Clinical trial NCT03189719
Conditions: Esophageal Neoplasms
Keywords: Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death Receptor Ligand 1 (PDL1, PD-L1) Programmed Cell Death Receptor Ligand 2 (PDL2, PD-L2)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2017-07-25; Completion date: 2023-07-10
Enrollment: 749 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial is to evaluate efficacy and safety of pembrolizumab plus standard of care (SOC) chemotherapy with cisplatin and 5-fluorouracil (5-FU) versus placebo plus SOC chemotherapy with cisplatin and 5-FU as first-line treatment in participants with locally advanced or metastatic esophageal carcinoma.

The overall primary efficacy hypotheses are as follows:

1. In participants with esophageal squamous cell carcinoma (ESCC), participants whose tumors are programmed cell death-ligand 1 (PD-L1)-positive (defined as combined positive score \[CPS\] ≥10), ESCC participants whose tumors are PD-L1 positive (CPS ≥10), and in all participants, overall survival (OS) is superior with pembrolizumab plus SOC chemotherapy compared with placebo plus SOC chemotherapy.
2. In participants with ESCC, participants whose tumors are PD-L1 positive (CPS ≥10), and in all participants, progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by investigator is superior with pembrolizumab plus SOC chemotherapy compared with placebo plus SOC chemotherapy.

Detailed description:

Arms: arm 1: Participants receive pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) plus standard of care (SOC) chemotherapy with cisplatin 80 mg/m\^2 IV Q3W and 5-FU 800 mg/m\^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments will be administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle. arm 2: Participants receive placebo to pembrolizumab (saline) IV Q3W plus SOC chemotherapy with cisplatin 80 mg/m\^2 IV Q3W and 5-FU 800 mg/m\^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments will be administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.
Interventions: intervention 1: Pembrolizumab intervention 2: Placebo intervention 3: Cisplatin intervention 4: 5-FU
Intervention descriptions: intervention 1: 200 mg administered IV Q3W on Day 1 of each 3-week cycle, up to 35 administrations. intervention 2: Placebo to pembrolizumab (saline) administered IV Q3W on Day 1 of each 3-week cycle, up to 35 administrations. intervention 3: 80 mg/m\^2 administered IV Q3W on Day 1 of each 3-week cycle. Duration of cisplatin treatment will be capped at 6 doses. intervention 4: 800 mg/m\^2/day (4000 mg/m\^2 total per cycle) administered as continuous IV infusion on Days 1 to 5 (120 hours) of each 3-week cycle, or per local standard for 5-FU administration, up to 35 administrations.

Protocol documents:
Prot_SAP_002.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Randomized, Double-Blind, Placebo-Controlled Phase III 
Clinical Trial of Pembrolizumab (MK-3475) in Combination 
with Cisplatin and 5-Fluorouracil versus Placebo in 
Combination with Cisplatin and 5-Fluorouracil as First-Line 
Treatment in Subjects with Advanced/Metastatic 
Esophageal Carcinoma (KEYNOTE-590)
17-Oct-2022
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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).
SPONSOR:
Merck Sharp & Dohme LLC 
(hereafter referred to as the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Randomized, Double-Blind, Placebo-Controlled Phase III Clinical Trial of Pembrolizumab 
(MK-3475) in Combination with Cisplatin and 5-Fluorouracil versus Placebo in Combination 
with Cisplatin and 5-Fluorouracil as First-Line Treatment in Subjects with 
Advanced/Metastatic Esophageal Carcinoma (KEYNOTE-590)
IND NUMBER:  123,482
EudraCT NUMBER:  2017-000958-19
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 12
SUMMARY OF CHANGES................................................................................................ 14
1.0
TRIAL SUMMARY.................................................................................................. 16
2.0
TRIAL DESIGN........................................................................................................ 17
Trial Design ........................................................................................................... 17
Trial Diagram........................................................................................................ 20
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 21
Primary Objective(s) & Hypothesis(es).............................................................. 21
Secondary Objective(s) & Hypothesis(es)........................................................... 22
4.0
BACKGROUND & RATIONALE.......................................................................... 23
Background ........................................................................................................... 23
Pharmaceutical and Therapeutic Background .................................................... 23
Preclinical and Clinical Trials............................................................................. 24
Ongoing Clinical Trials....................................................................................... 24
4.1.3.1
Ongoing Clinical Trials in Esophageal Cancer............................................ 24
Information on Other Trial-related Therapy....................................................... 25
Rationale................................................................................................................ 25
Rationale for the Trial and Selected Subject Population .................................... 25
Rationale for Dose Selection/Regimen/Modification......................................... 27
4.2.2.1
Justification for Treatment Regimen ........................................................... 27
4.2.2.2
Rationale for Fixed Dose Pembrolizumab................................................... 29
Rationale for Endpoints ...................................................................................... 30
4.2.3.1
Rationale for Efficacy Endpoints................................................................. 30
4.2.3.1.1
Primary Efficacy Endpoints.................................................................. 30
4.2.3.1.2
Secondary Efficacy Endpoints.............................................................. 31
Immune-related RECIST................................................................ 31
4.2.3.2
Rationale for Patient-reported Outcomes..................................................... 31
4.2.3.3
Rationale for Safety Endpoints.................................................................... 32
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4.2.3.4
Planned Biomarker Research....................................................................... 32
4.2.3.4.1
Biomarker Research for Primary Objectives........................................ 32
4.2.3.4.2
Biomarker Research for Exploratory Objectives.................................. 32
4.2.3.5
Future Biomedical Research........................................................................ 34
Benefit/Risk ........................................................................................................... 34
5.0
METHODOLOGY ................................................................................................... 35
Entry Criteria........................................................................................................ 35
Diagnosis/Condition for Entry into the Trial...................................................... 35
Subject Inclusion Criteria.................................................................................... 35
Subject Exclusion Criteria .................................................................................. 37
