A Phase III, Randomized, Open-label Study to Evaluate Pembrolizumab as Neoadjuvant Therapy and in Combination With Standard of Care as Adjuvant Therapy for Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC)
Phase: PHASE3
Conditions: Head and Neck Neoplasms
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase III, Randomized, Open-label Study to 
Evaluate Pembrolizumab as Neoadjuvant Therapy and 
in Combination With Standard of Care as Adjuvant 
Therapy for Stage III-IVA Resectable Locoregionally 
Advanced Head and Neck Squamous Cell Carcinoma 
(LA HNSCC)
NCT03765918
29-Mar-2024

PRODUCT:  MK-3475 
1
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
TITLE PAGE
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase III, Randomized, Open-label Study to Evaluate Pembrolizumab as 
Neoadjuvant Therapy and in Combination With Standard of Care as Adjuvant Therapy for 
Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell 
Carcinoma (LA HNSCC)
Protocol Number: 689-09
Compound Number: MK-3475
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND NUMBER:   122,325
EudraCT NUMBER: 2017-001139-38
EU CT NUMBER: 2022-500254-41-00
jRCT NUMBER: 2080224953
Approval Date: 29 March 2024
08KM9X

PRODUCT:  MK-3475 
2
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
08KM9X

PRODUCT: MK-3475 
3
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-689-09
29-MAR-2024
To update the assumptions of the survival distribution of the control arm 
 
3475-689-08
07-SEP-2023
To amend the statistical analysis plan,
 
3475-689-07
07-JUN-2022
To update contraception language to include required duration of contraception for males and 
women of childbearing potential (WOCBP) after radiotherapy (RT). Additional minor updates, 
corrections, and clarifications were also made.
3475-689-06
03-MAR-2022
1) To add pregnancy testing for women of childbearing potential (WOCBP) at monthly 
intervals during study treatment until 120 days after the last dose of pembrolizumab and 180 
days after the last dose of cisplatin, including at the end of treatment visit.
2) To allow imaging and/or biopsy assessments to continue for participants who have not 
experienced an event.
3) To update the contraception requirements and make additional minor corrections and 
clarifications throughout the protocol.
3475-689-05
13-MAY-2021
To update the dose modification and toxicity management guidelines for immune-related 
adverse events (irAEs).
CCI
CCI
08KM9X

PRODUCT: MK-3475 
4
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Document
Date of Issue
Overall Rationale
3475-689-04
17-JUN-2019
To add both biomarker-driven hypotheses and the stratification factor of tumor proportion
score (TPS) ≥ 50%.
 
 
3475-689-03
02-AUG-2018
To clarify the definitions of residual disease used in the pathological assessment used for this 
study and to clarify the roles of the local and central pathologists, to align the pembrolizumab 
dose modification table with the most current safety information, and to remove iRECIST 
assessment which is not relevant for this study. Additional clarifications and corrections were 
also made.
3475-689-02
10-MAY-2018
To align with regulatory requirements at German and French sites as well as to align with the 
cisplatin SmPC as required for German and French sites.
3475-689-01
13-JAN-2018
To provide for more frequent pregnancy testing and to extend the prohibition of live vaccines 
to 3 months after the end of study treatment.
3475-689-00
24-AUG-2017
Initial protocol
CCI
08KM9X

PRODUCT: MK-3475 
5
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 09
Overall Rationale for the Amendment: To update the assumptions of the survival distribution of the control arm based on historical 
data and update with more conservative HR assumption for EFS in CPS≥10 population based on study data from KEYNOTE-412.
Summary of Changes Table
Section Number and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 10.1, Statistical 
Analysis Plan Summary
To update the assumptions of the survival distribution of the 
control arm
 
Changes made were to address strategy.
 
Additional Changes
Section 1, Synopsis
Number of Participants: Updated planned sample sizes in 
CPS≥10, CPS≥1, and ITT populations.
To reflect the actual enrollment in CPS≥10, CPS≥1, and ITT populations.
Section 5.1, Overall Design
Updated planned sample sizes in CPS≥10, CPS≥1, and ITT 
populations.
Refer to the rationale provided for Section 1 above regarding the number of 
participants enrolled.
Section 5.2, Number of 
Participants
Updated planned sample sizes in CPS≥10, CPS≥1, and ITT 
populations.
Refer to the rationale provided for Section 1 above regarding the number of 
participants enrolled.
Section 10.1, Statistical 
Analysis Plan Summary
Treatment Assignment: Updated planned sample sizes in 
CPS≥10, CPS≥1, and ITT populations.
Refer to the rationale provided for Section 1 above regarding the number of 
participants enrolled.
Section 10.1, Statistical 
Analysis Plan Summary
Interim Analyses: Added clarification that 
 
 
Updated the
 
Section 10.1, Statistical 
Analysis Plan Summary
Sample Size and Power: Updated planned sample sizes in 
CPS≥10, CPS≥1, and ITT populations.
Refer to the rationale provided for Section 1 above regarding the number of 
participants enrolled.
Section 10.1, Statistical 
Analysis Plan Summary
Sample Size and Power: Removed specification that the final 
analysis of the study is event driven.
This statement is not applicable in sample size and power section.  
CCI
CCI
CCI
CCI
08KM9X

PRODUCT: MK-3475 
6
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Section Number and Name
Description of Change
Brief Rationale
Section 10.7.1, Efficacy 
Interim Analysis 
Table 16: Updated the timing for interim and final analyses.
Refer to the rationale provided for Section 10.1 above regarding 
 
Section 10.7.1, Efficacy 
Interim Analysis
Table 16: Added clarification that 
 
 
Refer to the rationale provided for Section 10.1 above regarding 
 
 
Section 10.8.1.1, Event-Free 
Survival
Updated
 
.
Refer to the rationale provided for Section 10.1 above regarding 
 
Section 10.8.1.1, Event-Free 
Survival
Table 18: Updated 
 
Refer to the rationale provided for Section 10.1 above
 
.
Section 10.8.1.1, Event-Free 
Survival
Updated
 
Refer to the rationale provided for Section 10.1 above
 
.
Section 10.8.1.1, Event-Free 
Survival
Table 19: Updated 
Refer to the rationale provided for Section 10.1 above regarding 
 
Section 10.8.1.1, Event-Free 
Survival
Table 20: Updated 
 
Refer to the rationale provided for Section 10.1 above regarding 
 
.
Section 10.8.1.2, Major 
Pathologic Response
Table 21: Updated 
 
 
  
Section 10.8.1.3, Overall 
Survival
Updated
 
Refer to the rationale provided for Section 10.1 above
 
.
Section 10.8.1.3, Overall 
Survival
Table 22: Updated 
 
Refer to the rationale provided for Section 10.1 above
 
.
Section 10.8.1.3, Overall 
Survival
Table 23: Updated e
 
Refer to the rationale provided for Section 10.1 above
 
.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
08KM9X

PRODUCT: MK-3475 
7
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Section Number and Name
Description of Change
Brief Rationale
Section 10.8.1.3, Overall 
Survival
Table 24: Updated 
 
.
Refer to the rationale provided for Section 10.1 above regarding 
 
Section 10.9, Sample Size 
and Power Calculations
Refer to the rationale provided for Section 10.1 above regarding 
 
Section 10.9, Sample Size 
and Power Calculations
Refer to the rationale provided for Section 10.1 above regarding 
 
Section 10.9, Sample Size 
and Power Calculations
Refer to the rationale provided for Section 10.1 above regarding 
 
Section 10.9, Sample Size 
and Power Calculations
Refer to the rationale provided for Section 10.8.1.2 above 
 
Section 10.10, Subgroup 
Analyses
Removed stratification factors from subgroup analyses.
Primary tumor site, tumor stage, and PD-L1 status will be based on eCRF 
data.
Appendix 3: Regulatory, 
Ethical, and Study 
Governance Considerations
Added clarification that records and documents under EU CTR 
regulation must be retained for 25 years after the end of the 
study.
Refer to the rationale provided for Appendix 3 above regarding compliance 
with Regulation (EU) 536/2014.
Appendix 3: Regulatory, 
Ethical, and Study 
Governance Considerations
Added statement that the clinical trial will be conducted in 
compliance with Regulation (EU) 536/2014.
This change was made to comply with Regulation (EU) 536/2014.
Appendix 3: Regulatory, 
Ethical, and Study 
Governance Considerations
Added serious breach reporting requirements. 
Refer to the rationale provided for Appendix 3 above regarding compliance 
with Regulation (EU) 536/2014.
Throughout document
Minor administrative, formatting, grammatical, and/or 
typographical changes were made throughout the document.
To ensure clarity and accurate interpretation of the intent of the protocol.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
08KM9X

PRODUCT:  MK-3475 
8
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................5
1
SYNOPSIS......................................................................................................................17
2
SCHEDULE OF ACTIVITIES (SOA).........................................................................24
2.1
Study Screening and Treatment 1 Phases (Arm A/Pembrolizumab) .............24
2.2
Post-surgery Treatment 2 Phase (Arm A/Pembrolizumab).............................32
2.3
Study Screening, Surgery and Post-surgery Treatment 2 Phases (Arm 
B/SoC) ...................................................................................................................39
2.4
End of Treatment and Follow-up Visits (Arms A and B) ................................48
3
INTRODUCTION..........................................................................................................54
3.1
Study Rationale....................................................................................................54
3.2
Background ..........................................................................................................54
3.2.1
Pharmaceutical and Therapeutic Background .............................................55
3.2.2
Pre-clinical and Clinical Studies..................................................................56
3.2.3
Ongoing Clinical Studies.............................................................................56
3.3
Benefit/Risk Assessment......................................................................................61
4
OBJECTIVES/HYPOTHESES AND ENDPOINTS..................................................61
5
STUDY DESIGN............................................................................................................67
5.1
Overall Design......................................................................................................67
5.1.1
Study Diagram .............................................................................................70
5.2
Number of Participants.......................................................................................71
5.3
Beginning and End of Study Definition .............................................................72
5.3.1
Clinical Criteria for Early Study Termination .............................................72
5.4
Scientific Rationale for Study Design.................................................................72
5.4.1
Rationale for Endpoints ...............................................................................75
5.4.1.1
Efficacy Endpoints.............................................................................75
5.4.1.1.1
Major Pathological Response ..................................................75
5.4.1.1.2
Pathological Complete Response.............................................75
5.4.1.1.3
Event-Free Survival .................................................................76
5.4.1.1.4
Overall Survival.......................................................................77
5.4.1.1.5
Rationale for Prospective Stratification and Evaluation of 
Biomarker Subpopulation........................................................77
5.4.1.2
Safety Endpoints................................................................................78
5.4.1.3
Rationale for Patient Reported Outcomes (PROs).............................78
5.4.1.4
Planned Exploratory Biomarker Research.........................................80
5.4.1.5
Future Biomedical Research..............................................................81
5.4.2
Rationale for the Use of Comparator...........................................................81
08KM9X

PRODUCT:  MK-3475 
9
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
5.5
Justification for Dose...........................................................................................82
5.5.1
Maximum Dose/Exposure for This Trial.....................................................83
6
STUDY POPULATION ................................................................................................83
6.1
Inclusion Criteria.................................................................................................83
6.2
Exclusion Criteria................................................................................................89
6.3
Lifestyle Restrictions ...........................................................................................91
6.3.1
Meals and Dietary Restrictions....................................................................91
6.3.2
Caffeine, Alcohol, and Tobacco ..................................................................91
6.3.3
Activity ........................................................................................................91
6.3.4
Contraception...............................................................................................91
6.3.5
Pregnancy.....................................................................................................92
6.3.6
Use in Nursing Women................................................................................92
6.4
Screen Failures.....................................................................................................92
6.5
Participant Replacement Strategy......................................................................92
7
TREATMENTS..............................................................................................................93
7.1
Treatments Administered ...................................................................................93
7.2
Dose Modification (Escalation/Titration/Other)...............................................96
7.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................96
7.2.2
Dose Modification for Radiotherapy .........................................................104
7.2.3
Dose Modification for Cisplatin ................................................................104
7.2.3.1
Cisplatin-Related Toxicity...............................................................105
7.2.3.2
Dose Modification for Cisplatin ......................................................105
7.3
Method of Treatment Assignment....................................................................108
7.3.1
Stratification...............................................................................................108
7.4
Blinding...............................................................................................................108
7.5
Preparation/Handling/Storage/Accountability ...............................................108
7.5.1
Dose Preparation........................................................................................108
7.5.2
Handling, Storage and Accountability.......................................................108
7.6
Treatment Compliance......................................................................................109
7.7
Concomitant Therapy........................................................................................109
7.7.1
Rescue Medications & Supportive Care....................................................111
7.7.1.1
Supportive Care Guidelines for Pembrolizumab.............................111
7.7.1.2
Supportive Care Guidelines for Surgery..........................................112
7.7.1.3
Supportive Care Guidelines for Radiation.......................................112
7.7.1.4
Supportive Care Guidelines for Cisplatin........................................112
7.8
Treatment After the End of the Study.............................................................112
7.9
Clinical Supplies Disclosure..............................................................................112
08KM9X

PRODUCT:  MK-3475 
10
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
8
DISCONTINUATION/WITHDRAWAL CRITERIA .............................................112
8.1
Discontinuation of Study Treatment................................................................112
8.2
Withdrawal from the Study..............................................................................113
8.3
Lost to Follow Up...............................................................................................114
9
STUDY ASSESSMENTS AND PROCEDURES......................................................114
9.1
Administrative and General Procedures .........................................................115
9.1.1
Informed Consent.......................................................................................115
9.1.1.1
General Informed Consent...............................................................115
9.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research...........................................................................................116
9.1.2
Inclusion/Exclusion Criteria ......................................................................116
9.1.3
Participant Identification Card...................................................................116
9.1.4
Medical History .........................................................................................116
9.1.4.1
Disease Details.................................................................................116
9.1.5
Prior and Concomitant Medications Review.............................................117
9.1.5.1
Prior Medications.............................................................................117
9.1.5.2
Concomitant Medications................................................................117
9.1.5.3
Post-study Anticancer Therapy Status.............................................117
9.1.6
Presurgery Tumor Tissue Collection .........................................................117
9.1.7
Survival Status ...........................................................................................118
9.1.8
Assignment of Screening Number.............................................................118
9.1.9
Assignment of Treatment/Randomization Number...................................118
9.1.10
Treatment Administration..........................................................................119
9.1.10.1
Timing of Dose Administration.......................................................119
9.1.10.1.1
Pembrolizumab (Arm A Only) ..............................................119
9.1.10.1.2
Radiotherapy..........................................................................120
9.1.10.1.2.1
Volume Definition .......................................................123
9.1.10.1.2.2
Treatment Verification and Accuracy..........................127
9.1.10.1.2.3
Supportive Care for Head and Neck Radiotherapy......128
9.1.10.1.2.4
Treatment Interruptions / Modifications......................128
9.1.10.1.3
Cisplatin.................................................................................128
9.1.10.2
Surgery Guidelines...........................................................................130
9.1.10.2.1
Pre-operative Assessment......................................................130
9.1.10.2.2
Surgical Procedure Guidelines...............................................130
9.1.10.2.3
Post-operative Complications................................................131
9.1.10.2.3.1
Evaluation and Reporting of Post-operative 
Complications ..............................................................131
9.1.10.2.4
Post-operative Care................................................................132
9.1.10.2.5
Pathology Specimen...............................................................132
08KM9X

PRODUCT:  MK-3475 
11
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9.1.11
Withdrawal/Discontinuation......................................................................133
9.1.11.1
Withdrawal From Future Biomedical Research ..............................133
9.1.12
Participant Blinding/Unblinding................................................................134
9.1.13
Domiciling .................................................................................................134
9.1.14
Calibration of Equipment...........................................................................134
9.2
Efficacy Assessments .........................................................................................134
9.2.1
Tumor Imaging and Assessment of Disease..............................................134
9.2.1.1
Initial Tumor Imaging......................................................................135
9.2.1.2
Tumor Imaging During the Study....................................................135
9.2.1.3
End of Treatment and Follow-up Tumor Imaging...........................136
9.2.1.4
RECIST 1.1 Assessment of Disease................................................136
9.2.2
Tumor Tissue Collection and Assessment of Pathological Response .......137
9.2.3
Survival......................................................................................................137
9.2.4
Patient Reported Outcomes........................................................................138
9.3
Adverse Events, Serious Adverse Events and Other Reportable Safety 
Events..................................................................................................................138
9.3.1
Time Period and Frequency for Collecting AE, SAE and Other 
Reportable Safety Event Information ........................................................139
9.3.2
Method of Detecting AE, SAE and Other Reportable Safety Events........140
9.3.3
Follow-up of AE, SAE and Other Reportable Safety Event Information..140
9.3.4
Regulatory Reporting Requirements for SAE ...........................................141
9.3.5
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs........................................................................141
9.3.6
Pregnancy and Exposure During Breastfeeding ........................................141
9.3.7
Events of Clinical Interest (ECI)................................................................142
9.4
Treatment of Overdose......................................................................................142
9.5
Safety...................................................................................................................143
9.5.1
Physical Examinations...............................................................................143
9.5.1.1
Full Physical Exam ..........................................................................143
9.5.1.2
Directed Physical Exam...................................................................143
9.5.2
Vital Signs, Height and Weight .................................................................143
9.5.3
Electrocardiograms ....................................................................................144
9.5.4
Performance Assessment ...........................................................................144
9.5.4.1
Eastern Cooperative Oncology Group Performance Status.............144
9.5.5
Oral and Dental Check-up .........................................................................144
9.5.6
Neurological Examination .........................................................................144
9.5.7
Audiometric Testing ..................................................................................145
9.5.8
Fiber Optic Examination............................................................................145
9.5.9
Clinical Safety Laboratory Assessments ...................................................145
08KM9X

PRODUCT:  MK-3475 
12
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9.5.9.1
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)........................................................................................146
9.5.9.2
Pregnancy Test.................................................................................146
9.5.9.3
HIV, HBV and HCV Serology ........................................................147
9.6
Pharmacokinetics...............................................................................................147
9.6.1
Blood Collection for RNA Analysis and Plasma and Serum Biomarker 
Analyses.....................................................................................................147
9.7
Pharmacodynamics............................................................................................147
9.8
Future Biomedical Research Sample Collection.............................................147
9.9
Biomarkers .........................................................................................................147
9.9.1
Planned Genetic Analysis Sample Collection............................................148
9.10
Visit Requirements.............................................................................................148
9.10.1
Screening....................................................................................................148
9.10.2
Treatment Periods......................................................................................149
9.10.2.1
Neoadjuvant Treatment (Treatment 1).............................................149
9.10.2.2
Definitive Surgery............................................................................150
9.10.2.3
Post-surgery Safety Follow-up ........................................................150
9.10.2.4
Adjuvant Treatment (Treatment 2)..................................................150
9.10.3
Post-Treatment Visit..................................................................................150
9.10.3.1
End of Treatment Visit.....................................................................151
9.10.3.2
Safety Follow-up Visit.....................................................................151
9.10.3.3
Follow-up Visits...............................................................................151
9.10.3.4
Survival Follow-up ..........................................................................152
9.10.4
Participants Discontinued From Study Treatment but Continuing to be 
Monitored in the Study ..............................................................................152
10
STATISTICAL ANALYSIS PLAN ...........................................................................152
10.1
Statistical Analysis Plan Summary...................................................................153
10.2
Responsibility for Analyses/In-House Blinding ..............................................155
10.3
Hypotheses/Estimation ......................................................................................155
10.4
Analysis Endpoints.............................................................................................155
10.4.1
Efficacy Endpoints.....................................................................................156
10.4.1.1
Primary Efficacy Endpoint ..............................................................156
10.4.1.2
Secondary Efficacy Endpoints.........................................................156
10.4.2
Safety Endpoints........................................................................................156
10.4.3
Patient Reported Outcome (PRO) Endpoints ............................................156
10.5
Analysis Populations..........................................................................................157
10.5.1
Efficacy Analysis Population.....................................................................157
10.5.2
Safety Analysis Population........................................................................157
10.5.3
Patient Reported Outcome Analysis Population........................................157
08KM9X

PRODUCT:  MK-3475 
13
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
10.6
Statistical Methods.............................................................................................157
10.6.1
Statistical Methods for Efficacy Analyses.................................................157
10.6.1.1
Event-Free Survival .........................................................................158
10.6.1.2
Major Pathological Response ..........................................................159
10.6.1.3
Overall Survival...............................................................................159
10.6.1.4
Pathological Complete Response.....................................................160
10.6.1.5
Summary of Efficacy Analysis Methods.........................................160
10.6.2
Statistical Methods for Safety Analyses ....................................................161
10.6.3
Statistical Methods for Patient Reported Outcome Analyses: EORTC 
QLQ-C30 & QLQ-H&N35........................................................................163
10.6.4
Summaries of Baseline Characteristics and Demographics.......................164
10.7
Interim Analyses ................................................................................................164
10.7.1
Efficacy Interim Analyses..........................................................................164
10.7.2
Safety Interim Analyses.............................................................................165
10.8
Multiplicity .........................................................................................................166
10.8.1
Multiplicity Control for Efficacy Interim Analyses...................................166
10.8.1.1
Event-Free Survival .........................................................................167
10.8.1.2
Major Pathologic Response .............................................................170
10.8.1.3
Overall Survival...............................................................................171
10.8.2
Multiplicity Control for Safety Interim Analyses......................................174
10.9
Sample Size and Power Calculations ...............................................................174
10.10 Subgroup Analyses.............................................................................................175
10.11 Compliance (Medication Adherence)...............................................................176
10.12 Extent of Exposure.............................................................................................176
11
REFERENCES.............................................................................................................177
12
APPENDICES..............................................................................................................188
Appendix 1: Abbreviations and Trademarks..............................................................188
Appendix 2: Clinical Laboratory Tests........................................................................191
Appendix 3: Regulatory, Ethical, and Study Governance Considerations ..............193
Code of Conduct for Clinical Trials.............................................................................193
Financial Disclosure...................................................................................................195
Data Protection...........................................................................................................195
Confidentiality of Data ..............................................................................................195
Confidentiality of Participant Records.......................................................................195
Confidentiality of IRB/IEC Information....................................................................196
Committees Structure.................................................................................................196
Scientific Advisory Committee............................................................................196
Trial Steering Committee.....................................................................................196
08KM9X

PRODUCT:  MK-3475 
14
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Executive Oversight Committee..........................................................................196
Data Monitoring Committee................................................................................196
Publication Policy................................................................................................197
Compliance with Trial Registration and Results Posting Requirements...................197
Compliance with Law, Audit and Debarment ...........................................................198
Data Quality Assurance .............................................................................................198
Source Documents .....................................................................................................199
Study and Site Closure...............................................................................................199
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................200
Definitions of Medication Error, Misuse, and Abuse................................................200
Definition of AE ........................................................................................................200
Definition of SAE ......................................................................................................202
Recording AE and SAE .............................................................................................203
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor............207
Appendix 5: Contraceptive Guidance and Pregnancy Testing..................................208
Contraception Requirements......................................................................................208
Pregnancy Testing......................................................................................................210
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research..............................................................................................................211
Appendix 7: Country-specific Requirements..............................................................215
Appendix 8: Country-specific Protocol Requirements...............................................216
Appendix 9: Technical Note for the Poisson Mixture Model and Piecewise 
Exponential Survival Model..............................................................................223
08KM9X

PRODUCT:  MK-3475 
15
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values.................................................88
Table 2
Study Treatment(s)...........................................................................................94
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...............................................................98
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ......................................................................................................102
Table 5
Dose Levels for Cisplatin...............................................................................104
Table 6
Cisplatin Dose Reduction for Renal Toxicity................................................106
Table 7
Dose Modification for Cisplatin – Other Toxicities ......................................107
Table 8
Radiotherapy Dose Parameters......................................................................121
Table 9
Standard Organs at Risk.................................................................................125
Table 10
Dose Volume Objectives ...............................................................................126
Table 11
Radiotherapy Compliance Criteria ................................................................127
Table 12
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events...............................................................................140
Table 13
Censoring Rules for Primary and Sensitivity Analyses of EFS.....................159
Table 14
Analysis Strategy for Primary and Secondary Efficacy Endpoints ...............161
Table 15
Analysis Strategy for Safety Parameters........................................................163
Table 16
165
Table 17
Summary of Interim Analyses Strategy for Safety........................................166
Table 18
168
Table 19
169
Table 20
170
Table 21
171
Table 22
172
Table 23
173
Table 24
174
Table 25
Protocol-Required Safety Laboratory Assessments.......................................191
Table 26
Highly Effective Contraception Methods......................................................210
CCI
CCI
08KM9X

PRODUCT:  MK-3475 
16
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
LIST OF FIGURES
Figure 1
Study Design....................................................................................................71
Figure 2
167
CCI
08KM9X

PRODUCT:  MK-3475 
17
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
1
SYNOPSIS
Protocol Title:  
A Phase III, Randomized, Open-label Study to Evaluate Pembrolizumab as Neoadjuvant 
Therapy and in Combination With Standard of Care as Adjuvant Therapy for Stage III-IVA 
Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA 
HNSCC)
Short Title: 
MK-3475 (SCH 9000475) as neoadjuvant and adjuvant therapy in Stage III-IVA resectable 
LA HNSCC
Objectives/Hypotheses and Endpoints:
All objectives and hypotheses apply to male/female adult participants (≥18 years of age) 
with resectable locoregionally advanced head and neck squamous cell carcinoma (LA 
HNSCC).
Throughout this protocol, the term RECIST 1.1 refers to the modification of RECIST 1.1 to 
include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Refer 
to Section 5.4.1.1.3 for further details.
08KM9X

PRODUCT:  MK-3475 
18
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Objective/Hypothesis
Endpoint
Primary
•
Objective 1: To compare pembrolizumab 
as neoadjuvant therapy and in combination
with radiotherapy (RT) ± cisplatin as 
adjuvant therapy to only RT ± cisplatin as 
adjuvant therapy with respect to the 
event-free survival (EFS), per RECIST 
1.1, as assessed by blinded independent 
central review (BICR) in participants 
whose tumors express PD-L1 CPS≥10, 
CPS≥1, and in all participants, regardless 
of CPS status.
-
Hypothesis #1: Pembrolizumab as 
neoadjuvant therapy and in 
combination with RT ± cisplatin as 
adjuvant therapy after surgical 
resection is superior to standard of care 
(SoC) surgical resection followed by 
RT ± cisplatin adjuvant therapy with 
respect to EFS, per RECIST 1.1, by 
BICR in participants whose tumors 
express PD-L1 CPS≥10.
-
Hypothesis #2: Pembrolizumab as 
neoadjuvant therapy and in 
combination with RT ± cisplatin as 
adjuvant therapy after surgical 
resection is superior to standard of care 
(SoC) surgical resection followed by 
RT ± cisplatin adjuvant therapy with 
respect to EFS, per RECIST 1.1, by 
BICR in participants whose tumors 
express PD-L1 CPS≥1.
-
Hypothesis #3: Pembrolizumab as 
neoadjuvant therapy and in 
combination with RT ± cisplatin as 
adjuvant therapy after surgical 
resection is superior to standard of care 
(SoC) surgical resection followed by 
RT ± cisplatin adjuvant therapy with 
respect to EFS, per RECIST 1.1, by 
BICR in all participants.
•
EFS –time from the date of 
randomization to the date of first 
record of any of the following events: 
radiographic disease progression
(exceptions specified in Section 
10.4.1.1), radiographic disease 
progression during the neoadjuvant 
phase that precludes surgery, local or 
distant disease progression or 
recurrence, as assessed with imaging 
or biopsy as indicated, death due to 
any cause; a secondary primary 
malignancy is not considered an EFS 
event
08KM9X

PRODUCT:  MK-3475 
19
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Secondary
•
Objective 2: To compare pembrolizumab 
neoadjuvant therapy to no neoadjuvant 
therapy with respect to the rate of major 
pathological response (mPR) as assessed 
by the central pathologist at the time of 
definitive surgery in participants whose 
tumors express PD-L1 CPS≥10, CPS≥1,
and in all participants regardless of CPS 
status.
-
Hypothesis #4: Pembrolizumab 
neoadjuvant therapy is superior to no 
neoadjuvant therapy with respect to 
rate of mPR at the time of surgery in 
participants whose tumors express PD-
L1 CPS≥10.
-
Hypothesis #5: Pembrolizumab 
neoadjuvant therapy is superior to no 
neoadjuvant therapy with respect to 
rate of mPR at the time of surgery in 
participants whose tumors express PD-
L1 CPS≥1.
-
Hypothesis #6: Pembrolizumab 
neoadjuvant therapy is superior to no 
neoadjuvant therapy with respect to 
rate of mPR at the time of surgery in 
all participants.
•
mPR – having less than or equal to 
10% invasive squamous cell 
carcinoma within the resected 
primary tumor specimen and all 
sampled regional lymph nodes
08KM9X

PRODUCT:  MK-3475 
20
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
•
Objective 3: To compare pembrolizumab 
as neoadjuvant therapy and in combination
with radiotherapy (RT) ± cisplatin as 
adjuvant therapy to only RT ± cisplatin as 
adjuvant therapy with respect to overall 
survival (OS) in participants whose tumors 
express PD-L1 CPS≥10, CPS≥1, and in all 
participants, regardless of CPS status.
-
Hypothesis #7: Pembrolizumab as 
neoadjuvant therapy and in 
combination with RT ± cisplatin as 
adjuvant therapy after surgical 
resection is superior to SoC surgical 
resection followed by RT ± cisplatin 
adjuvant therapy with respect to OS in 
participants whose tumors express PD-
L1 CPS≥10.
-
Hypothesis #8: Pembrolizumab as 
neoadjuvant therapy and in 
combination with RT ± cisplatin as 
adjuvant therapy after surgical 
resection is superior to SoC surgical 
resection followed by RT ± cisplatin 
adjuvant therapy with respect to OS in 
participants whose tumors express PD-
L1 CPS≥1.
-
Hypothesis #9: Pembrolizumab as 
neoadjuvant therapy and in 
combination with RT ± cisplatin as 
adjuvant therapy after surgical 
resection is superior to SoC surgical 
resection followed by RT ± cisplatin 
adjuvant therapy with respect to OS in 
all participants.
•
OS - time from the date of 
randomization to the date of death 
due to any cause
•
Objective 4: To evaluate the rate of 
pathological complete response (pCR), as 
assessed by the central pathologist at the 
time of definitive surgery, in participants 
whose tumors express PD-L1 CPS≥10, 
CPS≥1, and in all participants regardless 
of CPS status.
•
pCR - having no residual invasive 
squamous cell carcinoma within the 
resected primary tumor specimen and 
all sampled regional lymph nodes
08KM9X

PRODUCT:  MK-3475 
21
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
•
Objective 5: To evaluate global health 
status/quality of life (QoL) and physical 
functioning scores using the European 
Organisation for Research and Treatment 
of Cancer (EORTC) QoL questionnaire 
(QLQ)-C30, and swallowing, speech and 
pain symptoms using the EORTC Head 
and Neck–Specific QoL questionnaire 
(EORTC QLQ-H&N35) in participants 
whose tumors express PD-L1 CPS≥10, 
CPS≥1, and in all participants, regardless 
of CPS status.
•
EORTC QLQ C30 global health 
status/QoL scales (items 29 and 30) 
•
EORTC QLQ-C30 physical 
functioning scales (items 1-5) 
•
EORTC QLQ-H&N35 swallowing 
multi-item scale (items 35-38), speech
multi-item scale (items 46, 53-54), 
and pain multi-item scale (items 31-
34) 
•
Objective 6: To determine the safety and 
tolerability of pembrolizumab as 
neoadjuvant therapy and in combination 
with RT ± cisplatin as adjuvant therapy.
•
Adverse events (AEs)
•
Study drug discontinuations due to 
AEs
The study is considered to have met its objective if pembrolizumab is superior to SoC with 
respect to EFS at either its interim analysis (IA) or the final analysis.
Overall Design:
Study Phase
Phase III
Clinical Indication
The treatment of participants with Stage III-IVA, resectable, 
locoregionally advanced head and neck squamous cell 
carcinoma (LA HNSCC)
Population
Treatment naïve participants with Stage III-IVA resectable LA 
HNSCC
Study Type
Interventional
Type of Design
Randomized, open-label
Type of Control
Active control no placebo
Study Blinding
Unblinded Open-label
Estimated Duration of 
Trial
The Sponsor estimates that the trial will require approximately 
7 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.
08KM9X

PRODUCT:  MK-3475 
22
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Number of Participants:
The number of participants planned to be enrolled in the study was 704. The actual number 
of participants enrolled in the study will be 714 participants, which will result in 
approximately 65% (~462) participants whose tumors express PD-L1 CPS≥10 and 
approximately 95% (~680) participants whose tumors express PD-L1 CPS≥1.
Treatment Groups and Duration:
Treatment Groups
There are 2 treatment arms: 
•
Treatment Arm A/pembrolizumab: Neoadjuvant therapy:
pembrolizumab (2 cycles) prior to surgical resection.  
Adjuvant therapy: Pembrolizumab (15 cycles) plus SoC RT 
with/without cisplatin.
•
Treatment Arm B/SoC: Neoadjuvant therapy: no treatment 
prior to surgical resection.  Adjuvant: SoC RT with/without 
cisplatin.
Pembrolizumab: 200 mg fixed dose, intravenously (IV) every 
3 weeks (Q3W), in the neoadjuvant and adjuvant treatment 
periods.
No crossover from SoC to pembrolizumab will be permitted.
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 28 days, eligible participants will be 
stratified and randomly assigned to receive study treatment until 
an event/disease progression is radiographically documented and 
verified by BICR, unacceptable AE(s), intercurrent illness that 
prevents further administration of treatment, investigator’s 
decision to discontinue the participant, withdrawal of consent, or 
administrative reasons requiring cessation of treatment, or until 
the participant has received 17 administrations of 
pembrolizumab (approximately 1 year).
After the end of treatment, each participant will be followed for 
the occurrence of AEs and spontaneously reported pregnancy as 
described under Section 9.3.
Participants who discontinue for reasons other than an 
event/disease progression/recurrence will have post treatment 
follow-up imaging for disease status until an event/disease 
progression/recurrence as per Section 10.4.1.1, withdrawing 
consent, or becoming lost to follow-up.  All participants will be 
followed by telephone for OS until death, withdrawal of consent, 
or the end of the study.
08KM9X

PRODUCT:  MK-3475 
23
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
A list of abbreviations used in this document can be found in Appendix 1. Study governance 
considerations are outlined in Appendix 3.
08KM9X

PRODUCT:  MK-3475
24
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
2
SCHEDULE OF ACTIVITIES (SOA)
2.1
Study Screening and Treatment 1 Phases (Arm A/Pembrolizumab)
Study Screening and Treatment 1 Phases (Arm A/Pembrolizumab)
Study Period
Screening
Treatment randomization
Treatment 1
Presurgery 
Imaging/ 
Safetyc
Surgeryc
Post-surgery 
Safety Follow-
up
Notes:
Participants that discontinue study treatment 
for reasons other than an event/disease 
progression will enter post-treatment study 
follow-up.
Participants who discontinue study treatment 
due to an event/disease progression will 
enter Safety and Survival Follow-up.
Visit Number/Title
Pembro 
neoadjuvant
Treatment Cycle
1
2
Week
1
4
6
Scheduled Day (s)
1
1
1
Scheduling Window (Days, unless 
noted)
-28 
to -1
+3
±3
±10
7-30 days 
post-surgery
Administrative Procedures
Informed Consent
X
Documented informed consent must be 
obtained prior to performing any 
protocol-specified procedures. Results of a 
test performed prior to the participant
providing documented informed consent as 
part of routine clinical management are 
acceptable in lieu of a screening test, if 
performed within the specified time frame.
If the investigator plans to treat beyond the 
initial radiologic disease progression per 
RECIST 1.1, additional consent will be 
required prior to post-progression treatment
(see Section 9.1.1.1).
Informed Consent for Future Biomedical 
Research (FBR; optional)
X
Participant Identification Card
X
X
Distribute at screening and add the
randomization number at the time of
randomization.
Inclusion/Exclusion Criteria
X
Demographics, Disease Details and 
Complete Medical History (includes 
substance usage)
X
Substances: alcohol and tobacco.
08KM9X

PRODUCT:  MK-3475
25
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Study Screening and Treatment 1 Phases (Arm A/Pembrolizumab)
Study Period
Screening
Treatment randomization
Treatment 1
Presurgery 
Imaging/ 
Safetyc
Surgeryc
Post-surgery 
Safety Follow-
up
Notes:
Participants that discontinue study treatment 
for reasons other than an event/disease 
progression will enter post-treatment study 
follow-up.
Participants who discontinue study treatment 
due to an event/disease progression will 
enter Safety and Survival Follow-up.
Visit Number/Title
Pembro 
neoadjuvant
Treatment Cycle
1
2
Week
1
4
6
Scheduled Day (s)
1
1
1
Scheduling Window (Days, unless 
noted)
-28 
to -1
+3
±3
±10
7-30 days 
post-surgery
Prior/Concomitant Medication Review
X
X
X
X
X
Prior medications – Record all medications 
taken within 28 days of randomization.  
Concomitant medications – Enter new 
medications started during the study through 
the post-treatment Safety Follow-up.
Treatment Randomization via IVRS
X
Site personnel will access the IVRS after 
screening and determining if the participant 
is eligible for randomization.  Sites will 
contact participants and advise of the 
assigned treatment arm and date of first visit.
Pembrolizumab Administration
X
X
Treatment 1, Cycle 1 must be given within 
3 days of treatment randomization via IVRS. 
Pembrolizumab to be administered on Day 1 
of each cycle after all procedures/
assessments have been completed.
Surgery
X
Performed as part of planned SoC after 
presurgery imaging. 
Participants who do not undergo surgery as 
originally planned, for reasons other than 
centrally verified radiographic disease 
progression, may proceed directly to 
Treatment 2 and receive salvage RT plus 
cisplatin plus pembrolizumab.
08KM9X

PRODUCT:  MK-3475
26
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Study Screening and Treatment 1 Phases (Arm A/Pembrolizumab)
Study Period
Screening
Treatment randomization
Treatment 1
Presurgery 
Imaging/ 
Safetyc
Surgeryc
Post-surgery 
Safety Follow-
up
Notes:
Participants that discontinue study treatment 
for reasons other than an event/disease 
progression will enter post-treatment study 
follow-up.
Participants who discontinue study treatment 
due to an event/disease progression will 
enter Safety and Survival Follow-up.
Visit Number/Title
Pembro 
neoadjuvant
Treatment Cycle
1
2
Week
1
4
6
Scheduled Day (s)
1
1
1
Scheduling Window (Days, unless 
noted)
-28 
to -1
+3
±3
±10
7-30 days 
post-surgery
Efficacy Procedures
CT/MRI head and neck, chest, upper 
abdomen
X
X*
(X) optional at 
site discretion
If the participant had received CT/MRI scan 
prior to providing documented informed 
consent and within 28 days prior to 
randomization, the assessment can be 
accepted.  For each participant, the same 
modality should be used throughout the 
study for response evaluation.  The upper 
abdominal CT/MRI should cover the liver in 
its entirety. *Presurgery scans are required 
within 14 days prior to the date of surgery. 
Repeat imaging is required if imaging is 
done >14 days prior to the date of surgery.
FDG-PET or FDG-PET/CT
X
If the participant had received FDG-PET or 
FDG-PET/CT scan prior to providing 
documented informed consent and within 
28 days prior to randomization, the 
assessment can be accepted.
Tissue Collection for Histopathology 
(mPR and pCR assessment)
X
Assessment of surgical margins / gross 
lesions will be performed by the local 
pathologist.
08KM9X

PRODUCT:  MK-3475
27
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Study Screening and Treatment 1 Phases (Arm A/Pembrolizumab)
Study Period
Screening
Treatment randomization
Treatment 1
Presurgery 
Imaging/ 
Safetyc
Surgeryc
Post-surgery 
Safety Follow-
up
Notes:
Participants that discontinue study treatment 
for reasons other than an event/disease 
progression will enter post-treatment study 
follow-up.
Participants who discontinue study treatment 
due to an event/disease progression will 
enter Safety and Survival Follow-up.
Visit Number/Title
Pembro 
neoadjuvant
Treatment Cycle
1
2
Week
1
4
6
Scheduled Day (s)
1
1
1
Scheduling Window (Days, unless 
noted)
-28 
to -1
+3
±3
±10
7-30 days 
post-surgery
Patient Reported Outcomes
EQ-5D-5L
X
X
X
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: EQ-5D-5L, EORTC QLQ-
C30, EORTC QLQ-H&N35.
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.
EORTC QLQ-C30 
X
X
X
EORTC QLQ-H&N35
X
X
X
Safety Procedures
Full physical examination including 
neurological exam and Height*
X
X
To be performed by the investigator or 
qualified designee.
Documented routine neurological exams 
performed within 6 weeks of randomization 
are acceptable and do not need to be 
repeated in Screening.
*Height will be measured at Screening only.
Directed physical examination
X
X
X
ECOG Performance Status
X
X
X
X
X
Screening (within 10 days prior to 
randomization).  Investigator or designee to 
confirm no deterioration prior to initiating 
study treatment.  ECOG performance status 
must be 0 or 1 on the first day of dosing.
To be assessed prior to dosing.
Weight and Vital Signs
X
X
X
X
X
Vital signs to be collected include: 
temperature, resting pulse, resting 
respiratory rate, blood pressure.
08KM9X

