MR, Chang ALS, 
Chung CH, Dunn LA, Guminski A, et al. 
Primary analysis of phase 2 results for 
cemiplimab, a human monoclonal anti-
PD-1, in patients with metastatic 
cutaneous squamous cell carcinoma. 
Poster session presented at: 2018 
American Society of Clinical Oncology 
(ASCO) Annual Meeting; 2018 Jun 1-5; 
Chicago, IL. Abstract no. 9519.
[04YHB9]
[Rogers, H. W., et al 2015]
Rogers HW, Weinstock MA, Feldman 
SR, Coldiron BM. Incidence estimate of 
nonmelanoma skin cancer (keratinocyte 
carcinomas) in the US population, 2012. 
JAMA Dermatol. 2015;151(10):1081-6.
[04Y004]
[Seiwert, T. Y., et al 2016]
Seiwert TY, Burtness B, Mehra R, Weiss 
J, Berger R, Eder JP, et al. Safety and 
clinical activity of pembrolizumab for 
treatment of recurrent or metastatic 
squamous cell carcinoma of the head and 
neck (KEYNOTE-012): an open-label, 
multicentre, phase 1b trial. Lancet Oncol. 
2016 May 27. [Epub ahead of print].
[04FZSF]
[Seymour, L., et al 2017]
Seymour L, Bogaerts J, Perrone A, Ford 
R, Schwartz LH, Mandrekar S, et al. 
iRECIST: guidelines for response criteria 
for use in trials testing 
immunotherapeutics. Lancet Oncol. 2017 
Mar;18(3):e143-52.
[04P9RV]
[Sheppard, K-A, et al 2004]
Sheppard K-A, Fitz LJ, Lee JM, 
Benander C, George JA, Wooters J, et al. 
PD-1 inhibits T-cell receptor induced 
phosphorylation of the ZAP70/CD3zeta 
signalosome and downstream signaling to 
PKCtheta. FEBS Lett. 2004;574:37-41.
[00VMQC]
08RB5W

PRODUCT: MK-3475
181
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
[Smile, T. D., et al 2021]
Smile TD, Xiong DX, Varra V, Winter 
IW, Beal BT, Gastman BR, et al. Disease 
progression in cutaneous squamous cell 
carcinoma patients with satellitosis and 
in-transit metastasis. Anticancer Res. 
2021;41:289-95.
[08BVH5]
[Spain, L., et al 2016]
Spain L, Higgins R, Gopalakrishnan K, 
Turajlic S, Gore M, Larkin J. Acute renal 
allograft rejection after immune 
checkpoint inhibitor therapy for 
metastatic melanoma. Ann Oncol. 2016 
Jun;27(6):1135-7.
[04KRZ2]
[The Royal College of 
Radiologists 2019]
The Royal College of Radiologists. 
Radiotherapy dose fractionation; third 
edition. London (United Kingdom): The 
Royal College of Radiologists; 2019 Mar. 
16, Skin cancer; 6 p.
[06CKST]
[Toll, A., et al 2014]
Toll A, Lloveras B, Masferrer E, 
Ferrandiz-Pulido C, Garcoia-Patos V, 
Gheit T, et al. Human beta 
papillomavirus DNA study in primary 
cutaneous squamous cell carcinomas and 
their corresponding metastases. Arch 
Dermatol Res. 2014 Jan;306(1):93-5.
[04N4NQ]
[Tolstov, Y. L., et al 2009]
Tolstov YL, Pastrana DV, Feng H, 
Becker JC, Jenkins FJ, Moschos S, et al. 
Human Merkel cell polyomavirus 
infection II. MCV is a common human 
infection that can be detected by 
conformational capsid epitope 
immunoassays. Int J Cancer. 2009 Sep 
15;125(6):1250-6.
[04N4NR]
[Touze, A., et al 2011]
Touze A, Le Bidre E, Laude H, Fleury 
MJ, Cazal R, Arnold F, et al. High levels 
of antibodies against merkel cell 
polyomavirus identify a subset of patients 
with merkel cell carcinoma with better 
clinical outcome. J Clin Oncol. 2011 Apr 
20;29(12):1612-9.
[04N4NS]
08RB5W

PRODUCT: MK-3475
182
PROTOCOL/AMENDMENT NO.: 630-10
MK-3475-630-10 FINAL PROTOCOL
12-DEC-2024
[Trosman, S. J., et al 2021]
Trosman SJ, Zhu A, Nicolli EA, 
Leibowitz JM, Sargi ZB. High-risk 
cutaneous squamous cell cancer of the 
head and neck: risk factors for recurrence 
and impact of adjuvant treatment. 
Laryngoscope. 2021 Jan;131:E136-43.
[08DW90]
[Uno, H., et al 2015]
Uno H, Tian L, Claggett B, Wei LJ. A 
versatile test for equality of two survival 
functions based on weighted differences 
of Kaplan-Meier curves. Stat Med. 
2015;34:3680-95.
[04X5TT]
[Vandergriff, T., et al 2010]
Vandergriff T, Harting M, Rosen T. 
Managing skin cancer. Stockfleth E, 
Rosen T, Shumack S, editors. Heidelberg 
(Germany): Springer-Verlag GmbH; 
c2010. Chapter 5, Invasive squamous cell 
carcinoma of the skin; p. 61-78.
[04Y07M]
[World Health Organization 
1992]
World Health Organization, International 
Agency for Research on Cancer. IARC 
monographs on the evaluation of 
carcinogenic risks to humans: solar and 
ultraviolet radiation - Volume 55 
[Internet]. Lyon: International Agency for 
Research on Cancer; 1992. Available 
from: 
http://monographs.iarc.fr/ENG/Monograp
hs/vol55/mono55.pdf.
[04N4Q9]
[Zhang, X., et al 2004]
Zhang X, Schwartz J-CD, Guo X, Bhatia 
S, Cao E, Chen L, et al. Structural and 
functional analysis of the costimulatory 
receptor programmed death-1. Immunity 
2004;20:337-47.
[00VMQJ]
08RB5W