Trial Treatment(s) ................................................................................................ 40
Dose Selection/Modification .............................................................................. 41
5.2.1.1
Dose Selection (Preparation) ....................................................................... 41
5.2.1.2
Dose Modification (Escalation/Titration/Other).......................................... 41
5.2.1.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).......................................................................................... 42
5.2.1.2.2
Dose Modification for Cisplatin and 5-fluorouracil ............................. 48
Timing of Dose Administration.......................................................................... 51
5.2.2.1
Pembrolizumab ............................................................................................ 52
5.2.2.2
Placebo......................................................................................................... 52
5.2.2.3
Cisplatin....................................................................................................... 52
5.2.2.4
5-fluorouracil ............................................................................................... 52
Trial Blinding...................................................................................................... 53
Randomization ...................................................................................................... 53
Stratification.......................................................................................................... 53
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 53
Acceptable Concomitant Medications ................................................................ 53
Prohibited Concomitant Medication................................................................... 54
Concomitant Medications to Be Used with Caution........................................... 54
Rescue Medications & Supportive Care............................................................. 55
Supportive Care Guidelines for Pembrolizumab ................................................ 55
Supportive Care Guidelines for Cisplatin........................................................... 55
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Supportive Care Guidelines for 5-fluorouracil ................................................... 55
Diet/Activity/Other Considerations..................................................................... 55
Diet...................................................................................................................... 55
Contraception...................................................................................................... 56
Pregnancy............................................................................................................ 57
Use in Nursing Women....................................................................................... 57
5.7.4.1
Pembrolizumab Use in Nursing Women ..................................................... 58
5.7.4.2
Cisplatin Use in Nursing Women ................................................................ 58
5.7.4.3
5-fluorouracil Use in Nursing Women ........................................................ 58
Subject Withdrawal/Discontinuation Criteria................................................... 58
Discontinuation of Treatment ............................................................................. 58
Withdrawal from the Trial .................................................................................. 59
Lost to Follow-up................................................................................................ 59
Subject Replacement Strategy............................................................................. 60
Beginning and End of the Trial ........................................................................... 60
Clinical Criteria for Early Trial Termination ................................................... 60
6.0
TRIAL FLOW CHART ........................................................................................... 61
7.0
TRIAL PROCEDURES ........................................................................................... 65
Trial Procedures ................................................................................................... 65
Administrative Procedures.................................................................................. 65
7.1.1.1
Informed Consent......................................................................................... 65
7.1.1.1.1
General Informed Consent.................................................................... 65
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 66
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 66
7.1.1.3
Subject Identification Card .......................................................................... 66
7.1.1.4
Medical History ........................................................................................... 66
7.1.1.5
Disease Details............................................................................................. 66
7.1.1.6
Prior and Concomitant Medications Review............................................... 66
7.1.1.6.1
Prior Medications.................................................................................. 66
7.1.1.6.2
Concomitant Medications..................................................................... 67
Subsequent Anticancer Therapy Status.......................................... 67
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7.1.1.7
Assignment of Screening Number............................................................... 67
7.1.1.8
Assignment of Treatment/Randomization Number..................................... 67
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)................................... 67
Clinical Procedures/Assessments........................................................................ 68
7.1.2.1
Adverse Event Monitoring........................................................................... 68
7.1.2.2
Physical Exam.............................................................................................. 68
7.1.2.2.1
Full Physical Exam ............................................................................... 68
7.1.2.2.2
Directed Physical Exam........................................................................ 68
7.1.2.3
Vital Signs.................................................................................................... 68
7.1.2.4
12-Lead Electrocardiogram ......................................................................... 69
7.1.2.5
Tumor Imaging and Assessment of Disease................................................ 69
7.1.2.5.1
Initial Tumor Imaging........................................................................... 69
7.1.2.5.2
Tumor Imaging During the Trial .......................................................... 70
7.1.2.5.3
End of Treatment and Follow-up Tumor Imaging................................ 70
7.1.2.5.4
RECIST 1.1 Assessment of Disease..................................................... 71
7.1.2.5.5
irRECIST Assessment of Disease......................................................... 71
7.1.2.6
Performance and Quality of Life Assessments............................................ 75
7.1.2.6.1
Eastern Cooperative Oncology Group Performance Scale................... 75
7.1.2.6.2
Electronic Patient-reported Outcomes.................................................. 75
EQ-5D-5L....................................................................................... 75
EORTC QLQ-C30.......................................................................... 75