PRODUCT:  MK-3475
28
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Study Screening and Treatment 1 Phases (Arm A/Pembrolizumab)
Study Period
Screening
Treatment randomization
Treatment 1
Presurgery 
Imaging/ 
Safetyc
Surgeryc
Post-surgery 
Safety Follow-
up
Notes:
Participants that discontinue study treatment 
for reasons other than an event/disease 
progression will enter post-treatment study 
follow-up.
Participants who discontinue study treatment 
due to an event/disease progression will 
enter Safety and Survival Follow-up.
Visit Number/Title
Pembro 
neoadjuvant
Treatment Cycle
1
2
Week
1
4
6
Scheduled Day (s)
1
1
1
Scheduling Window (Days, unless 
noted)
-28 
to -1
+3
±3
±10
7-30 days 
post-surgery
12-lead ECG (local)
X
Urine or Serum β-hCG Pregnancy Test 
(WOCBP only) – as per local SOP
X
X
(x)
(x)
The protocol requires pregnancy testing at 
Screening and within 24 hours (urine) or 
within 72 hours (serum) before
randomization.
(x) = a pregnancy test must be performed 
every month during study treatment. More 
frequent pregnancy testing may be 
performed if required by local regulations or 
if determined necessary by the investigator 
(refer to Appendix 8 for UK-, Germany- and 
France-specific requirements).
HIV, hepatitis B and C screen (testing 
optional per site SOP)
X
HIV, hepatitis B and C testing are required 
when mandated by local health authority. 
Refer to Appendix 8 for Germany-specific 
requirements for HIV, Hepatitis B and C 
testing requirements.
Hematology
X
X
X
X
X
Screening.  Labs performed within 10 days 
of treatment initiation during screening, do 
not need to be repeated at Treatment 1: 
Cycle 1, Day 1 unless clinically indicated. 
Samples to be taken prior to pembrolizumab 
administration.  After Cycle 1 lab samples 
can be collected up to 3 days prior to the 
scheduled time point.
Chemistry
X
X
X
X
X
08KM9X

PRODUCT:  MK-3475
29
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Study Screening and Treatment 1 Phases (Arm A/Pembrolizumab)
Study Period
Screening
Treatment randomization
Treatment 1
Presurgery 
Imaging/ 
Safetyc
Surgeryc
Post-surgery 
Safety Follow-
up
Notes:
Participants that discontinue study treatment 
for reasons other than an event/disease 
progression will enter post-treatment study 
follow-up.
Participants who discontinue study treatment 
due to an event/disease progression will 
enter Safety and Survival Follow-up.
Visit Number/Title
Pembro 
neoadjuvant
Treatment Cycle
1
2
Week
1
4
6
Scheduled Day (s)
1
1
1
Scheduling Window (Days, unless 
noted)
-28 
to -1
+3
±3
±10
7-30 days 
post-surgery
Urinalysis
X
X
X
X
X
Screening.  Labs performed within 10 days 
of treatment initiation during screening, do 
not need to be repeated at Treatment 1: 
Cycle 1, Day 1 unless clinically indicated. 
Samples to be taken prior to pembrolizumab 
administration, after Cycle 1, lab samples 
can be collected up to 3 days prior to the 
scheduled time point.
Coagulation tests (PT/INR and 
aPTT/PTT)
X
------If Clinically Indicated------
--If Clinically 
Indicated--
Any participant receiving anticoagulant 
therapy should have coagulation tests 
monitored closely throughout the study.  
PTT may be performed if the local lab is 
unable to perform aPTT.
Thyroid Function (TSH) 
X
X
---If 
Clinically 
Indicated---
--If Clinically 
Indicated--
In case of elevated TSH, to add Free T3 and
Free T4. Free T4 should be performed on all 
participants with elevated TSH; Free T3 only 
needs to be performed if it is done as a part 
of local SOC. If the Free T3 and Free T4 are 
not available locally, they can be sent to the 
central laboratory to be performed (see 
Laboratory Manual for details).
AE/SAE review
X
---Continuous Reporting---
Oral and dental check-up
X
Recommended every 6 months throughout 
the study (frequency as per SoC/local 
guidelines).
Audiometric Testing
X
Documented routine exams performed 
within 6 weeks of randomization are 
acceptable and do not need to be repeated in 
Screening.
Fiber optic examination of primary tumor 
site
X
--If Clinically 
Indicated--
08KM9X

PRODUCT:  MK-3475
30
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Study Screening and Treatment 1 Phases (Arm A/Pembrolizumab)
Study Period
Screening
Treatment randomization
Treatment 1
Presurgery 
Imaging/ 
Safetyc
Surgeryc
Post-surgery 
Safety Follow-
up
Notes:
Participants that discontinue study treatment 
for reasons other than an event/disease 
progression will enter post-treatment study 
follow-up.
Participants who discontinue study treatment 
due to an event/disease progression will 
enter Safety and Survival Follow-up.
Visit Number/Title
Pembro 
neoadjuvant
Treatment Cycle
1
2
Week
1
4
6
Scheduled Day (s)
1
1
1
Scheduling Window (Days, unless 
noted)
-28 
to -1
+3
±3
±10
7-30 days 
post-surgery
Future Biomedical 
Research/Biomarkers
Blood for Genetic Analysis a
X
Drawn pre-dose. 
Blood for RNA Analysis
X
X
Whole blood samples should be collected 
pre-dose on Cycle 1 Day 1.
Leftover specimens will be stored for FBR if 
the participant consents to FBR.
Blood for Plasma Biomarker Analyses
X
X
Blood for Serum Biomarker Analyses
X
X
Blood for ctDNA
X
X
X
Tumor Tissue Sample Collection
Histology, including PD-L1 and p16 
biomarker analysis on all participants prior 
to randomization for stratification, b
X
Tumor tissue from core or excisional biopsy 
(FNA not adequate) from all participants.
Results of PD-L1 testing are required for 
stratification; p16 testing required only for 
participants with oropharyngeal cancer.
PD-L1 (tested centrally) and p16 biomarker
analysis (tested locally/centrally).
Tissue Collection for Biomarker 
Analysis b
X
X*
Core or excisional biopsy (FNA not 
adequate). *For participants who do not 
achieve a pCR, a tumor tissue sample is to 
be collected and submitted to the designated 
central laboratory for translational research.
08KM9X

PRODUCT:  MK-3475
31
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Refer to Appendix 8 for country-specific requirements. 
a
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected 
at the site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes.
If the sample is collected, leftover extracted DNA will be stored for Future Biomedical Research (FBR) if the participant (or their legally acceptable 
representative) provides documented informed consent for FBR. If the planned genetic analysis is not approved, but FBR is approved and consent is given, 
this sample will be collected for the purpose of FBR.
b
Baseline tumor tissue from a core or excisional biopsy (FNA not adequate) from participants with oropharyngeal cancer must be tested locally for HPV 
status (if HPV status not known) prior to randomization. If local p16 testing results are not available, or cannot be assessed locally by the specified method, 
a tumor tissue sample must be submitted for p16 testing at the designated central laboratory. For all participants, baseline tumor tissue must also be provided 
to the central vendor for PD-L1 biomarker testing (results required prior to randomization) and translational research. Refer to Section 9.2.2 for additional
information about tissue requirements. Detailed instructions for tissue collection, process and shipment are provided in the Vendor Manual.  If the 
participant provides documented informed consent for FBR, any leftover tissue that would ordinarily be discarded at the end of the main study will be 
retained for FBR. Newly obtained biopsies are permitted.
c
The timeframe for surgery (after the presurgery visit) is 6 weeks (±10 days) after randomization.  Participants in Arm A are allowed to go to surgery outside 
of this timeframe if delays are due to an AE. Participants with delays other than for an AE may be considered with sponsor consultation.
08KM9X

PRODUCT:  MK-3475
32
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
2.2
Post-surgery Treatment 2 Phase (Arm A/Pembrolizumab)
Post-surgery Treatment 2 Phase (Arm A/Pembrolizumab)
Study Period
Treatment 2 (adjuvant)
Notes
Participants that discontinue study treatment for reasons 
other than an event/disease progression will enter 
post-treatment study follow-up.
Participants who discontinue study treatment due to an 
event/disease progression will enter Safety and Survival 
Follow-up.
Upon completion of Treatment 2, participants move into 
post-treatment follow-up.
Visit Number/Title
Treatment Cycle
1
2
3
4
5
6
7
8-15
Week
1
2
3
4
5
6
7
10
13
16
19
22-43
Scheduled Day(s)
1
8
15
1
8
15
1
1
1
1
1
1
Scheduling Window (Days, 
unless noted)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Prior/Concomitant Medication 
Review 
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab Administration 
X
X
X
X
X
X
X
X
To be administered after all procedures/assessments have 
been completed.  If the start of RT is delayed, up to 4 
doses of pembrolizumab may be given. The timing of this 
dose of pembrolizumab can be adjusted based on timing of 
surgery. Treatment cycles are named according to 
pembrolizumab treatment. If cycle(s) of pembrolizumab 
are administered prior to initiation of RT, see section 
9.1.10.1.1 for guidance. Weekly visits are only required 
during RT and the timing of these visits will change if 
pembrolizumab is administered prior to initiation of RT.  
All participants may receive no more than 17 cycles. If a 
dose of pembrolizumab is skipped, see Section 9.1.10.1.1 
for guidance on additional treatment cycles.
Radiotherapy (IMRT/IGRT)
X
X
X
X
X
X
(X*)
2 Gy/day in 30 fractions for a total of 60 Gy. 
*Participants considered high-risk: 2 Gy/day in 
33 fractions for a total of 66 Gy.  Participants with residual 
gross tumor; 2 Gy/day in 35 fractions for total of 70 Gy.
08KM9X

PRODUCT:  MK-3475
33
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Post-surgery Treatment 2 Phase (Arm A/Pembrolizumab)
Study Period
Treatment 2 (adjuvant)
Notes
Participants that discontinue study treatment for reasons 
other than an event/disease progression will enter 
post-treatment study follow-up.
Participants who discontinue study treatment due to an 
event/disease progression will enter Safety and Survival 
Follow-up.
Upon completion of Treatment 2, participants move into 
post-treatment follow-up.
Visit Number/Title
Treatment Cycle
1
2
3
4
5
6
7
8-15
Week
1
2
3
4
5
6
7
10
13
16
19
22-43
Scheduled Day(s)
1
8
15
1
8
15
1
1
1
1
1
1
Scheduling Window (Days, 
unless noted)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Conditional Cisplatin Treatment 
(100 mg/m2)
X
X
X
Cisplatin will only be administered to participants 
considered to be high-risk by local pathologist (see 
Section 9.1.10.2.5 Pathology Specimens for definition), 
and to participants who do not undergo surgical resection, 
or have incomplete resection (ie, gross disease left 
behind).  Cisplatin may be administered up to 1 week 
following completion of RT.  
To be administered after all procedures/ assessments have 
been completed. Permitted dose modifications are detailed 
in Section 7.2.3
Efficacy Procedures
CT/MRI head and neck, chest, 
upper abdomen
X
X
For all imaging, the clock will start at the end of RT ±
cisplatin.  Imaging to be performed 12 weeks (± 7 days) 
after end of RT ± cisplatin treatment and then every 
3 months (91 ± 7 days) until the end of Year 3; then every 
6 months (182 ± 14 days) thereafter up to the end of 
Year 5.  Imaging timing should follow calendar days and 
should not be recalculated based on the date of previous 
scans.  
FDG-PET or FDG-PET/CT
X*
* On-study imaging will be performed as clinically 
indicated.
08KM9X

PRODUCT:  MK-3475
34
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Post-surgery Treatment 2 Phase (Arm A/Pembrolizumab)
Study Period
Treatment 2 (adjuvant)
Notes
Participants that discontinue study treatment for reasons 
other than an event/disease progression will enter 
post-treatment study follow-up.
Participants who discontinue study treatment due to an 
event/disease progression will enter Safety and Survival 
Follow-up.
Upon completion of Treatment 2, participants move into 
post-treatment follow-up.
Visit Number/Title
Treatment Cycle
1
2
3
4
5
6
7
8-15
Week
1
2
3
4
5
6
7
10
13
16
19
22-43
Scheduled Day(s)
1
8
15
1
8
15
1
1
1
1
1
1
Scheduling Window (Days, 
unless noted)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Patient Reported Outcomes
EQ-5D-5L
X*
X*
X**
X**
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.
* To be completed in conjunction with RT ± cisplatin
treatment prior to treatment administration. If adjuvant 
pembrolizumab is started during the post-surgical recovery 
phase prior to start of radiotherapy, ePRO assessment 
should be delayed until radiotherapy begins.  ePRO 
assessments should then be performed on the day RT 
begins and then repeated during RT treatment on Day 29 ± 
3 days.
** To be administered 12 weeks after end of RT ± 
cisplatin treatment and then every 3 months (91 ± 7 days) 
until the end of Year 3; then every 12 months (365 days 
± 14 days) thereafter up to 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: EQ-5D-5L, EORTC QLQ-C30, EORTC 
QLQ-H&N35.
EORTC QLQ-C30
X*
X*
X**
X**
EORTC QLQ-H&N35
X*
X*
X**
X**
Safety Procedures
Full physical examination 
including neurological exam
X
Directed physical examination
X
X
X
X
X
X
X
X
X
X
X
For participants receiving cisplatin: to include routine 
neurological exam before each dose of cisplatin, thereafter 
if clinically indicated.
08KM9X

PRODUCT:  MK-3475
35
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Post-surgery Treatment 2 Phase (Arm A/Pembrolizumab)
Study Period
Treatment 2 (adjuvant)
Notes
Participants that discontinue study treatment for reasons 
other than an event/disease progression will enter 
post-treatment study follow-up.
Participants who discontinue study treatment due to an 
event/disease progression will enter Safety and Survival 
Follow-up.
Upon completion of Treatment 2, participants move into 
post-treatment follow-up.
Visit Number/Title
Treatment Cycle
1
2
3
4
5
6
7
8-15
Week
1
2
3
4
5
6
7
10
13
16
19
22-43
Scheduled Day(s)
1
8
15
1
8
15
1
1
1
1
1
1
Scheduling Window (Days, 
unless noted)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
X
To be assessed prior to dosing.
Weight and Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs to be collected include: temperature, resting 
pulse, resting respiratory rate, blood pressure.  
Urine or Serum β-hCG 
Pregnancy Test (WOCBP only) 
– as per local SOP
X
(x)
(x)
(x)
(x)
(x)
(x)
(x)
The protocol requires pregnancy testing within 24 hours of 
the first dose of adjuvant treatment. (x) = a pregnancy test 
must be performed every month during study treatment. 
More frequent pregnancy testing may be performed if 
required by local regulations or if determined necessary by 
the investigator (refer to Appendix 8 for UK-, Germany-
and France-specific requirements).
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
For participants who receive RT alone, labs are to be taken 
every 3 weeks before each cycle of pembrolizumab.  Labs 
are to be taken up to 3 days prior to pembrolizumab 
administration.  For participants who receive cisplatin, 
labs are to be taken weekly during RT + cisplatin 
treatment and thereafter before each cycle.  Labs can be 
taken up to 3 days prior to cisplatin administration and 
CrCl level assessment is to be repeated within 3 days prior 
to start of each cisplatin administration for management of 
dose reduction renal toxicity guidelines.  If these labs are 
within normal range, these labs do not need to be repeated 
within 24 hours of cisplatin administration.  Any abnormal 
labs should be repeated and assessed within 24 hours of 
cisplatin administration.
Chemistry 
X
X
X
X
X
X
X
X
X
X
X
X
08KM9X

PRODUCT:  MK-3475
36
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Post-surgery Treatment 2 Phase (Arm A/Pembrolizumab)
Study Period
Treatment 2 (adjuvant)
Notes
Participants that discontinue study treatment for reasons 
other than an event/disease progression will enter 
post-treatment study follow-up.
Participants who discontinue study treatment due to an 
event/disease progression will enter Safety and Survival 
Follow-up.
Upon completion of Treatment 2, participants move into 
post-treatment follow-up.
Visit Number/Title
Treatment Cycle
1
2
3
4
5
6
7
8-15
Week
1
2
3
4
5
6
7
10
13
16
19
22-43
Scheduled Day(s)
1
8
15
1
8
15
1
1
1
1
1
1
Scheduling Window (Days, 
unless noted)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Urinalysis 
X
X
X
X
Samples to be taken within 3 days prior to pembrolizumab 
administration. 
Collected every 2 months at Cycles 1, 4, 7, 10 and 13, 
unless clinically indicated.
Coagulation tests (PT/INR and 
aPTT/PTT)
---------------As Clinically Indicated-------------
Any participant receiving anticoagulant therapy should 
have coagulation tests monitored closely throughout the 
study. PTT may be performed if the local lab is unable to 
perform aPTT
Thyroid Function (TSH)
X
X
X
In case of elevated TSH, to add Free T3 and Free T4. Free 
T4 should be performed on all participants with an 
elevated TSH; Free T3 only needs to be performed if it is 
done as a part of local standard of care. If the Free T3 and 
Free T4 are not available locally, they can be sent to the 
central laboratory to be performed (see Laboratory Manual 
for details).
TSH to be tested on Day 1 of every 3rd cycle (ie, Cycles 2, 
5, 8, etc), unless clinically indicated.
AE/SAE review 
----------------Continuous Reporting------------
Oral and dental check-up 
--------------------------Recommended Every 6 months-------------------
Frequency as per SoC/local guidelines.
Audiometric Testing
---------------As Clinically Indicated-------------
Follow cisplatin label for ototoxicity management.
Fiber optic examination of 
primary tumor site
X
X
If clinically indicated. 
To be performed at Cycles 5, 9 and 13.
08KM9X

PRODUCT:  MK-3475
37
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Post-surgery Treatment 2 Phase (Arm A/Pembrolizumab)
Study Period
Treatment 2 (adjuvant)
Notes
Participants that discontinue study treatment for reasons 
other than an event/disease progression will enter 
post-treatment study follow-up.
Participants who discontinue study treatment due to an 
event/disease progression will enter Safety and Survival 
Follow-up.
Upon completion of Treatment 2, participants move into 
post-treatment follow-up.
Visit Number/Title
Treatment Cycle
1
2
3
4
5
6
7
8-15
Week
1
2
3
4
5
6
7
10
13
16
19
22-43
Scheduled Day(s)
1
8
15
1
8
15
1
1
1
1
1
1
Scheduling Window (Days, 
unless noted)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Future Biomedical 
Research/Biomarkers
Blood for RNA Analysis 
X
X
For all participants, to be completed in conjunction with 
RT ± cisplatin treatment prior to treatment administration.  
For high-risk participants who have approximately 6.5 
weeks of RT, blood collection should also align 
approximately with last dose of RT. If adjuvant 
pembrolizumab is started during the post-surgical recovery 
phase prior to start of radiotherapy, the initial blood 
biomarker collection during adjuvant treatment should be 
delayed until radiotherapy begins.  Blood biomarkers 
should then be collected on the day RT begins.
Whole blood samples should be collected pre-dose.
Leftover specimens will be stored for FBR if the 
participant consents to future biomedical research. For 
ctDNA collections after end RT, the clock will start at the 
end of RT ± cisplatin.  ctDNA to be collected 12 weeks 
(± 7 days) after end of RT ± cisplatin treatment and then 
every 3 months (91 ± 7 days) until end of Year 3; then 
every 6 months (182 ± 14 days) thereafter up to the end of 
Year 5.  
* ctDNA sample should be collected at the end of 
RT.
Blood for Plasma Biomarker 
Analyses 
X
X
Blood for Serum Biomarker 
Analyses 
X
X
Blood for ctDNA 
X
X*
X
X
08KM9X

PRODUCT:  MK-3475
38
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Post-surgery Treatment 2 Phase (Arm A/Pembrolizumab)
Study Period
Treatment 2 (adjuvant)
Notes
Participants that discontinue study treatment for reasons 
other than an event/disease progression will enter 
post-treatment study follow-up.
Participants who discontinue study treatment due to an 
event/disease progression will enter Safety and Survival 
Follow-up.
Upon completion of Treatment 2, participants move into 
post-treatment follow-up.
Visit Number/Title
Treatment Cycle
1
2
3
4
5
6
7
8-15
Week
1
2
3
4
5
6
7
10
13
16
19
22-43
Scheduled Day(s)
1
8
15
1
8
15
1
1
1
1
1
1
Scheduling Window (Days, 
unless noted)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Tumor Tissue Sample 
Collection
Tissue Collection for Biomarker 
Analysis (tested centrally) 
Optional biopsy may be collected at recurrence if 
participant consents.
Neck Dissection (per site 
discretions) ±
biopsy/photography
-----If Clinically Indicated---
Allowed after completion of RT per local SoC.
Refer to Appendix 8 for country-specific requirements. 
08KM9X

PRODUCT:  MK-3475
39
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
2.3
Study Screening, Surgery and Post-surgery Treatment 2 Phases (Arm B/SoC)
Study Screening, Surgery and Post-surgery Treatment 2 Phases (Arm B/SoC)
Study Period
Screening
Treatment randomization
Presurgery
Surgery
Post-surgery Safety 
Follow-up
Treatment 2 
Notes
Participants that discontinue study treatment for 
reasons other than an event/disease progression 
will enter post-treatment study follow-up.
Participants who discontinue study treatment due 
to an event/disease progression will enter Safety 
and Survival Follow-up.  
At the end of RT ± cisplatin (Treatment 2), 
participants in Arm B will enter post-treatment 
study follow-up.
Upon completion of RT ± cisplatin in Treatment 2, 
participants will enter post-treatment follow-up
Visit Number/Title
SoC RT ± cisplatin adjuvant
Week
0-4
1
2
3
4
5
6
7
Scheduled Day (s)
-28 
to 
-1
1
1
8
15
1
8
15
1
Scheduling Window (Days, 
unless noted)
7-30 days 
post-
surgery
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Informed Consent
X
Documented informed consent must be obtained 
prior to performing any protocol-specified 
procedures. Results of a test performed prior to the 
participant providing documented informed
consent as part of routine clinical management are 
acceptable in lieu of a screening test, if performed 
within the specified time frame.
If the investigator plans to treat beyond the initial 
radiologic disease progression per RECIST 1.1, 
additional consent will be required prior to post-
progression treatment (see Section 9.1.1.1).
Informed Consent for Future 
Biomedical Research (FBR; 
optional)
X
Participant Identification Card
X
X
Distribute at screening and add the randomization 
number at the time of randomization.
Inclusion/Exclusion Criteria
X
Demographics, Disease 
Details and Complete Medical 
History (includes substance 
usage)
X
Substances: alcohol and tobacco.
08KM9X

PRODUCT:  MK-3475
40
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Study Screening, Surgery and Post-surgery Treatment 2 Phases (Arm B/SoC)
Study Period
Screening
Treatment randomization
Presurgery
Surgery
Post-surgery Safety 
Follow-up
Treatment 2 
Notes
Participants that discontinue study treatment for 
reasons other than an event/disease progression 
will enter post-treatment study follow-up.
Participants who discontinue study treatment due 
to an event/disease progression will enter Safety 
and Survival Follow-up.  
At the end of RT ± cisplatin (Treatment 2), 
participants in Arm B will enter post-treatment 
study follow-up.
Upon completion of RT ± cisplatin in Treatment 2, 
participants will enter post-treatment follow-up
Visit Number/Title
SoC RT ± cisplatin adjuvant
Week
0-4
1
2
3
4
5
6
7
Scheduled Day (s)
-28 
to 
-1
1
1
8
15
1
8
15
1
Scheduling Window (Days, 
unless noted)
7-30 days 
post-
surgery
±3
±3
±3
±3
±3
±3
±3
Prior/Concomitant 
Medication Review 
X
X
X
X
X
X
X
X
X
X
Prior medications – Record all medications taken 
within 28 days of randomization.  
Concomitant medications – Enter new medications 
started during the study through the postadjuvant 
Safety Follow-up visit.
Treatment Randomization via 
IVRS 
X
Participants move straight to SoC surgery 
following randomization.
Radiotherapy (IMRT/IGRT)
X
X
X
X
X
X
(X*)
2 Gy/day in 30 fractions for a total of 60 Gy
*Participants considered high-risk: 2 Gy/day in 33 
fractions for a total of 66 Gy.  Participants with 
residual gross tumor: 2 Gy/day in 35 fractions for 
total of 70 Gy.
Conditional Cisplatin 
Treatment (100 mg/m2)
X
X
X
Cisplatin will only be administered to participants 
considered to be high-risk by local pathologist (see 
Section 9.1.10.2.5 Pathology Specimens for 
definition), and to participants who do not undergo 
surgical resection, or have incomplete resection (ie, 
gross disease left behind).  Cisplatin may be 
administered up to 1 week following completion of 
RT.
To be administered after all 
procedures/assessments have been completed.  
Permitted dose modifications are detailed in 
Section 7.2.3.
08KM9X

PRODUCT:  MK-3475
41
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Study Screening, Surgery and Post-surgery Treatment 2 Phases (Arm B/SoC)
Study Period
Screening
Treatment randomization
Presurgery
Surgery
Post-surgery Safety 
Follow-up
Treatment 2 
Notes
Participants that discontinue study treatment for 
reasons other than an event/disease progression 
will enter post-treatment study follow-up.
Participants who discontinue study treatment due 
to an event/disease progression will enter Safety 
and Survival Follow-up.  
At the end of RT ± cisplatin (Treatment 2), 
participants in Arm B will enter post-treatment 
study follow-up.
Upon completion of RT ± cisplatin in Treatment 2, 
participants will enter post-treatment follow-up
Visit Number/Title
SoC RT ± cisplatin adjuvant
Week
0-4
1
2
3
4
5
6
7
Scheduled Day (s)
-28 
to 
-1
1
1
8
15
1
8
15
1
Scheduling Window (Days, 
unless noted)
7-30 days 
post-
surgery
±3
±3
±3
±3
±3
±3
±3
Surgery
X
Performed as part of planned SoC.
Participants who do not undergo surgery as 
originally planned, for reasons other than centrally 
verified radiographic disease progression, may 
proceed to Treatment 2 and receive salvage RT 
plus cisplatin.
Efficacy Procedures
CT/MRI head and neck, 
chest, upper abdomen
X
X*
(X) 
optional at 
site 
discretion
If the participant had received CT/MRI scan prior 
to providing documented informed consent and 
within 28 days prior to randomization, the 
assessment can be accepted. For each participant,
the same modality should be used throughout the 
study for response evaluation.  The upper 
abdominal CT/MRI should cover the liver in its 
entirety.  *The screening scans will serve as 
presurgery scans except if the baseline scans are 
done >14 days prior to the date of surgery, then 
repeat imaging prior to surgery is required.
FDG-PET or FDG-PET/CT
X
If the participant had received FDG-PET or FDG-
PET/CT scan prior to providing documented 
informed consent and within 28 days prior to 
randomization, the assessment can be accepted.
Tissue Collection for 
Histopathology (mPR and 
pCR assessment) 
X
Assessment of surgical margins / gross lesions will 
be performed by the local pathologist.
08KM9X

PRODUCT:  MK-3475
42
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Study Screening, Surgery and Post-surgery Treatment 2 Phases (Arm B/SoC)
Study Period
Screening
Treatment randomization
Presurgery
Surgery
Post-surgery Safety 
Follow-up
Treatment 2 
Notes
Participants that discontinue study treatment for 
reasons other than an event/disease progression 
will enter post-treatment study follow-up.
Participants who discontinue study treatment due 
to an event/disease progression will enter Safety 
and Survival Follow-up.  
At the end of RT ± cisplatin (Treatment 2), 
participants in Arm B will enter post-treatment 
study follow-up.
Upon completion of RT ± cisplatin in Treatment 2, 
participants will enter post-treatment follow-up
Visit Number/Title
SoC RT ± cisplatin adjuvant
Week
0-4
1
2
3
4
5
6
7
Scheduled Day (s)
-28 
to 
-1
1
1
8
15
1
8
15
1
Scheduling Window (Days, 
unless noted)
7-30 days 
post-
surgery
±3
±3
±3
±3
±3
±3
±3
Patient Reported Outcomes
EQ-5D-5L
X
X*
X*
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.
* To be completed in conjunction with RT ± 
cisplatin treatment prior to treatment administration 
ePRO assessments should be performed on day RT 
begins and then repeated during RT treatment on 
Day 29 ± 3 days. 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: EQ-5D-5L, EORTC QLQ-C30, EORTC 
QLQ-H&N35.
EORTC QLQ-C30
X
X*
X*
EORTC QLQ-H&N35 
X
X*
X*
Safety Procedures
Full physical examination 
including neurological exam
and Height*
X
X
To be performed by the investigator or qualified 
designee.  Documented routine neurological exams 
performed within 6 weeks of randomization are 
acceptable and do not need to be repeated in 
Screening.
*Height will be measured at Screening only.
08KM9X

PRODUCT:  MK-3475
43
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Study Screening, Surgery and Post-surgery Treatment 2 Phases (Arm B/SoC)
Study Period
Screening
Treatment randomization
Presurgery
Surgery
Post-surgery Safety 
Follow-up
Treatment 2 
Notes
Participants that discontinue study treatment for 
reasons other than an event/disease progression 
will enter post-treatment study follow-up.
Participants who discontinue study treatment due 
to an event/disease progression will enter Safety 
and Survival Follow-up.  
At the end of RT ± cisplatin (Treatment 2), 
participants in Arm B will enter post-treatment 
study follow-up.
Upon completion of RT ± cisplatin in Treatment 2, 
participants will enter post-treatment follow-up
Visit Number/Title
SoC RT ± cisplatin adjuvant
Week
0-4
1
2
3
4
5
6
7
Scheduled Day (s)
-28 
to 
-1
1
1
8
15
1
8
15
1
Scheduling Window (Days, 
unless noted)
7-30 days 
post-
surgery
±3
±3
±3
±3
±3
±3
±3
Directed physical 
examination
X
X
X
X
X
X
X
X
To be performed by the investigator or qualified 
designee.  For participants receiving cisplatin: 
directed physical examination to include 
neurological exam before each dose of cisplatin.
ECOG Performance Status 
X
X
X
X
X
X
X
X
X
X
Screening (within 10 days prior to the start of study 
randomization).  Investigator or designee to 
confirm no deterioration prior to surgery.  ECOG 
performance status must be 0 or 1 presurgery.
To be assessed prior to dosing. 
Weight and Vital Signs 
X
X
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 (WOCBP 
only) – as per local SOP
X
(x)
X
(x)
(x)
The protocol requires pregnancy testing at 
Screening, within 24 hours (urine) or within 
72 hours (serum) before randomization, and within 
24 hours of the first dose of adjuvant treatment.
(x) = a pregnancy test must be performed every 
month during study treatment. More frequent 
pregnancy testing may be performed if required by 
local regulations or if determined necessary by the 
investigator (refer to Appendix 8 for UK-, 
Germany-, and France-specific requirements).
08KM9X

PRODUCT:  MK-3475
44
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Study Screening, Surgery and Post-surgery Treatment 2 Phases (Arm B/SoC)
Study Period
Screening
Treatment randomization
Presurgery
Surgery
Post-surgery Safety 
Follow-up
Treatment 2 
Notes
Participants that discontinue study treatment for 
reasons other than an event/disease progression 
will enter post-treatment study follow-up.
Participants who discontinue study treatment due 
to an event/disease progression will enter Safety 
and Survival Follow-up.  
At the end of RT ± cisplatin (Treatment 2), 
participants in Arm B will enter post-treatment 
study follow-up.
Upon completion of RT ± cisplatin in Treatment 2, 
participants will enter post-treatment follow-up
Visit Number/Title
SoC RT ± cisplatin adjuvant
Week
0-4
1
2
3
4
5
6
7
Scheduled Day (s)
-28 
to 
-1
1
1
8
15
1
8
15
1
Scheduling Window (Days, 
unless noted)
7-30 days 
post-
surgery
±3
±3
±3
±3
±3
±3
±3
HIV, hepatitis B and C screen 
(testing optional per site SOP)
X
HIV, hepatitis B and C testing are required when
mandated by local health authority. Refer to 
Appendix 8 for Germany-specific requirements for 
HIV, Hepatitis B and C testing.
Hematology 
X
X*
X
X
X
X
X
X
X
X
After Day 1, lab samples can be collected up to 
3 days prior to the scheduled time point.
During adjuvant treatment, labs are to be taken as 
per SoC for participants who receive RT alone and 
weekly if cisplatin is administered.  Labs can be 
taken up to 3 days prior to cisplatin administration 
and CrCl level assessment is to be repeated within 
3 days prior to start of each cisplatin administration
for management of dose reduction renal toxicity 
guidelines.  If these labs are within normal range, 
these labs do not need to be repeated within 
24 hours of cisplatin administration.  Any 
abnormal labs should be repeated and assessed 
within 24 hours of cisplatin administration.
*Labs at presurgery visit do not need to be repeated 
if presurgery visit occurs within 3 days of 
randomization.
Chemistry 
X
X*
X
X
X
X
X
X
X
X
Urinalysis
X
--If 
Clinically 
Indicated--
X
X
--If Clinically Indicated--
After Day 1 samples can be collected up to 3 days
prior to the scheduled time point.
08KM9X

PRODUCT:  MK-3475
45
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Study Screening, Surgery and Post-surgery Treatment 2 Phases (Arm B/SoC)
Study Period
Screening
Treatment randomization
Presurgery
Surgery
Post-surgery Safety 
Follow-up
Treatment 2 
Notes
Participants that discontinue study treatment for 
reasons other than an event/disease progression 
will enter post-treatment study follow-up.
Participants who discontinue study treatment due 
to an event/disease progression will enter Safety 
and Survival Follow-up.  
At the end of RT ± cisplatin (Treatment 2), 
participants in Arm B will enter post-treatment 
study follow-up.
Upon completion of RT ± cisplatin in Treatment 2, 
participants will enter post-treatment follow-up
Visit Number/Title
SoC RT ± cisplatin adjuvant
Week
0-4
1
2
3
4
5
6
7
Scheduled Day (s)
-28 
to 
-1
1
1
8
15
1
8
15
1
Scheduling Window (Days, 
unless noted)
7-30 days 
post-
surgery
±3
±3
±3
±3
±3
±3
±3
Coagulation tests (PT/INR 
and aPTT/PTT)
X
----If Clinically Indicated-----
Any participant receiving anticoagulant therapy 
should have coagulation tests monitored closely 
throughout the study. PTT may be performed if the 
local lab is unable to perform aPTT.
Thyroid Function (TSH)
X
X*
X
In case of elevated TSH, to add Free T3 and Free 
T4. Free T4 should be performed on all participants 
with elevated TSH; Free T3 only needs to be 
performed if it is done as a part of local standard of 
care. If the Free T3 and Free T4 are not available 
locally, they can be sent to the central laboratory to 
be performed (see Laboratory Manual for details).
*Laboratory tests at presurgery visit do not need to 
be repeated if presurgery visit occurs within 3 days 
of randomization.
AE/SAE review
X
-------Continuous Reporting-------
Oral and dental check-up 
X
---Recommended Every 6 months---
Frequency as per SoC/local guidelines.
Audiometric Testing 
X
----If Clinically Indicated----
Follow cisplatin label for ototoxicity management. 
Documented routine exams performed within 
6 weeks of randomization are acceptable and do 
not need to be repeated in Screening.
Fiber optic examination of 
primary tumor site
X
----If Clinically Indicated----
Documented routine exams performed within 
6 weeks of randomization are acceptable and do 
not need to be repeated in Screening.
08KM9X

PRODUCT:  MK-3475
46
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Study Screening, Surgery and Post-surgery Treatment 2 Phases (Arm B/SoC)
Study Period
Screening
Treatment randomization
Presurgery
Surgery
Post-surgery Safety 
Follow-up
Treatment 2 
Notes
Participants that discontinue study treatment for 
reasons other than an event/disease progression 
will enter post-treatment study follow-up.
Participants who discontinue study treatment due 
to an event/disease progression will enter Safety 
and Survival Follow-up.  
At the end of RT ± cisplatin (Treatment 2), 
participants in Arm B will enter post-treatment 
study follow-up.
Upon completion of RT ± cisplatin in Treatment 2, 
participants will enter post-treatment follow-up
Visit Number/Title
SoC RT ± cisplatin adjuvant
Week
0-4
1
2
3
4
5
6
7
Scheduled Day (s)
-28 
to 
-1
1
1
8
15
1
8
15
1
Scheduling Window (Days, 
unless noted)
7-30 days 
post-
surgery
±3
±3
±3
±3
±3
±3
±3
Future Biomedical 
Research/Biomarkers
Blood for Genetic Analysis a
X
Blood for RNA Analysis 
X
X
For all participants, to be completed in conjunction 
with RT ± cisplatin treatment prior to treatment 
administration. 
Whole blood samples should be collected pre-dose.
Leftover specimens will be stored for FBR if the 
participant consents to FBR.
* ctDNA sample should be collected at the end of 
RT.
Blood for Plasma Biomarker 
Analyses 
X
X
Blood for Serum Biomarker 
Analyses 
X
X
Blood for ctDNA 
X
X
X*
X*
Tumor Tissue Sample 
Collection
Histology, including PD-L1 
and p16 biomarker analysis 
on all participants prior to 
randomization for 
stratification, p16 evaluations 
b
X
Tumor tissue from core or excisional biopsy (FNA 
not adequate) from all participants. Results of 
PD-L1 testing are required for stratification; p16 
testing required only for participants with 
oropharyngeal cancer. PD-L1 tested centrally and 
p16 biomarker analysis tested locally/centrally. 
Tissue Collection for 
Biomarker Analysis b
X
X*
Core or excisional biopsy (FNA not adequate). 
*For participants who do not achieve a pCR, a 
tumor tissue sample is to be collected and 
submitted to the designated central laboratory for 
translational research.
08KM9X

PRODUCT:  MK-3475
47
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Study Screening, Surgery and Post-surgery Treatment 2 Phases (Arm B/SoC)
Study Period
Screening
Treatment randomization
Presurgery
Surgery
Post-surgery Safety 
Follow-up
Treatment 2 
Notes
Participants that discontinue study treatment for 
reasons other than an event/disease progression 
will enter post-treatment study follow-up.
Participants who discontinue study treatment due 
to an event/disease progression will enter Safety 
and Survival Follow-up.  
At the end of RT ± cisplatin (Treatment 2), 
participants in Arm B will enter post-treatment 
study follow-up.
Upon completion of RT ± cisplatin in Treatment 2, 
participants will enter post-treatment follow-up
Visit Number/Title
SoC RT ± cisplatin adjuvant
Week
0-4
1
2
3
4
5
6
7
Scheduled Day (s)
-28 
to 
-1
1
1
8
15
1
8
15
1
Scheduling Window (Days, 
unless noted)
7-30 days 
post-
surgery
±3
±3
±3
±3
±3
±3
±3
Neck Dissection (per site 
discretions) ±
biopsy/photography
--------------If Clinically Indicated------
Allowed after completion of RT per local SoC.
Refer to Appendix 8 for country-specific requirements. 
a
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected 
at the site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. 
If the sample is collected, leftover extracted DNA will be stored for Future Biomedical Research (FBR) if the participant (or their legally acceptable 
representative) provides documented informed consent for FBR. If the planned genetic analysis is not approved, but FBR is approved and consent is given, 
this sample will be collected for the purpose of FBR.
b
Baseline tumor tissue from a core or excisional biopsy (FNA not adequate) from participants with oropharyngeal cancer must be tested locally for HPV 
status (if HPV status not known) prior to randomization. If local p16 testing results are not available, or cannot be assessed locally by the specified method, 
a tumor tissue sample must be submitted for p16 testing at the designated central laboratory. For all participants, baseline tumor tissue must also be provided 
to the central vendor for PD-L1 biomarker testing (results required prior to randomization) and translational research. Refer to Section 9.2.2 for additional 
information about tissue requirements. Detailed instructions for tissue collection, process and shipment are provided in the Vendor Manual.  If the 
participant provides documented informed consent for FBR, any leftover tissue that would ordinarily be discarded at the end of the main study will be 
retained for FBR. Newly obtained biopsies are permitted.
08KM9X

PRODUCT:  MK-3475
48
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
2.4
End of Treatment and Follow-up Visits (Arms A and B)
End of Treatment and Follow-up Visits (Arms A and B)
Study Period
End of 
Treatment
Post-Treatment Follow-upa
Notes
Visit Number/Title
Discontinuation
Safety FU
Post-Treatment FU
Survival 
FU
Treatment Cycle/Day
Up to end 
of Year 3
Years 4-5
Scheduling Window (Days (unless 
noted)
At time of 
Treatment 
Discontinuation
30 days 
from last 
dose 
+14 days
Every 
3 months 
from last 
scan
±7 days
Q6M 
±14 days
Q12M 
±14 days
Every
3 months
±14 days
Administrative Procedures
Prior/Concomitant Medication Review 
X
X
----If Clinically Indicated---
Post-study Anticancer Therapy Status
X
By telephone contact in Survival FU.
In addition, upon Sponsor request, participants may 
be contacted for survival status at any time during 
the course of the study.
Participants who do not/will not have a scheduled 
study visit during the Sponsor-defined time period 
will be contacted by telephone for their survival 
status (excluding participants that have had a death 
event previously recorded). After 5 years, 
participants will be followed by telephone to monitor 
survival and anticancer treatment status every 
6 months (±1 month) for overall survival and/or 
other anticancer treatment until consent withdrawal
from study, becoming lost to follow-up, death or end 
of the study, whichever is earlier.
Survival status
X
08KM9X

PRODUCT:  MK-3475
49
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
End of Treatment and Follow-up Visits (Arms A and B)
Study Period
End of 
Treatment
Post-Treatment Follow-upa
Notes
Visit Number/Title
Discontinuation
Safety FU
Post-Treatment FU
Survival 
FU
Treatment Cycle/Day
Up to end 
of Year 3
Years 4-5
Scheduling Window (Days (unless 
noted)
At time of 
Treatment 
Discontinuation
30 days 
from last 
dose 
+14 days
Every 
3 months 
from last 
scan
±7 days
Q6M 
±14 days
Q12M 
±14 days
Every
3 months
±14 days
Efficacy Procedures
CT/MRI head and neck, chest, upper 
abdomen
X
X
*[X]
For all imaging, the clock will start at the end of RT 
± cisplatin.  Imaging to be performed 12 weeks 
(± 7 days) after end of RT ± cisplatin treatment and 
then every 3 months (91 ± 7 days) until the end of 
Year 3; then every 6 months (182 ± 14 days)
thereafter up to the end of Year 5.  Imaging timing 
should follow calendar days and should not be 
recalculated based on the date of previous scans.  
The upper abdominal CT/MRI should cover the liver 
in its entirety.
Continuation of imaging/biopsies is strongly 
recommended for participants who have not yet 
experienced an event/progression and have started a 
new anticancer treatment. 
*Additionally, imaging assessment/biopsies 
performed as part of SOC to evaluate disease status 
for participants in survival follow-up who have not 
yet experienced an event/progression should be 
collected during survival follow-up. All available 
images should be submitted to the central imaging 
vendor and recorded in the applicable eCRF.
08KM9X