EORTC QLQ-OES18..................................................................... 76
Laboratory Procedures/Assessments .................................................................. 76
7.1.3.1
Laboratory 
Safety 
Evaluations 
(Hematology, 
Chemistry, 
and
Urinalysis).................................................................................................... 76
7.1.3.2
Pregnancy Test............................................................................................. 77
7.1.3.3
HIV, Hepatitis B Virus, and Hepatitis C Virus Testing............................... 78
7.1.3.4
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 78
7.1.3.4.1
Blood Collection for Serum Pembrolizumab........................................ 78
7.1.3.4.2
Blood Collection for Anti-pembrolizumab Antibodies ........................ 78
7.1.3.4.3
Blood Collection for RNA Analysis and Plasma and Serum 
Biomarker Analyses.............................................................................. 78
7.1.3.5
Planned Genetic Analysis Sample Collection.............................................. 79
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7.1.3.6
Future Biomedical Research Samples ......................................................... 79
7.1.3.7
Tumor Tissue ............................................................................................... 79
Other Procedures................................................................................................. 79
7.1.4.1
Withdrawal/Discontinuation........................................................................ 79
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 80
7.1.4.1.2
Lost to Follow-up.................................................................................. 80
7.1.4.2
Subject Blinding/Unblinding ....................................................................... 80
7.1.4.3
Calibration of Equipment............................................................................. 81
Medical Resource Utilization and Health Economics ........................................ 81
Visit Requirements.............................................................................................. 82
7.1.6.1
Screening Visit............................................................................................. 82
7.1.6.2
Treatment Period Visits ............................................................................... 82
7.1.6.3
Post-Treatment Visits................................................................................... 83
7.1.6.3.1
Safety Follow-up Visit.......................................................................... 83
7.1.6.3.2
Follow-up Visits ................................................................................... 83
7.1.6.3.3
Survival Follow-up ............................................................................... 83
7.1.6.4
Survival Status ............................................................................................. 83
Assessing and Recording Adverse Events .......................................................... 83
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 84
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 85
Immediate Reporting of Adverse Events to the Sponsor.................................... 85
7.2.3.1
Serious Adverse Events ............................................................................... 85
7.2.3.2
Events of Clinical Interest............................................................................ 86
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 87
Evaluating Adverse Events................................................................................. 87
Sponsor Responsibility for Reporting Adverse Events ...................................... 91
TRIAL GOVERNANCE AND OVERSIGHT................................................... 91
Scientific Advisory Committee........................................................................... 91
Executive Oversight Committee......................................................................... 91
Data Monitoring Committee............................................................................... 91
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 92
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Statistical Analysis Plan Summary ..................................................................... 92
Responsibility for Analyses/In-house Blinding .................................................. 94
Hypotheses/Estimation......................................................................................... 94
Analysis Endpoints ............................................................................................... 95
Efficacy Endpoints.............................................................................................. 95
8.4.1.1
Primary Efficacy Endpoints......................................................................... 95
8.4.1.2
Secondary Efficacy Endpoints..................................................................... 95
Safety Endpoints ................................................................................................. 95
Patient-reported Outcome Endpoints.................................................................. 95
Analysis Populations............................................................................................. 96
Efficacy Analysis Populations ............................................................................ 96
Safety Analysis Populations ............................................................................... 96
Statistical Methods................................................................................................ 96
Statistical Methods for Efficacy Analyses.......................................................... 96
8.6.1.1
Progression-free Survival............................................................................. 97
8.6.1.2
Overall Survival........................................................................................... 99
8.6.1.3
Objective Response Rate ............................................................................. 99
8.6.1.4
Duration of Response................................................................................... 99
Patient-reported Outcome Analyses: EORTC QLQ-C30 and QLQ-OES18 .... 101
Statistical Methods for Safety Analyses ........................................................... 101
Summaries of Demographic and Baseline Characteristics ............................... 103
Interim Analyses ................................................................................................. 103
Safety Interim Analyses.................................................................................... 103
Efficacy Interim Analyses................................................................................. 104
Multiplicity .......................................................................................................... 105
Multiplicity Control for Efficacy Analyses ...................................................... 105
8.8.1.1
Progression-free Survival........................................................................... 105
8.8.1.2
Overall Survival......................................................................................... 107
8.8.1.3
Objective Response Rate ........................................................................... 110
Multiplicity Control for Safety Analyses.......................................................... 111
Sample Size and Power Calculations ................................................................ 111
Subgroup Analyses ............................................................................................. 112
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Compliance (Medication Adherence)................................................................ 113
Extent of Exposure.............................................................................................. 113
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 113
Investigational Product ...................................................................................... 113
Packaging and Labeling Information ............................................................... 114
Clinical Supplies Disclosure............................................................................... 115
Storage and Handling Requirements................................................................ 115
Discard/Destruction/Returns and Reconciliation ............................................ 115
Standard Policies................................................................................................. 115
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 116
Confidentiality..................................................................................................... 116
Confidentiality of Data ..................................................................................... 116
Confidentiality of Subject Records................................................................... 116
Confidentiality of Investigator Information...................................................... 116
Confidentiality of IRB/IEC Information........................................................... 117
Compliance with Financial Disclosure Requirements..................................... 117
Compliance with Law, Audit and Debarment ................................................. 117
Compliance with Trial Registration and Results Posting Requirements...... 119
Quality Management System............................................................................. 119
Data Management............................................................................................... 119
Publications ......................................................................................................... 120
11.0
LIST OF REFERENCES....................................................................................... 121
12.0
APPENDICES......................................................................................................... 125
Code of Conduct for Clinical Trials.................................................................. 125
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 128
ECOG Performance Status................................................................................ 132
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 133
List of Abbreviations .......................................................................................... 144
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Country-specific Appendix ................................................................................ 148
France-specific Requirements........................................................................... 148
13.0
SIGNATURES......................................................................................................... 149
Sponsor's Representative ................................................................................... 149
Investigator.......................................................................................................... 149
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values..................................................... 37
Table 2
Trial Treatments................................................................................................... 40
Table 3
Dose Modifications for Trial Medications .......................................................... 42
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ................................................................... 43
Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines............................................................................................................ 47
Table 6
Dose Modification Guidelines for Cisplatin Drug-Related Adverse Events....... 49
Table 7
Dose Modification Guidelines for 5-fluorouracil Drug-Related Adverse 
Events .................................................................................................................. 50
Table 8
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease................................................................................................................. 73
Table 9
Laboratory Tests.................................................................................................. 76
Table 10
Evaluating Adverse Events.................................................................................. 89
Table 11
Censoring Rules for Primary and Sensitivity Analyses of Progression-free 
Survival................................................................................................................ 98
Table 12
Censoring Rules for Duration of Response ....................................................... 100
Table 13
Analysis Strategy for Key Efficacy Endpoints.................................................. 101
Table 14
Analysis Strategy for Safety Parameters ........................................................... 103
Table 15
Summary of Interim and Final Analyses Strategy............................................. 104
Table 16
Efficacy Boundaries and Properties for Progression-free Survival Analyses ... 107
Table 17
Efficacy Boundaries and Properties for Overall Survival Analyses.................. 108
Table 18
Possible α Levels and Approximate Objective Response Rate Difference 
Required to Demonstrate Efficacy for Objective Response at Interim 
Analysis ............................................................................................................. 111
Table 19
Product Descriptions.......................................................................................... 114
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LIST OF FIGURES
Figure 1
Trial Design Schematic........................................................................................ 20
Figure 2
Imaging and Treatment for Clinically Stable Subjects After First Radiologic 
Evidence of PD Assessed by the Site .................................................................. 74
Figure 3
Multiplicity Diagram for Type I Error Control ................................................. 105
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 11 / Global
17-OCT-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to 
Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in 
an entity name change and update to the address.
Amendment 10 / Global
24-MAY-2021
To update the dose modification and toxicity management guidelines for irAEs.
Amendment 09 / Global
17-JUN-2020
Due to higher than expected discordance rate in assessment of progressive disease 
between BICR (blinded independent central review) and investigator and 
following input from the US regulatory agency on the statistical analyses plan, the 
protocol is amended as follows: (i) change in primary endpoint from PFS by BICR
to investigator-assessed and (ii) elimination of one of the two planned efficacy 
interim analyses.
Amendment 08 / Global
03-JAN-2020
1. Based on results from the KN181 study, 3 primary objectives and 
corresponding hypotheses were added:  OS in esophageal squamous cell 
carcinoma (ESCC) population; OS in ESCC whose tumors are PD-L1 
biomarker-positive (CPS ≥10) population; and PFS in ESCC population.
2. Secondary objectives updated accordingly with respect to ORR and DOR 
endpoints in the ESCC and ESCC PD-L1 CPS ≥10 populations. Exploratory 
objectives were updated for PFS per irRECIST in the ESCC and ESCC PD-L1 
CPS ≥10 populations.