PRODUCT:  MK-3475
50
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
End of Treatment and Follow-up Visits (Arms A and B)
Study Period
End of 
Treatment
Post-Treatment Follow-upa
Notes
Visit Number/Title
Discontinuation
Safety FU
Post-Treatment FU
Survival 
FU
Treatment Cycle/Day
Up to end 
of Year 3
Years 4-5
Scheduling Window (Days (unless 
noted)
At time of 
Treatment 
Discontinuation
30 days 
from last 
dose 
+14 days
Every 
3 months 
from last 
scan
±7 days
Q6M 
±14 days
Q12M 
±14 days
Every
3 months
±14 days
EQ-5D-5L
X
X
X
X
To be administered 12 weeks after end of RT ± 
cisplatin treatment and then every 3 months 
(91 ± 7 days) until end of Year 3; then every 
12 months (365 ± 14 days) thereafter up to the 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: 
EQ-5D-5L, EORTC QLQ-C30, EORTC 
QLQ-H&N35.
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.
EORTC QLQ-C30
X
X
X
X
EORTC QLQ-H&N35
X
X
X
X
Safety Procedures
Full physical examination
X
To be performed by the investigator or qualified 
designee.  
To include neurological exam if clinically indicated
Directed physical examination
X
X
X
ECOG Performance Status
X
X
X
X
Weight and Vital Signs 
X
----If Clinically Indicated------
To include: temperature, heart rate, respiratory rate, 
blood pressure.
08KM9X

PRODUCT:  MK-3475
51
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
End of Treatment and Follow-up Visits (Arms A and B)
Study Period
End of 
Treatment
Post-Treatment Follow-upa
Notes
Visit Number/Title
Discontinuation
Safety FU
Post-Treatment FU
Survival 
FU
Treatment Cycle/Day
Up to end 
of Year 3
Years 4-5
Scheduling Window (Days (unless 
noted)
At time of 
Treatment 
Discontinuation
30 days 
from last 
dose 
+14 days
Every 
3 months 
from last 
scan
±7 days
Q6M 
±14 days
Q12M 
±14 days
Every
3 months
±14 days
Urine or Serum β-hCG Pregnancy Test 
(WOCBP only) – as per local SOP
X*
X
*A pregnancy test is required at end of treatment for 
participants completing study treatment and 
participants who discontinue study treatment early. 
Monthly pregnancy testing should continue in 
post-treatment until 120 days after last dose of 
pembrolizumab and 180 days after last dose of 
cisplatin and/or radiotherapy. More frequent 
pregnancy testing may be performed if required by 
local regulations or if determined necessary by the 
investigator (refer to Appendix 8 for UK-, Germany-
and France-specific requirements).
Hematology, Chemistry, Urinalysis 
X
X
--If Clinically 
Indicated--
Unresolved abnormal lab results associated with 
drug-related AEs should be followed until resolution.
Coagulation tests (PT/INR and 
aPTT/PTT)
------If Clinically Indicated------
Thyroid Function (TSH) 
X
X
---If Clinically 
Indicated---
TSH; in case of elevated TSH to add Free T3 and 
Free T4. Free T4 should be performed on all 
participants with elevated TSH; Free T3 only needs 
to be performed if it is done as a part of local 
standard of care. If the Free T3 and Free T4 are not 
available locally, they can be sent to the central 
laboratory to be performed (see Laboratory Manual 
for details).
08KM9X

PRODUCT:  MK-3475
52
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
End of Treatment and Follow-up Visits (Arms A and B)
Study Period
End of 
Treatment
Post-Treatment Follow-upa
Notes
Visit Number/Title
Discontinuation
Safety FU
Post-Treatment FU
Survival 
FU
Treatment Cycle/Day
Up to end 
of Year 3
Years 4-5
Scheduling Window (Days (unless 
noted)
At time of 
Treatment 
Discontinuation
30 days 
from last 
dose 
+14 days
Every 
3 months 
from last 
scan
±7 days
Q6M 
±14 days
Q12M 
±14 days
Every
3 months
±14 days
AE/SAE review
----------------Continuous Reporting-------------
All AEs occurring up until 30 days following end of 
study treatment and SAEs occurring up until 90 days 
following end of treatment or 30 days if the 
participant initiates new anticancer therapy, 
whichever is earlier should be reported. Treatment-
related late toxicity may be collected for up to 
5 years.
Oral and dental check-up
----
Recommended 
every 6 months---
Frequency as per SoC/local guidelines.
Audiometric Testing 
------If Clinically Indicated------
Fiber optic examination of primary 
tumor site
------Every 12 months----
or as per site discretion
Future Biomedical 
Research/Biomarkers
Blood for RNA Analysis 
X
Blood for Plasma Biomarker Analyses 
X
Blood for Serum Biomarker Analyses 
X
Blood for ctDNA 
X
X*
X*
*For ctDNA collections after end RT, the clock will 
start at the end of RT ± cisplatin.  ctDNA to be 
collected 12 weeks (± 7 days) after end of 
RT ± cisplatin treatment and then every 3 months
(91 ± 7 days) until end of Year 3; then every 
6 months (182 ± 14 days) thereafter up to the end of 
Year 5.  
Tumor Tissue Sample Collection
Tissue Collection for Biomarker 
Analysis (tested centrally)
Optional biopsy may be collected at recurrence if 
participant consents.
08KM9X

PRODUCT:  MK-3475
53
PROTOCOL/AMENDMENT NO.: 689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Refer to Appendix 8 for country-specific requirements. 
a
In participants who discontinue study therapy without an event/disease progression, every effort should be made to continue monitoring their disease status 
by radiologic imaging every 3 months (91 ± 7 days) until end of Year 3 (measured from the date of randomization); thereafter every 6 months (182 ± 14 
days) until end of Year 5, until (1) an event/disease progression, (2) pregnancy, (3) withdrawal of consent, (4) death, or (5) the end of the study, whichever 
occurs first.
A participant may discontinue from study treatment for reasons other than disease recurrence/progression or start of a new anticancer therapy but will remain 
in the study for post-treatment follow-up for disease progression as outlined in Section 8, as long as the participant does not withdraw consent for post-
treatment follow-up for disease progression.
Participants who discontinue study treatment due to an event/disease progression will enter Survival Follow-up.
08KM9X

PRODUCT:  MK-3475 
54
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
3
INTRODUCTION
Pembrolizumab as neoadjuvant therapy and in combinations with standard of care (SoC) 
radiotherapy (RT) with/without cisplatin as adjuvant therapy is being investigated for 
participants with newly diagnosed Stage III/IVA, resectable, locoregionally advanced head 
and neck squamous cell cancers (LA HNSCC).  Its efficacy and safety are being evaluated 
against SoC treatment in this randomized, open-label, Phase III study.
Pembrolizumab (trade name Keytruda®) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4) / kappa isotype designed to 
directly block the interaction between Programmed Cell Death 1 (PD-1) receptor and its 
ligands, Programmed Death Ligand 1 (PD-L1) and Programmed Death Ligand 2 (PD-L2).  
This blockade enhances functional activity of the target lymphocytes to facilitate tumor 
regression and ultimately immune rejection.
Pembrolizumab is currently in clinical development for a number of advanced malignancies.  
For more detail on specific indications, please refer to the Pembrolizumab Investigator’s
Brochure.
3.1
Study Rationale 
Pembrolizumab has demonstrated durable clinical activity in participants with 
recurrent/metastatic HNSCC and was granted accelerated approval for participants with 
recurrent/metastatic HNSCC with disease progression on or after platinum-containing 
chemotherapy by Food and Drug Administration (FDA) on 05-Aug-2016.  In addition, 
preliminary data from 21 participants in a Phase II Merck Investigator Studies Program 
(MISP) study, presented at the American Society of Clinical Oncology (ASCO) Annual 
Meeting 2017, evaluating preoperative pembrolizumab prior to resection in resectable LA
HNSCC at high risk for recurrence (eg, T4 or Stage IVB) demonstrated treatment effect in 
the pathological samples in 43% of participants, and clinical-to-pathologic downstaging at 
the time of surgery in 48% of participants (NCT02296684).  Thirty-eight percent of patients 
had high risk pathologic features compared to an expected rate of 80%.  At the time of 
presentation, no unexpected surgical delays or complications had been observed.  
Considering the potential activity of pembrolizumab with durable responses and tumor 
downstaging further investigation of neoadjuvant and adjuvant combinations in a larger study 
to compare efficacy and safety against SoC is warranted. The objective of this study is to 
evaluate whether pembrolizumab as neoadjuvant therapy can increase pathological response 
in the surgical specimen and as adjuvant therapy can increase locoregional control in 
combination with SoC RT ± cisplatin in a high-risk population with newly diagnosed 
resectable LA HNSCC. 
3.2
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.  
08KM9X

PRODUCT:  MK-3475 
55
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an intravenous (IV) immunotherapy for advanced malignancies.  Keytruda®
(pembrolizumab) is indicated for the treatment of patients across a number of indications 
because of its mechanism of action to bind the PD-1 receptor on the T-cell.  For more details
on specific indications refer to the Investigator’s brochure.
3.2.1
Pharmaceutical and Therapeutic Background
Head and neck squamous cell carcinoma is the seventh most common cancer worldwide with 
around 600,000 new cases diagnosed per year [Siegel, R., et al 2013].  The most frequent 
tumor sites of HNSCC are the larynx, the pharynx, and the oral cavity.
Alcohol and tobacco consumption are the main risk factors for oral cavity, larynx, 
oropharynx, and hypopharynx cancers and account for 75% of HNSCC.  In addition, the 
oncogenic human papillomavirus (HPV) infection, mainly HPV-16, is an established cause 
of oropharyngeal cancer (tonsils and base of tongue) [Ang, K. K., et al 2010] [Gillison, M. L. 
2004].  Globally, the incidence of HPV-induced oropharyngeal cancer increases, but varies 
from less than 10% to 70% of all oropharyngeal cancers depending on the geographic area, 
being more frequent in industrialized countries.  The etiologic role of HPV in other HNSCC 
sites than oropharynx is unclear.
Treatment choice depends on the location of the primary tumor, stage of the disease, and 
expected oncological and functional outcomes.  Union for International Cancer 
Control/American Joint Committee on Cancer (UICC/AJCC) early stage (I/II) HNSCC is 
usually treated with single modality therapy, ie, surgery or RT.  The management of locally 
advanced disease (UICC/AJCC Stage III/IV) generally requires various combinations of RT, 
surgery, and chemotherapy or cetuximab.  The survival rates for all participants with HNSCC 
are around 70% at 1 year and 40-60% at 5 years. 
Factors that affect clinical outcome of patients with LA HNSCC include performance status, 
tumor stage at diagnosis, and HPV status.  Expression of p16 is highly correlated to infection 
with HPV in oropharyngeal cancer [Lassen, P., et al 2009] [Weinberger, P. M., et al 2006]
and the strong prognostic impact of p16-immunohistochemistry for oropharyngeal cancer has 
been demonstrated in several clinical studies [Ang, K. K., et al 2010] [Lassen, P., et al 2009] 
[Lassen, P., et al 2011] [Lassen, P., et al 2010].  The prevalence of HPV positivity varies by 
stage of disease, with frequencies in HPV endemic areas reported at 50%-59% in local 
disease (or Stages I/II), 75%-78% in regional disease (or Stages III-IVB), and 67% in distant 
metastatic disease [OSullivan, B., et al 2016] [Steinau, M., et al 2014].  
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 correlates with improved prognosis and 
long-term survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; 
hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating 
lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor 
08KM9X

PRODUCT:  MK-3475 
56
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
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 
immunoglobulin (Ig) superfamily member related to CD28 and cytotoxic 
T-lymphocyte-associated protein 4 (CTLA-4) which has been shown to negatively regulate 
antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004].  PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type domain 
responsible for ligand binding and a cytoplasmic tail responsible for binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif.  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases Src 
homology region 2 domain-containing phosphatase (SHP)-1 and SHP-2 to the 
immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 
T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 2004] [Sheppard, K-
A, et al 2004] [Riley, J. L. 2009].  The mechanism by which PD-1 down-modulates T-cell 
responses is similar to, but distinct from, that of CTLA-4, because both molecules regulate an 
overlapping set of signaling proteins [Parry, R. V., et al 2005] [Francisco, L. M., et al 2010].  
As a consequence, the PD 1/PD-L1 pathway is an attractive target for therapeutic 
intervention in LA HNSCC.
Keytruda® is currently approved in the United States (US) and in several global locations for 
the treatment of recurrent or metastatic HNSCC with disease progression on or after 
platinum-containing chemotherapy.  
3.2.2
Pre-clinical and Clinical Studies
Details of preclinical and clinical studies are provided in the Investigator’s Brochure.
Clinical studies with pembrolizumab have demonstrated efficacy in participants with 
advanced melanoma, non-small cell lung cancer, head and neck cancer (HNC), bladder 
cancer, Hodgkin’s lymphoma, and microsatellite instability (MSI) high cancers.
3.2.3
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 Investigator’s Brochure.
08KM9X

PRODUCT:  MK-3475 
57
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
The clinical program for HNSCC consists of the completed and ongoing studies for 
recurrent/metastatic disease (KN012, KN055, KN040, KN048, and KN412), as well as this 
study, KN689.
Analyses from studies KN012, KN055, KN040 and KN048 demonstrate clinical activity in 
participants with recurrent/metastatic disease.  In addition, the overall number, type, and 
frequency of adverse events (AEs) and serious adverse events (SAEs) reported in these 
studies are representative of patients with HNSCC and are not indicative of any new safety 
concerns for this program.  
KEYNOTE-012 (KN012) 
KN012 is a Phase IB, multi-cohort study evaluating the single-agent activity of 
pembrolizumab in various solid tumors, including 2 cohorts of participants (Cohorts B and 
B2) with recurrent/metastatic HNSCC. Cohort B consisted of 60 participants with PD-L1 
positive HNSCC who received pembrolizumab 10 mg/kg every 2 weeks (Q2W).  Cohort B2 
consisted of 132 participants regardless of PD-L1 status, who received pembrolizumab 
200 mg every 3 weeks (Q3W).  Responses were seen in both HPV-positive and HPV-
negative participants. This was the first immunotherapy demonstrating clinically meaningful 
antitumor activity in a heavily pretreated incurable HNSCC population with 
recurrent/metastatic disease. Enrollment is closed, but participants are ongoing in the study.
The efficacy and safety results after long term follow-up based on pooled data from Cohorts 
B and B2 were presented at ASCO 2016 [Mehra, R., et al 2016].  In the recurrent/metastatic
HNSCC population (n=192), the objective response rate (ORR) was 21.9% (95% confidence 
interval [CI]; 12.5%, 34.0%) in HPV-positive participants and 15.9% (95% CI: 10.0%, 
23.4%) in HPV-negative participants.  In a separate publication, when PD-L1 expression 
analyses were restricted to only tumor cells (tumor proportion scoring, TPS), there was no 
statistically significant increase ORR with PD-L1 positive (≥1) versus (vs.) negative (<1) 
tumors.  Conversely, when immune cells were included in the scoring system (CPS), PD-L1 
expression on tumor and immune cells significantly correlated with ORR, progression free 
survival (PFS), and overall survival (OS) [Chow, L. Q., et al 2016].  The ORR with 
pembrolizumab is greater than that of existing standard single-agent cytotoxic 
chemotherapies such as methotrexate, which in the setting of second-line recurrent/metastatic
disease has an ORR of approximately 4%. Median OS was 8.5 months (95% CI: 6.5, 10.5), 
compared to the historical OS rate of 6 months for participants who progress following first-
line treatment.  The 6-month PFS rate was 24.9%.
Importantly, the responses seen with pembrolizumab were durable. Among participants with 
recurrent/metastatic HNSCC, the median duration of response (DOR) ranged from 1.8+ to 
21.8+ months, and the median was not reached. Among participants who progressed, 85% 
were in response for the at least 6 months, and 71% of responders had ongoing responses.  
Efficacy and safety of pembrolizumab based on additional long-term follow-up in KN012 
was subsequently reported [Mehra, R., et al 2018]. Median follow-up was 9 months (range 
0.2-32). No deaths due to treatment were observed. ORR was 18% (34/192; 95% CI, 13%-
24%). Eight patients (4%) experienced CR and 26 (14%) patients experienced PR. Eighty 
08KM9X

PRODUCT:  MK-3475 
58
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
five percent of responses lasted ≥ 6 months and OS at 12 months was 38%. The median time 
to response was 2 months (range 2 to 17 months). Median DOR was not reached (range 2+ to 
30+ months).
These results demonstrate the consistent durability of responses seen with pembrolizumab 
treatment and compare favorably to SoC chemotherapy or epidermal growth factor receptor
inhibitors, which have reported median DOR of 4 to 6 months. These results of KN012 
demonstrate consistent and clinically meaningful activity of pembrolizumab in heavily 
pretreated participants with HNSCC and demonstrate a robust and unprecedented antitumor 
activity observed compared to available current SoC chemotherapy agents.  The prolonged 
DOR seen in the majority of participants that respond to pembrolizumab is substantially 
distinct from what is expected with chemotherapy in previously treated patients with 
HNSCC.  
KEYNOTE-055 (KN055)
KN055 is a Phase II, nonrandomized, single cohort study of pembrolizumab (200 mg Q3W) 
monotherapy in a heavily pretreated population of patients with recurrent/metastatic HNSCC
who have progressed on prior platinum and cetuximab therapy. Results from 171 
participants treated with pembrolizumab were presented by Bauml et al [Bauml, J., et al 
2017].  When confirmed responses were evaluated, the ORR was 16% (complete response, 
n=1; partial response, n=27; 95% CI: 11%, 23%) with a median DOR of 8 months (range, 2+
to 12+ months); the stable disease rate was 19% (n=33; 95% CI: 14%, 26%).  Response rates 
were slightly higher in participants that were PD-L1 positive; 18% of participants with CPS 
≥1 PD-L1 expression responded to pembrolizumab compared with 12% of participants with
CPS <1 expression.  Nonetheless, PD-L1–negative participants responded to pembrolizumab 
at a rate that is clinically meaningful; 6- and 12-month PFS and OS rates were relatively 
similar between PD-L1–negative and PD-L1–positive participants. The results presented by 
Bauml et al confirm findings from KN012 in the recurrent/metastatic HNSCC population; 
pembrolizumab monotherapy demonstrates consistent and clinically meaningful activity of 
pembrolizumab 200 mg Q3W in heavily pretreated participants with HNSCC.
KEYNOTE-040 (KN040) 
KN040 is an ongoing Phase III, randomized, active-controlled, open-label study of 
pembrolizumab versus the choice of 3 different SoC therapies in participants with 
recurrent/metastatic HNSCC. Approximately 495 participants with recurrent/metastatic
HNSCC were stratified by Eastern Cooperative Oncology Group (ECOG) performance status
(0 vs. 1), HPV status (Oropharynx – p16 positive vs. Oropharynx – p16 negative or 
larynx/hypopharynx/oral cavity HNSCC), and PD-L1 status (strong positive or not; strong 
positive was defined as TPS ≥50% PD-L1 testing by IHC), before being randomized 1:1 to 
receive pembrolizumab 200 mg Q3W or the investigator’s choice of one of the following 
therapies, to be chosen prior to randomization: single agent methotrexate, single agent 
docetaxel, or single agent cetuximab, for up to 2 years.  The primary objective of the study is 
to evaluate OS in participants with recurrent/metastatic HNSCC treated with pembrolizumab 
compared to SoC treatment.  Enrollment is closed, but participants are receiving ongoing 
treatment in the study.  
08KM9X

PRODUCT:  MK-3475 
59
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
The efficacy and safety data from the final analysis were reported in The Lancet in 2019
[Cohen, E. E. W., et al 2019]. As of the data cut-off of the final analysis, 181 (73%) of 247 
patients in the pembrolizumab group and 207 (83%) of 248 patients in the SoC group had 
died. The median overall survival in the Intention-To-Treat population was 8.4 months (95% 
CI 6.4-9.4) with pembrolizumab and 6.9 months (5.9-8.0) with SOC (hazard ratio 0.8, 0.65-
0.98; nominal p=0.0161). The HR for all examined subgroups was similar. Fewer patients 
treated with pembrolizumab than with SOC had grade 3 or worse treatment-related adverse 
events (33 [13%] of 246 vs 85 [36%] of 234). 
For participants with a PD-L1 CPS of 1 or higher, the HR for death was 0.74 (95% CI 0.58-
0.93; nominal p=0.0049). Median survival was 8.7 months (95% CI 6.9-11.4) with 
pembrolizumab and 7.1 months (5.7-8.3) with standard of care. For participants with a 
PD-L1 CPS less than 1, the HR for death was 1.28 (95% CI 0.80-2.07; p=0.8476). Median 
overall survival was 6.3 months (3.9-8.9) in the pembrolizumab group and 7 months (5.1-9.0) 
in the standard-of-care group. 
In participants with a PD-L1 TPS of 50% or higher, the HR for death was 0.53 (95% CI 0.35-
0.81; nominal p=0.0014). Median overall survival was 11.6 months (95% CI 8.3-19.5) with 
pembrolizumab and 6.6 months (4.8-9.2) with standard of care. In participants with a PD-L1 
TPS of less than 50%, the HR was 0.93 (95% CI 0.73-1.17; p=0.2675) with pembrolizumab. 
Median overall survival was 6.5 months (95% CI 5.6-8.8) with pembrolizumab and 
7.1 months (95% CI 5.7-8.1) with standard of care. 
The median duration of response was 18.4 months in the pembrolizumab group compared 
with only 5 months in the SOC group. In summary, the responses to pembrolizumab for this 
patient population was durable, similar to the KN012 and KN055 studies. In addition, the 
benefit of pembrolizumab compared with SOC was greater in patients with PD-L1 
expression on their tumors or in the tumor microenvironment compared to those without PD-
L1 expression.  The safety profile was also better for pembrolizumab than compared to the 
SOC.
KEYNOTE-048 (KN048)
KN048 is an ongoing Phase III, randomized, active-controlled, open-label study of 
pembrolizumab, or pembrolizumab plus platinum plus 5-fluorouracil chemotherapies versus
platinum plus 5-fluorouracil plus cetuximab (EXTREME regimen) in participants with 
advanced HNC.  A total of 882 participants with first-line recurrent or metastatic HNSCC 
were randomized worldwide 1:1:1 between the 3 arms of the study to examine the efficacy 
and safety of pembrolizumab (n= 301 subjects), pembrolizumab plus chemotherapy (n= 281 
subjects) versus SoC with cetuximab and chemotherapy (n= 300 subjects).  Prior to 
randomization, participants were stratified by PD-L1 tumor expression (strongly positive 
TPS ≥50% vs. not strongly positive), HPV status for oropharyngeal cancer (positive vs.
negative), and ECOG performance status (0 vs. 1).  The primary endpoints of the study are 
PFS, per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 as assessed by blinded 
independent central review (BICR), and OS. Enrollment is closed, but participants are 
receiving ongoing treatment in the study.
08KM9X

PRODUCT:  MK-3475 
60
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
The data presented at European Society of Medical Oncology (ESMO) 2018 for KEYNOTE-
048, compared pembrolizumab monotherapy, and pembrolizumab + chemotherapy (platinum 
based chemotherapy plus fluorouracil) to the EXTREME regimen (platinum based 
chemotherapy plus fluorouracil and cetuximab) for first-line treatment of R/M HNSCC 
[Burtness, B., et al 2018]. Pembrolizumab monotherapy demonstrated a higher OS when 
compared to the EXTREME regimen in R/M HNSCC that expressed PD-L1. The data in 
participants with combined positive score (CPS ≥ 20) yielded OS that was significantly 
longer with pembrolizumab than the EXTREME regimen (HR 0.61, [95% CI 0.45-0.83];
p=0.0007; median 14.9 vs. 10.7 months). The results were similar in participants with a 
lower cut point of PD-L1 expression (CPS ≥ 1). For this population, HR 0.78 (95% CI 0.64-
0.96); p=0.0086 and the median OS was 12.3 vs. 10.3 months. In addition, OS for 
pembrolizumab was noninferior to the EXTREME regimen.
Confirmed ORR (pembrolizumab versus EXTREME) was 23% vs 36% for CPS ≥20, 19% vs 
35% for CPS ≥ 1, and 17% vs 36% for the total population. Median DOR (pembrolizumab 
versus EXTREME) was 20.9 vs 4.2 months for CPS ≥20, 20.9 versus 4.5 months for CPS ≥ 
1, and 20.9 vs 4.5 months for the total population. For the pembrolizumab arm Grade 3-5 
AE rates were 17% compared to 69% for the EXTREME arm. Pembrolizumab + 
chemotherapy significantly improved OS in this total population (HR 0.77 [95% CI 0.63-
0.93]; p=0.0034; median 13.0 vs 10.7 months,). The safety profiles for pembrolizumab + 
chemotherapy and the EXTREME regimen were comparable.
In summary, for first-line R/M HNSCC, pembrolizumab significantly improved OS over the 
EXTREME regimen in both the CPS ≥ 20 and CPS ≥ 1 populations and was also noninferior 
in the total population with a favorable toxicity profile. Pembrolizumab plus chemotherapy 
improved OS in the total population with a comparable safety profile. Responses to 
pembrolizumab were durable, and safety was comparable to EXTREME regimen. Therefore, 
pembrolizumab based treatment may be established as a new first-line standard of care for 
R/M HNSCC.
KEYNOTE-412 (KN412)
KN412 is an ongoing, Phase III, randomized, placebo-controlled, multi-site, triple-blind, two 
arm study to determine the efficacy and safety of pembrolizumab given concomitantly with 
chemoradiation (CRT) and as maintenance therapy, versus placebo plus CRT in participants
with LA HNSCC.  Participants will be stratified at randomization by tumor site/p16 status
(Oropharynx – p16 positive vs. Oropharynx – p16 negative vs. tumor site other than 
oropharynx), Stage III versus Stage IV, and RT regimen (accelerated fractionation vs. 
standard fractionation).  Approximately 780 participants will be randomly assigned 1:1 to 
receive either: CRT plus pembrolizumab 200 mg Q3W; or CRT plus placebo (Q3W).  
Chemotherapy will include cisplatin 100 mg/m2 IV on Days 8, 29, and 50 of RT.  A primary 
objective in this study is to compare event-free survival (EFS) per RECIST 1.1 as assessed 
by BICR between treatment arms.
08KM9X

PRODUCT:  MK-3475 
61
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
3.3
Benefit/Risk Assessment
Participants will receive SoC treatment or SoC treatment plus the addition of pembrolizumab
in this clinical study. 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.  However, 
surgery followed by RT ± cisplatin is SoC for participants with LA HNSCC.  
Pembrolizumab (Keytruda®) has been approved by the FDA for recurrent/metastatic HNSCC 
with disease progression on or after platinum-containing chemotherapy.  
This study will assess the safety and efficacy of pembrolizumab used as neoadjuvant 
treatment prior to surgical resection and as adjuvant treatment in combination with RT ±
cisplatin in participants with previously untreated resectable LA HNSCC. The benefit of 
pembrolizumab as neoadjuvant and 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 Investigator’s Brochure and informed 
consent documents.
4
OBJECTIVES/HYPOTHESES AND ENDPOINTS
All objectives and hypotheses apply to male/female adult participants (≥18 years of age) with 
resectable LA HNSCC.
Throughout this protocol, the term RECIST 1.1 refers to the modification of RECIST 1.1 to 
include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Refer 
to Section 5.4.1.1.3 for further details.
08KM9X

PRODUCT:  MK-3475 
62
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Objective/Hypothesis
Endpoint
Primary
•
Objective 1: To compare
pembrolizumab as neoadjuvant therapy 
and in combination with radiotherapy 
(RT) ± cisplatin as adjuvant therapy to 
only RT ± cisplatin as adjuvant therapy 
with respect to EFS per RECIST 1.1 as 
assessed by BICR in participants whose 
tumors express PD-L1 CPS≥10, CPS≥1,
and in all participants regardless of CPS 
status.
-
Hypothesis #1: Pembrolizumab as 
neoadjuvant therapy and in 
combination with RT ± cisplatin as 
adjuvant therapy after surgical 
resection is superior to SoC surgical 
resection followed by RT ± cisplatin 
adjuvant therapy with respect to EFS 
per RECIST 1.1 by BICR in 
participants whose tumors express
PD-L1 CPS≥10.
-
Hypothesis #2: Pembrolizumab as 
neoadjuvant therapy and in 
combination with RT ± cisplatin as 
adjuvant therapy after surgical 
resection is superior to SoC surgical 
resection followed by RT ± cisplatin 
adjuvant therapy with respect to EFS 
per RECIST 1.1 by BICR in 
participants whose tumors express 
PD-L1 CPS≥1.
-
Hypothesis #3: Pembrolizumab as 
neoadjuvant therapy and in 
combination with RT ± cisplatin as 
adjuvant therapy after surgical 
resection is superior to standard of 
care (SoC) surgical resection 
followed by RT ± cisplatin adjuvant 
therapy with respect to EFS per 
RECIST 1.1 by BICR in all 
participants.
•
EFS – time from the date of 
randomization to the date of first record 
of any of the following events: 
radiographic disease progression
(exceptions specified in Section 
10.4.1.1), radiographic disease 
progression during the neoadjuvant 
phase that precludes surgery, local or 
distant disease progression or recurrence 
as assessed with imaging or biopsy as 
indicated, death due to any cause; a 
secondary primary malignancy is not 
considered an EFS event
08KM9X

PRODUCT:  MK-3475 
63
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Objective/Hypothesis
Endpoint
Secondary
•
Objective 2: To compare 
pembrolizumab neoadjuvant therapy to 
no neoadjuvant therapy with respect to 
the rate of major pathological response 
(mPR) as assessed by the central 
pathologist at the time of definitive 
surgery in participants whose tumors 
express PD-L1 CPS≥10, CPS≥1, and in 
all participants regardless of CPS status.
-
Hypothesis #4: Pembrolizumab 
neoadjuvant therapy is superior to 
no neoadjuvant therapy with respect 
to rate of mPR at the time of surgery 
in participants whose tumors express 
PD-L1 CPS≥10.
-
Hypothesis #5: Pembrolizumab 
neoadjuvant therapy is superior to 
no neoadjuvant therapy with respect 
to rate of mPR at the time of surgery 
in participants whose tumors express 
PD-L1 CPS≥1.
-
Hypothesis #6: Pembrolizumab 
neoadjuvant therapy is superior to 
no neoadjuvant therapy with respect 
to rate of mPR at the time of surgery 
in all participants.
•
mPR – having less than or equal to 10% 
invasive squamous cell carcinoma 
within the resected primary tumor 
specimen and all sampled regional 
lymph nodes
08KM9X

PRODUCT:  MK-3475 
64
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Objective/Hypothesis
Endpoint
•
Objective 3: To compare 
pembrolizumab as neoadjuvant therapy 
and in combination with radiotherapy 
(RT) ± cisplatin as adjuvant therapy to 
only RT ± cisplatin as adjuvant therapy 
with respect to OS in participants whose 
tumors express PD-L1 CPS≥10, CPS≥1,
and in all participants regardless of CPS 
status.
-
Hypothesis #7: Pembrolizumab as 
neoadjuvant therapy and in 
combination with RT ± cisplatin as 
adjuvant therapy after surgical 
resection is superior to SoC surgical 
resection followed by RT ± cisplatin 
adjuvant therapy with respect to OS 
in participants whose tumors express 
PD-L1 CPS≥10.
-
Hypothesis #8: Pembrolizumab as 
neoadjuvant therapy and in 
combination with RT ± cisplatin as 
adjuvant therapy after surgical 
resection is superior to SoC surgical 
resection followed by RT ± cisplatin 
adjuvant therapy with respect to OS 
in participants whose tumors express 
PD-L1 CPS≥1.
-
Hypothesis #9: Pembrolizumab as 
neoadjuvant therapy and in 
combination with RT ± cisplatin as 
adjuvant therapy after surgical 
resection is superior to SoC surgical 
resection followed by RT ± cisplatin 
adjuvant therapy with respect to OS 
in all participants.
•
OS – time from the date of 
randomization to the date of death due 
to any cause
08KM9X

PRODUCT:  MK-3475 
65
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Objective/Hypothesis
Endpoint
•
Objective 4: To evaluate the rate of 
pathological complete response (pCR) 
as assessed by the central pathologist at 
the time of definitive surgery in 
participants whose tumors express PD-
L1 CPS≥10, CPS≥1, and in all 
participants regardless of CPS status.
•
pCR – having no residual invasive 
squamous cell carcinoma within the 
resected primary tumor specimen and all 
sampled regional lymph nodes
•
Objective 5: To evaluate global health 
status/quality of life (QoL) and physical 
functioning scores using the European 
Organisation for Research and 
Treatment of Cancer (EORTC) QoL 
questionnaire (QLQ)-C30, and 
swallowing, speech and pain symptoms 
using the EORTC Head and Neck–
Specific QoL questionnaire (EORTC 
QLQ-H&N35) in participants whose 
tumors express PD-L1 CPS≥10, CPS≥1,
and in all participants regardless of CPS 
status.
•
EORTC QLQ C30- global health 
status/QoL scales (items 29 and 30) 
•
EORTC QLQ-C30 physical functioning 
scales (items 1-5) 
•
EORTC QLQ-H&N35 swallowing 
multi-item scale (items 35-38), speech
multi-item scale (items 46, 53-54), and 
pain multi-item scale (items 31-34)
•
Objective 6: To determine the safety and 
tolerability of pembrolizumab as 
neoadjuvant therapy and in combination 
with RT ± cisplatin as adjuvant therapy.
•
AEs
•
Study drug discontinuations due to AEs
Exploratory
•
Objective 7: To compare 
pembrolizumab as neoadjuvant therapy 
and in combination with RT ± cisplatin 
as adjuvant therapy to only 
RT ± chemotherapy as adjuvant therapy, 
with respect to:
-
Local Regional Control
-
Distant Metastases-Free Survival 
(DMFS) 
-
Incidence of second Head and Neck 
and Other Cancers
•
Local regional control -  time from date 
of randomization to the date of first 
record of radiographic disease 
progression (exceptions specified in 
Section 10.4.1.1), local recurrence as 
assessed with imaging or biopsy as 
indicated
•
DMFS  - time from date of 
randomization to the date of first record 
of appearance of distant metastasis or 
death due to any cause
•
Number of second Head and Neck and 
Other Cancers
08KM9X

PRODUCT:  MK-3475 
66
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Objective/Hypothesis
Endpoint
•
Objective 8: To compare EFS and OS 
between participant who receive 
pembrolizumab neoadjuvant therapy 
and pembrolizumab with RT ± cisplatin 
as adjuvant therapy and participants 
who receive only RT ± cisplatin as 
adjuvant therapy in:
-
High risk participants
-
Low risk participants
•
EFS –time from the date of 
randomization to the date of first record 
of any of the following events: 
radiographic disease progression 
(exceptions specified in Section 
10.4.1.1), radiographic disease 
progression during the neoadjuvant 
phase that precludes surgery, local or 
distant progression or recurrence as 
assessed with imaging or biopsy as 
indicated, death due to any cause, a 
secondary primary malignancy is not 
considered an EFS event
•
OS –time from date of randomization to 
date of death due to any cause
•
Objective 9: To characterize health 
utilities in participants whose tumors 
express PD-L1 CPS≥10, CPS≥1, and in 
all participants regardless of CPS status
•
EuroQol-5 dimensions (EQ-5D-5L)
•
Objective 10: To identify molecular 
(genomic, metabolic and/or proteomic) 
biomarkers (eg, PD-L1 IHC, gene 
expression profiling etc) that may be 
indicative of clinical 
response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of pembrolizumab 
used as neoadjuvant and in combination 
with RT ± chemotherapy as adjuvant.
•
Objective 11: To evaluate correlation of 
clinical response (mPR/pCR and 
survival) to tumor/ circulating markers 
at Screening and after treatments.
•
The relationship between baseline 
biomarkers and clinical activity will be 
assessed by evaluating molecular 
(genomic, metabolic and/or proteomic) 
determinants of response or resistance to 
treatments, using blood and/or tumor 
tissue.  The relationship between 
baseline biomarkers and clinical activity 
will be assessed by evaluating 
biomarkers and their association with 
mPR, pCR, EFS and OS.
08KM9X

PRODUCT:  MK-3475 
67
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Objective/Hypothesis
Endpoint
•
Objective 12: To compare 
pembrolizumab as neoadjuvant therapy 
and in combination with radiotherapy 
(RT) ± cisplatin as adjuvant therapy to 
only RT ± cisplatin as adjuvant therapy 
with respect to mPR, EFS, and OS in 
participants whose tumors express CPS 
≥ 50.
•
mPR – having less than or equal to 10% 
invasive squamous cell carcinoma 
within the resected primary tumor 
specimen and all sampled regional 
lymph nodes
•
EFS –time from the date of 
randomization to the date of first record 
of any of the following events: 
radiographic disease progression 
(exceptions specified in Section 
10.4.1.1), local or distant progression or 
recurrence, as assessed with imaging or 
biopsy as indicated, death due to any 
cause
•
OS –time from date of randomization to 
date of death due to any cause
•
Objective 13: to compare 
pembrolizumab as neoadjuvant therapy 
and in combination with radiotherapy 
(RT) ± cisplatin as adjuvant therapy to 
only RT ± cisplatin as adjuvant therapy 
on the rate of in situ 
carcinoma/dysplasia observed in 
surgically resected specimens.
•
The presence of in situ carcinoma or 
dysplasia present in any of the surgically 
resected specimens from the primary 
tumor site and/or neck lymph nodes. 
The study is considered to have met its objective if pembrolizumab is superior to SoC with 
respect to EFS at either its interim analysis (IA) or the final analysis (FA).
5
STUDY DESIGN 
5.1
Overall Design 
This is a Phase III, randomized, active-controlled, multisite, open-label study of 
pembrolizumab as neoadjuvant therapy and pembrolizumab in combination with SoC RT 
with/without cisplatin as post-surgical adjuvant therapy in treatment naïve participants with 
newly diagnosed Stage III/IVA, resectable LA HNSCC.  The study will be conducted in 
conformance with Good Clinical Practices (GCP).
08KM9X

PRODUCT:  MK-3475 
68
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
714 participants will be enrolled in the study, which will result in approximately 65% (~462)
participants whose tumors express PD-L1 CPS≥10 and approximately 95% (~680)
participants whose tumors express PD-L1 CPS≥1, randomized in a 1:1 ratio to:
•
Treatment Arm A/pembrolizumab: Pembrolizumab (2 cycles) as neoadjuvant therapy 
followed by surgical resection followed by adjuvant therapy with pembrolizumab 
(15 cycles) plus SoC RT ± cisplatin.
•
Treatment Arm B/SoC: No neoadjuvant therapy prior to surgical resection and adjuvant 
therapy with SoC RT ± cisplatin (see Figure 1).
Participants will be stratified by primary tumor site (oropharynx/oral cavity vs. larynx vs. 
hypopharynx), tumor stage (III vs. IVA), and PD-L1 status (TPS≥50% vs. TPS<50%).  
Stratification factors are described in Section 7.3.1.
A participant’s HNSCC status for eligibility at Screening will be based on investigator 
assessment in accordance with the inclusion/exclusion criteria described in Section 6.1 –
Inclusion Criteria and 6.2 – Exclusion Criteria.  A formalin-fixed paraffin-embedded (FFPE) 
tumor tissue sample or slides obtained at a participant’s initial diagnosis will be submitted to 
a designated central laboratory for PD-L1 status determination and for retrospective 
translational research.  
Presurgery neoadjuvant treatment in the pembrolizumab arm (Arm A) should begin within 
3 days of randomization or as close as possible to that date on which the participant is 
allocated or assigned.  The timeframe for surgery (after the presurgery visit) is within 6
weeks (±10 days) after randomization.  Participants in Arm A are allowed to proceed to 
surgery outside of this timeframe if the delays are due to an AE. Participants with delays 
other than for an AE may be considered with Sponsor consultation.
Participants in the SoC control arm (Arm B) will receive no neoadjuvant and will proceed 
directly to surgery as per local practice.  
In both the pre- and post-operative treatment periods in Arm A, pembrolizumab will be 
administered IV 200 mg fixed dose Q3W; treatment will begin on Day 1 of each 3-week 
dosing cycle.  Note: the required screening period and neoadjuvant treatment in Arm A are 
not expected to cause excessive delays in receipt of SoC surgery and post-surgical treatment, 
since surgery and RT require institutional planning and quality assurance (QA) procedures, 
as described in the Radiation Therapy Quality Assurance (RT QA) manual.
All participants in the pembrolizumab arm (Arm A) will have an imaging assessment prior to 
surgery at Week 6 (± 10 days).  In the SoC arm (Arm B), the screening image will serve as 
the presurgery imaging. If the presurgery scans in Arm A or baseline scans in Arm B were 
done > 14 days prior to the date of surgery, then repeat imaging is required prior to surgery.  
All imaging assessments will be submitted for BICR.  All participants will undergo a 
potentially curative surgical resection performed as part of the local SoC.  A thorough 
evaluation of tumor status, pathological staging per AJCC Cancer Staging Manual (8th
edition) and assessment of surgical margins and extranodal extension will be performed by 
08KM9X