3. Due to the short interval (~5 months) between the last subject enrolled in the 
Global Cohort (n=711) and in the China Extension Study (n=38), these 2 
subject groups are merged into 1 “Global Study” for the primary analyses 
(N=749).
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Document
Date of Issue
Overall Rationale
4. To include assessment of DOR, QoL (C30) and QoL (OES18) in all pre-
specified populations.
The statistical analyses plan is updated accordingly.
Amendment 07 / Global
Not activated
N/A
Amendment 06 / France-
specific
28-JAN-2019
Apply changes from Global Amendment 05 to France-specific Amendment 03.
Amendment 05 / Global
12-DEC-2018
To extend the enrollment period beyond the Global Cohort to achieve the required 
sample size of the China Cohort to investigate efficacy and safety in Chinese 
subjects.
Amendment 04 / China-
specific 
21-SEP-2018
Remove all sampling, analysis and objectives for exploratory biomarkers for 
subjects from China as these were not approved by HGRAC.
Amendment 03 / France-
specific 
02-FEB-2018
Apply changes from Global Amendment 02 to France-specific Amendment 01.
Amendment 02 / Global
19-DEC-2017
Change primary biomarker from GEP to PD-L1; clarify 5-FU dosing; update 
Statistical Analysis Plan; reduce PK/ADA sampling.
Amendment 01 / France-
specific
20-OCT-2017
To address French HA requests for monthly pregnancy tests and mandatory 
audiograms for cisplatin use.
Original Protocol
14-MAR-2017
Not applicable.
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
Title Page
7.1.2.5.5
7.1.4.1.1
7.2.4 Table 10
10.3
10.4
10.7
12.1
12.2
Title Page
irRECIST Assessment of Disease
Withdrawal from Future Biomedical 
Research
Evaluating Adverse Events
Compliance with Law, Audit and 
Debarment
Compliance with Trial Registration and 
Results Posting Requirements
Publications
Code of Conduct for Clinical Trials
Collection and Management of Specimens 
for Future Biomedical Research
Sponsor entity name and 
address change.
Merck Sharp & Dohme Corp. 
underwent an entity name and 
address change to Merck Sharp 
& Dohme LLC, Rahway, NJ, 
USA. This conversion resulted 
only in an entity name change 
and update to the address.
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.10
Beginning and End of the Trial
Added language for enrollment 
in a study extension.
Subjects may be enrolled in a 
pembrolizumab extension study 
upon study completion.
5.11
Clinical Criteria for Early Trial 
Termination
Updated language describing 
early trial termination criteria.
Add flexibility to allow for
early study termination.
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1.0 TRIAL SUMMARY
Abbreviated Title
First-line Esophageal Carcinoma Study with Chemo vs. Chemo + 
Pembrolizumab
Sponsor Product Identifiers
MK-3475
Pembrolizumab
Trial Phase
Phase III
Clinical Indication
First-line treatment of subjects with locally advanced unresectable or 
metastatic
adenocarcinoma or
squamous cell carcinoma of the 
esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the 
esophagogastric junction.
Trial Type
Interventional
Type of control
Placebo
Route of administration
Intravenous
Trial Blinding
Double-blind
Treatment Groups
Arm 1: Pembrolizumab + cisplatin + 5-fluorouracil
Arm 2: Placebo + cisplatin + 5-fluorouracil
Number of trial subjects
The Global Cohort: approximately 700 subjects will be enrolled. The 
China Cohort will enroll approximately eligible 90 subjects in two 
enrollment periods: 1) The Global enrollment period: part of enrollment 
in the China Cohort will contribute towards enrollment in the Global 
Cohort until the Global Cohort completes enrollment of approximately 
700 subjects. 2) The China extension enrollment period: remaining 
enrollment in China Cohort will occur in the China extension period 
until approximately 90 total subjects are enrolled in the China Cohort.
Note: The sample size for China Cohort was updated to 106 from 90. 
The global cohort (n=711) and China extension study (n=38) will be
merged into the Global Study population (N=749) for primary analyses.
The study is fully enrolled.
Estimated duration of trial
The Global Cohort: The Sponsor estimates that the trial will require 
approximately 46 months from the time the first subject signs the 
informed consent until the last subject’s last study-related phone call or 
visit. The China Cohort: The Sponsor estimates that the cohort will 
require approximately 32 months from the time the first subject signs in 
the informed consent until that last subject’s last visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the informed consent form through the final protocol-specified contact.