PRODUCT:  MK-3475 
69
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
the local pathologist on all the tissues removed during the surgery. Resected surgical 
specimens will be submitted to the designated central laboratories for blinded pathological 
response assessment, determination of high risk pathologic features and translational research 
as described in Section 9 –Study Assessment and Procedures.  A final and optional biopsy 
will also be performed at the time of recurrence, if applicable, for participants who agree to 
participate.
Adjuvant treatment will start when participants have recovered adequately from the 
morbidity and/or complications from the surgery and is recommended within 6 weeks of
surgery.  For adjuvant treatment, participants considered high-risk for recurrence (ie, positive 
margins [< 1 mm] or extranodal extension [defined as extension of SCC from within a lymph 
node through the fibrous capsule and into the surrounding connective tissue] in the surgical 
specimen), will receive RT plus concurrent cisplatin (3 cycles of 100 mg/m2 Q3W) plus 
pembrolizumab (15 cycles of 200 mg Q3W) in the pembrolizumab arm (Arm A) and without 
pembrolizumab in the SoC arm (Arm B); participants considered lower risk for recurrence
(ie, without positive margins or extranodal extension following surgical resection) will 
receive RT plus pembrolizumab (15 cycles of 200 mg Q3W) in the pembrolizumab arm 
(Arm A) and without pembrolizumab in the SoC arm (Arm B).  Participants in the 
pembrolizumab arm may start pembrolizumab adjuvant treatment before starting RT ± 
cisplatin.
Participants who do not undergo surgical resection as originally planned, or have incomplete 
resection (ie, gross disease left behind) may receive salvage RT plus cisplatin ± 
pembrolizumab, depending on the assigned treatment arm.  These participants may receive a 
total dose of RT up to 70 Gy and up to 3 cycles of cisplatin.
All participants will have post-RT imaging performed 12 weeks (± 7 days) after the end of 
RT ± cisplatin treatment and then every 3 months (91 ± 7 days) until the end of Year 3, the 
imaging schedule may then be reduced to every 6 months (182 ± 14 days) up to the end of
Year 5.  If an unplanned imaging assessment is performed before the first scheduled post-RT 
imaging and a disease progression is assessed per RECIST 1.1 and verified by BICR, this 
will be an EFS event.  Participants who do not undergo the planned surgery, for whatever 
reason, will be followed by imaging assessments at the same time intervals from last dose of 
post-operative radiotherapy.  Imaging scans will be performed until a primary efficacy 
endpoint event is observed for a participant (see Section 10.4 Analysis Endpoint for the 
definition of a primary efficacy analysis event).  
Participants that display disease recurrence or have an event/progression and subsequently 
receive any anticancer treatment not specified in the protocol will discontinue study 
treatment and enter follow-up; any treatment would be considered post-study anticancer 
treatment.
Adverse events will be monitored throughout the study and graded in severity according to 
the guidelines outlined in the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.0.  
08KM9X

PRODUCT:  MK-3475 
70
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Safety follow-up will be performed for participants who receive study treatment and for 
those with Early Discontinuations.  All participants will be followed for OS until death, 
withdrawal of consent, or the end of the study.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial SoA - Section 2. Details of each procedure 
are provided in Section 9 – Study Assessments and Procedures.
This study will use an independent, external Data Monitoring Committee (eDMC) and an
Executive Oversight Committee to monitor safety and efficacy. There will be 2 formal IA 
for efficacy. These are detailed in Appendix 3 and Section 10.7.
5.1.1
Study Diagram
The study design is depicted in Figure 1.
08KM9X

PRODUCT:  MK-3475 
71
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
*If there are delays in cisplatin treatment, cisplatin may continue for up to 1 week following completion of RT.
FU = follow-up; IV = intravenous; mPR = major pathological response; pCR = pathological complete response; 
PD-L1 = programmed cell death ligand 1; Pembro = pembrolizumab; Q3W = every 3 weeks; RT = 
radiotherapy; TPS = tumor proportion score.
Figure 1
Study Design
5.2
Number of Participants
In this study, 714 participants will be randomized as described in Section 10.9. Given the 
prevalence of PD-L1 positivity in tumors of patients with R/M HNSCC enrolled on KN048 
and KN040 studies, it is expected that approximately 462 out of 714 participants enrolled in 
this study will have tumors with PD-L1 positive expression of CPS≥ 10 and approximately 
680 participants whose tumors express PD-L1 CPS≥1.
08KM9X

PRODUCT:  MK-3475 
72
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
5.3
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory 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.
5.3.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable.  In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
5.4
Scientific Rationale for Study Design 
A current SoC treatment regimen for newly diagnosed Stage III/IV resectable LA HNSCC 
consists of surgical resection of the tumor and involved lymph nodes, followed by either RT 
alone or in combination with cisplatin (100 mg/m2 Q3W) based on the presence of high risk 
pathologic features of extranodal extension or positive margins [National Comprehensive 
Cancer Network 2017] [Cooper, J. S., et al 2004] [Bernier, J., et al 2004].  
Around 50% of HNSCC are diagnosed at a locally advanced stage.  The 5-year OS rate of 
HPV-negative Stage III/IV HNSCC remains low (40 to 60%).  Participants with HPV-
positive oropharyngeal cancer have a better prognosis, with the exception of participants with 
T4 or N3 disease for which the 5-year OS is around 50 to 60% (independently of their age 
and smoking status) [Huang, S. H., et al 2015].  
Recurrent/metastatic HNSCC has potentially devastating impacts on basic functions such as 
eating, swallowing, speaking and breathing.  In addition, the pain associated with recurrence, 
and the social isolation as well as potential disfigurement from the disease in the head/neck 
region, all point to the value of preventing progression in this potentially devastating disease. 
Furthermore, the prognosis of R/M HNSCC is poor with a median overall survival of under 1 
year. There is thus an unmet medical need to support the development of new treatment 
strategies to improve the outcome of patients with newly diagnosed Stage III/IV LA HNSCC. 
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.  Pembrolizumab was granted accelerated approval for 
08KM9X

PRODUCT:  MK-3475 
73
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
participants with recurrent/metastatic HNSCC with disease progression on or after platinum-
containing chemotherapy by FDA on 05-Aug-2016.  The efficacy of pembrolizumab in other 
indications is summarized in the Investigator’s Brochure.  
Based on the potential to improve responses in patients with combination therapy that can 
activate different mechanisms of action, pembrolizumab is being evaluated in a number of 
combinations.
This study is designed to evaluate pembrolizumab as neoadjuvant therapy (presurgery) and 
pembrolizumab in combination with RT ± cisplatin (post-surgery) for Stage III-IVA
resectable LA HNSCC. Pembrolizumab has shown significant clinical anticancer activity in 
recurrent/metastatic HNSCC (see Section 3.2.3).
Neoadjuvant treatment is an important part of the treatment strategy for locally advanced 
triple negative breast cancer and non-small cell lung cancer (NSCLC), both demonstrating a 
positive and significant correlation of pCR with long-term clinical benefit such as EFS and 
OS [Francisco, L. M., et al 2010].  
The aim of presurgical neoadjuvant therapy in LA HNSCC is to shrink the tumor, increase 
rate of pCR and thus increase locoregional control with the potential to impact survival.  
An initial Phase II MISP study (NCT02296684) [Uppaluri, R., et al 2017] of pembrolizumab 
has been initiated to evaluate the efficacy and safety of pembrolizumab as neoadjuvant 
therapy.  In preliminary analysis of 21 participants who had received pembrolizumab 
2 weeks prior to resection of high-risk (Stage IVA) LA HNSCC, nearly half (48%) 
demonstrated downstaging in pathologic sample resulting in 38% participants with high risk 
features (vs. expected 80%).  Tumor shrinkage (>10%) in pathological samples was observed 
in 43% of participants with 6/21 (29%) having pathological treatment effect in ≥70% of the 
resected tissue area.  No participants experienced recurrence, metastases, or death from 
disease (range of follow-up 3 to 18 months, half the participants had >12 months follow-up) 
and the post-operative treatment recommendation for CRT were altered (de-intensified).  
This Phase III study will seek to confirm these efficacy results in a larger population.
Pre-clinical investigations, as well as initial clinical observations provide a strong rationale 
for testing RT and cisplatin as potentiators of immune checkpoint inhibitors.  The abscopal 
effect refers to a phenomenon of tumor regression at a site distant from the primary site of 
RT. Following the report of an abscopal effect in a participant with metastatic melanoma 
treated with RT and ipilimumab, interest in potential synergistic treatment combining 
radiation and immunotherapy have emerged [Postow, M. A., et al 2012].  A series of 
preclinical experiments have further developed the rationale for such combinations.  RT has 
been combined with inhibitors of PD-1/PD-L1 pathway in various murine models 
(melanoma, breast, glioblastoma, colon) with an improvement in the tumor growth control 
and survival of the mice compared to single treatment modality [Sharabi, A. B., et al 2015] 
[Zeng, J., et al 2013]. 
Recent evidence has shown that besides their effects on DNA, RT and chemotherapy induce 
immunomodulatory effects that could contribute to their therapeutic efficacy.  Both have the 
08KM9X

PRODUCT:  MK-3475 
74
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
potential to overcome some of the mechanisms of tumor immune escape [Machiels, J. P., et 
al 2001].
Radiotherapy used at therapeutic doses as well as some cytotoxic agents induce 
immunogenic cell death and the release of tumor antigens that can effectively prime antigen 
presenting cells.  Radiotherapy and chemotherapy act on the microenvironment to decrease 
its immunosuppressive properties by inducing the release of cytokines and chemokines that 
have the ability to attract T-cells [Golden, E. B. 2015].  In addition, RT may augment the 
tumor-infiltrating lymphocytes numbers and broaden their T-cell receptor repertoire [Derer, 
A., et al 2016] [Esposito, A., et al 2015] of cytotoxic effectors cells [de Biasi, A. R., et al 
2014].  RT also increases the expression of PD-L1 on tumor cells, which can also explain 
part of the synergism [Deng, L., et al 2014]. 
The effects of RT and chemotherapy on the immune system are a dynamic process.  A lot of 
uncertainties remain in regard to the optimal dose, sequencing and timing of each modality to 
use but results of the current study will certainly contribute to improve our knowledge in this 
field.  
There is a need to identify new treatment strategies that can increase the efficacy of CRT 
particular in patients considered at high risk of recurrence post-surgical resection.  Preclinical 
studies investigating the sequence of PD-1 immunotherapy in relationship to CRT have not 
been well studied.  However, preclinical studies suggesting the importance of immune 
priming would support the notion that administering pembrolizumab prior to CRT may be 
important.  In this study, pembrolizumab will be used as neoadjuvant and an add-on to SoC 
RT ± cisplatin adjuvant therapy post-surgical resection in an arm of randomized LA HNSCC 
participants.  Pembrolizumab will be given concurrently with RT ± cisplatin and continued as 
maintenance (total duration of pembrolizumab treatment approximately 1 year).  The control
SoC treatment arm will receive SoC surgery followed by RT ± cisplatin adjuvant therapy.
An initial Phase II MISP study of pembrolizumab in combination with CRT for LA HNSCC 
has been initiated to evaluate the safety and tolerability of pembrolizumab combined with 
cisplatin and RT (NCT02296684) [Uppaluri, R., et al 2017].  Currently, this study has 
enrolled 25 out of 46 participants.  Treatment consists of a loading dose of pembrolizumab 
200 mg IV given 7 days prior to initiation of CRT and continued Q3W during CRT and 
following completion of CRT for a total of 8 doses. Chemoradiotherapy is administered in 
this MISP study using weekly cisplatin treatment followed by additional pembrolizumab. 
Thus far, the combination does not appear to show significant changes compared to standard 
CRT in terms of toxicity, but a formal analysis of toxicities has not yet been done. The 
efficacy and safety of pembrolizumab in combination with RT plus cisplatin, in unresectable 
LA HSNCC, is currently under further investigation in the ongoing Phase III study KN412
(see Section 3.2.3).
08KM9X

PRODUCT:  MK-3475 
75
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
5.4.1
Rationale for Endpoints
5.4.1.1
Efficacy Endpoints
5.4.1.1.1
Major Pathological Response
Although OS is the standard endpoint for Phase 3 oncology studies, using this primary 
endpoint in studies in primary resectable HNSCC would require a decade or longer to 
complete, slowing patient access to potential new therapies.  In this study, mPR defined as 
having less than or equal to 10% invasive squamous cell carcinoma within the resected 
primary tumor specimen and all sampled regional lymph nodes, is being used as a predictive 
endpoint of long-term survival, in LA HNSCCs treated with neoadjuvant pembrolizumab, 
and can be measured closer to the post-surgical window rather than waiting for the accrual of 
OS events.
In breast cancer, pCR rate has been used as an endpoint in numerous studies of neoadjuvant 
systemic therapy and is a well-established predictive endpoint for FDA registration based on 
currently approved systemic neoadjuvant therapy in breast cancer.  However, the 
achievement of pCR can be rare in other cancers, which may restrict its use as a predictive 
endpoint.  Thus researchers have evaluated less restrictive definitions of pathological 
response after neoadjuvant chemotherapy, including mPR.  In lung cancer, whereas median 
pCR rate reported from studies of neoadjuvant chemotherapy is 4% (range 0 to 16%), mPR 
rate is approximately 22%, establishing that the endpoint is sufficiently frequent to allow 
statistically relevant assessments with reasonable sample sizes [Hellmann, M. D., et al 2014].  
Across published lung cancer study of neoadjuvant systemic therapy, mPR rate has been 
demonstrated to be a consistently valid predictive endpoint for OS establishing the clinical 
relevance of this endpoint [Hellmann, M. D., et al 2014] [Pataer, A., et al 2012].
Consistent with this observation, prior literature in resectable locoregionally advanced oral 
cavity HNSCC has also identified significant long term survival benefit for individual 
patients who attain mPR.  In a randomized study of neoadjuvant chemotherapy versus SoC 
surgery, Zhong et al. (2015) identified that patients who achieved mPR (28%) with 
neoadjuvant chemotherapy had a more than 80% 5-year OS rate [Zhong, L. P., et al 2015].  
The mPR rate was associated with statistically significant improvement in 5-year OS both in 
comparison with patients in the neoadjuvant treatment arm who did not achieve mPR (hazard 
ratio [HR] =0.37, 95% CI: 0.15, 0.87, p=0.023) and in comparison with SoC surgery 
(HR=0.35, 95% CI: 0.15, 0.82, p=0.014).  These comparisons were also statistically 
significant for the 5-year disease free survival, locoregional recurrence-free survival, and 
DMFS endpoints.  
5.4.1.1.2
Pathological Complete Response
Pathological complete response, defined as no residual invasive squamous cell carcinoma
within the resected primary tumor specimen and all sampled regional lymph nodes, is 
associated with a reduced risk of recurrent/metastatic disease and in this study is being used 
as a surrogate of survival in LA HNSCCs treated with neoadjuvant pembrolizumab.  
08KM9X

PRODUCT:  MK-3475 
76
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
In breast cancer, patients who achieve pCR using systemic therapy have demonstrated 
sustained clinical benefit with significant improvements in survival for individual patients 
who attain pCR [Carey, L. A., et al 2007] [Liedtke, C., et al 2008] [Cortazar, P., et al 2014].  
In this study, pCR is included as a secondary endpoint because the achievement of pCR can 
be rare in other cancers, which may restrict its use as a predictive endpoint.
In resectable Stage II-IV local or locoregionally advanced oral cavity HNSCC, a randomized 
control study of neoadjuvant chemotherapy found that patients with a pCR (27%) had a 
significant survival improvement when compared with those without a pCR (10-year OS: 
76% vs. 41%, p=0.0004; HR 0.23) [Bossi, P., et al 2014]. The benefit in survival mainly 
depended on better locoregional control of disease: the crude cumulative incidence of 
locoregional recurrence at 10 years was 11.1% for patients achieving a pCR, while was 33% 
for patients with residual disease after chemotherapy (p=0.029).  Notably, patients who 
achieved a pCR with neoadjuvant chemotherapy had a relatively less advanced stage at 
diagnosis, with 41% Stage II, 50% Stage III and 9% Stage IV disease, highlighting the rarity 
of pCR achieved in the Stage III-IV population to be studied in the proposed study of 
pembrolizumab. 
5.4.1.1.3
Event-Free Survival
Event-free survival is a common surrogate endpoint for OS that is used to evaluate the 
efficacy of neoadjuvant and adjuvant cancer therapy and is sometimes used as primary 
endpoint. In this study, EFS does not include a pathologic component and rather defines a
presurgical radiographic event as a progression that precludes surgery. This is to align with 
the ongoing and recently completed neoadjuvant trials across disease types. These trials 
notably do not contain pathologic cutoffs in the definition of an event [NCT: 03221426,
NCT: 03924895, NCT: 03425643, NCT: 03924856] [Patel, S. P., et al 2023] [Schmid, P., et 
al 2020] [Forde, P. M., et al 2022]. Additionally, emerging concepts and pathologic response 
data among the neoadjuvant HNSCC clinical landscape have demonstrated a survival benefit 
among a broader population of pathologic responders, expanded beyond the strict definitions 
of mPR and pathologic complete response (pCR; 0% remaining invasive cancer) [Menzies, 
A. M., et al 2021] [Wise-Draper, T. M., et al 2022] [Uppaluri, R., et al 2020] [Dogan, S. 
2023] [Topalian, S. L., et al 2020]. See Section 10.4 for the primary and secondary endpoint 
definitions.
Event-free survival represents a clinically significant endpoint for patients with this disease, 
given the morbidity associated with recurrent HNSCC and its potentially devastating impact 
on basic functions such as eating, swallowing, speaking and breathing.  The use of BICR and 
RECIST 1.1 to assess disease progression is typically considered acceptable by regulatory 
authorities.  RECIST 1.1 will be used by the BICR when assessing images for efficacy 
measures and by the local site when determining eligibility (Section 9.2.1.4).  Although 
traditional RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, 
this protocol has implemented a modification to RECIST 1.1 to allow a maximum of 10 
target lesions in total and 5 per organ. Images will be read by a central imaging vendor 
blinded to treatment assignment to minimize bias in the response assessment. In addition, the 
final determination of radiologic progression will be based on the central assessment of 
progression, rather than a local site investigator/radiology assessment.  Real time 
08KM9X

PRODUCT:  MK-3475 
77
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
determination of radiologic progression as determined by central review will be 
communicated to the site. 
The recent clinical study results of PD-1 inhibitors in the recurrent or metastatic HNSCC 
setting points to the likelihood of their wide-spread availability in the near future.  Thus their 
use in the recurrent setting will likely impact the OS endpoint, as participants who are 
randomized to the SoC control arm (Arm B) may subsequently receive a PD-1 inhibitor at 
recurrence.
5.4.1.1.4
Overall Survival
Overall survival 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 key secondary endpoint.  The OS endpoint may be potentially 
confounded by subsequent therapy, thus limiting its utility as a primary endpoint.  For 
example, the impact of unintended cross-over from approval of PD-1 inhibitors in the 
recurrent/metastatic HNSCC setting will likely result in wide-spread availability and usage of 
PD-1 inhibitors in the near future.  Their use in the recurrent setting will likely impact the OS 
endpoint, as participants who are randomized to the SoC control arm may subsequently 
receive a PD-1 inhibitor at recurrence due to their approved usage in the recurrent setting.  
Also, 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 participants who 
survive more than 2 to 3 years have an OS impact mainly driven by participant co-
morbidities and second primaries, rather than by disease recurrence.  For all the reasons 
stated above, EFS is the primary endpoint and OS will be a secondary endpoint.
5.4.1.1.5
Rationale for Prospective Stratification and Evaluation of Biomarker 
Subpopulation
Studies in additional indications (melanoma and lung) suggest that participants respond to 
pembrolizumab even if their tumors show little or no PD-L1 by IHC, although potentially at 
a lower rate of response than when tumors are more positive for PD-L1. In R/M HNSCC, 
KEYNOTE-012 participants in Cohort B were evaluated to determine whether participants 
whose tumors express PD-L1 participants are more likely to demonstrate higher ORRs than 
anticipated for participants whose tumors do not express PD-L1 (see Section 3.2.3). In a 
pooled analysis, higher response rates were observed in patients with PD-L1 versus
without PD-L1 expression using CPS≥ 1 (21% vs. 6%; one-sided P = 0.023) [Mehra, R., et 
al 2018].
In addition, data from KEYNOTE-040 demonstrated a survival benefit with higher PD-L1 
expression for pembrolizumab relative to SoC when PD-L1 expression is higher on tumors 
and in the tumor microenvironment [Cohen, E. E. W., et al 2019]. The hazard ratio (HR) for 
OS for both participants with PD-L1 CPS ≥ 1 (HR 0.74, nominal p=0.0049) and TPS ≥ 50% 
(HR 0.53, nominal p=0.0014) demonstrated the benefit of pembrolizumab compared with 
SoC in KEYNOTE-040. Data from KEYNOTE-048 showed that pembrolizumab 
significantly improved OS in both the PD-L1 CPS ≥ 20 (HR 0.61 [95% CI 0.45-0.83], 
08KM9X

PRODUCT:  MK-3475 
78
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
p=0.0007), and CPS ≥ 1 (HR 0.78, p=0.0086) populations compared to the EXTREME 
regimen, supporting pembrolizumab monotherapy for 1L treatment of PD-L1 positive R/M 
HNSCC [Burtness, B., et al 2018].
Based on these results observed in first-line and second-line R/M HNSCC, it is reasonable to 
expect that biomarker enrichment effects are also likely to be seen in locally advanced HNC. 
Most recently, in post hoc analysis of KEYNOTE-412, a numerically improved survival 
benefit was demonstrated in the CPS>10 (EFS HR=0.73, CI: 0.53-1.02; OS HR=0.72, CI: 
0.50-1.04) and CPS>20 populations (EFS HR=0.73, CI: 0.49-1.06; OS HR=0.67, CI: 0.43-
1.04) that was not similarly observed in a CPS unselected (OS HR=0.90; CI: 0.71-1.15) or
CPS≥1 populations (EFS HR=0.80, CI: 0.64-1.00; OS HR=0.88, CI: 0.68-1.14) [Machiels, J. 
P., et al 2022] [Rugo, H. S., et al 2022].Therefore biomarker-driven hypotheses for efficacy 
endpoints will be assessed in this study and the selected populations for analysis will be 
CPS≥10, CPS≥1, and all participants.
Further details of the statistical approach to evaluating this population are described in 
Section 10.5.1. In addition, to safeguard against differences in allocation of subjects with 
TPS ≥ 50%, subjects will be stratified based on their TPS.
5.4.1.2
Safety Endpoints
The safety objective of this study is to evaluate the safety of pembrolizumab used as
neoadjuvant and as an adjuvant in combination with RT ± cisplatin in participants with 
resectable LA HNSCC.  Safety parameters commonly used for evaluating investigational 
systemic anticancer treatments are included as safety endpoints including, but not limited to, 
the incidence of, causality, and outcome of AEs/ SAEs; and changes in vital signs and 
laboratory values. Adverse events 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.  
5.4.1.3
Rationale for Patient Reported Outcomes (PROs)
As part of the analyses for this study, participants will provide information regarding their 
health-related quality of life using the EORTC QLQ-C30 and EORTC-QLQ-H&N35 patient 
reported outcome (PRO) instruments.  Health utilities will be evaluated using the EuroQol-
5D (EQ-5D-5L) PRO instrument.  These PRO assessments are not pure efficacy or safety 
endpoints because they are affected by both disease progression and treatment tolerability.  
EORTC QLQ-C30 and EORTC QLQ-H&N35
The EORTC QLQ-C30 is the most widely used cancer specific health related QoL 
instrument, which contains 30 items and measures 5 functional dimensions (physical, role, 
emotional, cognitive and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 6 
single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial 
impact), and a global health and QoL scale [Aaronson, N. K., et al 1993].  The EORTC 
QLQ-C30 is a psychometrically and clinically validated instrument appropriate for assessing 
QoL in oncology studies [Aaronson, N. K., et al 1993].  
08KM9X

PRODUCT:  MK-3475 
79
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
The EORTC QLQ-H&N35 is a disease specific questionnaire developed to measure QoL in 
HNC.  The EORTC QLQ-H&N35 consists of 7 multi-item scales (pain in the mouth, 
problems with swallowing, senses, speech, social eating, social contact, and sexuality), and 
11 single-item scales (problems with teeth, mouth opening, dry mouth, sticky saliva, 
coughing, feeling ill, use of analgesics, use of nutritional supplements, use of feeding tube, 
weight gain, and weight loss) [Bjordal, K., et al 1994]. 
The EORTC QLQ-C30 and EORTC QLQ-H&N35 are psychometrically and clinically 
validated instruments appropriate for assessing QoL in participants with HNCs [Bjordal, K., 
et al 1994] [Bjordal, K., et al 2000].  These instruments have been widely used in Phase 3
studies of participants with locoregionally advanced HNSCC [van Herpen, C. M., et al 2010] 
[Bottomley, A., et al 2014] [Curran, D., et al 2007].  
Clinically meaningful symptoms for HNSCC patients have been extensively studied, and 
commonly identified symptoms include: problems with swallowing, problems with speech, 
and pain in the mouth [Bjordal, K., et al 2000] [Chera, B. S., et al 2014].  Thus, secondary 
objectives are to assess mean changes from baseline in the global health status/QoL and 
physical functioning scores from the EORTC QLQ-C30, as well as the above-mentioned 
symptom scores from the EORTC QLQ-H&N35.  A difference of 10 points on the 100-point 
EORTC QLQ-C30 and EORTC QLQ-H&N35 scales either from baseline or between the 
cohorts is considered as clinically relevant [Bjordal, K., et al 1994] [Bjordal, K., et al 2000].
EuroQoL-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. and de 
Charro, F. 2001].  The 5 health state dimensions in the EQ-5D-5L include the following: 
mobility, 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-5L 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].
08KM9X

PRODUCT:  MK-3475 
80
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
5.4.1.4
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents.  
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients.  Thus, to aid future patients, it is important to investigate the 
determinants of response or resistance to cancer immunotherapy, as well as determinants of 
AEs in the course of our clinical studies.  These efforts will identify novel 
predictive/pharmacodynamic biomarkers and generate information that will better guide 
single-agent and combination therapy with immuno-oncology drugs.  To identify novel 
biomarkers, biospecimens (ie, blood components, tumor material) will be collected to support 
analyses of cellular components (eg, protein, DNA, RNA, metabolites) and other circulating 
molecules.  Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, single-nucleotide polymorphism [SNP] analyses, 
whole exome sequencing, whole genome sequencing):  
This research will evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation.  If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations.  Finally, MSI may be evaluated 
as this is an important biomarker for some cancers (ie, colorectal cancer).
Genetic (DNA) analyses from tumor:
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability etc.).  Key molecular changes of interest to immune-oncology 
drug development include (for example) the mutational burden of tumors and the clonality of 
T-cells in the tumor microenvironment.  Increased mutational burden (sometimes referred to 
as a ‘hyper-mutated’ state) may generate neo-antigen presentation in the tumor 
microenvironment.  To conduct this type of research, it is important to identify tumor-
specific mutations that occur across all genes in the tumor genome.  Thus, genome wide 
approaches may be used for this effort. Note that in order to understand tumor-specific 
mutations; it is necessary to compare the tumor genome with the germline genome.  
Microsatellite instability may also be evaluated as this is an important biomarker for some 
cancers (ie, colorectal cancer). Circulating tumor DNA and/or RNA may also be evaluated 
from blood samples.
Tumor and blood RNA analyses:
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with pembrolizumab or other immunotherapies.  
Pembrolizumab induces a response in tumors that likely reflects an inflamed/immune 
phenotype.  Specific immune-related gene sets (ie, those capturing interferon-gamma 
08KM9X

PRODUCT:  MK-3475 
81
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
transcriptional pathways) may be evaluated and new signatures may be identified.  Individual 
genes related to the immune system may also be evaluated (eg, IL-10).  MicroRNA profiling 
may also be pursued.
Proteomics and immunohistochemistry using blood or tumor:
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic device has 
been developed for use with pembrolizumab in NSCLC.  Preliminary data indicates that this 
association may also be true in additional cancer types (ie, triple negative breast cancer, head 
and neck, and gastric).  Additional tumor or blood-derived proteins may also correlate with 
response to pembrolizumab.  Therefore, tumor tissue may be subjected to proteomic analyses
using a variety of platforms that could include but are not limited to immunoassays and 
liquid chromatography/mass spectrometry.  This approach could identify novel protein 
biomarkers that could aid in patient selection for pembrolizumab therapy.
Other blood-derived biomarkers:
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood.  Assays such as enzyme-linked immunoassay 
measure such proteins in serum.  Correlation of expression with response to pembrolizumab 
therapy may identify new approaches for predictive biomarkers in blood, representing a 
major advance from today’s reliance on assessing tumor biomarkers.  This research would 
serve to develop such assays for future clinical use.
5.4.1.5
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  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 future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
Future Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time.  The 
details of this Future Biomedical Research are presented in Appendix 6  – Collection and 
Management of Specimens for Future Biomedical Research.
5.4.2
Rationale for the Use of Comparator
In this study, the comparator is SoC treatment.  In clinical practice, there is no established 
neoadjuvant therapy for newly diagnosed LA HSNCC, as multiple Phase III studies have 
08KM9X

PRODUCT:  MK-3475 
82
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
been conducted using various chemotherapy regimens without an established standard.  In 
this study, in the neoadjuvant period, treatment naïve participants will be treated with either 
pembrolizumab (Arm A) or no therapy before surgery (Arm B).  A placebo is not being used 
in the neoadjuvant treatment period to avoid participant burden and delays in receipt of 
available recommended surgery/treatment in a high-risk population; participants randomized 
to no neoadjuvant therapy will go directly to surgery.
In the post-surgery (adjuvant) phase, all participants will be treated with SoC RT ± cisplatin.  
Treatment with cisplatin will be based on the local pathological assessment of the 
participant’s surgical specimen and their risk for the development of recurrent/metastatic 
disease post-surgery.  In clinical studies, pembrolizumab has demonstrated clinical anticancer 
activity in patients with recurrent/metastatic HNSCC and in this study its efficacy as an add-
on to post-surgery SoC RT ± cisplatin in newly diagnosed HNSCC will be explored.
5.5
Justification for Dose 
The planned dose of pembrolizumab for this study is 200 mg Q3W.  Based on the totality of 
data generated in the Keytruda® development program, 200 mg Q3W is the appropriate dose 
of pembrolizumab for adults across all indications and regardless of tumor type. The fixed 
dose regimen of 200 mg Q3W is also in line with the approved labeling for 
recurrent/metastatic HNSCC with disease progression on or after platinum-containing 
chemotherapy.  As outlined below, this dose is justified by:
•
Clinical data from 8 randomized studies demonstrating flat dose- and exposure- efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg Q2W, 
•
Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg 
Q3W across multiple indications, and
•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from physiologically based pharmacokinetic [PBPK] 
analysis) at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg 
Q2W (KN001 B2, KN001 D, KN002, KN010 and KN021), and 3 studies compared 
10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 B3, KN001 F2 and KN006). All of these 
studies demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5 to 7.5-fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat 
dose-/exposure-response relationships were also observed in other tumor types including 
HNC, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg 
Q3W as the appropriate dose independent of the tumor type. These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune 
cells, and not via direct binding to cancer cells.
08KM9X

PRODUCT:  MK-3475 
83
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. 
Secondly, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
5.5.1
Maximum Dose/Exposure for This Trial
Late responders have been observed with pembrolizumab up to 1 year of treatment in the 
recurrent/metastatic setting supporting the 1-year duration of treatment with pembrolizumab.  
Participants in Arm A will receive pembrolizumab 200 mg Q3W for up to 17 cycles in total.
6
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 3), our studies include people 
of varying age, race, ethnicity, and sex. The collection and use of these demographic data are 
to follow all local laws and guidelines in keeping with the needs for participant 
confidentiality while supporting the study of the disease, its related factors, and the IMP 
under investigation.
Male/Female participants with newly diagnosed Stage III or IVA resectable LA HNSCC of 
at least 18 years of age will be enrolled in this trial.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Have histologically confirmed new diagnosis of resectable, non-metastatic, squamous 
cell carcinoma as assessed by the Investigator based on baseline imaging and clinical 
assessment that is either:
a.
Stage III oropharyngeal p16 positive that is T4 (N0-N2), M0
OR
08KM9X

PRODUCT:  MK-3475 
84
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
b. Stage III or IVA oropharyngeal p16 negative
OR
c.
Stage III or IVA larynx/hypopharynx/oral cavity (independent of p16).
Note: Participants with multiple primary HNSCC tumors are eligible for the study if 
at least one of the tumors meets eligibility criteria based on staging after consultation 
with and approval by the Sponsor.
Note: If an excisional or incisional biopsy has been performed, participants remain 
eligible for the study provided the residual disease meets the staging criteria required 
for the study (eg, excisional biopsy of a lymph node with residual T4a primary).
Note: Prior surgical debulking, including tonsillectomy, for the head and neck cancer 
under study is not allowed.
2. Be eligible for primary surgery based on investigator decision and per local practice.
This decision must be validated by members of a multidisciplinary team, including 
the surgical oncologist, medical oncologist and radiation oncologist.
Demographics
3. Male/female participants who are at least 18 years of age at the time of providing
informed consent.
Male participants:
4. If male, agrees to the following during the intervention period and for at least the time 
needed to eliminate each study intervention after the last dose of study intervention. 
The length of time required to continue contraception for each study intervention is as 
follows:
-
Pembrolizumab: no contraception requirement
-
Cisplatin: 180 days
-
Radiotherapy: 90 days
•
Refrains from donating sperm
PLUS either:
•
Abstains from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agrees to remain abstinent
OR
08KM9X

PRODUCT:  MK-3475 
85
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
•
Uses contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause, documented from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview) 
as detailed below:
-
Uses a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to 
remain abstinent from penile-vaginal intercourse or use a male condom during
each episode of penile-vaginal penetration.
-
Contraceptive use by men should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical 
studies. If the contraception requirements in the local label for any of the 
study interventions is more stringent than the requirements above, the local 
label requirements are to be followed.
Female participants:
5. A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies:
•
Not a WOCBP
OR
•
A WOCBP and:
-
Uses a contraceptive method that is highly effective (with a failure rate of 
<1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 5 during the intervention period 
and for at least the time needed to eliminate each study intervention after the 
last dose of study intervention and agrees not to donate eggs (ova, oocytes) to 
others or freeze/store for her own use for the purpose of reproduction during 
this period. The length of time required to continue contraception for each 
study intervention is as follows:
◦
Pembrolizumab: 120 days
◦
Cisplatin: 180 days
◦
Radiotherapy: 180 days
The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention. Contraceptive use by women should be consistent with local 
regulations regarding the methods of contraception for those participating in 
clinical studies. If the contraception requirements in the local label for any of the 
study interventions is more stringent than the requirements above, the local label 
requirements are to be followed. 
08KM9X

PRODUCT:  MK-3475 
86
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
•
Has a negative highly sensitive pregnancy test (urine or serum as required by 
local regulations) within 24 hours for urine or within 72 hours for serum 
before randomization. If a urine test cannot be confirmed as negative (eg, an 
ambiguous result), a serum pregnancy test is required. In such cases, the 
participant must be excluded from participation if the serum pregnancy result 
is positive. Additional requirements for pregnancy testing during and after 
study intervention are in Section 9.5.9.2.
•
Abstains from breastfeeding during the study intervention period and for at 
least 120 days after the last dose of pembrolizumab and 180 days after the last 
dose of cisplatin.
•
Medical history, menstrual history, and recent sexual activity has been 
reviewed by the investigator to decrease the risk for inclusion of a woman 
with an early undetected pregnancy.
Informed Consent
6. The participant (or legally acceptable representative) 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.
Study Assessments
7. Have evaluable tumor burden (measurable and/or non-measurable tumor lesions)
assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI), 
based on RECIST 1.1 as assessed by the local site investigator/radiology.  
8. Have provided newly obtained core or excisional biopsy of a tumor lesion not 
previously irradiated for central PD-L1 biomarker analysis from a core or excisional 
biopsy (fine needle aspirate [FNA] is not adequate) for stratification prior to 
randomization.  Repeat samples may be required if adequate tissue is not provided. 
Formalin-fixed, paraffin embedded tissue blocks are preferred to slides.  
Note: If submitting unstained cut slides, newly cut slides should be submitted to the 
testing laboratory within 14 days from the date slides are cut (details pertaining to 
tumor tissue submission can be found in the Vendor Manual).
9. Have results from (local) testing of HPV status for oropharyngeal cancer defined as 
p16 IHC testing using CINtec® p16 Histology assay (Ventana Medical Systems Inc., 
Tucson AZ) using standard protocol.  Positive p16 expression is defined as strong and 
diffuse nuclear and cytoplasmic staining in 70% or more of the tumor cells (please 
see Section 9.1.6 - Presurgery Tumor Tissue Collection for details). If HPV status 
was previously tested using this method, no additional testing is required.
Note:  HPV testing will be performed using local testing of HPV status in participants 
with oropharyngeal cancer using the specified method.
08KM9X

PRODUCT:  MK-3475 
87
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Note: If local p16 testing results are not available, or cannot be assessed locally by the 
specified method, a tumor tissue sample must be submitted for p16 testing at the 
designated central laboratory.
Note: Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV 
testing by p16 IHC as by convention these tumor locations are assumed to be 
HPV-negative.
10. Have an ECOG performance status of 0 to 1 performed within 10 days of 
randomization.
Note: Investigators to confirm no deterioration prior to initiation of treatment.
11. Have adequate organ function as defined in the following table (Table 1).  Specimens 
must be collected within 10 days prior to randomization. If a screening lab does not 
meet eligibility criteria and is repeated and assessed on Day 1 and the Day 1 lab 
meets eligibility criteria, the participant is eligible, ie, the Day 1 lab result will be 
used for eligibility.  
08KM9X

PRODUCT:  MK-3475 
88
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count 
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L
Renal
Measured or calculateda creatinine clearance
(CrCl; glomerular filtration rate [GFR] can 
also be used in place of CrCl)
≥60 mL/min
Calcium (corrected for albumin)c
≤11.5 mg/dL or ≤2.9 mmol/L
Albumin
Result used to provide corrected calcium 
value only
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)
or Partial Thromboplastin Time (PTT)b
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT 
is within therapeutic range of intended use 
of anticoagulants
Abbreviations: ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic 
transaminase); AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase); CrCl = creatinine clearance; GFR = glomerular filtration rate; ULN = upper 
limit of normal.
a
Cockcroft Gault calculation of CrCl preferred, but CrCl can be calculated per 
institutional standard. The formula used to calculate creatinine clearance should be the 
same and consistent for all participants at the site.
b
PTT may be performed if the local lab is unable to perform aPTT.
c
Calcium corrected for albumin is required during screening only for participants with 
albumin outside the normal range.
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.
08KM9X

PRODUCT:  MK-3475 
89
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
6.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions 
1. Has Stage T4B and/or N3 LA HNSCC and/or distant metastases.
Note: As per the AJCC Cancer Staging Manual, 8th edition, the diagnosis of ENE
(eg, N3b disease) requires clear evidence of gross ENE on clinical examination 
supported by strong radiographic evidence. Chapter 5, Staging Head and Neck 
Cancers, in the AJCC Cancer Staging Manual, 8th edition, defines criteria for 
evidence of gross ENE on clinical evaluation.  
2. Has cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity, such as 
nasopharyngeal, sinus, other para-nasal, or other unknown primary HNC.  
3. A WOCBP who has a positive pregnancy test within 24 hours (urine) or within 
72 hours (serum) before randomization or within 24 hours prior to the start of 
RT ± cisplatin (see Section 9.5.9.2).  If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required.  In such cases, the 
participant must be excluded from participation if the serum pregnancy result is 
positive.
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 co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, 
CD137).
5. Has received prior radiotherapy treatment or systemic anticancer therapy including 
investigational agents for the HNC under study prior to randomization/allocation. 
Note: Radiation therapy to treat a prior HNC is also grounds for exclusion. 
6. Has received a live vaccine within 30 days prior to randomization.  Examples of live 
vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®
[Influenza Vaccine Live, AstraZeneca]) are live attenuated vaccines and are not 
allowed.
Refer to Section 7.7 for information on COVID-19 vaccines.
Prior/Concurrent Clinical Study Experience
7. Is currently participating in or has participated in a study of an investigational agent 
or has used an investigational device within 4 weeks prior to randomization.
Note:  Participants who have entered the follow-up phase of an investigational study 
may participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
08KM9X

PRODUCT:  MK-3475 
90
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Diagnostic assessments
8. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to randomization.
9. Has a known additional malignancy that is progressing or has required active 
treatment within the past 3 years.  
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, or carcinoma in situ (eg, in situ cervical cancer or breast carcinoma) that 
have undergone potentially curative therapy are not excluded.
10. Has radiographically detectable (even if asymptomatic and/or previously treated) 
central nervous system metastases and/or carcinomatous meningitis as assessed by 
local site investigator and radiology review.
11. Has Grade ≥2 audiometric hearing loss. 
Note: Audiometric abnormalities without corresponding clinical symptoms of Grade 
≥2 hearing loss will not be grounds for exclusion.
Note: Participants with complete non-tumor-related hearing loss (ie, congenital 
deafness) are eligible for this study.
12. Has Grade ≥2 neuropathy. 
13. Has Grade 3-4 bleeding due to the underlying malignancy.
14. If participant has received major surgery, and the participant has not recovered 
adequately from the toxicity and/or complications from the intervention prior to 
randomization.
15. Has had previous allogeneic tissue/solid organ transplant.
16. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients 
(refer to the Investigator’s Brochure for a list of excipients), RT or cisplatin or their 
analogs.
17. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs).  Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a form of 
systemic treatment and is allowed.
18. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
19. Has an active infection requiring systemic therapy.
20. Has a known history of human immunodeficiency virus (HIV) infection.  No HIV 
testing is required unless mandated by local health authority. Refer to Appendix 8 for 
Germany-specific requirements.
08KM9X