After a screening phase of 28 days, each subject will be assigned to 
receive trial treatment until disease progression is confirmed by the site 
per immune-related Response Evaluation Criteria in Solid Tumors 
(irRECIST), unacceptable adverse event(s), intercurrent illness that 
prevents further administration of treatment, investigator’s decision to 
discontinue the subject, noncompliance with trial treatment or procedure 
requirements or administrative reasons requiring cessation of treatment, 
or 
until 
the 
subject 
has 
received 
35 
administrations 
of 
pembrolizumab/placebo (approximately 2 years).
After the end of 
treatment, each subject will be followed for the occurrence of adverse 
events and spontaneously reported pregnancy as described under Section 
7.2 – Assessing and Recording Adverse Events.
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Subjects who discontinue for reasons other than disease progression will 
have post-treatment follow-up for disease status until disease 
progression is confirmed by the site per irRECIST, initiating a 
non-study cancer treatment, withdrawing consent, or becoming lost to 
follow-up.  All subjects will be followed by telephone for overall 
survival until death, withdrawal of consent, or the end of the study.
Randomization Ratio
1:1
A list of abbreviations used in this document can be found in Section 12.5 – List of 
Abbreviations.
2.0 TRIAL DESIGN
Trial Design
This is a randomized, double-blind, placebo-controlled multi-site Phase III trial to evaluate 
the efficacy and safety of pembrolizumab in combination with cisplatin and 5-fluorouracil 
(5-FU) versus placebo in combination with cisplatin and 5-FU as first-line treatment in 
subjects with locally advanced unresectable or metastatic adenocarcinoma or squamous cell 
carcinoma of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the 
esophagogastric junction (EGJ).
Subjects will be required to have an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1 and to provide a tumor sample adequate for central laboratory 
analysis of biomarkers that may be predictive of response to pembrolizumab.
The study will be enrolling into 2 cohorts: Global and China Cohorts. The enrollment period 
is divided into 2 periods: Global and China extension enrollment periods.
The Global Cohort
Approximately 700 eligible subjects will be randomized (1:1) to one of the following 
treatment arms, with allocation stratified by geographic region, histology, and ECOG 
performance score (see Section 5.4 – Stratification for more details).
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Treatment Arm
Treatment Dose and Schedule
Treatment Arm 1*
Pembrolizumab 200 mg IV Q3W
Cisplatin 80 mg/m2 IV Q3W
5-FU 800 mg/m2/day continuous IV infusion on each of Days 1 to 5 Q3W
(total of 4000 mg/m2 per 3-week cycle) **
Treatment Arm 2*
Placebo IV Q3W
Cisplatin 80 mg/m2 IV Q3W
5-FU 800 mg/m2/day continuous IV infusion on each of Days 1 to 5 Q3W
(total of 4000 mg/m2 per 3-week cycle) **
  The body surface area in m2 should be calculated per local guidance.
* Duration of cisplatin treatment will be capped at 6 doses; however, treatment with 5-FU may 
continue per local standard. 5-FU treatment is not to exceed a maximum of 35 cycles.
** Or per local standard for 5-FU administration duration as long as total dose of 4000 mg/m2 per 
cycle Q3W is followed (eg, 1000 mg/m2/day on each of Days 1 to 4).  5-FU treatment is not to 
exceed a maximum of 35 cycles.
Abbreviations: 5-FU=5-fluorouracil, IV=intravenous, Q3W=every 3 weeks
Study treatment in both arms will begin on Day 1 of each 3-week dosing cycle.
Beginning with screening, all imaging assessments will be submitted for central imaging 
vendor review and will be evaluated using Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 for determining assessment of response. On-study imaging assessments will 
be performed every 9 weeks (63 days ± 7 days) following the date of randomization until 
progression of disease is documented with radiologic imaging (computed tomography [CT] 
or magnetic resonance imaging [MRI]).  Imaging timing should follow calendar days and 
should not be adjusted for delays in cycle starts.
The primary efficacy endpoints are overall survival (OS) and progression-free survival 
(PFS). The primary PFS analysis will be based on RECIST 1.1 by investigator assessment. 
RECIST 1.1 will be used by the local site for treatment decisions until verification of 
progressive disease (PD) by the central imaging vendor. Following verification of PD by the 
central imaging vendor, treatment decisions may be made by the adaptation of RECIST 1.1, 
as described in Section 7.1.2.5.5 – irRECIST Assessment of Disease, termed immune-related 
RECIST (irRECIST), to accommodate for the tumor response patterns seen with 
pembrolizumab treatment (eg, tumor flare). This was first described by Nishino, et al. 2013 
[1], but is further modified for the programmed cell death-1 (PD-1) program. For a clinically 
stable subject with first radiologic evidence of PD, it is at the discretion of the site 
investigator to continue treating the subject with study medication until PD is confirmed at 
least 4 weeks from the date of the first tumor imaging suggesting PD per the site investigator. 
If radiologic PD is confirmed by the subsequent tumor imaging, the subject should be 
discontinued from treatment unless, in the opinion of the investigator, the subject is 
achieving a clinically meaningful benefit; an exception to continue treatment may be 
considered following consultation with the Sponsor.