PRODUCT:  MK-3475 
91
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
21. Has a known history of or is positive for Hepatitis B (defined as hepatitis B surface 
antigen [HBsAg] reactive) or known active Hepatitis C (defined as Hepatitis C virus 
[HCV] RNA [qualitative] is detected).  Refer to Appendix 8 for Germany-specific 
requirements.
Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority.
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant's 
participation for the full duration of the study, or is not in the best interest of the 
participant to participate, in the opinion of the treating investigator.
23. 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
24. Removed in Amendment 07 for duplication of requirement with inclusion criteria #4 
and #5.
25. Refer to Appendix 8 for additional France-specific exclusion criterion.
26. Refer to Appendix 8 for additional France-specific exclusion criterion.
27. Refer to Appendix 8 for additional France-specific exclusion criterion.
6.3
Lifestyle Restrictions
6.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
Insertion of feeding tube is allowed for nutritional purposes and, if procedure is performed as 
a planned hospitalization, would not meet that criterion for SAE.
6.3.2
Caffeine, Alcohol, and Tobacco
No caffeine, alcohol or tobacco restrictions are required.
6.3.3
Activity
No activity restrictions are required.
6.3.4
Contraception
Pembrolizumab, cisplatin, and RT may have adverse effects on a fetus in utero.  Refer to 
Appendix 5 for approved methods of contraception.  Refer to Appendix 8 for Germany-
specific guidance.
08KM9X

PRODUCT:  MK-3475 
92
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
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 
throughout the study period up to 120 days after the last dose of pembrolizumab (applicable 
for WOCBP only), 180 days after the last dose of cisplatin, and 90 days (males) or 180 days 
(WOCBP) after the last dose of radiotherapy.  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. 
6.3.5
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study treatment.  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has 
been completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (eg, death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn).  The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor.  If a male participant impregnates his female partner, the study personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
followed as described in Section 9.3.6.
6.3.6
Use in Nursing Women
Pembrolizumab: It is unknown whether pembrolizumab is excreted in human milk.  Since 
many drugs are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, participants who are breastfeeding are not eligible for 
enrollment.
Cisplatin: Cisplatin has been reported to be found in human milk; participants receiving 
cisplatin injection should not breast-feed.
6.4
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 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events or serious adverse events 
(SAE) meeting reporting requirements as outlined in the entry guidelines.
6.5
Participant Replacement Strategy
A participant who discontinues from study treatment or withdraws from the study will not be 
replaced.
08KM9X

PRODUCT:  MK-3475 
93
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
7
TREATMENTS
Study treatment is defined as any investigational treatment(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 treatment(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.
7.1
Treatments Administered
The study treatment(s) to be used in this trial are outlined below in Table 2.
Refer to Appendix 8 for country-specific requirements. 
08KM9X

PRODUCT:  MK-3475 
94
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 2
Study Treatment(s)
Arm 
Name
Arm 
Type
Intervention
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admini-
stration
Regimen/ Treatment 
Period
Use
IMP/ 
NIMP/ 
AxMP Sourcing
Arm A
Experi-
mental
Pembrolizumab
Drug
Solution for 
infusion
100 mg/vial
200 mg
IV infusion
Q3W for up to 
17 cycles
Test Product
IMP
Central
Arm A
Experi-
mental
Radiotherapy
Radiation
NA 
(Radiation)
2 Gy/fraction
2 Gy/day
Internal
radiation -
systemic
Low-risk participants: 
2 Gy/day in 
30 fractions for a total 
of 60 Gy
High-risk participants: 
2 Gy/day in 
33 fractions for a total 
of 66 Gy
Participants with gross 
residual disease: 
2 Gy/day in 
35 fractions for a total 
of 70 Gy
Background 
treatment
NIMP/ 
AxMP
Local
Arm A
Experi-
mental
Cisplatin
Drug
Solution for 
infusion
1 mg/mL
100 
mg/m2
IV infusion
Q3W for 3 cycles
Test Product
IMP
Local or 
central
Arm B
Active 
com-
parator
Radiotherapy
Radiation
NA 
(Radiation)
2 Gy/fraction
2 Gy/day
Internal 
radiation -
systemic
Low-risk participants: 
2 Gy/day in 
30 fractions for a total 
of 60 Gy
High-risk participants: 
2 Gy/day in 
33 fractions for a total 
of 66 Gy
Participants with gross 
residual disease: 
2 Gy/day in 
35 fractions for a total 
of 70 Gy
Background 
treatment
NIMP/ 
AxMP
Local
08KM9X

PRODUCT:  MK-3475 
95
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Arm 
Name
Arm 
Type
Intervention
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admini-
stration
Regimen/ Treatment 
Period
Use
IMP/ 
NIMP/ 
AxMP Sourcing
Arm B
Active 
com-
parator
Cisplatin
Drug
Solution for 
infusion
1 mg/mL
100 
mg/m2
IV infusion
Q3W for 3 cycles
Test Product
IMP
Local or 
central
Abbreviations: AxMP=auxiliary medicinal product; EEA =European Economic Area; IMP=investigational medicinal product; IV=intravenous; NA=not 
applicable; NIMP=noninvestigational medicinal product; Q3W=every 3 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 EEA. Country 
differences with respect to the definition/classification of IMP/NIMP/AxMP may exist. In these circumstances, local legislation is followed.
Pembrolizumab and cisplatin are allowed to be given on the same day.
Intensity modulated radiation therapy (IMRT) is mandatory.  Dose is 60 Gy prescribed to at least 95% of the planning target volume (PTV).  If image-guided 
radiation therapy (IGRT) is used, it should be daily to assure that error/variance is <3 mm. Dose-limiting normal tissue constraints are listed in Table 10.
Cisplatin will be provided locally in some countries by the study site, subsidiary or designee, depending on local country operational or regulatory requirements.
08KM9X

PRODUCT:  MK-3475 
96
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
All supplies indicated in Table 2 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements.  Every attempt should be made to source these 
supplies from a single lot/batch number. The trial 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 9.1.10 for details regarding administration of the study treatment.
All study treatments will be administered as per local SoC.  Pembrolizumab may be 
administered on an out-patient basis; cisplatin will be prepared and administered as per the 
approved product labels.
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.
7.2
Dose Modification (Escalation/Titration/Other) 
If appropriate, the investigator may attribute each toxicity event to cisplatin, radiation or 
pembrolizumab alone and use a stepwise dose reduction according to Table 3 to Table 7.  For 
individual participants requiring a dose modification, treatment for each new cycle may be 
delayed if the scheduled off-drug periods are not adequate to allow for recovery to Grade ≤1 
or the baseline status of the participant.  Every effort should be made to continue RT without 
interruption even in the case of pembrolizumab or cisplatin toxicity.  
Pembrolizumab dose reductions are not permitted.  Pembrolizumab treatment should be 
interrupted or discontinued due to toxicity.  If a dose reduction for toxicity occurs with 
cisplatin, the dose may not be re-escalated. Participants can have a maximum of 2 dose 
modifications throughout the course of the study for toxicities.  If a participant experiences 
several toxicities and there are conflicting recommendations, please follow the most 
conservative dose adjustment recommended (dose reduction appropriate to the most severe 
toxicity).
If one or more of the study medications (ie, pembrolizumab, cisplatin and/or radiation 
therapy) is discontinued, the participant may continue with the other study medications if 
indicated. The last dose of cisplatin must be administered within 1 week of completion of RT
as the chemoradiosensitizing effects will still be present.
7.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab.
If cisplatin and/or radiation therapy is discontinued, the participant may continue on 
treatment with pembrolizumab.  
08KM9X

PRODUCT:  MK-3475 
97
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
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. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 3.
08KM9X

PRODUCT:  MK-3475 
98
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid dose 
is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after 
corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
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
08KM9X

PRODUCT:  MK-3475 
99
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
irAEs
Toxicity Grade 
(CTCAEv4.0)
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
Withhold a
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 
discontinue a
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 
discontinue a
08KM9X

PRODUCT:  MK-3475 
100
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
irAEs
Toxicity Grade 
(CTCAEv4.0)
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 
discontinue b
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).
08KM9X

PRODUCT:  MK-3475 
101
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Dose modification and toxicity management of infusion-reactions related to pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4.
08KM9X

PRODUCT:  MK-3475 
102
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug infusion, the infusion 
may be restarted at 50% of the original infusion rate (eg, from 100 mL/hr 
to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and 
the participant should be premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
study drug treatment
Participant may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500 to 1000 mg po (or 
equivalent dose of analgesic).
08KM9X

PRODUCT:  MK-3475 
103
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (eg, 
renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used immediately.
Participant is permanently discontinued from further study drug 
treatment.
No subsequent dosing
Abbreviations: CTCAE = Common Terminology Criteria for AEs; IV = intravenous; NCI = National Cancer Institute; NSAIDs = nonsteroidal anti-inflammatory drugs; 
po = per os; oral(ly).
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 Version 4.0 at http://ctep.cancer.gov
08KM9X

PRODUCT:  MK-3475 
104
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Other allowed dose interruptions for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 6 weeks of the last dose administered, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the participant’s study record.
7.2.2
Dose Modification for Radiotherapy
All RT treatments must begin as per planned SoC following recovery from surgery, as 
determined by the investigator.  Ideally, this should be within 6 weeks of surgery.  Treatment 
interruptions are to be avoided unless medically necessary.  Treatment breaks must be clearly 
indicated in the treatment record along with the reason(s) for the treatment break(s). 
Treatment breaks, if necessary, ideally should not exceed 7 treatment days at a time and 
14 treatment days total.  Sites should consult the PI prior to giving any RT treatment breaks.  
Treatment breaks should be allowed only for resolution of severe acute toxicity and/or for 
intercurrent illness and not for social or logistical reasons.  Any treatment break(s) exceeding 
2 treatment days for reasons other than toxicity/illness will be considered a protocol 
deviation.
Missed treatments should be compensated for with a twice a day treatment with minimum 6-
hour inter-fraction interval to compensate for missed days including holidays and those for 
toxicity or illness once sufficiently recovered with the goal of keeping the overall treatment 
time confined to 6 weeks or 45 consecutive days.  If BID treatments are not a part of local 
standard of care, RT should be continued until all 35 fractions are completed.
If cisplatin and/or pembrolizumab are discontinued, participants may stay on study treatment 
to complete radiation therapy.
7.2.3
Dose Modification for Cisplatin
Participants can have 2 levels of dose reductions of cisplatin throughout the course of the 
study for toxicities as described in Table 5.  
If further toxicity occurs or the criteria for resuming treatment are not met, the participant 
must be discontinued from that drug and continue to participate in the study.  If a participant 
experiences several toxicities and there are conflicting recommendations, follow the most 
conservative dose adjustment recommended (dose reduction appropriate to the most severe 
toxicity).
If pembrolizumab is discontinued, the participants may continue with cisplatin and radiation 
therapy.
Table 5
Dose Levels for Cisplatin
Dose Level 0
Dose Level -1
Dose Level -2
Dose Level -3
Cisplatin
100 mg/m2
80 mg/m2
60 mg/m2
Discontinue
08KM9X

PRODUCT:  MK-3475 
105
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
7.2.3.1
Cisplatin-Related Toxicity
The major dose-limiting toxicities observed with single-agent cisplatin are the following:
•
Gastrointestinal toxicity: nausea and vomiting.
•
Nephrotoxicity: renal function impairment associated with tubular damage and 
manifested with elevation in serum creatinine and urea and decrease in CrCl. It is also 
associated with serum electrolyte disturbances, like hypomagnesemia, hypocalcemia, 
hyponatremia, hypokalemia and hypophosphatemia.
•
Ototoxicity: cumulative and not reversible damage, manifesting with hearing loss in the 
high frequency.
•
Hemotoxicity: neutropenia, thrombocytopenia, anemia.
•
Neurotoxicity: manifesting with peripheral neuropathy and paresthesia in both upper and 
lower extremities.
7.2.3.2
Dose Modification for Cisplatin
For every treatment infusion, a full dose of cisplatin will be given if neutrophils are 
≥1.0 × 109/L and platelets ≥75 × 109/L. If these levels are not reached, blood counts should 
be performed at the investigator's judgment but it is recommended at least weekly to 
document recovery.  Once a participant has recovered, cisplatin should be administered 
(without waiting for the next cycle).  If hematological toxicity has not resolved, the 
participant should not receive further cisplatin. The participant can continue with RT with or 
without pembrolizumab (depending on assigned treatment arm), and will be followed-up 
according to study protocol. Cisplatin may be administered up to 1 week following 
completion of RT.
The following dose reductions of cisplatin should be applied and should be carried over 
through all subsequent infusions (ie, no dose escalation). In the event that cisplatin treatment 
is stopped, no substitution with, for example, carboplatin, will be allowed. Cessation of 
cisplatin therapy is not, in itself, a reason for discontinuing the participant from the study.
Dose Reduction for Neutropenia
In the case of treatment delay due to delayed neutrophil recovery, the following policies are 
recommended:
•
If neutrophil count has resolved to ≥1.0 × 109/L in ≤1 week, administer the full dose of 
cisplatin.
•
If neutrophil count has resolved to ≥1.0 × 109/L in >1 week but ≤2 weeks, proceed with a 
dose reduction of cisplatin.
08KM9X

PRODUCT:  MK-3475 
106
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Dose Reductions for Febrile Neutropenia
In case of any febrile neutropenia (at least CTCAE 4.0 Grade 3: absolute neutrophil count 
<1000/mm3 with a single temperature of >38.3oC (101oF) or a sustained temperature of 
≥38oC (100.4oF) for more than 1 hour), it is recommended that the participant is hospitalized 
and treated with antibiotics as appropriate. After a period of febrile neutropenia, additional 
precautions have to be taken for the subsequent infusions and the cisplatin dose should be 
reduced.
Dose Reductions for Thrombocytopenia
If complicated thrombocytopenia ≥Grade 3, with hemorrhage and/or requiring 
prophylactic/therapeutic platelet transfusions (recommended at <10 × 109/L, but dependent 
upon local transfusion policy) occurs at any point during the treatment, appropriate 
supportive care should be given and cisplatin treatment should be delayed until platelets are 
≥75 × 109/L. 
In any case at the occurrence of Grade 4 thrombocytopenia at nadir (<25 × 109/L), cisplatin 
dose reduction should take place in the subsequent infusion.
Dose Reduction for Renal Toxicity
In case of renal toxicity, the cisplatin dose must be reduced as in Table 6:
Table 6
Cisplatin Dose Reduction for Renal Toxicity
Creatinine Clearance
Cisplatin
≥60 mL/min
100 mg/m2
50-59 mL/min
80 mg/m2
40-49 mL/min
60 mg/m2
<40 mL/min
Discontinue
Dose Reduction for Peripheral Neuropathy
A neurological examination should be performed at screening, before the second cisplatin 
injection per local regulations by the investigator or qualified designee.  In case of symptoms 
or signs experienced by the participant, more frequent examinations should be performed per 
local regulations by the investigator or qualified designee and the following dose 
modifications are required:
Grade 0, 1 (CTCAE v.4.0): No change.
Grade 2 (CTCAE v.4.0): Cisplatin will be reduced to 60 mg/m2.
Grade ≥3 (CTCAE v.4.0): Cisplatin will be discontinued.
08KM9X

PRODUCT:  MK-3475 
107
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Dose Reduction for Ototoxicity
Cisplatin is known to cause high frequency hearing loss.  Follow local product label and 
institutional guidelines (eg, for France see Appendix 7 for the most recent version of the 
medicines SmPC). The following dose modifications are required:
•
If Grade 1 or 2 hearing loss (CTCAE v.4.0) occurs, the risk of additional hearing loss 
versus the potential benefit of continuing cisplatin chemotherapy should be made.
•
Grade 3 and 4 hearing loss (CTCAE v.4.0) is an indication to discontinue cisplatin.
Dose Modification for Other Toxicities
If toxicity has not resolved the participant should not receive further cisplatin.  The 
participant will continue with RT and will be followed-up according to the study protocol.  
Cisplatin can be administered up to 1 week following completion of RT.
Please also refer to the Multinational Association of Supportive Care in Cancer and European 
Society for Medical Oncology guidelines for treatment and prevention of emesis caused by 
highly emetic compounds [Roila, F., et al 2016]. Dose Modification for Cisplatin for other 
toxicities are presented in Table 7.
Table 7
Dose Modification for Cisplatin – Other Toxicities
Category
Toxicity
Hold 
Cisplatin 
Treatment 
for Grade
Timing for 
Restarting 
Cisplatin 
Treatment
Dose Level for 
Restarting 
Cisplatin 
Treatment
Discontinue 
Platinum
Non-
hematologic
Creatinine 
clearance 
Decreased
Please see Table 6 for guidance on dose level 
reduction and discontinuation.
All other non-
hematologic 
toxicitiesb
3-4a
Toxicity 
resolves to 
Grade 0-1 
Reduce by 1 
dose level
Toxicity does not 
resolve or if >2 
Dose Level 
reductions 
exceeded
Laboratory 
adverse eventb
4
Toxicity 
resolves to 
Grade 2 or 
less 
Reduce by 1 
dose level
Toxicity does not 
resolve or if >2 
Dose Level 
reductions 
exceeded
a. Permanent discontinuation should be considered for any severe or life-threatening event.  Consult Sponsor 
before restarting treatment after Grade 4 drug-related AE
b. Participants with intolerable or persistent Grade 2 drug-related AEs may hold at physician discretion.  
Permanently discontinue from cisplatin for persistent Grade 2 adverse reactions for which treatment has 
been held, and did not recover to Grade 0-1 of the last dose.  With investigator and Sponsor agreement, 
participants with a laboratory AE still at Grade 2 may continue in the study only if asymptomatic and 
controlled.
08KM9X

PRODUCT:  MK-3475 
108
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
7.3
Method of Treatment Assignment 
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).  There are 2 study treatment arms.  
Participants will be assigned randomly in a 1:1 ratio to pembrolizumab plus SoC (Arm A) 
and SoC (Arm B), respectively.
7.3.1
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
•
Primary tumor site (oropharynx/oral cavity vs. larynx vs. hypopharynx)
•
Tumor Stage III vs. IVA
•
PD-L1 status defined by TPS 50% (TPS≥50% vs. TPS<50%)
7.4
Blinding 
This is an open-label trial; therefore, the Sponsor, investigator and participant will know the 
study treatment administered.
Imaging and pathology data for the planned study analyses will be centrally reviewed by 
independent radiologist(s) and pathologist(s), respectively, without knowledge of participant 
treatment assignment.  The participant-level PD-L1 biomarker results will be masked in the 
database to the investigator (see Section 10.2).
7.5
Preparation/Handling/Storage/Accountability
7.5.1
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual.  
Preparation of cisplatin should follow the local product label (eg, for France see Appendix 7
for the most recent version of the medicines SmPC). The body surface area in m2 should be 
calculated per local guidance.
7.5.2
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments 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.
08KM9X

PRODUCT:  MK-3475 
109
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all trial 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 trial 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.
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 
treatments in accordance with the protocol and any applicable laws and regulations.
7.6
Treatment Compliance
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 due to medical/surgical events or 
logistical reasons not related to study therapy (eg, elective surgery, unrelated medical events, 
participant vacation, and/or holidays) >6 weeks between pembrolizumab doses and/or 
>12 weeks between pembrolizumab doses for drug-related AEs associated with 
pembrolizumab exposure (see Section 7.2.1 for dose modification guidelines for drug-related 
events) require consultation between the investigator and the Sponsor and written 
documentation of the collaborative decision on participant management.
7.7
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during study treatment through follow-up (refer to Appendix 8 for Germany-specific 
guidances).  If there is a clinical indication for any medication or vaccination specifically 
prohibited, discontinuation from study therapy may be required.  The investigator should 
discuss any questions regarding this with the Sponsor 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 treatment 
requires the mutual agreement of the investigator, the Sponsor and the participant.
The following are prohibited concomitant therapy or vaccination during the course of the 
study:
1. Antineoplastic systemic chemotherapy or biological therapy, including prior therapy with 
an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-
inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
08KM9X

PRODUCT:  MK-3475 
110
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
2. Immunotherapy not specified in this protocol
3. Chemotherapy not specified in this protocol
4. Radiation therapy not specified in this protocol, including prior RT for the HNC under 
study.
5. Investigational agents other than pembrolizumab, including prior use of investigational 
agents for the HNC under the study.
6. Live vaccines within 30 days prior to the randomization, while participating in the study
and receiving study treatment, and for 3 months after the end of study treatment.  
Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, chicken pox, yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid (oral) 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and 
are allowed. However, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines, and are not allowed. Refer to Appendix 8 for Germany-specific requirements.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated 
just as any other concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
7. Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE
that is suspected to have an immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor. Note the following:
•
A short course of steroids may be used as concomitant medication for either treatment of 
an AE or medical condition with Sponsor approval.
•
Inhaled steroids are allowed for management of asthma.
•
Use of prophylactic corticosteroids to avoid allergic reactions (eg, to IV contrast dye) is 
permitted.
•
Use of steroids for antiemetic purposes is permitted.
•
Use of steroids for premedication for study treatment is permitted.
8. No upfront prophylactic growth factor support with granulocyte-colony stimulating factor 
is allowed during CRT treatment. However, treatment of neutropenia with granulocyte-
colony stimulating factor is allowed, if clinically indicated.  Use of erythropoietin is not 
permitted.
08KM9X

PRODUCT:  MK-3475 
111
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9. During Cisplatin treatment only: Cisplatin is a potentially nephrotoxic drug which can be 
potentiated by other nephrotoxic agents such as aminoglycoside antibiotics. Use of 
aminoglycosides (such as streptomycin, dihydrostreptomycin, kanamycin, gentamicin,
neomycin, tobramycin, netilmicin, and amikacin) should be administered with caution 
given the risk of nephrotoxicity. The serum creatinine, blood urea nitrogen, and 
electrolytes should be monitored carefully when additional nephrotoxic agents are used. 
Participants receiving cisplatin and other potentially ototoxic drugs such as 
aminoglycosides should also be closely monitored for signs of ototoxicity. If the 
administration of aminoglycosides is required, additional audiometric testing may be 
necessary for further safety monitoring. Please contact the Sponsor if aminoglycosides 
are administered to a study participant in order to discuss renal management as well as 
frequency of audiometric assessments. Refer to Appendix 8 for Germany-specific 
guidance.
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the electronic case report form 
(eCRF) including all prescription, over-the-counter 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 randomization and up to 
30 days after the last dose of study treatment should be recorded.  Concomitant medications 
administered 30 days after the last dose of study treatment should be recorded for SAEs and 
ECIs as defined in Section 9.3.
There are no prohibited therapies in the Post-Treatment Follow-up Visits.
7.7.1
Rescue Medications & Supportive Care
7.7.1.1
Supportive Care Guidelines for Pembrolizumab
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined in Section 7.2 Table 3.  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. 
08KM9X

PRODUCT:  MK-3475 
112
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Note: if after the evaluation the event is determined not to be related, 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.
7.7.1.2
Supportive Care Guidelines for Surgery
Supportive care will be provided as per local SoC and any AEs will be captured in the 
database (see Section 9.1.10.2.3).
7.7.1.3
Supportive Care Guidelines for Radiation
Supportive care will be provided as per local SoC (see Section 9.1.10.1.2.3)
7.7.1.4
Supportive Care Guidelines for Cisplatin
See Section 9.1.10.1.3
7.8
Treatment After the End of the Study 
There is no study-specified treatment following the end of the study.
7.9
Clinical Supplies Disclosure
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or 
designee are not blinded. Study treatment (name, strength or potency) is included in the label 
text; random code/disclosure envelopes or lists are not provided.
8
DISCONTINUATION/WITHDRAWAL CRITERIA 
8.1
Discontinuation of Study Treatment 
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment 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 treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
will still continue to participate in the study as specified in Section 2 - Schedule of Activities 
and Section 9.1.11 – Withdrawal/Discontinuation.
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 9.1.11 – Withdrawal/Discontinuation.
08KM9X

PRODUCT:  MK-3475 
113
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
A participant must be discontinued from study treatment 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 treatment.
•
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 treatment.
•
The participant has a confirmed positive serum pregnancy test.
•
BICR verified radiographic disease progression outlined in Section 9.2.1.4.
-
Exceptions:
◦
Participants with no histologic evidence of invasive cancer after definitive biopsy 
of the progressed lesion will not meet criteria for an event.
-
Radiographic disease progression during the neoadjuvant phase that precludes
surgery will be considered an event.
•
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment.
•
Recurrent Grade 2 pneumonitis.
•
Completion of 17 doses of treatments with pembrolizumab.
Note: 2 doses of study medication (pembrolizumab) are administered prior to surgery, at 
3-week intervals from the date of the first dose.  A subsequent 15 doses are administered 
post-surgery, calculated in 3-week intervals from the date of the first dose post-surgery.
•
Administrative reasons.
Refer to Appendix 8 for additional Germany-specific guidance. 
For participants who are discontinued from study treatment but continue to be monitored in 
the trial, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study treatment is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study treatment.
8.2
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 treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from Future Biomedical Research, are 
outlined in Section 9.1.11 – Withdrawal/Discontinuation. Refer to Appendix 8 for additional 
08KM9X

PRODUCT:  MK-3475 
114
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Germany-specific guidance. 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 8.3.
8.3
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, phone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note:  A participant is not considered lost to follow-up until the last scheduled visit for 
the individual participant.  The amount of missing data for the participant will be 
managed via the pre-specified data handling and analysis guidelines.
9
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 assuring that procedures are conducted by 
appropriately qualified or trained staff.  Delegation of trial site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).
•
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 utilized for 
screening or baseline purposes provided the procedure met the protocol-specified criteria 
and were performed within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to subject safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
08KM9X

PRODUCT:  MK-3475 
115
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
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.
Refer to Appendix 8 for country-specific requirements. 
9.1
Administrative and General Procedures
9.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or Future Biomedical 
Research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate documented informed consent is in place. 
9.1.1.1
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.
08KM9X

PRODUCT:  MK-3475 
116
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the Future Biomedical Research 
consent to the participant, or the participant’s legally acceptable representative, answer all of 
his/her questions, and obtain documented informed consent before performing any procedure 
related to Future Biomedical Research. A copy of the informed consent will be given to the 
participant before performing any procedure related to Future Biomedical Research.
9.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the study.
9.1.3
Participant Identification Card
All participants will be given a Participant Identification Card identifying them as 
participants in a research study. The card will contain trial site contact information (including 
direct telephone numbers) to be utilized 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 
treatment allocation/randomization, site personnel will add the treatment/randomization 
number to the Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
9.1.4
Medical History
Demographics and a complete medical history, including details of alcohol and tobacco,
usage will be obtained by the investigator or qualified designee. The medical history will 
collect all active conditions and any condition diagnosed within the prior 10 years that the 
investigator considers to be clinically significant. Details regarding the disease for which the 
participant has enrolled in this study will be recorded separately and not listed as medical 
history. 
9.1.4.1
Disease Details
Details regarding participants HNSCC 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, etc. Refer to Sections 6.1
and 6.2 to ensure participant’s disease status meets the relevant inclusion and exclusion 
criteria for study entry.
08KM9X

PRODUCT:  MK-3475 
117
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9.1.5
Prior and Concomitant Medications Review
9.1.5.1
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 prior to randomization. Prior treatment for other cancers will also be recorded 
as a prior medication.
9.1.5.2
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, including AEs and SAEs following definitive surgery should be 
recorded as defined in Appendix 4.
9.1.5.3
Post-study Anticancer Therapy Status
Investigator or qualified designee will record anticancer therapy medication, if any, taken by 
the participant after discontinuing from study treatment and through study follow-up.
9.1.6
Presurgery Tumor Tissue Collection
In accordance with the study inclusion criteria, participants are required to provide baseline 
tumor tissue from FFPE tissue specimens, obtained during the participant’s initial diagnosis, 
for PD-L1 and HPV assessment.  
HPV p16 testing
Participants must have assessment of HPV status from tumor tissue prior to randomization 
(see Section 6.1).  In this study, HPV testing may be performed using local testing of HPV 
p16 status in participants with oropharynx cancer using the specified method.  Oral cavity, 
hypopharynx, and larynx cancer are not required to undergo local HPV testing as by 
convention these tumor locations are assumed to be HPV-negative.
Tumor p16 expression must be evaluated by assessment of IHC analysis with CINtec® p16 
Histology assay (Ventana Medical Systems Inc., Tucson AZ) using standard protocol.  
Positive p16 expression is defined as strong and diffuse nuclear and cytoplasmic staining in 
70% or more of the tumor cells.
If local p16 testing results are not available, or cannot be assessed by the specified method, a 
tumor tissue sample must be submitted for p16 testing at the designated central laboratory.
A tissue sample (regardless of tumor location: oropharyngeal, oral cavity, hypopharynx, or 
larynx cancer) used for PD-L1 testing can be used for HPV testing if required (see Vendor 
Manual).
08KM9X

PRODUCT:  MK-3475 
118
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
PD-L1 testing
Participants must have central laboratory assessment of PD-L1 status from tumor tissue prior 
to randomization for stratification (see Section 6.1).  
This specimen may be the diagnostic sample for participants with a new diagnosis of LA 
HNSCC.  
9.1.7
Survival Status
All participants that are on study will receive on study follow-up as specified in the Section 2 
– Schedule of Activities until Year 5 and thereafter every 3 months (91 ±14 days) to assess 
for survival status until death, withdrawal of consent, or at the end of the study, whichever 
occurs first. Once a participant experiences an event/disease progression/recurrence verified 
by BICR review, the participant should still be assessed for survival status every 3 months
(91 ±14 days). Survival status could be collected by telephone contact. When assessing for 
survival status for participants in survival follow-up who have not experienced an 
event/progression, also evaluate and document whether the participant has had additional 
imaging assessments or biopsy-confirmed progression (see Section 2.4).
To ensure current and complete survival data is available at the time of database locks, the 
Sponsor may request survival status to be assessed at additional time points during the course 
of the study.  For example, these additional assessments may be requested prior to an eDMC 
safety review, IA, and/or final analysis.  Upon Sponsor notification, all participants who do 
not/will not have a scheduled study visit or study contact during the Sponsor defined time 
period will be contacted for their survival status (excluding participants that have a 
previously recorded death event in the collection tool).
9.1.8
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization.  Each participant 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different participants.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 9.10.1.  
9.1.9
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization.  Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
08KM9X

PRODUCT:  MK-3475 
119
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9.1.10
Treatment Administration
Study medication will be administered by the investigator and/or study staff according to the 
specifications within the Pharmacy Manual. 
For the pembrolizumab arm (Arm A), presurgery neoadjuvant treatment (Treatment 1) 
should begin within 3 days of randomization. The timeframe for surgery (after the 
presurgery visit) is within 6 weeks (±10 days) after randomization. Participants in Arm A are 
allowed to go to surgery outside of this timeframe if delays are due to an AE. Participants 
with delays other than for an AE may be considered with sponsor consultation. In the SoC 
arm (Arm B), following randomization participants will proceed directly to surgery as per 
local practice.  In both treatment arms, post-surgery adjuvant treatment will start when 
participants have recovered adequately from the morbidity and/or complications from the 
surgery with RT ± cisplatin starting at a recommended minimum range of within 6 weeks 
after surgery.
9.1.10.1
Timing of Dose Administration
The dose and schedule modifications of pembrolizumab, cisplatin and RT are provided in 
Section 7.2 - Dose Modification (Escalation/Titration/Other).
9.1.10.1.1
Pembrolizumab (Arm A Only)
Pembrolizumab will be administered on Day 1 of each 3-week dosing cycle after all 
procedures and assessments are completed according to the SoA (Section 2.0).
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion. 
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a window 
between -5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes-5 min / 
+10 min).
Participants in Arm A are to receive 2 cycles of pembrolizumab presurgery in the 
neoadjuvant treatment phase.  Each cycle is 21 days.  Note: Participants in the 
pembrolizumab arm (Arm A) may proceed to surgery after 1 dose of pembrolizumab, if 
deemed appropriate, if the investigator has documented clinical evidence of tumor 
progression, preferably supported by radiographic evidence.
Participants in Arm A can start to receive pembrolizumab as adjuvant, once they have 
recovered adequately from the morbidity and/or complications from the surgery, as 
determined by the investigator.  Post-surgery, participants can receive up to 4 doses of 
pembrolizumab Q3W, prior to the start of RT ± cisplatin, and if RT ± cisplatin is delayed the 
timing of these doses can be adjusted based on timing of surgery.  If this occurs, assessments 
obtained for cycles of pembrolizumab administered prior to initiation of RT should mimic 
assessments required on cycle 2 day 1 of adjuvant treatment for Arm A in the SoA, except 
ePROs should only be obtained during RT, as outlined in the SoA. The weekly visits outlined 
in cycles 1 and 2 of the SoA should be completed during RT as weekly visits are only 
required during RT.
08KM9X

PRODUCT:  MK-3475 
120
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
In addition, participants can receive pembrolizumab during RT ± cisplatin and then 
continued as monotherapy for a total number of 15 pembrolizumab infusions post-surgery 
(total duration of pembrolizumab ~1 year).  If, within 3 weeks of surgery, pembrolizumab 
was not started because participants have not recovered adequately, pembrolizumab will 
restart concurrently with RT ± cisplatin.
For the combination portions of the study, treatment will be administered in the order: 
Pembrolizumab infusion is administered first followed by cisplatin infusion (high-risk 
participants only) and then RT.
Participants may receive up to 17 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 3-week interval schedule, but 
all future doses should be recalculated in 3-week intervals. Participants should be 
administered all planned 17 cycles, which could extend beyond the 1-year timeframe of the 
study. If a dose of pembrolizumab is skipped and additional treatment cycles are required to 
reach 17 doses of pembrolizumab, perform all assessments in the additional cycles as 
indicated in the SoA (Section 2.2) under Cycle 8-15.
The Pharmacy Manual contains specific instructions for the pharmacist for the preparation of 
the pembrolizumab infusions and administration of infusion solutions.
9.1.10.1.2
Radiotherapy
It is recommended that RT is started within 6 weeks after surgery.  All participants in the 
study will be treated with 6 to 10 MV photons.  The administration of standard fractionated 
RT regimen should follow the dose parameters in Table 8.  Linear accelerator or 
Tomotherapy based equipment is allowed.  Use of intensity modulated radiation therapy 
(IMRT) is required, with either a sequential boost technique or Simultaneous Integrated 
Boost (SIB-IMRT).
Center credentialing will be performed according to criteria defined in the RT QA Manual.  
Participating institutions must comply with the RT QA requirements and procedures 
described in the RT QA manual.  Sites that do not conform to the requirements of the 
credentialing will not be allowed to participate.
Both static and dynamic techniques IMRT techniques (including VMAT) are allowed.  Dose 
planning, prescription, specification and reporting will be done according to International 
Commission on Radiation Units (ICRU) report 83 recommendations.  Dose-volume 
constraints will be used for both dose specification and dose reporting in planning target 
volume (PTV) and planning organs at risk volumes (PRV)/organs at risk (OAR) (see Section 
9.1.10.1.2.1).  The dose-volume objectives that will be used for planning, dose specification 
and dose reporting in PTV, PRV and OAR are described in Section 9.1.10.1.2.1.
08KM9X

PRODUCT:  MK-3475 
121
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 8
Radiotherapy Dose Parameters
Sequential Boost Plan
Simultaneous Integrated 
Boost 
(followed by additional boost 
if needed)
Low Risk for Microscopic 
Diseasea
50 - 54 Gy in 25 - 27 
fractions
54 Gy in 30 fractions
Intermediate Risk for 
Microscopic Diseaseb
60 Gy in 30 fractions
60 Gy in 30 fractions
Regions at High Riskc
66 Gy in 33 fractions
66 Gy in 33 fractions
Gross Residual Tumord
70 Gy in 35 fractions
70 Gy in 35 fractions
CTV=clinical target volume; GTV=gross tumor volume; IGRT=image guided radiation therapy; 
PTV=planning target volume; RT=radiotherapy.
a. CTV_5000 or CTV_5400 defined as the area that is low risk for microscopic disease.  This is the non-
dissected neck.  This RT dose is applicable for participants in the low-risk and high-risk groups.
b. CTV_6000 defined to include the post-operative tumor bed and nodal regions at risk of microscopic 
spread that have not been operated on according to standard anatomic guidelines relative to location and 
extent of gross disease.  Please note all operated sites should receive 60 Gy.  This RT dose is applicable
for participants in the low-risk and high-risk groups.
c. CTV_6600 defined to include 0.5 cm expansion on regions thought to be at high risk of recurrence (eg, 
areas of extranodal extension or positive margins of resection).  This RT dose is applicable for 
participants in the high-risk group.
d. For participants who do not undergo planned curative surgery or for incomplete resection with gross 
residual tumor: primary surgical tumor bed encompassing preoperative GTVs plus up to 0.5 cm to define 
CTV_7000.
All PTVs defined as 0.3 to 0.5 cm expansions on CTVs based on method and frequency of IGRT.
Radiotherapy treatment for participants that undergo surgery will be delivered over 6 to 
6.5 weeks, depending on risk of recurrence, by incorporating 5 fractions per week (example: 
5 fractions over 5 days (1 fraction per day), 2 days off).
Participants that do not undergo surgery as planned, for whatever reason, and proceed 
directly to salvage CRT may receive a RT dose of 70 Gy (total of 35 fractions) over 6.5 to 
7 weeks.
When Sequential Boost IMRT is used, planning and delivery should be as follows: 50 Gy in 
25 fractions or 54 Gy delivered in 27 fractions of 2 Gy/fraction, followed by a boost of 6 Gy 
in 3 additional fractions of 2 Gy/fraction.  If an additional boost is required for high risk area 
such as areas of extranodal extension and/or positive margins, an additional 6 Gy can be 
delivered in 2 Gy/fraction in 3 fractions.  
If SIB-IMRT is used, potential planning and delivery can be as follows: 60 Gy delivered in 
30 fractions of 2 Gy/fraction given simultaneously with 54 Gy in 1.8 Gy/fraction.  If an 
additional boost is required for high risk area such as areas of extranodal extension and/or 
positive margins, an additional 6 Gy can be delivered in 2 Gy/fraction for 3 fractions.  
08KM9X

PRODUCT:  MK-3475 
122
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
If all of the surgical area is considered at high risk for disease recurrence, another potential 
prescription option can be 66 Gy fractions given in 33 fractions at 2 Gy/fraction.  
If gross disease is identified, in the case of a participant with incomplete resection, an 
additional boost up to 70 Gy may be delivered to the gross disease area.
If there is any doubt of the level of risk for recurrence after surgery but before RT based on 
physical examination and/or imaging, pathologic confirmation prior to start of RT is highly 
encouraged.  
For participants in Arm A receiving treatment with pembrolizumab, the radiotherapy plan 
should be based on disease evaluation completed prior to initiation of neoadjuvant treatment 
regardless of response to treatment. An exception to this is that, in cases of tumor 
progression, a more extensive radiotherapy plan could be necessary for adequate coverage of 
tumor.    
Questions relating to target volume delineation, treatment planning and treatment delivery 
can be submitted to the Sponsor as detailed in the RT QA Manual.
Radiotherapy plans for each participant should be submitted for approval to the RT vendor 
with any additional documentation as detailed in the RT QA Manual prior to initiation of RT.
Participant position and data acquisition
All participants will be irradiated in the supine position. Immobilization devices such as 
customized masks have to be used to ensure the accuracy and reproducibility of participants 
positioning during RT. Preferably, mask immobilization of the head, neck and shoulders will 
be used. For all participants, a planning CT scan will be performed in the immobilization 
device to capture slices extending from the level of the base of skull to the lower border of 
the clavicle. Slice thickness of preferably 2 to 3 mm will be used.  Images will be 
constructed with at least 512 × 512 pixel matrices.  It is acceptable to have the simulation CT 
scan as part of the diagnostic PET/CT scan with IV contrast so long the slice thickness is 
≤3 mm.
To enhance vascular and soft tissue contrast and to facilitate delineation of both target 
volumes and OAR’s the use of IV contrast enhancement is strongly recommended during 
simulation, unless medically contraindicated. If IV contrast is not used for the planning scan,
it is mandatory the participant has either a contrast enhanced diagnostic CT and/or MRI 
performed no longer than 4 weeks prior to simulation. A PET/CT scan is encouraged to 
obtain a baseline status after surgery but before post-operative RT.  This scan should be 
performed at least 4 weeks after surgery to minimize inflammation secondary to surgery.  
These images will have to be co-registered to the planning CT for contouring purposes and 
will be submitted along with the planning CT for QA.  
08KM9X

PRODUCT:  MK-3475 
123
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9.1.10.1.2.1
Volume Definition
The definition of volumes will be in accordance with ICRU Reports #50, #62 and #83 [ICRU 
1993; ICRU 1999; ICRU 2010]. Volumes will be named according to the target and OAR
naming convention published by Santanam et al (2012) [Santanam, L., et al 2012].
Gross Tumor Volume (GTV)
A GTV will be defined only in cases where surgery was not performed or there is a concern 
of gross tumor identified post-operatively and where further surgery is not possible.  In those 
cases a primary GTV (labeled GTVp) will be defined as all known areas of gross disease 
determined from CT, MRI, clinical information, and endoscopic findings.  A nodal GTV 
(labeled GTVn) will encompass grossly involved lymph nodes defined as those >1.5 cm in 
long axis or >1 cm in short (axial) axis or nodes of any size with radiologic evidence of 
necrosis.  Acceptable diagnostic imaging studies will include contrast enhanced CT and MRI 
and may be co-registered with the planning CT data set to facilitate GTV delineation.  
Fluorodeoxyglucose-positron emission tomography if available may be used to guide tumor 
identification but should not be used to define GTV borders given the uncertain relationship 
between the margin of the PET signal and tumor border. 
Clinical Target Volumes 
Clinical target volumes (CTVs) will be defined and named according to the doses intended to 
be delivered. The CTV_6000 will encompass the post-operative bed along with any areas
considered at risk of microscopic tumor involvement (including nodal levels at risk). The 
CTV_6600 will encompass the highest risk disease area (ie, areas of extranodal extension 
and/or microscopic positive margin).  The CTV_6600 is encompassed within CTV_6000.  
The CTV_5000 or CTV_5400 will encompass the lower risk microscopic region, typically 
the non-surgically violated area.  
Clinical Target Volumes are defined as described below, limited according to natural barriers 
of spread and expanded to include anatomic regions at risk of microscopic spread. A high 
risk volume may be defined at the clinical discretion of the treating physician with defined 
individual department protocols.  This optional volume can be used when the investigator 
prefers to give a higher dose than the microscopic risk region understanding it does not 
harbor gross tumor.  Often, this volume encompasses areas of extranodal extension and/or 
positive margins.
Please note that the oral cavity composes of lip, buccal mucosa, oral tongue, floor of mouth, 
gingiva, hard palate, and retromolar trigone.  Each of these subsites within the oral cavity 
have different patterns of spread which needs to be encompassed within the respective CTVs.  
A more detailed description of coverage of each of these subsites is provided in the RT QA 
Manual.
08KM9X