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Treatment will continue until confirmed PD, unacceptable adverse events (AEs), intercurrent 
illness that prevents further administration of treatment, investigator’s decision to withdraw 
the subject, subject withdraws consent, pregnancy of the subject, noncompliance with trial 
treatment or procedure requirements, completion of 35 administrations (approximately 
2 years) of treatment with study medication or achievement of a complete response (CR), or 
administrative reasons.
AEs will be monitored throughout the trial 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 (v4.0). At the end of treatment, each subject will be followed 
for a minimum of 30 days for AE monitoring. Serious adverse events (SAEs) occurring 
within 90 days following cessation of treatment, or 30 days following cessation of treatment 
if the subject initiates new anticancer therapy, will be collected, whichever is earlier.  
Subjects who discontinue treatment for reasons other than PD will have post-treatment 
follow-up for disease status until PD, initiating a non-study cancer treatment, withdrawing 
consent, or becoming lost to follow-up.  All subjects will be followed by telephone contact 
for OS until death, withdrawal of consent, or the end of the trial, whichever comes first.
This study will be conducted in conformance with Good Clinical Practice (GCP).
This trial will use a group sequential design based on pre-specified criteria, using an 
independent, external Data Monitoring Committee (DMC) to monitor safety and efficacy.  
There will be one efficacy interim analysis (IA) for OS which will also be the final analysis 
(FA) for PFS and periodic safety monitoring.  The efficacy IA is event-driven. If all OS and 
PFS hypotheses are rejected, objective response rate (ORR) will also be tested. Results of 
the efficacy IA will be reviewed by the DMC.  More details are in Section 8.7 – Interim 
Analyses. 
No crossover from placebo arm to pembrolizumab arm will be allowed.
The China Cohort
Approximately 106 eligible subjects from China will be enrolled in the China Cohort. This 
will include subjects enrolled in China during the Global enrollment period as well as the 
China Extension Study enrollment period. After the enrollment of the Global Cohort is 
closed, subjects from China will continue to be enrolled in the China Extension Study until a 
total of 106 subjects from China are enrolled. The China Extension Study will be identical to 
the Global Cohort with respect to key study characteristics (eg, inclusion and exclusion 
criteria, study endpoints, primary and secondary objectives, study procedures). The Global 
Cohort and China Extension Study will be merged for the primary analyses, and henceforth 
will be referred to as the Global Study population. Further details of the analyses in this 
Cohort are provided in the supplemental SAP.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
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Trial Diagram
The trial design is depicted in Figure 1.
Abbreviations: EGJ=esophagogastric junction, 5-FU=5-fluorouracil, ECOG PS=Eastern 
Cooperative 
Oncology 
Group
performance 
status, 
PS=Performance 
Score, 
RECIST=Response Evaluation Criteria in Solid Tumors, Q3W=every 3 weeks, 
Q9W=every 9 weeks
Figure 1
Trial Design Schematic
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
The following objectives and hypotheses will be evaluated in subjects with locally advanced 
unresectable or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or 
advanced/metastatic Siewert type 1 adenocarcinoma of the EGJ. The chemotherapy regimen 
in each study arm comprises 5-FU and cisplatin.
The primary biomarker in this study is programmed cell death-ligand 1 (PD-L1) expression,
and PD-L1 biomarker-positive is defined as combined positive score (CPS) ≥10 (see Section 
4.2.3.4.1 – Biomarker Research for Primary Objectives for further details).
Primary Objective(s) & Hypothesis(es)
(1)
Objective: To compare OS between treatment arms in subjects with esophageal 
squamous cell carcinoma (ESCC) whose tumors are PD-L1 biomarker-positive (CPS 
≥10).
Hypothesis: OS is superior with pembrolizumab plus chemotherapy compared with 
placebo plus chemotherapy in subjects with ESCC whose tumors are PD-L1
biomarker-positive (CPS ≥10).
(2)
Objective: To compare OS between treatment arms in subjects with ESCC.
Hypothesis: OS is superior with pembrolizumab plus chemotherapy compared with 
placebo plus chemotherapy in subjects with ESCC.
(3)
Objective: To compare OS between treatment arms in subjects whose tumors are PD-
L1 biomarker-positive (CPS ≥10).
Hypothesis: OS is superior with pembrolizumab plus chemotherapy compared with 
placebo plus chemotherapy in subjects whose tumors are PD-L1 biomarker-positive 
(CPS ≥10).
(4)
Objective: To compare OS between treatment arms in all subjects.
Hypothesis: OS is superior with pembrolizumab plus chemotherapy compared with 
placebo plus chemotherapy in all subjects.
(5)
Objective: To compare PFS per RECIST 1.1, as determined by investigator, in 
subjects with ESCC.