PRODUCT:  MK-3475 
124
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Clinical Target Volume for Gross Residual Disease (CTV_7000)
The CTV_7000 will consist of a 5 mm isotropic expansion of the GTVp and a 5 mm 
isotropic expansion of the GTVn.  The CTV_7000 should be constrained to exclude regions 
protected by physical or anatomic barriers such as air (cavities or external to participant
contour), bone (mandible or vertebral body) or fascial planes through which tumor spread is 
not apparent.
The CTV_7000 will be contained within the CTV_6000 and CTV_5000 or CTV_5400 
defined to cover microscopic disease/prophylactic nodal regions at risk.
Clinical Target Volumes for Regions at High Risk of Tumor Recurrence (CTV_6600)
The CTV_6600 will encompass the post-operative tumor bed along with any areas 
considered at risk of microscopic tumor involvement.  This volume will be used when the 
investigator prefers to give a higher dose than the microscopic risk region understanding it 
does not harbor gross tumor.  It will be defined at the clinical discretion of the treating 
physician based on the pathology report after surgical resection.  
Clinical Target Volumes for Regions at Low or Intermediate Risk of Microscopic Tumor 
Involvement 
The CTV_6000 and CTV_5000 or CTV_5400 will encompass:
1. A 5 to 10 mm expansion on the post-operative tumor bed constrained to exclude regions 
protected by physical or anatomic barriers such as air (cavities or external to participant
contour), bone (mandible or vertebral body) or facial planes through which tumor spread 
is not apparent.
2. Nodal levels deemed at risk of microscopic tumor involvement.  The neck node levels 
will be delineated on each CT slice according to the updated guidelines defined by a 
consensus panel for the node-negative and the node-positive neck [Gregoire, V., et al 
2014].  In case of infiltration (or suspicion of infiltration) of the sternocleidomastoid 
muscle, the muscle will be included in the low to intermediate risk CTVs.
Delineation of the Planning Target Volume 
Planning target volumes PTV_7000, PTV_6600, PTV_6000 and PTV_5000 or PTV_5400 
will be defined to enclose the corresponding CTV, respectively. Radiation dose will be 
prescribed, planned, and evaluated to these PTVs.  Planning Target Values are used to 
account for participant movement, variation and residual error in day to day setup and will be 
generated by an isotropic expansion of their associated CTVs. Centers employing image 
guided radiation therapy (IGRT) using daily volumetric imaging (accelerator mounted kV or 
MV cone beam or tomotherapy MV CT) may generate PTVs with a 3 mm expansion. All 
others must use a 5 mm expansion.
In cases for which disease extends close to the participant external contour, depending on the 
equipment used, tissue equivalent bolus may be used to properly irradiate all parts of the 
08KM9X

PRODUCT:  MK-3475 
125
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
CTV, and the PTV extended to the external contour beneath the bolus. Planning Target 
Values will also be limited in regions where they may overlap with critical organ PRVs 
(spinal cord and brains stem) see Table 9.  In cases that do not have skin involvement with 
disease, the PTV does not have to extend beyond the skin surface.
Delineation of Organs at Risk 
Standard OARs are included in the following list and must be contoured on the planning CT 
data set according to the guidelines of Brouwer et al [Brouwer, C. L., et al 2015], utilizing 
the indicated naming convention. Guidelines for OAR contouring are provided in Table 9
and as published by Brouwer et al [Brouwer, C. L., et al 2015].
Table 9
Standard Organs at Risk
OAR
Standard Name
Spinal cord
SpinalCord
Brain stem
BrainStem
Lips
Lips
Oral cavity (beyond PTV)
OralCavity
Mandible
Mandible
Right Parotid
Parotid_R
Left Parotid
Parotid_L
Right Submandibular
Submandibular_R
Left Submandibular
Submandibular_L
Pharynx (beyond PTV)
Pharynx
Cervical Esophagus (beyond PTV)
Esophagus
Optic structures if needed
Optic-Structures
Larynx
Larynx
Cochlea
Cochlea
External border of participant
External
Abbreviations: OAR = organs at risk; PTV = planning target volume
Planning Organ at Risk Volume 
A planning OAR volume (PRV) for the critical OARs spinal cord and brainstem will be 
generated with an isotropic expansion for the purpose of dose evaluation and limitation to 
these structures. The PRVs represent a safety margin for these critical structures to account 
for variability in day to day positioning.  Centers utilizing daily volumetric imaging 
(accelerator mounted kV or MV cone beam or tomotherapy MV CT) may generate PRVs 
with a 3 mm expansion. All others must use a 5 mm expansion.
08KM9X

PRODUCT:  MK-3475 
126
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Treatment Planning
Participants will be treated by IMRT or volumetric modulated arc RT using 6 to 10 MV 
photons.  For linear accelerators, field arrangements are left to the discretion of the medical 
physicists to produce an optimal dose distribution matching the dose-volume constraints for 
PTV, PRV and OAR.  Non-coplanar field arrangements are allowed, but beam directions 
through the eyes are not allowed unless unavoidable.  All field entrance and exits should be 
within the planning CT range in order to avoid any inadequate dose calculations.
Treatment plans will be computed using modern type B dose calculation algorithms such as 
convolution/superposition, Monte Carlo, collapsed cone or equivalent algorithms.  The dose 
calculation matrix to be used must be less than 4 mm.  Dose calculations must account for 
tissue heterogeneity. 
The following dose-volume objectives (Table 10) will be used for planning, dose 
specification and dose reporting for PTV, PRV and OAR:
Table 10
Dose Volume Objectives
PTV
D95%1
Dnear-
min
Dnear-max
D5%
Median 
Dose
OAR / PRV
Or D98 %
Or D2%
Or D50%
Mean Dose
PTV_7000
≥95% of 
planned 
dose
≥90% of 
planned 
dose
-
≤107% 
of 
planned 
dose
70 Gy ± 2%
-
PTV_6600 
(optional high 
risk volume)
≥95% of 
planned 
dose
≥90% of 
planned 
dose
-
≤107% 
of 
planned 
dose
66 Gy ± 2%
-
PTV_6000
≥95% of 
planned 
dose
≥90% of 
planned 
dose
-
≤107% 
of 
planned 
dose
60 Gy ± 2%
-
PTV_5000 or 
PTV_5400
≥95% of 
planned 
dose
≥90% of 
planned 
dose
-
-
54 Gy or 
50 Gy ± 2%
-
PRV spinal cord
-
-
≤45 Gy
-
-
-
PRV brain stem
-
-
≤50 Gy
-
-
-
Contralateral 
parotid
-
-
-
-
-
≤25 Gy
Ipsilateral 
parotid
-
-
-
-
-
≤30 Gy
Oral cavity
-
-
-
-
-
≤30 Gy
Larynx
-
-
-
<55 Gy
-
≤44 Gy
Mandible
-
-
≤70 Gy
-
-
-
1 Dv: Dose in v% of the volume
Abbreviations: OAR = organs at risk; PRV = Planning Organ at Risk Volume; PTV = planning target volume.
08KM9X

PRODUCT:  MK-3475 
127
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9.1.10.1.2.2
Treatment Verification and Accuracy
All participants must have routine imaging performed to verify treatment set up.  The 
minimum imaging requirement is once weekly orthogonal KV images commencing on the 
first day of treatment and reviewed by the managing radiation oncologist. Centers are 
strongly encouraged to employ daily volumetric image guidance with either accelerator 
mounted KV or MV cone beam CT or tomotherapy CT images utilizing matching of bony 
anatomy.  The margin for PTV can be reduced to 3 mm if daily IGRT is performed.
Table 11 details radiotherapy compliance criteria.
Table 11
Radiotherapy Compliance Criteria
Per Protocol
Variation Acceptable
Deviation 
Unacceptable
Prescription 
Dose
Delivered daily or total 
dose to any PTV is within 
5% of the protocol dose. 
Delivered  daily or total 
dose to any PTV differs 
from the protocol 
specified dose by 6-10% 
Delivered daily or total 
dose to any PTV differs 
from the 
protocol specified dose 
by >10%
Dose 
Uniformity
Dose to 95% of any PTV 
is > 95% of prescribed 
dose.
Dose to 95% of any PTV 
<95% of the prescribed 
dose; >10% of the highest 
dose PTV >110% of 
prescribed dose
Dose to 95% of any 
PTV <90% of the 
prescribed dose; >10% 
of the highest dose PTV 
>120% of prescribed 
dose
Volume
Volumes follow protocol 
guidelines
PTV margins are less than 
the protocol specified 
margins or excessively 
large
CTV does not 
encompass areas at risk.
Organs at 
Risk
Dose to 2% of PRV 
spinal cord >50 Gy
Dose to 2% of PRV 
brainstem >54 Gy
Interruptions
Uncompensated 
Interruptions more than 2 
days for reasons other 
than toxicity
Uncompensated 
Interruptions more than 
10 days for reasons 
other than toxicity
Abbreviations: CTV = clinical target volume; PRV = Planning Organ at Risk Volume; PTV = planning 
target volume.
08KM9X

PRODUCT:  MK-3475 
128
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9.1.10.1.2.3
Supportive Care for Head and Neck Radiotherapy
Radiation-induced head and neck toxicity is well known and has been well described. It is 
expected to vary according to the total dose and the concomitant use of chemotherapy.
Locoregional toxicity will be monitored during treatment using CTCAE v. 4.0 and will be 
reported in the database.  Supportive care will be provided according to local SoC. 
Reversible mucositis and pharyngitis is expected, and supportive care will be initiated (eg, 
pain medication, mouth wash, adaptation of the diet, use of a nasogastric or percutaneous 
endoscopic gastrostomy feeding tube). In very rare cases of severe Grade 4 mucositis (eg, 
bleeding); it may be necessary to interrupt RT for a few days. However, it is mandatory to 
limit the break to a strict minimum.
Various degrees of skin reaction (typically Grade 2, less frequently Grade 3) are expected in 
the treated area. Other expected acute reactions include fatigue, xerostomia, dysgeusia, 
ageusia and dysphagia. 
Central nervous system events in terms of nausea and vomiting are expected. Late effects 
include some degree of xerostomia and occasionally persistent dysphagia.
Mandibular osteoradionecrosis may occur in less than 5% of the participants. Thorough 
dental evaluation and, if necessary, adequate care performed before the start of RT, will 
substantially decrease this risk.
9.1.10.1.2.4
Treatment Interruptions / Modifications
Treatment interruptions are to be avoided unless medically necessary.  Any breaks in RT 
should be minimized. See Section 7.2.2 – Dose Modification for Radiotherapy.  
9.1.10.1.3
Cisplatin
Three doses of cisplatin will be administered to those participants, in both treatment arms, 
considered at high-risk of recurrence based on the pathological features ie, positive margins 
(< 1 mm) or extranodal extension in the surgical specimen assessed by the local pathologist.  
If there are delays in cisplatin treatment, cisplatin may be administered up to 1 week 
following completion of RT.  Participants that deviate from receiving planned cisplatin due 
to medical considerations may continue on the study after discussion with Sponsor and 
review of dose modification options (see Section 7.2.3).  Three doses of cisplatin are
permitted in those participants that do not undergo planned surgery and proceed directly to 
salvage CRT.  
Cisplatin will be administered after all procedures and assessments are completed according 
to the Schedule of Activities in Section 2.0.  
Cisplatin is given as a dose of 100 mg/m2 using an infusion duration of 60 minutes (or 
infusion duration according to local practice).
08KM9X

PRODUCT:  MK-3475 
129
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Note:  For body surface area over 2 m2 the cisplatin dose will be capped at the one calculated 
for body surface area = 2 m2.
Before and after administration of cisplatin, adequate hydration is required and can be given 
as normally used in each institution.  It is advised that participants can be hospitalized for at 
least 24 hours to allow optimal hydration before and after drug injection, if required per local 
regulations; or cisplatin may be administered on an outpatient basis, if adequate hydration 
can be managed and if allowed per local regulations.  If hydration is performed as a planned 
hospitalization, it would not meet that criterion for SAE.
Administration of Cisplatin
The administration of cisplatin can follow the standard local practice and/or international 
guidelines. However, it is highly recommended to follow the instructions as reported below.
It is recommended that cisplatin start on the first day of RT (±2 days).  Follow local product 
label and institutional guidelines.  Cisplatin can be administered up to 1 week following 
completion of RT regimen.
Before starting the treatment with cisplatin, the following criteria must be met:
•
Neutrophils:
≥1.0 × 109/L
•
Platelets:
≥75 × 109/L
•
Creatinine clearance: ≥60 mL/min (Cockcroft-Gault formula).  It is recommended that 
participants whose creatinine clearance is <60 mL/min on the scheduled day of cisplatin 
administration receive IV fluid hydration for 1 to 2 days followed by a repeat CrCL.  The 
cisplatin can be dosed based on the follow up CrCl level (see Table 6).
Recommendations:
•
Encourage the participant to drink 2 to 3 liters of water per day during the days preceding 
and following cisplatin infusion.
•
Any pre-existing dehydration must be corrected before starting the hydration related to 
cisplatin administration.
•
Assess the hydration status during physical examination.
•
Antiemetic medications should include: 
-
serotonin type 3 antagonist (eg, granisetron 1-3 mg IV or ondansetron 8-32 mg IV or 
palonosetron IV 0.25 mg IV; 30 minutes before cisplatin infusion), 
-
aprepitant (eg, 125 mg orally [per os; po] 30 minutes before cisplatin infusion and 
80 mg/day PO during the 2 following days, or 150 mg IV on Day 1),
08KM9X

PRODUCT:  MK-3475 
130
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
-
corticosteroids (eg, dexamethasone 20 mg [12 mg if given with aprepitant] 
30 minutes before cisplatin infusion and dexamethasone 8 mg twice per day [8 mg 
once per day if given with aprepitant] po during the 3 following days). Another 
equivalent corticosteroid regimen is allowed according to local practice. The 
maximum dose of steroids for antiemetic treatment or prophylaxis is 20 mg/day [12 
mg if given with aprepitant] dexamethasone or its steroid equivalent),
-
any "as-needed" antiemetics according to each institutional guideline 
(metoclopramide, alizapride, additional steroids, etc.). 
•
Intravenous pre- and post-hydration per local guidelines. Following cisplatin infusion, an 
overnight additional hydration is also allowable, per local regulations.
•
Cisplatin infusion: mannitol before cisplatin infusion is allowed according to local 
practice. Cisplatin should be prepared according to local practice and should be infused 
over 60 minutes.
•
Urinary output: >100 mL/hour before starting cisplatin infusion and also after cisplatin 
infusion during at least 4-6 hours (400 mL/4 hours). If this level is not reached, 
furosemide (LASIX® [furosemide, Sanofi Aventis]) 20 mg IV should be given.
•
Participants may be weighed before and after cisplatin infusion, if weight gain 
furosemide (LASIX®) could be given.
•
Replace potassium and magnesium as needed.
•
Check for presence of ototoxicity.
9.1.10.2
Surgery Guidelines
9.1.10.2.1
Pre-operative Assessment
Preoperative assessment should proceed as per institutional guidelines and participant’s 
Charlson co-morbidity index, ASA-score, and nutritional status are recommended to be 
assessed.  Also routine hematology and chemistry tests will be performed as detailed in 
Section 2.0 – Schedule of Activities.  Preoperative imaging should be performed as described 
in Section 2.0 - Schedule of Activities and Section 9.2.1 - Tumor Imaging and Assessment of 
Disease.  In case of procedures with potential long-term swallowing compromise the treating 
surgeon may obtain pulmonary function tests or a barium swallow as per local SoC.  
Surgeons are recommended to document the primary tumor and lymphadenectomy surgical 
plan at initial evaluation. This may include either photo documentation or appropriate 
drawings to identify the planned surgical margin of resection (in case of tumor response with 
intervention).  
9.1.10.2.2
Surgical Procedure Guidelines
Routine general anesthesia according to institutional guidelines should be performed.  
Perioperative antibiotics and steroids are administered per institutional guidelines.  Surgeons 
are encouraged to avoid the use of steroids where possible. Prohibited medications are 
detailed in Section 7.7 – Concomitant Therapy.  Any permitted perioperative steroids should 
08KM9X

PRODUCT:  MK-3475 
131
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
be administered after all study related tissue and blood samples have been collected where 
possible.
Surgical procedures are tailored to the location of the tumor.  The standard surgical 
procedures for this study are detailed in the Surgical Brochure.  Importantly, surgical 
resection should be performed to margins identified at initial presentation as documented by 
the surgeon in Section 9.1.10.2.1. Also, the planned lymphadenectomy determined at initial 
presentation should be performed as documented by the surgeon in Section 9.1.10.2.1. In 
case of tumor progression, a more extensive procedure could be necessary in order to achieve 
negative resection margins. All study related biopsies should ideally be collected prior to 
resection being completed.  The resection at each site should provide margins of at least 
5 mm in the primary specimen, unless there are surgical contra-indications ie, proximity of 
great vessels.  For the pembrolizumab treatment arm, the original surgical margins 
determined prior to initiation of pembrolizumab should be used to guide surgical resection.  
The choice of procedure as well as the choice of reconstruction, if deemed necessary, is at the 
discretion of the surgeon as per local SoC.  The surgeon should describe in their operation 
report the extent of macroscopic disease with particular comparison to extent at initial 
presentation.
9.1.10.2.3
Post-operative Complications
Complications after major head and neck surgery encompass intraoperative and post-
operative issues.  Intraoperative issues may include hemostasis and tissue quality during 
dissections.  Post-operative complications may be local and include bleeding, infection, or 
wound healing issues including pharyngeal fistulas, chylous fistulas, spinal accessory, 
hypoglossal and/or facial nerves, and other local, regional or free flap failure. These may 
contribute to increased length of inpatient hospital stay and time to initiation of post-
operative RT ± cisplatin. In the absence of guidelines for the management of those, it will be 
to the discretion of the treating surgeon to manage these complications at the best of his/her 
knowledge as per local SoC.
9.1.10.2.3.1
Evaluation and Reporting of Post-operative Complications
Surgical complications will depend on the extent of the procedures, the site of intervention, 
and the technique of reconstruction.  Given the variety of possible interventions a large 
variety of complications have to be foreseen.  Potential post-operative complications include, 
but are not limited to:
Endoscopy:
•
Dysphagia
•
Odynophagia
•
Voice changes and hoarseness
•
Dyspnea
•
Teeth damage
08KM9X

PRODUCT:  MK-3475 
132
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
•
Esophageal perforation
•
Mediastinitis
Tumor Resection with or Without Reconstruction (Free or Regional/local Flap):

Hemorrhage/hematoma (requiring 
drainage, blood transfusion, or surgical 
intervention to stop bleeding)

Loss of voice and hoarseness

Epistaxis

Partial or total flap loss

G-tube complication

Seroma

Infection (including flap donor site and 
tracheostomy site)

Spinal accessory nerve damage

Fistula

Hypoglossal nerve damage

Wound healing complication

Vagal nerve damage

Dysphagia

Facial nerve damage

Odynophagia

Phrenic nerve damage

Tracheostomy complication

Sympathetic trunk damage 
(Horner syndrome)

Trismus

Chyle leak
All post-operative complications will be reported and graded in the same way as other AEs 
(see Appendix 4) and will be identified by the investigator and/or surgeon as post-surgical 
complications.  See Section 9.3.1 for reporting requirements for all AEs and SAEs 
considered to be post-surgical complications by the investigator.
9.1.10.2.4
Post-operative Care
Post-operative rehabilitation should proceed per institutional guidelines.  These relate to 
tracheostomy status and resumption of oral diet.  In general, all efforts should be made to de-
cannulate participants with tracheostomies as fast as possible and start the participant on an 
oral diet. Sites are encouraged to get early involvement from speech and language 
pathologists, as per institutional guidelines, and to mobilize the participant as fast as his/her 
condition allows. These decisions need to be made by the treating head and neck surgeon 
and should be individualized to the participant’s ability and needs.
9.1.10.2.5
Pathology Specimen
The resection specimen submitted to a local pathologist should include an entire surgically 
resected lesion with appropriate orientation and all resected lymph nodes (as well as tumor 
bed, if applicable), as per the guidelines provided in the Surgical Brochure and Pathology 
Manual.  On pathologic exam, margins are defined as negative if ≥5 mm from the invasive 
front of tumor, close margin if between 1-5 mm, and positive margin if <1 mm in the primary 
08KM9X

PRODUCT:  MK-3475 
133
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
resection specimen; an extranodal extension is defined as any extension of SCC from within 
a lymph node through the fibrous capsule and into the surrounding connective tissue.  
Surgeons may use margins from the tumor bed after resection and guidelines from the 
Surgical Brochure should be followed in this regard.  
Neck dissection specimens should be processed per guidelines in the Vendor Manual but 
should include separation of the specimen into distinct neck levels prior to pathology 
submission.
Communication from surgeon to local pathologist should follow local practice and 
institutional guidelines. Sample transport, storage and shipment instructions for pathology 
specimens obtained during surgery will be provided in the Vendor Manual. 
Representative specimens (slides) of tumor tissue collected during surgery from all 
participants will be submitted to the designated central laboratories (see Pathology Manual) 
for blinded pathological response assessment of the pCR and mPR endpoints, determination 
of high risk pathologic features (defined by evidence of positive margins or extranodal
extension following surgical resection), and translational research (see Section 9.2.2).
9.1.11
Withdrawal/Discontinuation
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the End of Study Visit should be performed at the time of withdrawal.  Any 
AEs which are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in Section 9.3 - Adverse Events, Serious 
Adverse Events and Other Reportable Safety Events.
Refer to Appendix 8 for Germany-specific guidance. 
9.1.11.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the principal investigator for the main trial.  If 
medical records for the main trial are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@msd.com).  Subsequently, the 
participant's consent for Future Biomedical Research will be withdrawn.  A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal.  Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research trial data and results.  
No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
08KM9X

PRODUCT:  MK-3475 
134
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
participant’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
9.1.12
Participant Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
9.1.13
Domiciling
Participants will be hospitalized for the protocol specified surgery and discharged as per local 
SoC.
At the discretion of the investigator, participants may report to the clinical research unit the 
evening prior to the schedule day of cisplatin administration and remain in the unit until 
24 hours post-dose to ensure proper hydration.  At the discretion of the investigator, 
participants may be requested to remain in the clinical research unit longer.
9.1.14
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
9.2
Efficacy Assessments 
9.2.1
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central imaging vendor can be 
found in the SIM.  Tumor imaging (head and neck, chest, and upper abdomen) is strongly 
preferred to be acquired by CT with contrast.  Magnetic resonance imaging of the head and 
neck and upper abdomen should be used when CT with iodinated contrast is contraindicated 
or when mandated by local practice, or for imaging of the brain. The upper abdomen 
CT/MRI should cover the liver in its entirety. The choice between CT and MRI for the head 
and neck and upper abdomen imaging is left to the discretion of the investigator, but the 
same imaging technique, regarding modality and the use of contrast should be used in a 
participant throughout the study to optimize the visualization of existing and new tumor 
burden.
Participant eligibility will be determined using local assessment (investigator assessment) 
based on RECIST 1.1.  All scheduled images for all study participants from the sites will be 
submitted to the central imaging vendor for BICR.  In addition, images (including via other 
modalities) that are obtained at an unscheduled time point to determine disease progression, 
as well as imaging obtained for other reasons, but captures radiologic progression, should 
also be submitted to the central imaging vendor.
08KM9X

PRODUCT:  MK-3475 
135
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
When the investigator identifies radiographic progression per RECIST 1.1, the central 
imaging vendor will perform expedited verification of radiologic progressive disease (PD)
and communicate the results to the study site and Sponsor via email (see Section 9.2.1.4).  
Treatment should continue until PD/recurrence has been verified, initiation of a new 
anticancer treatment, pregnancy, death, withdrawal of consent, study conclusion or early 
termination, whichever occurs first (refer to Sec 8.1 – Discontinuation of Study Treatment).  
9.2.1.1
Initial Tumor Imaging
Initial tumor imaging at Screening (contrast enhanced head and neck, chest, and upper 
abdomen CT scan or chest CT scan plus head and neck and abdomen MRI, and FDG-PET or 
FDG-PET/CT) must be performed within 28 days prior to the date of randomization.  The 
site study team must review screening images to confirm the participant has evaluable 
disease per RECIST 1.1 prior to submitting to central imaging vendor.
The screening images must be submitted to the central imaging vendor for retrospective 
review.
Scans performed as part of routine clinical management are acceptable for use as screening 
tumor imaging if they are of diagnostic quality and performed within 28 days prior to the 
date of randomization and can be assessed by the central imaging vendor.
Fluorodeoxyglucose-positron emission tomography (FDG-PET or FDG-PET/CT) scans will 
only be performed at screening to help guide potential SoC neck dissections, if required.  
Diagnostic quality CT can be acquired on the PET/CT scanner while performing FDG-PET if 
that is the local standard practice (see procedure detail described in the SIM).
9.2.1.2
Tumor Imaging During the Study
The same modality (CT/MRI head and neck, chest, and upper abdomen) used at screening 
should be used during neoadjuvant and adjuvant treatment and during the post-treatment 
follow-up visits at the scheduled time points detailed in Section 2.0 – Schedule of Activities.
For participants in the pembrolizumab arm (Arm A), the first on-study imaging assessment 
should be performed after completion of 2 cycles of pembrolizumab treatment, at 
approximately Week 6 (±10 days) from the date of randomization and before surgery.  If the 
presurgery scan shows tumor flare this should not alter the timing or decision to proceed to 
surgery unless the tumor is unresectable. In the SoC arm (Arm B), the screening imaging will 
serve as the presurgery imaging. If the presurgery scans for Arm A or baseline scans for Arm 
B are done > 14 days prior to the date of surgery, then repeat imaging prior to surgery will be 
required.
The first post-surgery imaging should be performed 12 weeks (± 7 days) after the end of 
RT ± cisplatin.  Subsequent tumor imaging should then be performed every 3 months (91 
± 7 days), or more frequently if clinically indicated, until the end of Year 3 after 
randomization, then every 6 months (182 ±14 days) until the end of Year 5.  For all post-
surgery imaging, the clock will start at the end of RT ± cisplatin (ie, last dose of).  All of 
these visits should stay on track using the last dose of RT ± cisplatin as the starting clock, ie, 
08KM9X

PRODUCT:  MK-3475 
136
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
if one of the imaging visits is late (even the first scan post-surgery), the participants will stay 
on the original schedule starting with the last dose of RT ± cisplatin for all future visits; do 
not recalculate.  Imaging timing should follow calendar days and should not be adjusted for 
delays in cycle starts.  When the investigator identifies radiographic progression per RECIST 
1.1, the site should submit the imaging with verification of progression (VOP) request to the 
central imaging vendor as soon as possible. Expedited VOP read will be performed by BICR 
and the results will be communicated to the site and Sponsor via email. If initial site-assessed 
PD was not verified by BICR, each subsequent imaging must be submitted to central imaging 
vendor with VOP request until PD has been verified. Treatment should continue until PD has 
been verified by BICR, initiation of a new anticancer treatment, pregnancy, death, 
withdrawal of consent, study conclusion or early termination, whichever occurs first. Of note, 
a participant will only discontinue from study treatment during the neoadjuvant phase if PD 
precludes surgery (refer to Sec 8.1 – Discontinuation of Study Treatment).
9.2.1.3
End of Treatment and Follow-up Tumor Imaging
For participants who discontinue study treatment without a documented event/disease 
progression, every effort should be made to continue monitoring their disease status by tumor 
imaging using the same imaging schedule used while on treatment (every 3 months
[91 ± 7 days] until the end of Year 3, thereafter every 6 months [182 ± 14 days] until the end 
of Year 5) to monitor disease status until an event/disease progression, pregnancy, death, 
withdrawal of consent, or the end of the study, whichever occurs first.  For participants who 
discontinue study treatment due to an event/documented disease progression, this is the final 
required tumor imaging.
9.2.1.4
RECIST 1.1 Assessment of Disease
During the neoadjuvant period and for those participants who do not have surgery 
RECIST 1.1 by BICR will be used as the primary measure for assessment of disease 
progression, locoregional failure status, and as a basis for all protocol guidelines related to 
disease status (eg, discontinuation of study therapy).  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.  Initial tumor imaging showing site-assessed PD/recurrence should be 
submitted immediately to BICR for verification of PD/recurrence.  The site will be notified if 
the BICR verifies PD using RECIST 1.1. 
In the post-surgery adjuvant phase, imaging will be performed with assessments based on 
disease recurrence.  If indicated, biopsy confirmation of recurrent lesion/s will be performed.
If an unplanned imaging is performed before 12 weeks after the end of RT ± cisplatin and 
disease progression is assessed per RECIST 1.1 and verified by BICR, this will be an EFS 
event.
The complete RECIST 1.1 criteria are included in the published RECIST document 
(available at http://www.eortc.be/RECIST).
08KM9X

PRODUCT:  MK-3475 
137
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9.2.2
Tumor Tissue Collection and Assessment of Pathological Response
All participants will undergo potentially curative surgical resection performed as part of the 
local SoC (see Section 9.1.10.2).  Details regarding date of surgery, type of surgery, tumor 
resectability etc. will be recorded in the appropriate eCRF.  
Detailed evaluation of tumor staging per AJCC Cancer Staging Manual (8th edition) and 
assessment of surgical margins will be performed by the local pathologist on all tissues 
removed during the surgery and recorded in the appropriate eCRF.  Local pathology results 
will be used to guide post-surgery treatment decisions.
The primary evaluation of pathologic response (pCR or mPR) and assessment of surgical 
margins will be conducted by blinded central pathologists.  In all cases, the central 
pathologist interpreting surgical specimens for assessment of pCR/mPR will be blinded to 
treatment assignment.  A summary note will be provided to the study pathologist that 
includes a general overview of the study.  The note should also include the major clinical, 
radiographic, and operative findings including a description or diagram of the original size 
and location of the tumor, the presence or absence of multifocality, the extent of preoperative 
lymph node involvement, and type of surgery.  The study pathologists will send the 
representative specimens (slides) including surgical margin, the deepest focus of visible 
malignant epithelium in the head and neck, and any carcinoma found or suspicious cells in 
the lymph node for central pathologist confirmation, as detailed in the Pathology Manual.
All study pathologists will be required to complete formal training. The Pathology Manual 
will be provided, outlining standard guidelines for pathological evaluation of specimens. 
For participants who do not achieve a pCR, a tumor tissue sample is to be collected and 
submitted to the designated central laboratory for translational research as specified in 
Section 5.4.1.4 – Planned Exploratory Biomarker Research.  Any leftover tissue at the time 
of this surgery or any further head and neck surgeries will be archived for FBR if the 
participant has provided documented informed consent for FBR as specified in Section 
5.4.1.5 – Future Biomedical Research.
An optional core biopsy may be collected post-surgery at the time of recurrence, if 
applicable, and submitted to the central laboratory for translational research, for participants 
who agree to participate, as specified in Section 5.4.1.5 – Planned Exploratory Biomarker 
Research.  Any leftover tissue will be archived for FBR if the participant has provided 
documented informed consent for FBR as specified in Section 5.4.1.6 – Future Biomedical 
Research.
Detailed instructions for tissue collection, processing and shipment are provided in the 
Vendor Manual.
9.2.3
Survival 
Event-free survival and OS data will be collected from the time of randomization throughout 
the study.  Definitions of the survival endpoints are provided in Section 10.4.1 and censoring 
rules are presented in Section 10.6.1. 
08KM9X

PRODUCT:  MK-3475 
138
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9.2.4
Patient Reported Outcomes
The EQ-5D-5L, EORTC QLQ-C30 and EORTC QLQ-H&N35 questionnaires will be 
administered by trained site personnel and completed electronically by participants in the 
following order: EQ-5D-5L first, then EORTC QLQ-C30, followed by EORTC QLQ-
H&N35. The questionnaires are to be administered from baseline, defined as Treatment 1 
Cycle 1 in the Pembrolizumab Arm (Arm A) or prior to surgery in the SoC Arm (Arm B), 
until Year 5 as specified in the Schedule of Activities (Section 2.0). 
It is best practice and strongly recommended that electronic PROs (ePROs) are administered 
to randomized participants prior to drug administration, AE evaluation, and disease status 
notification.  If the participant does not complete the ePROs at a scheduled time point, the 
MISS_MODE form must be completed to capture the reason the assessment was not 
performed.
9.3
Adverse Events, Serious Adverse Events and Other Reportable Safety Events 
The definitions of an adverse event (AE) or serious adverse event (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 4.
AE, 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, who is a qualified physician, and any designees are responsible for 
detecting, assessing, 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 AE, SAEs and other reportable safety events for outcome according to Section 
9.3.3.
Adverse events will not be collected for participants during the pre-screening 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.
08KM9X

PRODUCT:  MK-3475 
139
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9.3.1
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information 
AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before treatment allocation/randomization, must be 
reported by the investigator if the event causes the participant to be excluded from the trial, 
or is the result of a protocol-specified intervention, including, but not limited to washout or 
discontinuation of usual therapy, diet, or a procedure. 
•
All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study treatment must be reported by the investigator. 
•
All adverse events considered to be post-surgical complications by the investigator from 
time of protocol-specified surgery through 30 days following surgery, must be reported 
by the investigator.
•
All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following cessation of 
study treatment if the participant initiates new anticancer therapy, whichever is earlier 
must be reported by the investigator. 
•
All SAEs that are considered to be post-surgical complications by the investigator, from 
the time of protocol-specified surgery through 90 days following surgery or 30 days 
following protocol-specified surgery if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through the time required to eliminate systemic exposure after 
cessation of study treatment as described in Sections 6.1 and 9.5.9.2, or 30 days after 
cessation of study treatment if the participant initiates new anticancer therapy must be 
reported by the investigator. 
•
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered to be drug-related. Subjects in post-treatment follow-up will be actively 
followed for treatment-related late SAEs for up to 5 years.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment 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 timeframes as indicated in Table 12.
08KM9X

PRODUCT:  MK-3475 
140
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 12
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to 
protocol-
specified 
intervention
- causes 
exclusion
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
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
9.3.2
Method of Detecting AE, SAE and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and non-leading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
9.3.3
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 AE, SAE and other reportable safety events 
08KM9X

PRODUCT:  MK-3475 
141
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
including pregnancy and exposure during breastfeeding, ECI, Cancer and Overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 8.3). In addition, the investigator will 
make every attempt to follow all non-serious AEs that occur in randomized participants for 
outcome.  Further information on follow-up procedures is given in Appendix 4.
9.3.4
Regulatory Reporting Requirements for SAE
•
Prompt notification (within 24 hours) by the investigator to the sponsor of SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment 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 treatment under clinical 
investigation. All Adverse Events will be reported to regulatory authorities, IRB/IECs 
and investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R1) Guidelines for Good Clinical Practice.
•
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
•
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
9.3.5
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 9.3.1.  
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression/recurrence of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study.  Any suspected endpoint which upon review 
is not progression of the cancer under study will be forwarded to global safety as a SAE 
within 24 hours of determination that the event is not progression of the cancer under study.
9.3.6
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
reported to the investigator or their designee), including the pregnancy of a male participant's 
female partner, that occurs during the trial are reportable to the Sponsor.
08KM9X

PRODUCT:  MK-3475 
142
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events).  If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
9.3.7
Events of Clinical Interest (ECI)
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
Events of clinical interest for this trial include: 
1. an overdose of study intervention, as defined in Section 9.4 – Treatment of Overdose, 
that is not associated with clinical symptoms or abnormal laboratory results.
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The trial site guidance for assessment and 
follow-up of these criteria can be found in the Investigator Trial File Binder (or equivalent).
9.4
Treatment of Overdose
Pembrolizumab overdose
In 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.
Cisplatin overdose
There is no specific antidote for cisplatin overdose. Overdose may result in the side effects 
associated with the drug occurring in an excessive manner. 
Otherwise, overdose should be managed according to local label and practice.
Radiation Overdose
In this study, an overdose of radiation will be defined as any dose ≥20% over the prescribed 
dose for the CRT treatments. There is no specific antidote for radiation overdose. In the event 
08KM9X

PRODUCT:  MK-3475 
143
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
of an overdose, the participant should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated.
Reporting of overdose is detailed in Section 9.3 and Appendix 4.
9.5
Safety 
Details regarding specific safety 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 pre-study to post-study visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Vendor 
Manual.
Planned time points for all safety assessments are provided in the SoA.
9.5.1
Physical Examinations
A complete physical examination will be conducted as per institutional standard. Height and 
weight will also be measured and recorded.
A brief directed physical examination will be conducted as per institutional standard as per 
the Schedule of Activities (Section 2.0)
Investigators should pay special attention to symptom monitoring (eg, swallowing function) 
and clinical signs related to previous serious illnesses.
9.5.1.1
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam, including the 
presence/absence of feeding tube and a neurological exam (see Section 9.5.6), during the 
Screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  Further full physical examinations will be performed prior to administration of RT ± 
cisplatin post-surgery (Treatment 2) and upon treatment discontinuation.  The time points for 
full physical exams are described in Section 2.0.  After the first dose of study treatment, new 
clinically significant abnormal findings should be recorded as AEs.
9.5.1.2
Directed Physical Exam
For cycles that do not require a full physical exam as defined in Section 2.0, the investigator 
or qualified designee will perform a directed physical exam, including the presence/absence 
of feeding tube and neurological exam, as clinically indicated prior to the administration of 
the study treatment.  New clinically significant abnormal findings should be recorded as AEs.
9.5.2
Vital Signs, Height and Weight
The investigator or qualified designee will take weight and vital signs at screening and as 
specified in the Section 2.0 – Schedule of Activities; height will be measured at Screening 
only.  Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
08KM9X

PRODUCT:  MK-3475 
144
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
include temperature, systolic and diastolic blood pressure, pulse and respiratory rate. Vital 
signs should be measured prior to administration of each dose of study treatment and prior to 
blood collections.
9.5.3
Electrocardiograms
A standard 12-lead electrocardiogram (ECG) will be performed using local standard 
procedures once at screening.  Clinically significant abnormal findings should be recorded as 
medical history. Additional time points may be performed as clinically necessary.
9.5.4
Performance Assessment
9.5.4.1
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG performance status (see http://ecog-
acrin.org/resources/ecog-performance-status) at Screening, prior to dosing during each 
treatment cycle and during Post-Treatment Follow-up visits.
9.5.5
Oral and Dental Check-up
All participants should have an oral and dental examination including clinical and 
radiological examination by the investigator or other appropriate healthcare provider, per 
local institutional guidelines, during screening. When clinically indicated, extraction of 
dental elements should be carried out. The interval between extractions and start of RT ± 
cisplatin should be as long as possible to permit healing and participant comfort prior to the 
commencement of treatment. If more than 2 teeth are to be extracted this should be done 
prior to RT simulation.  Oral/dental check-ups are recommended every 6 months throughout 
the study (can be per SoC/local guidelines).  Adequate dental care (including daily fluorine 
application) should be recommended as an option to all participants, at least during follow-
up. Documented routine oral and dental check-up performed within 6 weeks of 
randomization is acceptable and does not need to be repeated in Screening.
The frequency of oral and dental check-ups is as per local SoC, but it is recommended that 
participants have a check-up every 6 months during the study.
9.5.6
Neurological Examination
Neurological examinations will be conducted as part of the physical examinations and must 
be performed for all participants at Screening as per local standards by the investigator or 
qualified designee.  For participants at high risk of recurrence post-surgery a neurological 
exam should be repeated before each cisplatin injection, and thereafter as clinically indicated. 
In case of symptoms or signs experienced by the participant, more frequent examinations 
should be performed per local standards by the investigator or qualified designee and the 
following dose modification (see Section 7.2.3). Documented routine neurological exam 
performed within 6 weeks of randomization is acceptable and does not need to be repeated in 
Screening.
08KM9X

PRODUCT:  MK-3475 
145
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9.5.7
Audiometric Testing
Audiometric assessments should be performed by a qualified audiologist or qualified 
designee for all participants at Screening (within 6 weeks prior to randomization). The 
procedure used for the conduct of the audiometric examination may be conducted according 
to local institutional practice. If auditory symptoms develop after the Screening assessment 
and prior to randomization, the audiometric assessments should be repeated prior to 
randomization. Additional comprehensive audiometric assessments should be conducted as 
deemed appropriate by the audiologist or qualified designee and following local cisplatin 
product label to provide continued safety assessment (See also, Section 2.0 – Schedule of 
Activities). Documented routine audiometric testing performed within 6 weeks of 
randomization is acceptable and does not need to be repeated in Screening.
9.5.8
Fiber Optic Examination
At screening, fiber optic examination (under general anesthesia, as appropriate) of the upper-
aerodigestive tract (with biopsies of the primary lesions(s) if clinically indicated) is required 
as a baseline exam for all patients. Documented routine fiber optic exam performed within 
6 weeks of randomization is acceptable and does not need to be repeated in Screening.  
While on study treatment, if clinically indicated based on investigator assessment, fiber optic 
examination of primary tumor site will be performed (under general anesthesia, as 
appropriate) of the upper-aerodigestive tract with biopsies of the primary lesion(s) and any 
suspicious lesions. Photographs of the lesion(s) should be routinely performed to ease GTV
delineation, if clinically indicated.
9.5.9
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 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 non-protocol 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 treatment, 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. 
08KM9X

PRODUCT:  MK-3475 
146
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
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 pre-study to post-study visits), including approximate blood/tissue 
volumes drawn/collected by visit and by sample type per participant can be found in the 
Study Vendor Manual.  Refer to the Schedule of Activities (Section 2) for the timing of 
laboratory assessments.
Only safety labs affecting potential treatment must be reviewed prior to study therapy 
administration following the Screening Visit.  Labs that would not affect potential treatment 
of the participant can be reviewed, in a timely manner, by an investigator after the date of 
study therapy administration.  Similarly, if a site is unable to obtain the thyroid function 
testing (thyroid stimulating hormone [TSH], Free T3 and Free T4) results prior to scheduled 
dosing, review of the thyroid function test results after dosing is acceptable and poses no 
additional immediate safety risk to participants.
9.5.9.1
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.  All 
laboratory tests to determine eligibility and Drug-Induced Liver Injury (DILI) (see 
Section 5.1 – Entry Criteria [Table 1] and Section 9.3.7 – Events of Clinical Interest, 
respectively) are mandatory; all other additional laboratory tests are recommended and may 
be performed according to local institutional standard.
9.5.9.2
Pregnancy Test
•
Pregnancy testing for WOCBP:
-
Pregnancy testing requirements for study inclusion are described in Section 6.1.
-
Pregnancy test is required to be repeated within 24 hours prior to starting 
RT ± cisplatin adjuvant treatment.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention and at the end of treatment.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted for the time required to eliminate systemic exposure after the last dose of 
each study intervention(s) as noted in Section 6.1. The length of time required to 
continue pregnancy testing for each study intervention is as follows:
◦
Pembrolizumab: 120 days
◦
Cisplatin: 180 days
◦
Radiotherapy: 180 days
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study. Refer to 
Appendix 8 for UK-, Germany-, and France-specific requirements.
08KM9X

PRODUCT:  MK-3475 
147
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9.5.9.3
HIV, HBV and HCV Serology
Screening tests are not required unless mandated by local regulations.  HIV, HBV, and HCV 
serology will be conducted on participants per local regulations and site SOPs. Active 
Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a 
known positive Hep C Ab result and known HCV RNA results greater than the lower limits 
of detection of the assay. Refer to Appendix 8 for Germany-specific requirements for HIV, 
HBV, and HCV testing.
9.6
Pharmacokinetics
Pharmacokinetic samples are not collected in this trial.  
9.6.1
Blood Collection for RNA Analysis and Plasma and Serum Biomarker 
Analyses
Blood should be drawn according to the collection schedule for all participants (Section 2.0).  
Leftover RNA, plasma, and serum will be stored at the end of the study for FBR if the 
participant has consented (see Section 9.8). Further details are provided in the Vendor 
Manual.
9.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
9.8
Future Biomedical Research Sample Collection 
The following specimens are to be obtained as part of Future Biomedical Research:
•
DNA for future research
•
Leftover RNA from RNA analyses
•
Leftover plasma from plasma biomarker analyses
•
Leftover serum from serum biomarker analyses
•
Leftover plasma from ctDNA
•
Leftover main study tumor
9.9
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants in this 
study as specified in the SoA:
•
Blood for Genetic Analysis
•
Blood for RNA Analysis
08KM9X

PRODUCT:  MK-3475 
148
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
•
Blood for Serum Biomarker Analysis
•
Blood for Plasma Biomarker Analysis
•
Blood for ctDNA Analysis
•
Tissue Collection for Biomarker Analysis
9.9.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be obtained pre-dose on Day 1 but may be 
collected at the next scheduled blood draw, if needed. Sample collection, storage and 
shipment instructions for planned genetic analysis samples will be provided in the Vendor 
Manual.  Samples should be collected for planned analysis of associations between genetic 
variants in germline/tumor DNA and drug response.  If a documented law or regulation 
prohibits (or local IRB/Independent Ethics Committee [IEC] does not approve) sample 
collection for these purposes, then such samples should not be collected at the corresponding 
sites.  Leftover DNA extracted from planned genetic analysis samples will be stored for FBR 
only if participant provides documented informed consent for FBR. 
9.10
Visit Requirements
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA).  Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
9.10.1
Screening
Approximately 28 days prior to treatment randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 6.1.  
Screening procedures may be repeated after consultation with the Sponsor.
Documented informed consent must be obtained prior to performing any protocol-specific 
procedure.  Results of a test performed prior to the participant providing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame.  Screening procedures are to be completed within 28 days prior 
randomization except for the following:
•
Laboratory tests are to be performed within 10 days prior to randomization.  An 
exception is hepatitis testing which may be done up to 28 days prior to randomization.
•
Evaluation of ECOG performance status is to be performed within 10 days prior to 
randomization.
•
For WOCBP, a urine or serum pregnancy test will be performed within 24 hours (urine) 
or within 72 hours (serum) before randomization.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test will be required (performed by the local 
study site laboratory).
08KM9X

PRODUCT:  MK-3475 
149
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
•
For cases where newly obtained tumor sample is collected within 90 days of 
randomization, tumor sample collection is not required to be obtained within 28 days 
prior to randomization for PD-L1 testing for all participants and for HPV p16 testing for 
participants with oropharyngeal cancers.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria
after consultation 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.
After screening, eligible participants will be randomly assigned to treatment.  Sites will 
contact the participants to advise them on their assigned treatment arm and schedule the first 
post-screening visit as determined by their assigned treatment arm.
9.10.2
Treatment Periods
Visit requirements are outlined in the Schedule of Activities (Section 2.0).  Specific 
procedure-related details are provided in Section 9.1.
In the Neoadjuvant Treatment Phase, there are 2 treatment arms: Arm A/pembrolizumab and 
Arm B/SoC (no neoadjuvant).  Post-definitive surgery, participants will receive adjuvant 
treatment with RT ± cisplatin plus pembrolizumab in Arm A and without pembrolizumab in 
SoC arm (Arm B), as assigned during randomization. No crossover from SoC to
pembrolizumab will be permitted.  Participants who subsequently receive any anticancer 
treatment not specified in the protocol will discontinue study treatment and enter Follow-up; 
any treatment would be considered post-study anticancer treatment.  
9.10.2.1
Neoadjuvant Treatment (Treatment 1)
Only participants in Treatment Arm A/pembrolizumab will receive neoadjuvant 
pembrolizumab; participants in Treatment Arm A/pembrolizumab should proceed to surgery 
directly following the presurgery visit (within 6 weeks [±10 days]) after randomization). 
Participants in Arm A are allowed to go to surgery outside this timeframe if delays are due to 
an AE. Participants with delays other than for an AE may be considered with sponsor 
consultation. Participants in the Treatment Arm B/SoC will proceed directly to surgery
following within 4 weeks after randomization.
Visit timing requirements during the treatment period for Arm A are as follows:
•
Assessments/procedures should be performed on Day 1 for each cycle.
•
Pembrolizumab treatment cycles are 3 weeks (21 days).
•
The window for each visit is ± 3 days, unless otherwise noted. Cycle 1 treatment should
begin within 3 days of randomization or as close as possible to that date on which the 
participant is allocated or assigned.
08KM9X

PRODUCT:  MK-3475 
150
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9.10.2.2
Definitive Surgery
All participants will have presurgical assessments performed at Week 0-4 (± 10 days) for the 
SoC arm (Arm B) or Week 6 (± 10 days) for the pembrolizumab arm (Arm A), to allow 
assessment of disease status, PROs and safety monitoring.  The window for this visit allows 
participants to proceed to surgery up to 10 days earlier or later if deemed necessary by the 
investigator.
Definitive surgery will be performed as per local SoC (Arm B/SoC) and following 
completion of neoadjuvant treatment (Arm A/pembrolizumab).  Note: Participants in the 
pembrolizumab arm (Arm A) may proceed to surgery after 1 dose of pembrolizumab, if 
deemed appropriate, if the investigator has documented clinical evidence of tumor 
progression, preferably supported by radiographic evidence.
Participants who do not undergo surgery as originally planned may proceed directly to 
Treatment 2 and receive salvage RT plus cisplatin ± pembrolizumab, depending on treatment 
assignment at the discretion of the investigator in consultation with the Sponsor. 
9.10.2.3
Post-surgery Safety Follow-up
The mandatory Post-surgery Safety Follow-up Visit should be conducted approximately 7 to 
30 days post-surgery.  All AEs that occur post-surgery and prior to the Post-surgery Safety 
Follow-up Visit should be recorded.  Section 9.3.1 details the reporting requirements for AEs 
and SAEs considered to be post-surgical complications by the investigator.  Complications 
and mortality as a consequence of the surgical procedures will be reported as per other AEs 
and SAEs (see Section 9.1.10.2.3).  
Participants considered to have adequately recovered from surgery may proceed directly to 
adjuvant treatment.  
9.10.2.4
Adjuvant Treatment (Treatment 2)
The post-surgery adjuvant treatment period (Treatment 2) is expected to start when 
participants have recovered adequately from the morbidity and/or complications from the 
surgery and with RT ± cisplatin commencing at a recommended minimum range of within 
6 weeks after definitive surgery.  If performed outside of this window, Sponsor consultation 
will be required.  If the start of RT is delayed, up to 4 doses of pembrolizumab may be given. 
The timing of this dose of pembrolizumab can be adjusted based on timing of surgery after 
discussion with the Sponsor.  The first dose of pembrolizumab given during radiation therapy 
should be given such that pembrolizumab continues to be given every 21 +/- 3 days.
9.10.3
Post-Treatment Visit
Post-treatment visit requirements are outlined in the Schedule of Activities (Section 2.4).  
08KM9X

PRODUCT:  MK-3475 
151
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9.10.3.1
End of Treatment Visit 
The End of Treatment visit should occur at the time study treatment is discontinued for any 
reason. 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 for a reason other than disease progression will 
still be considered on study and should continue with regularly scheduled assessments (also 
refer to Section 8.1), including collecting participant information on the start of new 
anticancer therapy, disease progression, and death.
9.10.3.2
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study treatment or before the initiation of a new anticancer treatment, whichever 
comes first.  
Reporting requirement for post-treatment follow-up of treatment-related late toxicities 
meeting serious criteria is detailed in Section 9.3.1.
9.10.3.3
Follow-up Visits
Participants who complete study treatment or discontinue study treatment for a reason other 
than an event/disease progression/recurrence will move into the Post-Treatment Follow-up 
Phase and should be assessed in office every 3 months (91 ± 7 days) until the end of Year 3
(measured from the date randomization) to monitor disease status.  In Years 4 and 
5, participants should be assessed in office every 6 months (182 ± 14 days) to monitor 
disease status.  After Year 5, participants will move into Survival Follow-up.  Any additional 
tests/investigations or imaging assessments for progressive/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 an event/disease progression, 
death, withdrawal of consent or end of study.  Information regarding post-study anticancer 
treatment will be collected if new treatment is initiated. Participants who have completed all 
efficacy assessments must enter Survival Follow-up. Participants who discontinue efficacy 
assessments early, and have not experienced an event/progression, will be requested for 
standard of care imaging assessments/biopsy to evaluate disease status.
For a participant who dies during the Follow-up period, date and cause of death should be 
recorded in the appropriate eCRF.
Participants in Post-Treatment Follow-up will be followed for treatment-related late toxicities 
for up to Year 5 and should be recorded.
08KM9X

PRODUCT:  MK-3475 
152
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
9.10.3.4
Survival Follow-up
All participants who complete Post-Treatment Follow-up, experience an event or disease 
progression/recurrence verified by BICR will move into the Survival Follow-up Phase and 
should be contacted by telephone every 3 months (91 ± 14 days) 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 study treatment and who will not enter the Post-
Treatment Follow-up Phase, the first survival follow-up contact will be scheduled 
3 months (91 ± 14 days) after the End of Treatment Visit and/or Safety Follow-up Visit 
(whichever is last).
•
For participants who completed assessments in the Post-Treatment Follow-up Phase, the 
first survival follow-up contact will be scheduled 3 months (91 ± 14 days) after the last 
efficacy assessment follow-up visit has been performed. 
The Sponsor may request survival status to be assessed at additional time points during the 
course of the study.  For example, survival status may be requested prior to the eDMC safety 
review, efficacy IAs and 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.
9.10.4
Participants Discontinued From Study Treatment but Continuing to be 
Monitored in the Study
Participants who discontinue study treatment for reasons other than an event/disease 
progression/recurrence will enter Safety and Post-Treatment Follow-up and undergo all 
assessments at the scheduled time points are per the Schedule of Activities (Section 2.4) as 
described in Sections 9.10.3.2, 9.10.3.3 and 9.10.3.4.
Participants that discontinue study treatment due to an event/disease progression/recurrence 
will enter Safety Follow-up and then proceed directly to Survival Follow-up as described in 
Section 9.10.3.4 (refer to Sec 8.1 – Discontinuation of Study Treatment). Participants who 
discontinue study treatment because of the start of new anticancer treatment will enter Safety 
Follow-up and then proceed directly to Follow-up as described in Section 9.10.3.3.
10
STATISTICAL ANALYSIS PLAN 
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9).  Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analysis, will be 
documented in a supplemental Statistical Analysis Plan (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study.  Separate analysis plans may be developed for biomarker 
08KM9X

PRODUCT:  MK-3475 
153
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
analysis and genetic data analysis.  Post-hoc exploratory analyses will be clearly identified in 
the Clinical Study Report.  The PRO analysis plan will also be included in the sSAP.
10.1
Statistical Analysis Plan Summary
Key elements of the Statistical Analysis Plan are summarized below; the comprehensive plan 
is provided in Sections 10.2 to 10.12. 
Study Design 
Overview
A Phase III, Randomized, Open-label Study to Evaluate Pembrolizumab as 
Neoadjuvant therapy and Pembrolizumab plus Radiotherapy with and without 
Chemotherapy as Adjuvant Therapy for Stage III-IVA Resectable 
Locoregionally Advanced Head and Neck Squamous Cell Carcinoma 
(LA HNSCC)
Treatment 
Assignment
In this study, 714 participants have been enrolled, which will result in 
approximately 462 participants whose tumors express PD-L1 CPS≥10 (based 
on a prevalence rate of ~65% of the CPS≥10 participants among all 
participants) and approximately 680 participants whose tumors express PD-L1 
CPS≥1  (based on a prevalence rate of ~95% of the CPS≥1 participants among 
all participants) will be randomized in a 1:1 ratio between 2 treatment arms: 
1.
Pembrolizumab as neoadjuvant therapy and in combination with RT ± 
cisplatin as adjuvant therapy after surgical resection (referred as 
pembrolizumab arm)
2.
No neoadjuvant therapy and RT ± cisplatin as adjuvant therapy after 
surgical resection (referred as SoC arm)
This study will be conducted as an open-label study.  Stratification factors are 
as follows:
•
Primary tumor site (oropharynx/oral cavity vs. larynx vs. hypopharynx)
•
Tumor Stage: III vs. IVA
•
PD-L1 status (TPS ≥ 50% vs. TPS<50%)
This study will be conducted as an open-label study.
Analysis 
Populations
Efficacy: Intention-to-Treat (ITT)
Safety: All Participants as Treated (APaT) 
PRO: Full Analysis Set (FAS)
Primary 
Endpoint(s)
Event-free survival (EFS)
Secondary 
Endpoint(s)
1.
Major pathological response (mPR)
2.
Overall survival (OS)
3.
Pathological complete response (pCR)
08KM9X

PRODUCT:  MK-3475 
154
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Statistical 
Methods for 
Key Efficacy 
Analyses
The primary hypothesis for EFS and key secondary hypothesis for OS will be 
evaluated by comparing the pembrolizumab arm to the SoC arm using a 
stratified log-rank test.  Estimation of the 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 key secondary hypothesis for mPR will be evaluated by comparing the 
pembrolizumab arm to the SoC arm with respect to the rate of mPR using the 
stratified Miettinen and Nurminen method with strata weighting by sample size.  
The between-treatment difference in percentages, its 95% CI and p-value will 
be provided.
Statistical 
Methods for 
Key Safety 
Analyses
For analyses in which 95% CIs will be provided for between-treatment 
differences in the percentage of participants with events, the analyses will be 
provided using the Miettinen and Nurminen (M&N) method [Miettinen, O. and 
Nurminen, M. 1985].
Interim 
Analyses
Efficacy:
Two IAs will be performed.  Results will be reviewed by an eDMC.  These IAs 
and the final analysis (FA) are summarized below.  Details are provided in 
Section 10.7. 
Safety:
An interim safety analysis will be performed and reviewed by the eDMC when 
the first 15 participants in the pembrolizumab arm have completed RT during 
the post-surgery adjuvant treatment phase.  Afterwards, the eDMC will review 
safety data periodically in the study.
CCI
08KM9X

PRODUCT:  MK-3475 
155
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Multiplicity
Sample Size 
and Power 
The planned sample size is 714 participants, which will result in approximately 
462 participants whose tumors express PD-L1 CPS≥10 and approximately 680
participants whose tumors express PD-L1 CPS≥1. 
10.2
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.
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IVRS.
Although the study is open-label, analyses or summaries generated by randomized treatment 
assignment and actual treatment received will be limited and documented. Further 
documentation will be provided in the sSAP.  The central pathologists interpreting surgical 
specimens for assessment of mPR and pCR will be blinded to treatment assignment.  In 
addition, the independent radiologist(s) will perform the central imaging review without 
knowledge of treatment group assignment.
Blinding issues related to the planned interim analyses are described in Section 10.7.  
10.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 4.0.
10.4
Analysis Endpoints
Primary and secondary efficacy, safety and PRO endpoints that will be evaluated for within-
and/or between-treatment differences are listed below.  Exploratory endpoints will be 
described in the sSAP.
CCI
CCI
08KM9X

PRODUCT:  MK-3475 
156
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
10.4.1
Efficacy Endpoints
10.4.1.1
Primary Efficacy Endpoint
•
Event-free survival (EFS): the time from randomization to the first of the following 
events:
-
Radiographic disease progression per RECIST 1.1.
Exception:
◦
Participants who undergo a definitive biopsy of the progressed lesion and are 
found to have no histologic evidence of invasive cancer will not meet criteria for 
an event.
-
Radiographic disease progression during neoadjuvant phase that precludes surgery 
will be considered an event.
-
Local or distant progression or recurrence (as assessed with imaging or biopsy as 
indicated).
-
Death due to any cause.
A secondary malignancy is not considered an EFS event.
See Section 10.6.1 for definition of censoring.
10.4.1.2
Secondary Efficacy Endpoints
•
Major Pathological Response (mPR):  having ≤10% invasive squamous cell carcinoma
within the resected primary tumor specimen and all sampled regional lymph nodes as 
assessed by blinded central pathologists.  
•
Overall survival (OS): the time from randomization to death due to any cause.
•
Pathological Complete Response (pCR): having no residual invasive squamous cell 
carcinoma within the resected primary tumor specimen and all sampled regional lymph 
nodes as assessed by blinded central pathologists.
10.4.2
Safety Endpoints
Safety measurements are described in Section 5.4.1.2 Safety Endpoints and Section 9.5.
10.4.3
Patient Reported Outcome (PRO) Endpoints
The following key PRO endpoints will be evaluated as described in Section 5.4.1.3:
•
Global health status/QoL and physical functioning scores from the EORTC QLQ-C30
08KM9X

PRODUCT:  MK-3475 
157
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
•
Symptom sub-scale and single item scores from the EORTC QLQ-H&N35 including the
following:
-
problems with swallowing
-
problems with speech
-
pain in the mouth
Additional scales of the EORTC QLQ-C30/QLQ-H&N35 and exploratory PRO endpoints as
described in Section 5.4.1.3 will be evaluated. Details will be provided in the sSAP.
10.5
Analysis Populations
10.5.1
Efficacy Analysis Population
The Intention-to-Treat (ITT) population will serve as the primary population for efficacy 
analyses in this study, which consists of all randomized participants. Participants will be 
included in the treatment group to which they are randomized for the analysis of efficacy 
data using the ITT population.  
10.5.2
Safety Analysis Population
Safety analyses will be conducted in the All Participants as Treated (APaT) population, 
which consists of all randomized participants who received study treatment (note that surgery 
is part of study treatment). Participants will be included in the treatment group 
corresponding to the study treatment they actually received for the analysis of safety data 
using the APaT population.  This will be the treatment group to which they are randomized 
except for participants who take incorrect study treatment for the entire treatment period; 
such participants will be included in the treatment group corresponding to the study treatment 
actually received.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of the respective safety parameter.  
To assess change from baseline, a baseline measurement is also required.
10.5.3
Patient Reported Outcome Analysis Population
The PRO analyses are based on the PRO full analysis set (FAS) population, defined as 
participants who have received treatment and have at least one PRO assessment available.  
10.6
Statistical Methods
10.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives.  Methods related to exploratory objectives will be described in the sSAP.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 10.8, Multiplicity. Nominal p-values 
08KM9X

PRODUCT:  MK-3475 
158
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
may be computed for other efficacy analyses, but should be interpreted with caution due to 
potential issues of multiplicity.
The 3 stratification factors used for randomization, including primary tumor site, tumor 
stage, and PD-L1 status defined by TPS 50% will be applied to all stratified analyses; in 
particular, stratified log-rank test, stratified Cox model, and stratified Miettinen and 
Nurminen method [Miettinen, O. and Nurminen, M. 1985]. For participants who were 
randomized prior to Amendment 04 without stratification factor for PD-L1 status at 
randomization, the TPS raw score will be used retrospectively to derive the stratification 
factor for PD-L1 status in the analyses.  In the event that there are small strata, for the 
purpose of analysis, strata will be combined to ensure sufficient number of participants, 
responses or events in each stratum.  Details regarding the pooling strategy will be pre-
specified in the sSAP prior to the database lock for 
, based 
on a blinded review of participants and event counts by stratum.
10.6.1.1
Event-Free Survival 
The non-parametric Kaplan-Meier method will be used to estimate the EFS curve in each 
treatment group.  The treatment difference in EFS will be assessed by the stratified log-rank 
test.  A stratified Cox proportional hazard (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 arms.  The HR and its 95% CI from the stratified Cox model with Efron’s method 
of tie handling and with a single treatment covariate will be reported. The stratification 
factors used for randomization (see Section 7.3) will be applied to both the stratified log-rank 
test and the stratified Cox model.  
Since disease progression/recurrence is assessed periodically, disease progression/recurrence 
can occur any time in the time interval between the last assessment where the event was not 
documented and the assessment when the event is first documented.  The true date of disease 
progression/recurrence will be approximated by the date of the first assessment at which the 
event is objectively documented.  Death is always considered as an event.  Participants who 
do not experience a disease progression/recurrence event will be censored at the last disease 
assessment.  Sensitivity analyses will be performed for comparison of EFS based on 
investigator’s assessment.
In order to evaluate the robustness of the EFS endpoint, 1 primary and 1 sensitivity analyses
with a different set of censoring rules will be performed.  The primary analysis follows the 
Intention-To-Treat principle.  That is, PDs/ recurrences/deaths are counted as events
regardless of missed study visits or initiation of new anticancer therapy.  For the sensitivity 
analysis, if the events (disease progression, recurrence or death) are immediately after more 
than 1 missed disease assessment, the data are censored at the last disease assessment prior to 
missing visits.  Also data after new anticancer therapy are censored at the last disease 
assessment prior to the initiation of new anticancer therapy.  If a participant meets multiple 
criteria for censoring, the censoring criterion that occurs earliest will be applied.  The 
censoring rules for primary and sensitivity analyses are summarized in Table 13.
CCI
08KM9X

PRODUCT:  MK-3475 
159
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 13
Censoring Rules for Primary and Sensitivity Analyses of EFS
Situation
Primary Analysis
Sensitivity
Analysis
Disease progression, recurrence, 
or death documented after ≤ 1 
missed disease assessment and 
before new anticancer therapy, if 
any
EFS event at date of 
documented disease 
progression, recurrence, or 
death
EFS event at date of 
documented disease 
progression, recurrence, or 
death
Disease progression, recurrent or 
death documented immediately 
after ≥ 2 consecutive missed 
disease assessments or after new 
anticancer therapy, if any
EFS event at date of 
documented disease 
progression, recurrence, or 
death
Censored at last disease 
assessment prior to the earlier 
date of ≥2 consecutive missed 
visits and new anticancer 
therapy, if any
No disease progression, no 
recurrence and no death; and new 
anticancer therapy is not initiated
Censored at last disease 
assessment 
Censored at last disease 
assessment
No disease progression, no 
recurrence and no death; new 
anticancer therapy is initiated
Censored at last disease 
assessment 
Censored at last disease 
assessment before new 
anticancer therapy
Abbreviations: EFS = event-free survival
10.6.1.2
Major Pathological Response
mPR rate is defined as the proportion of participants with an mPR.  The stratified Miettinen 
and Nurminen’s method with strata weighting by sample size will be used for the comparison 
of mPR rates between the pembrolizumab arm and SoC arm.  The stratification factors used 
for randomization (see Section 7.3) will be applied to the stratified Miettinen and Nurminen’s 
method. 
Participants who are discontinued from the study treatment and continue with other 
neoadjuvant treatment not specified by the study prior to definitive surgery will be classified 
as not having an mPR (non-responders) in the efficacy analyses, regardless of the results 
obtained from the surgery.  Participants who are discontinued from study treatment due to the 
reasons that preclude surgery are considered non-responders.
10.6.1.3
Overall Survival 
The non-parametric Kaplan-Meier method will be used to estimate the survival curves.  The 
treatment difference in survival will be assessed by the stratified log-rank test.  A stratified 
Cox 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 stratified Cox PH 
model with Efron’s methods of tie handling and with a single treatment covariate will be 
reported.  The stratification factors used for randomization (see Section 7.3) will be applied 
to both the stratified log-rank test and the stratified Cox model.  
08KM9X

PRODUCT:  MK-3475 
160
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
10.6.1.4
Pathological Complete Response
pCR rate is defined as the proportion of participants with a pCR.  The same method used to 
analyze mPR rate will be used to analyze pCR rate.  
10.6.1.5
Summary of Efficacy Analysis Methods
Table 14 summarizes the primary analysis approach for primary and secondary efficacy 
endpoints.
08KM9X

PRODUCT:  MK-3475 
161
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 14
Analysis Strategy for Primary and Secondary Efficacy Endpoints
Endpoint/Variable
(Description, Time 
Point)
Statistical 
Method†
Analysis Population
Missing Data 
Approach
Primary:
EFS
Test: stratified Log-
rank test 
Estimation: 
stratified Cox 
model with Efron’s 
tie handling method
ITT

Participants whose 
tumors express 
PD-L1 CPS≥10

Participants whose 
tumors express 
PD-L1 CPS≥1

All participants
Primary censoring 
rule 
Sensitivity analysis 1
(More details are in 
Table 13)
Secondary:
mPR
Stratified M&N 
method
ITT

Participants whose 
tumors express 
PD-L1 CPS≥10

Participants whose 
tumors express 
PD-L1 CPS≥1

All participants
Participants with 
relevant data missing are
considered non-
responders
OS 
Test: stratified Log-
rank test 
Estimation: 
stratified Cox 
model with Efron’s 
tie handling method 
ITT

Participants whose 
tumors express 
PD-L1 CPS≥10

Participants whose 
tumors express 
PD-L1 CPS≥1

All participants
Censored at last date 
participant was known 
to be alive
pCR
Stratified M&N 
method
ITT

Participants whose 
tumors express 
PD-L1 CPS≥10

Participants whose 
tumors express 
PD-L1 CPS≥1

All participants
Participants with 
relevant data missing are 
considered non-
responders
† Statistical models are described in further detail in the text. For stratified analyses, the 
stratification factors used for randomization (see Section 7.3.1 – Stratification) will be applied to 
the analysis model.
Abbreviations:  CPS = combined positive score; EFS = Event-free survival; ITT = Intention-To-Treat; 
M&N = Miettinen and Nurminen; mPR = major pathological response; OS = overall survival; 
pCR = pathological complete response; PD-L1 = programmed cell death ligand 1. 
10.6.2
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.
08KM9X

PRODUCT:  MK-3475 
162
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
The overall safety evaluation will include a summary of the number and percentage of 
participants with at least one AE, drug-related, SAE, 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 10% of 
participants in any treatment group. The threshold of at least 10% of participants was chosen 
because the population enrolled in this study is in critical condition and usually experiences 
various AEs of similar types regardless of treatment; events reported less frequently than 
10% of participants would obscure the assessment of the overall safety profile and add little 
to the interpretation of potentially meaningful treatment differences. In addition, difference in 
the percentage of participants with specific Grade 3-5 AEs (≥5% of participants in any 
treatment group) and SAEs (≥5% of participants in any treatment group) will also be 
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 V4.0
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.
08KM9X

PRODUCT:  MK-3475 
163
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 15
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Overall Safety 
Assessment
Specific Grade 3-5 AE (incidence ≥5% of 
participants in one of the treatment groups)
X
X
Specific serious AE (incidence ≥5% of 
participants in one of the treatment groups)
X
X
Specific AEs, SOCs (incidence ≥10% of 
participants in one of the treatment groups)
X
X
Any AE
X
Any Grade 3-5 AE
X
Any Serious AE 
X
Any Drug-Related AE
X
Any Serious and Drug-Related AE
X
Any Grade3-5 and Drug-Related AE
X
Discontinuation due to AE
X
Death
X
Specific AEs, SOCs (incidence > 0% of 
participants in all of the treatment groups)
X
Change from Baseline Results (lab toxicity 
shift)
X
Assessment of 
safety topics of 
special interest
Pembrolizumab AEOSI
X
Abbreviations: AE = adverse event; AEOSI = adverse event of special interest; CI = confidence interval; SOC = system 
organ class.
10.6.3
Statistical Methods for Patient Reported Outcome Analyses: EORTC QLQ-
C30 & QLQ-H&N35
Change from baseline (the Treatment 1 Cycle 1 assessment in the pembrolizumab arm and 
the presurgery assessment in the SoC arm) in the following secondary QoL outcomes will be
assessed:
•
EORTC QLQ-C30 Global health status/QoL score
•
EORTC QLQ-C30 Physical functioning score
•
QLQ- H&N35 Swallowing symptom score
•
QLQ- H&N35 Speech symptom score
•
QLQ-H&N35 Pain symptom score
08KM9X

PRODUCT:  MK-3475 
164
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
To assess the treatment effects on the QoL outcomes, a constrained longitudinal data analysis 
model will be applied, with the PRO score as the response variable, and treatment, time, the 
treatment by time interaction and stratification factors as covariates. The least square mean 
change from baseline will be summarized for each outcome.  The short-term treatment effect 
on PRO score change from baseline in the pembrolizumab arm will be evaluated during 
neoadjuvant treatment and at the presurgery assessment.  The long-term treatment effect on 
PRO score change from baseline will be primarily evaluated and compared in both treatment 
arms approximately 6 and 12 months following the completion of RT ± cisplatin.
Details of PRO analyses will be described in the sSAP.
10.6.4
Summaries of Baseline Characteristics and Demographics
The 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 will be summarized by treatment either by descriptive 
statistics or categorical tables.
10.7
Interim Analyses
There are 2 planned IAs. Access to the allocation schedule for summaries or analyses for 
presentation to the eDMC will be restricted to an unblinded statistician and an unblinded 
scientific programmer performing the interim analysis, who will have no other 
responsibilities associated with the study.
The eDMC will serve as the primary reviewer of the results of the interim analyses and will 
make recommendations for discontinuation of the study or modification to the Executive 
Oversight Committee of the Sponsor.  If the eDMC recommends modifications to the design 
of the protocol or discontinuation of the study, this Executive Oversight Committee and 
potentially other limited Sponsor personnel may be unblinded to results at the treatment level 
in order to act on these recommendations.  The extent to which individuals are unblinded 
with respect to results of interim analyses will be documented by the unblinded team.  
Additional logistic details will be provided in the eDMC Charter.  
Treatment level results of the interim analysis will be provided by the unblinded statistician 
to the eDMC.  Prior to final study unblinding, the unblinded statistician will not be involved 
in any discussions regarding modifications to the protocol or statistical methods, 
identification of protocol deviations, or data validation efforts after the interim analyses.
10.7.1
Efficacy Interim Analyses
The interim and final analyses strategy for efficacy is summarized in Table 16.
08KM9X

PRODUCT:  MK-3475 
165
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 16
Decisions to stop the study early will be based on DMC recommendations with review by the 
Executive Oversight Committee.  In the event that the study is stopped early for efficacy, the 
study will continue to follow participants for survival update.
Type I error control for the efficacy analyses as well as efficacy bounds are described in 
Section 10.8 Multiplicity.
10.7.2
Safety Interim Analyses
The DMC will be responsible for periodic interim safety reviews. An interim safety analysis 
will be performed when the first 15 participants in the pembrolizumab arm have completed 
RT during the post-surgery adjuvant treatment phase (approximately 5 months since first 
participant is randomized). Afterwards, the DMC will review safety data periodically in the 
study. Safety IAs will also be performed at the time of efficacy IAs. Details will be specified 
in the DMC charter.
CCI
CCI
08KM9X

PRODUCT:  MK-3475 
166
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
The interim analyses strategy for safety is summarized in Table 17.
Table 17
Summary of Interim Analyses Strategy for Safety
Key Endpoints
Timing
Estimated Months after 
First Participant 
Randomized
Primary Purpose 
of Analysis

AEs

Surgical 
delays 
First 15 participants in the 
pembrolizumab arm have 
completed RT during the 
post-surgery adjuvant 
treatment phase
Periodic interim safety 
reviews thereafter
~5 months
As specified in the 
DMC charter
Safety evaluation
Abbreviations: AE = Adverse Event; DMC = Data Monitoring Committee; RT = Radiotherapy
10.8
Multiplicity
10.8.1
Multiplicity Control for Efficacy Interim Analyses
CCI
08KM9X

PRODUCT:  MK-3475 
167
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Figure 2
10.8.1.1
Event-Free Survival
CCI
CCI
CCI
08KM9X

PRODUCT:  MK-3475 
168
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 18
 
CCI
CCI
CCI
08KM9X

PRODUCT:  MK-3475 
169
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 19
 
CCI
CCI
08KM9X

PRODUCT:  MK-3475 
170
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 20
10.8.1.2
Major Pathologic Response 
CCI
CCI
CCI
CCI
08KM9X

PRODUCT:  MK-3475 
171
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 21
 
10.8.1.3
Overall Survival
CCI
CCI
CCI
08KM9X

PRODUCT:  MK-3475 
172
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 22
 
CCI
CCI
CCI
08KM9X

PRODUCT:  MK-3475 
173
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 23
 
CCI
CCI
CCI
08KM9X

PRODUCT:  MK-3475 
174
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 24
10.8.2
Multiplicity Control for Safety Interim Analyses
The DMC has responsibility for assessment of overall risk: benefit. When prompted by 
safety concerns, the DMC can request corresponding efficacy data.  DMC review of efficacy 
data to assess the overall risk: benefit to study participants will not require a multiplicity 
adjustment typically associated with a planned efficacy IA. However, to account for any 
multiplicity concerns raised by the DMC review of unplanned efficacy data when prompted 
by safety concerns, a sensitivity analysis for OS adopting a conservative multiplicity 
adjustment will be pre-specified in the sSAP.
10.9
Sample Size and Power Calculations
CCI
CCI
CCI
08KM9X

PRODUCT:  MK-3475 
175
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
10.10 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 the primary 
endpoints will be estimated and plotted within each category of the following classification 
variables:

Primary tumor site (oropharynx/oral cavity vs. larynx vs. hypopharynx)

Tumor Stage (III vs. IVA)

PD-L1 status (TPS ≥ 50% versus TPS<50%)
•
Age category (<65 vs. ≥65 years)
CCI
08KM9X

PRODUCT:  MK-3475 
176
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
•
Sex (female vs. male)
•
Race (white vs. all others)
•
Smoking status (never vs. former vs. current)
•
Geographical regions (North America vs. European Union vs. Rest of the World)
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above, using unstratified methods.  In 
addition, a forest plot will be produced, which provides the estimated point estimates and 
confidence intervals 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% of the 
analysis population, the subgroup analysis will not be performed for this category of the 
subgroup variable, and the forest plot will not display this category of the subgroup variable. 
10.11 Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study.  Any 
deviation from protocol-directed administration will be reported.
10.12 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 the APaT population.
08KM9X

PRODUCT:  MK-3475 
177
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
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]
[Ang, K. K., et al 
2010]
Ang KK, Harris J, Wheeler R, Weber R, Rosenthal 
DI, Nguyen-Tan PF, et al. Human papillomavirus 
and survival of patients with oropharyngeal cancer. 
N Engl J Med. 2010 Jul 1;363(1):24-35.
[04FP0Y]
[Bauml, J., et al 2017]
Bauml J, Seiwert TY, Pfister DG, Worden F, Liu 
SV, Gilbert J, et al. Pembrolizumab for Platinum-
and Cetuximab-Refractory Head and Neck Cancer: 
Results From a Single-Arm, Phase II Study. J Clin 
Oncol. 2017 May 10;35(14):1542-1549.
[04QTG6]
[Bernier, J., et al 2004]
Bernier J, Domenge C, Ozsahin M, Matuszewska 
K, Lefèbvre J-L, Greiner RH, et al. Postoperative 
irradiation with or without concomitant 
chemotherapy for locally advanced head and neck 
cancer. N Engl J Med 2004;350(19):1945-52.
[03QCL4]
[Bjordal, K., et al 
1994]
Bjordal K, Ahlner-Elmqvist M, Tollesson E, 
Jensen AB, Razavi D, Maher EJ, et al. 
Development of a European Organization for 
Research and Treatment of Cancer (EORTC) 
questionnaire module to be used in quality of life 
assessments in  head and neck cancer patients. 
Acta Oncol 1994;33(8):879-85.
[03WNBB]
[Bjordal, K., et al 
2000]
Bjordal K, de Graeff A, Fayers PM, Hammerlid E, 
van Pottelsberghe C, Curran D, et al. A 12 country 
field study of the EORTC QLQ-C30 (version 3.0) 
and the head and neck cancer specific module 
(EORTC QLQ-H&N35) in head and neck patients. 
EORTC Quality of Life Group. Eur J Cancer. 2000 
Sep;36(14):1796-807.
[040VGM]
08KM9X

PRODUCT:  MK-3475 
178
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
[Bossi, P., et al 2014]
Bossi P, Lo Vullo S, Guzzo M, Mariani L, Granata 
R, Orlandi E, et al. Preoperative chemotherapy in 
advanced resectable OCSCC: long-term results of 
a randomized phase III trial. Ann Oncol. 2014 
Feb;25(2):462-6.
[04LC3W]
[Bottomley, A., et al 
2014]
Bottomley A, Tridello G, Coens C, Rolland F, 
Tesselaar ME, Leemans CR, et al. An international 
phase 3 trial in head and neck cancer: quality of 
life and symptom results: EORTC 24954 on behalf 
of the EORTC Head and Neck and the EORTC 
Radiation Oncology Group. Cancer. 2014 Feb 
1;120(3):390-8.
[04MS8V]
[Brouwer, C. L., et al 
2015]
Brouwer CL, Steenbakkers RJ, Bourhis J, Budach 
W, Grau C, Gregoire V, et al. CT-based 
delineation of organs at risk in the head and neck 
region: DAHANCA, EORTC, GORTEC, 
HKNPCSG, NCIC CTG, NCRI, NRG Oncology 
and TROG consensus guidelines. Radiother Oncol. 
2015 Oct;117(1):83-90.
[04KCT8]
[Burtness, B., et al 
2018]
Burtness B, Harrington KJ, Greil R, Soulieres D, 
Tahara M, De Castro G Jr, et al. KEYNOTE-048: 
phase III study of first-line pembrolizumab (P) for 
recurrent/metastatic head and neck squamous cell 
carcinoma (R/MHNSCC) [abstract]. Presented at: 
European Society for Medical Oncology (ESMO) 
2018 Congress; 2018 Oct 19-23; Munich 
(Germany). Ann Oncol. 2018 Oct;29(suppl 
8):viii729. Abstract no. LBA8_PR.
[053ZSC]
[Carey, L. A., et al 
2007]
Carey LA, Dees C, Sawyer L, Gatti L, Moore DT, 
Collichio F, et al. The triple negative paradox: 
primary tumor chemosensitivity of breast cancer 
subtypes. Clin Cancer Res 2007;13(8):2329-34.
[03R26K]
[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]
08KM9X

PRODUCT:  MK-3475 
179
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
[Chera, B. S., et al 
2014]
Chera BS, Eisbruch A, Murphy BA, Ridge JA, 
Gavin P, Reeve BB, et al. Recommended patient-
reported core set of symptoms to measure in head 
and neck cancer treatment trials. J Natl Cancer 
Inst. 2014 Jul 8;106(7):[4 p.].
[040WHF]
[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]
[Cohen, E. E. W., et al 
2019]
Cohen EEW, Soulieres D, Le Tourneau C, Dinis J, 
Licitra L, Ahn MJ, et al. Pembrolizumab versus 
methotrexate, docetaxel, or cetuximab for 
recurrent or metastatic head-and-neck squamous 
cell carcinoma (KEYNOTE-040): a randomised, 
open-label, phase 3 study. Lancet. 2019 Jan 
12;393:156-67.
[056TMW]
[Cooper, J. S., et al 
2004]
Cooper JS, Pajak TF, Forastiere AA, Jacobs J, 
Campbell BH, Saxman SB, et al. Postoperative 
concurrent radiotherapy and chemotherapy for 
high-risk squamous-cell carcinoma of the head and 
neck. N Engl J Med 2004;350(19):1937-44.
[03QCL3]
[Cortazar, P., et al 
2014]
Cortazar P, Zhang L, Untch M, Mehta K, 
Costantino JP, Wolmark N, et al. Pathological 
complete response and long-term clinical benefit 
in breast cancer: the CTNeoBC pooled analysis. 
Lancet. 2014 Jul 12;384(9938):164-72.
[046WPX]
[Curran, D., et al 2007]
Curran D, Giralt J, Harari PM, Ang KK, Cohen 
RB, Kies MS, et al. Quality of life in head and 
neck cancer patients after treatment with high-dose 
radiotherapy alone or in combination with 
cetuximab. J Clin Oncol. 2007 Jun 1;25(16):2191-
7. Erratum in: J Clin Oncol. 2007 Aug 
20;25(24):3790.
[0426KP]
08KM9X

PRODUCT:  MK-3475 
180
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
[de Biasi, A. R., et al 
2014]
de Biasi AR, Villena-Vargas J, Adusumilli PS. 
Cisplatin-induced antitumor immunomodulation: a 
review of preclinical and clinical evidence. Clin 
Cancer Res. 2014 Nov 1;20(21):5384-91.
[04G56T]
[Deng, L., et al 2014]
Deng L, Liang H, Burnette B, Beckett M, Darga T, 
Weichselbaum RR, et al. Irradiation and anti-PD-
L1 treatment synergistically promote antitumor 
immunity in mice. J Clin Invest. 2014 
Feb;124(2):687-95.
[04G598]
[Derer, A., et al 2016]
Derer A, Frey B, Fietkau R, Gaipl US. Immune-
modulating properties of ionizing radiation: 
rationale for the treatment of cancer by 
combination radiotherapy and immune checkpoint 
inhibitors. Cancer Immunol Immunother. 2016 
Jul;65(7):779-86.
[04QTB4]
[Disis, M. L. 2010]
Disis ML. Immune regulation of cancer. J Clin 
Oncol 2010;28(29):4531-8.
[058SQL]
[Dogan, S. 2023]
Dogan S. Conference report: European society for 
medical oncology congress 2022 [editorial]. Rare 
Tumors. 2023;15:1-7.
[08CVXD]
[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]
[Esposito, A., et al 
2015]
Esposito A, Criscitiello C, Curigliano G. Immune 
checkpoint inhibitors with radiotherapy and 
locoregional treatment: synergism and potential 
clinical implications. Curr Opin Oncol. 2015 
Nov;27(6):445-51.
[04G4JC]
[Forde, P. M., et al 
2022]
Forde PM, Spicer J, Lu S, Provencio M, 
Mitsudomi T, Awad MM, et al. Neoadjuvant 
nivolumab plus chemotherapy in resectable lung 
cancer. N Engl J Med. 2022 May 
26;386(21):1973-85.
[082D4W]
08KM9X

PRODUCT:  MK-3475 
181
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
[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]
[Gillison, M. L. 2004]
Gillison ML. Human papillomavirus-associated 
head and neck cancer is a distinct epidemiologic, 
clinical, and molecular entity. Semin Oncol. 2004 
Dec;31(6):744-54.
[04FQFB]
[Golden, E. B. 2015]
Golden EB, Apetoh L. Radiotherapy and 
immunogenic cell death. Semin Radiat Oncol. 
2015 Jan;25(1):11-7.
[04G54G]
[Greenwald, R. J., et al 
2005]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 
family revisited. Annu Rev Immunol 2005;23:515-
48.
[00VMQL]
[Gregoire, V., et al 
2014]
Gregoire V, Ang K, Budach W, Grau C, Hamoir 
M, Langendijk JA, et al. Delineation of the neck 
node levels for head and neck tumors: a 2013 
update. DAHANCA, EORTC, HKNPCSG, NCIC 
CTG, NCRI, RTOG, TROG consensus guidelines. 
Radiother Oncol. 2014 Jan;110(1):172-81.
[04G63Y]
[Hellmann, M. D., et al 
2014]
Hellmann MD, Chaft JE, William WN Jr, Rusch 
V, Pisters KM, Kalhor N, et al. Pathological 
response after neoadjuvant chemotherapy in 
resectable non-small-cell lung cancers: proposal 
for the use of major pathological response as a 
surrogate endpoint. Lancet Oncol. 2014 
Jan;15(1):e42-50.
[04LK2F]
[Huang, S. H., et al 
2015]
Huang SH, Xu W, Waldron J, Siu L, Shen X, Tong 
L, et al. Refining American Joint Committee on 
Cancer/Union for International Cancer Control 
TNM stage and prognostic groups for human 
papillomavirus-related oropharyngeal carcinomas. 
J Clin Oncol. 2015 Mar 10;33(8):836-45.
[04FQF7]
[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]
08KM9X

PRODUCT:  MK-3475 
182
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
[Lassen, P., et al 2009]
Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm 
T, Alsner J, Overgaard J. Effect of HPV-associated 
p16INK4A expression on response to radiotherapy 
and survival in squamous cell carcinoma of the 
head and neck. J Clin Oncol. 2009 Apr 
20;27(12):1992-8.
[04G648]
[Lassen, P., et al 2010]
Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm 
T, Alsner J, Overgaard J. HPV-associated p16-
expression and response to hypoxic modification 
of radiotherapy in head and neck cancer. Radiother 
Oncol. 2010 Jan;94(1):30-5.
[04G64D]
[Lassen, P., et al 2011]
Lassen P, Eriksen JG, Krogdahl A, Therkildsen 
MH, Ulhoi BP, Overgaard M, et al. The influence 
of HPV-associated p16-expression on accelerated 
fractionated radiotherapy in head and neck cancer: 
evaluation of the randomised DAHANCA 6&7 
trial. Radiother Oncol. 2011 Jul;100(1):49-55.
[04G64G]
[Liedtke, C., et al 
2008]
Liedtke C, Mazouni C, Hess KR, Andre F, Tordai 
A, Mejia JA, et al. Response to neoadjuvant 
therapy and long-term survival in patients with 
triple-negative breast cancer. J Clin Oncol. 2008 
Mar 10;26(8):1275-81.
[046KDF]
[Machiels, J. P., et al 
2001]
Machiels JP, Reilly RT, Emens LA, Ercolini AM, 
Lei RY, Weintraub D, et al. Cyclophosphamide, 
doxorubicin, and paclitaxel enhance the antitumor 
immune response of granulocyte/macrophage-
colony stimulating factor-secreting whole-cell 
vaccines in HER-2/neu tolerized mice. Cancer
Res. 2001 May 1;61(9):3689-97.
[04G4XW]
[Machiels, J. P., et al 
2022]
Machiels JP, Tao Y, Burtness B, Tahara M, 
Rischin D, Alves GV, et al. Primary results of the 
phase III KEYNOTE-412 study: pembrolizumab 
(pembro) with chemoradiation therapy (CRT) vs 
placebo plus CRT for locally advanced (LA) head 
and neck squamous cell carcinoma (HNSCC) 
[abstract]. Presented at: European Society for 
Medical Oncology (ESMO) Congress; 2022 Sep 9-
13; Paris (France). Ann Oncol. 2022;33(suppl 
7):S1399.
[08BB20]
08KM9X

PRODUCT:  MK-3475 
183
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
[Maurer, W. and Bretz, 
F. 2013]
Maurer W and Bretz F. Multiple testing in group 
sequential trials using graphical approaches. Stat 
Biopharm Res 2013;5(4):311-20.
[03XQVB]
[Mehra, R., et al 2016]
Mehra R, Seiwert TY, Mahipal A, Weiss J, Berger 
R, Paul Eder J et al. Efficacy and safety of 
pembrolizumab in recurrent/metastatic head and 
neck squamous cell carcinoma (R/M HNSCC): 
Pooled analyses after longterm followup in 
KEYNOTE012 [abstract]. J Clin Oncol. 
2016;34(suppl). Abstract no. 6012.
[04GZ3C]
[Mehra, R., et al 2018]
Mehra R, Seiwert TY, Gupta S, Weiss J, Gluck I, 
Eder JP, et al. Efficacy and safety of 
pembrolizumab in recurrent/metastatic head and 
neck squamous cell carcinoma: pooled analyses 
after long-term follow-up in KEYNOTE-012. Br J 
Cancer. 2018;119:153-9.
[056TMX]
[Menzies, A. M., et al 
2021]
Menzies AM, Amaria RN, Rozeman EA, Huang 
AC, Tetzlaff MT, van de Wiel BA, et al. 
Pathological response and survival with 
neoadjuvant therapy in melanoma: a pooled 
analysis from the International Neoadjuvant 
Melanoma Consortium (INMC). Nat Med. 2021 
Feb;27:301-9. Additional material; 12 p.
[087G99]
[Miettinen, O. and 
Nurminen, M. 1985]
Miettinen O and Nurminen M. Comparative 
Analysis of Two Rates. Stat Med 1985;4:213-26.
[03QCDT]
[National 
Comprehensive Cancer 
Network 2017]
National Comprehensive Cancer Network 
(NCCN). Clinical practice guidelines in oncology: 
Head and neck cancers: version 1.2017. Fort 
Washington, PA: NCCN; 2017. p. 187.
[04MXRG]
[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]
08KM9X

PRODUCT:  MK-3475 
184
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
[OSullivan, B., et al 
2016]
OSullivan B, Huang SH, Su J, Garden AS, Sturgis 
EM, Dahlstrom K. et al. Development and 
validation of a staging system for HPV-related 
oropharyngeal cancer by the International 
Collaboration on Oropharyngeal cancer Network 
for Staging (ICON-S): a multicentre cohort study. 
Lancet Oncol. 2016 Apr;17(4):440-51.
[04N002]
[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]
[Pataer, A., et al 2012]
Pataer A, Kalhor N, Correa AM, Raso MG, 
Erasmus JJ, Kim ES, et al. Histopathologic 
response criteria predict survival of patients with 
resected lung cancer after neoadjuvant 
chemotherapy. J Thorac Oncol. 2012 
May;7(5):825-32.
[04LK2R]
[Patel, S. P., et al 
2023]
Patel SP, Othus M, Chen Y, Wright GP Jr, Yost 
KJ, Hyngstrom JR, et al. Neoadjuvant-adjuvant or 
adjuvant-only pembrolizumab in advanced 
melanoma. N Engl J Med. 2023 Mar 2;388(9):813-
823.
[089PPW]
[Pickard, A. S., et al 
2007]
Pickard AS, Neary MP, Cella D. Estimation of 
minimally important differences in EQ-5D utility 
and VAS scores in cancer. Health Qual Life 
Outcomes 2007;5:1-8.
[00W0FM]
[Postow, M. A., et al 
2012]
Postow MA, Callahan MK, Barker CA, Yamada 
Y, Yuan J, Kitano S, et al. Immunologic correlates 
of the abscopal effect in a patient with melanoma. 
N Engl J Med. 2012 Mar 8;366(10):925-31.
[04G4RR]
[Rabin, R. and de 
Charro, F. 2001]
Rabin R, de Charro F. EQ-5D: a measure of health 
status from the EuroQol Group. Ann Med 
2001;33:337-43.
[03XLS2]
[Riley, J. L. 2009]
Riley JL. PD-1 signaling in primary T cells. 
Immunol Rev 2009;229:114-25.
[00VMQ9]
08KM9X

PRODUCT:  MK-3475 
185
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
[Roila, F., et al 2016]
Roila F, Molassiotis A, Herrstedt J, Aapro M, 
Gralla RJ, Bruera E, et al. 2016 MASCC and 
ESMO guideline update for the prevention of 
chemotherapy- and radiotherapy-induced nausea 
and vomiting and of nausea and vomiting in 
advanced cancer patients. Ann Oncol. 2016 
Sep;27(Suppl 5):v119-33.
[04VPX7]
[Rugo, H. S., et al 
2022]
Rugo HS, Bardia A, Marme F, Cortes J, Schmid P, 
Loirat D, et al. Primary results from TROPiCS-02: 
a randomized phase 3 study of sacituzumab 
govitecan (SG) versus treatment of physician’s 
choice (TPC) in patients (Pts) with hormone 
receptor–positive/HER2-negative (HR+/HER2-) 
advanced breast cancer [abstract]. Presented at: 
2022 American Society of Clinical Oncology 
(ASCO) Annual Meeting; 2022 Jun 3-7; Chicago, 
IL. J Clin Oncol. 2022;40(suppl 17).
[0883NV]
[Santanam, L., et al 
2012]
Santanam L, Hurkmans C, Mutic S, van Vliet-
Vroegindeweij C, Brame S, Straube W, et al. 
Standardizing naming conventions in radiation 
oncology. Int J Radiat Oncol Biol Phys. 2012 Jul 
15;83(4):1344-9.
[04KCT9]
[Schmid, P., et al 
2020]
Schmid P, Cortes J, Pusztai L, McArthur H, 
Kummel S, Bergh J, et al. Pembrolizumab for 
early triple-negative breast cancer. N Engl J Med. 
2020 Feb 27;382(9):810-21.
[05GBCT]
[Sharabi, A. B., et al 
2015]
Sharabi AB, Nirschl CJ, Kochel CM, Nirschl TR, 
Francica BJ, Velarde E, et al. Stereotactic 
Radiation Therapy Augments Antigen-Specific 
PD-1-Mediated Antitumor Immune Responses via 
Cross-Presentation of Tumor Antigen. Cancer 
Immunol Res. 2015 Apr;3(4):345-55.
[04G4RJ]
[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]
08KM9X

PRODUCT:  MK-3475 
186
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
[Siegel, R., et al 2013]
Siegel R, Naishadham D, Jemal A. Cancer 
statistics, 2013. CA Cancer J Clin. 2013 
Jan;63(1):11-30.
[048QSL]
[Steinau, M., et al 
2014]
Steinau M, Saraiya M, Goodman MT, Peters ES, 
Watson M, Cleveland JL. et al. Human 
papillomavirus prevalence in oropharyngeal cancer 
before vaccine introduction, United States. Emerg 
Infect Dis. 2014 May;20(5):822-8.
[04N006]
[Topalian, S. L., et al 
2020]
Topalian SL, Taube JM, Pardoll DM. Neoadjuvant 
checkpoint blockade for cancer immunotherapy. 
Science. 2020 Jan 31;367:525. Additional 
material; 1 p.
[08CW08]
[Uppaluri, R., et al 
2017]
Uppaluri R, Zolkind P, Lin T, Nussenbaum B, 
Jackson RS, Rich J, et al. Neoadjuvant 
pembrolizumab in surgically resectable locally 
advanced HPV negative head and neck squamous 
cell carcinoma (HNSCC) [abstract]. J Clin Onc 
2017; 35(Suppl 15). Abstract no. 6012.
[04PJDG]
[Uppaluri, R., et al 
2020]
Uppaluri R, Campbell KM, Egloff AM, Zolkind P, 
Skidmore ZL, Nussenbaum B, et al. Neoadjuvant 
and adjuvant pembrolizumab in resectable locally 
advanced, human papillomavirus-unrelated head 
and neck cancer: a multicenter, phase II trial. Clin 
Cancer Res. 2020 Oct 1;26(19):5140-52.
[08CVJ8]
[van Herpen, C. M., et 
al 2010]
van Herpen CM, Mauer ME, Mesia R, Degardin 
M, Jelic S, Coens C, et al. Short-term health-
related quality of life and symptom control with 
docetaxel, cisplatin, 5-fluorouracil and cisplatin 
(TPF), 5-fluorouracil (PF) for induction in 
unresectable locoregionally advanced head and 
neck cancer patients (EORTC 24971/TAX 323). 
Br J Cancer. 2010 Oct 12;103(8):1173-81.
[0425Y3]
[Weinberger, P. M., et 
al 2006]
Weinberger PM, Yu Z, Haffty BG, Kowalski D, 
Harigopal M, Brandsma J, et al. Molecular 
classification identifies a subset of human 
papillomavirus-associated oropharyngeal cancers 
with favorable prognosis. J Clin Oncol. 2006 Feb 
10;24(5):736-47.
[04G6TJ]
08KM9X

PRODUCT:  MK-3475 
187
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
[Wise-Draper, T. M., 
et al 2022]
Wise-Draper TM, Gulati S, Palackdharry S, 
Hinrichs BH, Worden FP, Old MO, et al. Phase II 
clinical trial of neoadjuvant and adjuvant 
pembrolizumab in resectable local-regionally 
advanced head and neck squamous cell carcinoma. 
Clin Cancer Res. 2022 Apr 1;28(7):1345-52.
[08CVJ3]
[Zeng, J., et al 2013]
Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, 
Ruzevick J, et al. Anti-PD-1 blockade and 
stereotactic radiation produce long-term survival in 
mice with intracranial gliomas. Int J Radiat Oncol 
Biol Phys. 2013 Jun 1;86(2):343-9.
[04G6TW]
[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]
[Zhong, L. P., et al 
2015]
Zhong LP, Zhang CP, Ren GX, Guo W, William 
WN Jr, Hong CS, et al. Long-term results of a 
randomized phase III trial of TPF induction 
chemotherapy followed by surgery and  radiation 
in locally advanced oral squamous cell carcinoma. 
Oncotarget. 2015 Jul 30;6(21):18707-14.
[04LC3Q]
08KM9X

PRODUCT:  MK-3475 
188
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
12
APPENDICES
Appendix 1: Abbreviations and Trademarks
Abbreviation
Definition
AE
Adverse event
AEOSI
Adverse event of special interest
AJCC
American Joint Committee on Cancer
ALT (SGPT)
Alanine aminotransferase (serum glutamic pyruvic transaminase)
APaT
All participants as treated
aPTT
Activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST (SGOT)
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase)
β-hCG
β-Human chorionic gonadotropin
BICR
Blinded independent central review
CD
Cluster of differentiation
CI
Confidence interval
Cmax
Maximum serum concentration
COVID-19
Coronavirus disease caused by severe acute respiratory syndrome 
coronavirus 2
CPS
Combined positive score
CrCl
Creatinine clearance
CRF
Case report form
CRT
Chemoradiation or Chemoradiotherapy
CT
Computed tomography
CTCAE
Common terminology criteria of adverse events
ctDNA
Circulating tumor DNA
CTFG
Clinical Trial Facilitation Group
CTLA-4
Cytotoxic T-lymphocyte associated protein 4
Ctrough
Trough concentration
CTV
Clinical target volume
DILI
Drug-induced liver injury
DMC
Data Monitoring Committee
DMFS
Distant metastases-free survival
DOR
Duration of response
ECG
Electrocardiogram
ECI
Events of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
eDMC
External Data Monitoring Committee
EEA
European Economic Area
EFS
Event-free survival
EORTC
European Organisation for Research and Treatment of Cancer
ePRO
Electronic patient-reported outcome
EQ-5D-5L
EuroQoL-5 dimension questionnaire
EU CTR
European Union Clinical Trials Regulation
FAS
Full analysis set
FBR
Future biomedical research
FDA
Food and Drug Administration
08KM9X

PRODUCT:  MK-3475 
189
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Abbreviation
Definition
FDG-PET
Fluorodeoxyglucose-positron emission tomography
FFPE
Formalin-fixed paraffin-embedded
FNA
Fine needle aspirate
FSH
Follicular stimulating hormone
FSR
First Site Ready
FU
Follow-up
GCP
Good clinical practice
GFR
Glomerular filtration rate
GTV
Gross tumor volume
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
IA
Interim analysis
ICF
Informed consent form
ICRU
International Commission on Radiation Units
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IgG4
Immunoglobulin G4
IGRT
Image guided radiation therapy
IMP
Investigational medicinal product
IMRT
Intensity modulated radiation therapy
irAEs
Immune-related adverse events
IRB
Institutional Review Board
ITT
Intent-to-treat
IUD
Intrauterine device
IUS
Intrauterine system
IV
Intravenous
IVRS
Interactive voice response system
IWRS
Interactive web response system
LA
Locoregionally advanced
mAb
Monoclonal antibody
MISP
Merck Investigator Studies Program
mPR
Major pathological response
MRI
Magnetic resonance imaging
MSI
Microsatellite instability
NCI
National Cancer Institute
NSAIDs
Nonsteroidal anti-inflammatory drugs
NSCLC
Non-small cell lung cancer
OAR
Organs at risk
ORR
Objective response rate
OS
Overall survival
PBPK
Physiologically based pharmacokinetic
pCR
Pathological complete response
PD
Progressive disease
PD-1
Programmed cell death 1
08KM9X

PRODUCT:  MK-3475 
190
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Abbreviation
Definition
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PFS
Progression-free survival
PH
Proportional hazard
PK
Pharmacokinetic
po
Per os; oral(ly)
PRO
Patient reported outcome
PRV
Planning organ at risk volume
PTV
Planning target volume
Q2W
Every 2 weeks
Q3W
Every 3 weeks
QA
Quality assurance
QLQ
Quality of life questionnaire
QoL
Quality of life
RECIST
Response evaluation criteria in solid tumors
R/M HNSCC
Recurrent or metastatic head and neck squamous cell carcinoma
RT
Radiotherapy
SAE
Serious adverse event
SAP
Statistical analysis plan
SHP
Src homology region 2 domain-containing phosphatase
SIB-IMRT
Simultaneous integrated boost-intensity modulated radiation therapy
SIM
Site imaging manual
SoA
Schedule of assessments
SoC
Standard of care
SOC
System organ class
SOP
Standard Operating Procedure
sSAP
Supplemental statistical analysis plan
T1DM
Type 1 diabetes mellitus
UICC
Union for International Cancer Control
ULN
Upper limit of normal
US
United States
VOP
Verification of progression
vs.
Versus
WOCBP
Woman of childbearing potential
08KM9X

PRODUCT:  MK-3475 
191
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Appendix 2: Clinical Laboratory Tests 
•
The tests detailed in Table 25 will be performed by the local laboratory. 
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 6.1 and 6.2 of the protocol.
•
All laboratory tests to determine eligibility, Drug-Induced Liver Injury (DILI) (see 
Section 5.1 – Entry Criteria Table 1 and Section 9.3.7 – Events of Clinical Interest, 
respectively), creatinine clearance prior to cisplatin dosing, and thyroid testing (as 
specified in footnote f) are mandatory; all other additional laboratory tests are 
recommended and may be performed according to local institutional standard.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 25
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
WBC count with 
Differential:
Neutrophils
Lymphocytes
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 
ULN)
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 
(nonfasting)
Calciumd
Alkaline 
phosphatase
Magnesium
Albumin
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
08KM9X

PRODUCT:  MK-3475 
192
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Laboratory 
Assessments
Parameters
Other Tests

Serum or urine β human chorionic gonadotropin (β hCG) pregnancy 
test (for WOCBP according to the requirements in Section 6.1 and 
Section 9.5.9.2).  
Refer to Appendix 8 for UK-, Germany-, and France-specific 
requirements.

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody) testing is not required unless mandated by 
local health authority. If required, testing will be conducted per local 
regulations and site SOPs. Refer to Appendix 8 for Germany-specific 
requirements.

Prothrombin (PT) or International normalized ratio (INR)

Activated partial thromboplastin time (aPTT)e

Free triiodothyronine (FT3)f

Free thyroxine (FT4)f

Thyroid stimulating hormone (TSH)
NOTES:
CrCl = creatinine clearance; GFR = glomerular filtration rate; MCH = mean corpuscular hemoglobin; MCV 
= mean corpuscular volume; RBC = red blood cell; SOPs = Standard Operating Procedures; ULN = upper 
limit of normal; WBC = white blood cell; WOCBP = women of childbearing potential.
a. BUN is preferred; if not available urea may be tested.
b. If available as standard of care 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.  CrCl to be repeated within 3 days prior to start of 
each cisplatin administration for management of dose reduction for renal toxicity guidelines.
d. Corrected calcium should be checked for participants with hypoalbuminemia.
e. PTT may be performed if the local laboratory is unable to perform aPTT.
f.
In case of elevated TSH, add Free T3 and Free T4.  Free T4 should be performed on all participants with 
elevated TSH; Free T3 only needs to be performed if it is done as a part of local standard of care. If the Free 
T3 and Free T4 are not available locally, they can be sent to the central laboratory to be performed (see 
Laboratory Manual for details).
Investigators must document their review of each laboratory safety report.
08KM9X

PRODUCT:  MK-3475 
193
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Appendix 3: Regulatory, Ethical, and Study Governance Considerations
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I.
Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted in 
compliance with local and/or national regulations (including all applicable data protection laws and regulations), 
Regulation (EU) 536/2014, and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also 
in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or which 
are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the full control 
of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial 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 (or individuals acting on behalf of MSD) 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.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus source 
documentation according to standard operating procedures. Per MSD policies and procedures, if potential fraud,
scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related Significant Quality Issues are 
reported, such matters are investigated. When necessary, appropriate corrective and/or preventative actions are 
defined and regulatory authorities and/or ethics review committees are notified. 
08KM9X

PRODUCT:  MK-3475 
194
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the extent 
scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important to patients, 
physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather than 
hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be underpowered 
and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named authors 
must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in publications. 
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority acceptance/authorization 
prior to implementation of the trial or amendment, in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance with 
local and/or national regulations. Changes to the protocol that are required urgently to eliminate an immediate hazard 
and to protect participant safety may be enacted in anticipation of ethics committee approval. MSD will inform 
regulatory authorities of such new measures to protect participant safety, in compliance with local and/or national 
regulations. 
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is obtained. 
Participants may withdraw from an MSD trial at any time, without any influence on their access to, or receipt of, 
medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all applicable 
data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on behalf of 
MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records that might 
identify the participant by name.  
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an ethics 
committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to enroll 
participants in its trials. However, when enrollment is particularly challenging, additional payments may be made to 
compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent on 
chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may wish 
to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As noted 
above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices. 
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
08KM9X

PRODUCT:  MK-3475 
195
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which 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.
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 institutional review board, ethics review committee (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 trial 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.
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 trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the participant 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the participant will be identified by unique code 
only; full names/initials will be masked prior to transmission to the Sponsor.
08KM9X

PRODUCT:  MK-3475 
196
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this trial in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Committees Structure
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Trial Steering Committee
This trial will be conducted in consultation with a Trial Steering Committee.  The Trial 
Steering Committee comprises:
•
Sponsor personnel 
•
Investigators participating in the trial 
•
Consulting therapeutic-area experts and clinical trialists 
The Trial Steering Committee will provide guidance on the operational aspects of the trial.  
Specific details regarding responsibilities and governance of the Trial Steering Committee 
will be described in a separate charter.
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
Data Monitoring Committee (DMC) or Trial Steering Committee regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
08KM9X

PRODUCT:  MK-3475 
197
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
be involved with the trial in any other way (eg, they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 10.7 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the external collaborating organization 
protocol team; meeting facilitation; the trial 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.
Publication Policy
The results of this study may be published or presented at scientific meetings. The sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before submission.  This allows the sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov,
www.clinicaltrialsregister.eu or other local registries.  MSD, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow participants to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
08KM9X

PRODUCT:  MK-3475 
198
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (eg, International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
Guideline and other generally accepted standards of good clinical practice); and all 
applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
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 MSD 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 trial 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
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 trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
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.
08KM9X

PRODUCT:  MK-3475 
199
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
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. 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial 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 regulatory authority as a result of an audit or inspection to cure 
deficiencies in the trial documentation and worksheets/case report forms.
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
(eg, EU CTR: 25 years after the end of the study). No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred 
to another location or party without written notification to the sponsor.
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Study and Site Closure
The sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
08KM9X

PRODUCT:  MK-3475 
200
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting
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 non-
therapeutic effect.
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
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 treatment.
●
NOTE: for purposes of AE definition, study treatment  includes any pharmaceutical 
product, biological product, vaccine, device, diagnostic agent or protocol specified 
procedure whether investigational (including placebo or active comparator product) or 
marketed, manufactured by, licensed by, provided by or distributed by the sponsor for 
human use in this study.
08KM9X

PRODUCT:  MK-3475 
201
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
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, or are considered clinically significant in 
the medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment 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 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, 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). 
Note: Progression of the cancer under study is not a reportable event. Refer to 
Section 9.3.5 for additional details.
Events NOT Meeting the AE Definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads 
to the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
●
Refer to section 9.3.5 for protocol specific exceptions
08KM9X

PRODUCT:  MK-3475 
202
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
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 
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation.  (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition 
that is diagnosed prior to the use of a MSD product and is documented in the patient’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) which 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 one 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.
08KM9X

PRODUCT:  MK-3475 
203
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Additional Events reported in the same manner as SAE
Additional Events which require reporting in the same manner as SAE
●
In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Recording AE and SAE
AE and SAE Recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related 
to the event.
●
The investigator will record all relevant AE/SAE information on the Adverse Event 
case report forms/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.
08KM9X

PRODUCT:  MK-3475 
204
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Assessment of Intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI Common Terminology for Adverse 
Events (CTCAE), version 4.0. Any adverse event which changes CTCAE grade over 
the course of a given episode will have each change of grade recorded on the adverse 
event case report forms/worksheets.
●
Grade 1: Mild; asymptomatic or mid 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 or hospitalization indicated; disabling; limiting self-
care ADL.
●
Grade 4: Life threatening consequences; urgent intervention indicated.
●
Grade 5: Death related to AE.
Assessment of Causality
●
Did the study intervention cause the adverse event?
●
The determination of the likelihood that the study intervention caused the adverse 
event 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 adverse event 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 adverse event:
●
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 trials with investigational 
medicinal product)?
08KM9X

PRODUCT:  MK-3475 
205
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
●
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 trial is a single-dose drug trial); or (4) study 
intervention (s) is/are only used one time.)
●
Rechallenge:  Was the participant re-exposed to the study intervention in this 
trial?
●
If yes, did the AE recur or worsen?
●
If yes, this is a positive rechallenge. 
●
If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or 
permanent disability, or (2) the trial is a single-dose drug trial); or (3) study 
intervention (s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH 
WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE STUDY 
INTERVENTION, OR IF RE-EXPOSURE 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 INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study treatment 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 his/her best clinical 
judgment, including consideration of the above elements.
●
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a 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 
08KM9X

PRODUCT:  MK-3475 
206
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
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.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
●
For studies in which multiple agents are administered as part of a combination 
regimen, the investigator may attribute each adverse event 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 adverse event to the 
single agent.
Follow-up of AE and SAE
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
●
New or updated information will be recorded in the CRF.
●
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
08KM9X

PRODUCT:  MK-3475 
207
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor 
AE, SAE, and Other Reportable Safety Event Reporting to Sponsor via Electronic 
Data Collection Tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool.  
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.  
●
Reference section 9.3.1 – Time Period and Frequency for Collecting AE and 
SAE and Other Reportable Safety Event Information 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 electronic data collection 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 electronic data collection 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 Trial File Binder (or 
equivalent).
SAE Reporting to the Sponsor via Paper CRF
●
If the electronic data collection tool is not operational, facsimile transmission or secure 
e-mail of the SAE paper CRF is the preferred method to transmit this information to 
the Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
08KM9X

PRODUCT:  MK-3475 
208
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Appendix 5: Contraceptive Guidance and Pregnancy Testing
Definitions 
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
◦
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Requirements
Male Participants:
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in Section 6.1: 
•
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent
08KM9X

PRODUCT:  MK-3475 
209
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
•
Use a male condom plus partner use of a contraceptive method with a failure rate of <1% 
per year as described in Table 26 when having penile-vaginal intercourse with a woman 
of childbearing potential who is not currently pregnant.
-
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 26
during the protocol-defined time frame in Section 6.1. 
08KM9X

PRODUCT:  MK-3475 
210
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Table 26
Highly Effective Contraception Methods
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb,c
•
IUSc,d
•
Non-hormonal IUD
•
Bilateral tubal occlusion
• Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
•
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b.
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c.
Male condoms must be used in addition to female participant hormonal contraception.
d.
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-
Male condom with cap, diaphragm, or sponge with spermicide.
-
Male and female condom should not be used together (due to risk of failure with friction).
Pregnancy Testing
Refer to Section 9.5.9.2 for pregnancy testing requirements during the study. Refer to
Appendix 8 for UK-, Germany- and France-specific requirements.
08KM9X

PRODUCT:  MK-3475 
211
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Appendix 6: Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
iomarker:  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 trial as outlined in Section 9.8 – Future 
Biomedical Research Samples will be used in various experiments to understand:
•
The biology of how drugs/vaccines work
•
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
•
Other pathways drugs/vaccines may interact with
•
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations with 
the greatest need.  All specimens will be used by the Sponsor or those working for or with 
the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical trial will be considered for enrollment in Future 
Biomedical Research.
08KM9X

PRODUCT:  MK-3475 
212
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
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 trial 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 trial site under secure storage for regulatory 
reasons.  
A template of each trial 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 electronic Case Report Forms (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 trial 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 participant' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing participant 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future Biomedical 
Research, the Sponsor has developed secure policies and procedures. All specimens will be 
single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens.  This code is a random number which does not contain any personally identifying 
information embedded within it. The link (or key) between participant identifiers and this 
unique code will be held at the trial site.  No personal identifiers will appear on the specimen 
tube.  
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific practices. 
Analyses using the Future Biomedical Research specimens may be performed by the 
Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third party analyses will conform to the specific 
scope of analysis outlined in Future Biomedical Research protocol and consent. Future 
08KM9X

PRODUCT:  MK-3475 
213
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
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 Future Biomedical Research and ask that their 
biospecimens not be used for Future Biomedical Research.  Participants may withdraw 
consent at any time by contacting the principal investigator for the main trial. If medical 
records for the main trial are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@msd.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study use 
only. If specimens were collected from study participants specifically for Future Biomedical 
Research, these specimens will be removed from the biorepository and destroyed. 
Documentation will be sent to the investigator confirming withdrawal and/or destruction, if 
applicable. It is the responsibility of the investigator to inform the participant of completion 
of the withdrawal and/or destruction, if applicable.  Any analyses in progress at the time of 
request for withdrawal/destruction or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research trial data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed. 
7. Retention of Specimens3, 4
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being answered. 
In this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to the 
Sponsor-designated biorepository. If a central laboratory is not utilized in a particular trial, 
the trial 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 trial 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.
08KM9X

PRODUCT:  MK-3475 
214
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
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 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized.  No additional 
risks to the participant have been identified as no additional specimens are being collected for 
Future Biomedical Research (ie, only leftover samples are being retained).
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 e-mailed directly to 
clinical.specimen.management@msd.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA AND SAMPLE CODING CATEGORIES - E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. 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. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
08KM9X

PRODUCT:  MK-3475 
215
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Appendix 7: Country-specific Requirements
Cisplatin Market Authorization
For France see http://base-donnes-publique.medicaments.gouv.fr for the most recent version 
of the medicines SmPC.
08KM9X

PRODUCT:  MK-3475 
216
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Appendix 8: Country-specific Protocol Requirements
For United Kingdom:
1. Monthly pregnancy testing is required throughout trial treatment.
Relates to sections:
2 - Schedule of Activities 
(2.1 2.2 and 2.3)
9.5.9.2 – Pregnancy Test
Appendix 2 - Clinical Laboratory Tests
Appendix 5 – Contraceptive Guidance and Pregnancy Testing
2. The prohibition against live vaccines is extended to 3 months after the end of study 
treatment. 
Relates to section:
7.7 - Concomitant Therapy 
08KM9X

PRODUCT:  MK-3475 
217
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
For Germany:
1. Monthly pregnancy testing is required throughout trial treatment and at treatment end for 
women of childbearing potential.
2. In Treatment Arm A only, a pregnancy test should be completed at the first treatment 
follow-up visit that takes place at or after 180 days following completion of treatment 
with pembrolizumab for female participants considered WOCBP. 
3. In Treatment Arm B only, female participants considered WOCBP should complete a 
pregnancy test at the first 2 post-treatment follow-up visits (at 12 weeks ± 7 days after the 
end of RT ± cisplatin treatment and at the subsequent visit 3 months thereafter (± 7 days). 
4. Women of childbearing potential must observe the protocol specified contraceptive 
guidelines beginning with the first screening visit.
Relates to sections:
2.1 Initial Treatment Phase
2.2 Post-surgery Treatment 2 Phase
2.4 End of Treatment and Follow-up Visits
6.3.4 Contraception
9.5.9.2 Pregnancy Test
Appendix 2:  Clinical Laboratory Tests
Appendix 5:  Contraceptive Guidance and Pregnancy Testing
5. HIV, Hepatitis B and Hepatitis C testing are required at screening visit.
Relates to sections:
2.0 Schedule of Activities (SoA)
9.5.9.3 HIV, HBV and HCV serology
Appendix 2:  Clinical Laboratory Tests
6. Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is 
required at screening visit.
Relates to section:
6.2 Exclusion Criterion #20
08KM9X

PRODUCT:  MK-3475 
218
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
7. Has a known history of or is positive for Hepatitis B (defined as hepatitis B surface 
antigen [HBsAg] reactive) or known active Hepatitis C (defined as Hepatitis C virus 
[HCV] RNA [qualitative] is detected).  Hepatitis B and Hepatitis C testing is required at 
screening visit.
Relates to section:
6.2 Exclusion Criterion #21
8. Prohibited concomitant therapies or vaccinations are prohibited during screening and 
study treatment phases only.
Relates to section:
7.7 Concomitant Therapy
9. Participants should not receive live vaccines within 30 days prior to randomization or 
during study treatment.
10. Participants should not receive live vaccines for at least 3 months following the last
administered dose of cisplatin. This guidance is applicable for participants in Arm B and 
for all participants who discontinue earlier than scheduled but had at least 1 treatment 
with cisplatin.
Relates to section:
7.7 Concomitant Therapy #6
11. Potentially nephrotoxic medications (cephalosporins, amphotericin B or contrast media) 
which could potentiate a toxic effect of cisplatin on kidney function should be used with 
caution during cisplatin treatment.
12. Loop diuretics, which could potentiate an ototoxic effect of cisplatin, should be used with 
caution during cisplatin treatment.
Relates to section:
7.7 Concomitant Therapy #9
13. At time of withdrawal or discontinuation, it is recommended that the investigator counsel 
the participant on appropriate preventive measures. These measures include avoiding live 
vaccines within 3 months from the last dose of cisplatin and maintaining contraceptive 
measures as detailed in Appendix 5.
08KM9X

PRODUCT:  MK-3475 
219
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Relates to sections:
8.1 Discontinuation of Study Treatment
8.2 Withdrawal from the Study
9.1.11 Withdrawal/Discontinuation
For France:
1. Monthly pregnancy testing is required throughout trial treatment and at treatment end for 
women of childbearing potential.
Relates to sections:
2.1 Initial Treatment Phase
2.2 Post-surgery Treatment 2 Phase
9.5.9.2 Pregnancy Test
Appendix 2:  Clinical Laboratory Tests
Appendix 5:  Contraceptive Guidance and Pregnancy Testing
2. Be eligible for primary surgery based on investigator decision and per local practice. This 
decision must be validated by members of a multidisciplinary team, including the 
surgical oncologist, medical oncologist, and radiation oncologist.
Relates to section:
6.1 Inclusion Criterion #2
NOTE: The addition of the italicized text above to criterion #2 has been incorporated into 
the main protocol body with this global amendment.
3. Subjects with cardiorespiratory disease contraindicating hyperhydration are not allowed 
in the study.
Relates to section:
6.2 Exclusion Criterion #25
4. Participants with a history of any contraindication to any components of pembrolizumab, 
RT or cisplatin or their analogs are not allowed.
08KM9X

PRODUCT:  MK-3475 
220
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Relates to section:
6.2 Exclusion Criterion #26
5. The use of phenytoin for seizure prophylaxis is prohibited during the study.
Relates to sections:
6.2 Exclusion Criterion #27
7.7 Concomitant Therapy
6. Requirement for permanent discontinuation of study treatment for:
•
Grade 4 skin reaction or confirmed Stevens-Johnson Syndrome or toxic-epidermal 
necrolysis, 
•
recurrent Grade 3 colitis, or
•
Grade 3 or 4 myocarditis (see Note below).
08KM9X

PRODUCT:  MK-3475 
221
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
France-specific additions to Table 3 Dose modification and toxicity management guidelines 
for immune-related adverse events 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 should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids 
cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral 
steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids.
Immune-
related AEs
Toxicity grade 
or conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management 
with corticosteroid 
and/or other 
therapies 
Monitor and follow up 
Colitis 
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.
Rash
Grade 4 skin 
reaction or 
confirmed 
Stevens-Johnson 
Syndrome or 
toxic epidermal 
necrolysis
Permanently 
discontinue

Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by taper.
Relates to section:
7.2.1 Dose Modifications for Pembrolizumab
NOTE: Dose modification and toxicity management guidelines for myocarditis have been 
incorporated in Table 3 in the main protocol body with this global amendment. 
08KM9X

PRODUCT:  MK-3475 
222
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
For Japan:
1. Cisplatin IV used in this study is categorized as “product(s) used in the clinical trial other 
than test product(s)” in Japan local regulation.
Relates to section:
7.1 Treatments Administered, Table 2
08KM9X

PRODUCT:  MK-3475 
223
PROTOCOL/AMENDMENT NO.:  689-09
MK-3475-689-09 Final Protocol
29-Mar-2024
Confidential
Appendix 9: Technical Note for the Poisson Mixture Model and Piecewise Exponential 
Survival Model
The Poisson mixture model is applied to account for the failure rates decreasing over time in 
the trial which is a mixture of participants suffering from disease progression/recurrence and 
others who have excellent long-term results. The survival function as a function of time t for 
the SoC arm is:
Sc(t) = exp(-θ(1-S0(t)))
where θ = - log (cure rate) and S0(t) is the survival distribution function for those who suffer 
from disease progression/recurrence (“not cured”).  For this trial, S0(t) takes the form of a 2-
piece piecewise exponential survival function with different hazard functions prior to and 
post-surgery, respectively.
Given a set of time points 0 = τ0 < τ1 < … < τm-1 < τm, the piecewise exponential survival 
function takes the following form:
where λ(t) is the piecewise constant hazard function defined as follows:
The survival function Si (t) for a given interval τi ≤ t < τi +1 simplifies to:
08KM9X