Hypothesis: PFS per RECIST 1.1, as determined by investigator, is superior with 
pembrolizumab plus chemotherapy compared with placebo plus chemotherapy in 
subjects with ESCC.
(6)
Objective: To compare PFS per RECIST 1.1, as determined by investigator, between 
treatment arms in subjects whose tumors are PD-L1 biomarker-positive (CPS ≥10).
Hypothesis: PFS per RECIST 1.1, as determined by investigator, is superior with 
pembrolizumab plus chemotherapy compared with placebo plus chemotherapy in 
subjects whose tumors are PD-L1 biomarker-positive (CPS ≥10).
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(7)
Objective: To compare PFS per RECIST 1.1, as determined by investigator, between 
treatment arms in all subjects.
Hypothesis: PFS per RECIST 1.1, as determined by investigator, is superior with 
pembrolizumab plus chemotherapy compared with placebo plus chemotherapy in all 
subjects.
The study is considered to have met its primary objective if at least one of the above
hypothesis is significant as defined in Section 8.8 – Multiplicity.
Secondary Objective(s) & Hypothesis(es)
Key Secondary Objective & Hypothesis:
(1)
Objective: Evaluate ORR per RECIST 1.1, as determined by investigator, between 
treatment arms in all subjects.
Hypothesis: ORR per RECIST 1.1, as determined by investigator, is superior with 
pembrolizumab plus chemotherapy compared with placebo plus chemotherapy in all 
subjects.
Other Secondary Objectives:
(2)
Objective: Evaluate ORR per RECIST 1.1, as determined by investigator, between 
treatment arms in subjects with ESCC whose tumors are PD-L1 biomarker-positive 
(CPS ≥10), in subjects with ESCC, and in subjects whose tumors are PD-L1 
biomarker-positive (CPS ≥10).
(3)
Objective: Evaluate DOR per RECIST 1.1, as determined by investigator, between 
treatment arms in all subjects, in subjects with ESCC whose tumors are PD-L1 
biomarker-positive (CPS ≥10), in subjects with ESCC, and in subjects whose tumors 
are PD-L1 biomarker-positive (CPS ≥10).
(4) 
Objective: Evaluate the safety and tolerability profile.
(5)
Objective: To evaluate changes from baseline in health-related quality of life using 
the European Organization for the Research and Treatment of Cancer (EORTC) 
Quality of Life Questionnaire C30 (QLQ-C30) and the EORTC Quality Of Life 
Questionnaire Oesophageal Module (QLQ-OES18) in all subjects, in subjects with 
ESCC whose tumors are PD-L1 biomarker-positive (CPS ≥10), in subjects with 
ESCC, and in subjects whose tumors are PD-L1 biomarker-positive (CPS ≥10),
treated with pembrolizumab plus chemotherapy compared with placebo plus 
chemotherapy.
Exploratory Objectives:
(1)
Objective: To characterize PRO utilities using the EQ-5D-5L questionnaire in all 
subjects, in subjects with ESCC whose tumors are PD-L1 biomarker-positive (CPS 
≥10), in ESCC subjects, and in subjects whose tumors are PD-L1 biomarker-positive 
(CPS ≥10) treated with pembrolizumab plus chemotherapy compared with placebo 
plus chemotherapy.
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(2)
Objective: Evaluate PFS per irRECIST as determined by investigator between 
treatment arms in subjects with ESCC whose tumors are PD-L1 biomarker-positive 
(CPS ≥10), in ESCC subjects, in subjects whose tumors are PD-L1 biomarker-positive 
(CPS ≥10), and in all subjects.
(3)
Objective: To identify molecular (genomic, metabolic, and/or proteomic) biomarkers 
that may be indicative of clinical response/resistance, safety, pharmacodynamic 
activity, and/or the mechanism of action of pembrolizumab and other treatments. This 
could include the evaluation of microsatellite instability (MSI), whole exome 
sequencing (WES), and/or gene expression profiling (GEP) in available tumor tissue.
Note: this is not applicable to China.
4.0 BACKGROUND & RATIONALE
Background
Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody with high 
specificity of binding to the PD-1 receptor, thus inhibiting its interaction with PD-L1 and 
programmed cell death-ligand 2 (PD-L2).  Based on preclinical in vitro data, pembrolizumab 
has high affinity and potent receptor blocking activity for PD-1.  Pembrolizumab has an 
acceptable preclinical safety profile and is in clinical development as an intravenous (IV) 
immunotherapy for advanced malignancies.  Keytruda™ (pembrolizumab) is indicated for 
the treatment of patients across a number of indications.  For more details on specific 
indications refer to the Investigator’s Brochure (IB).
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [2]. 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 responses in 
cancers such as melanoma [3] [4].
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 superfamily member related to cluster of differentiation 28 and cytotoxic 
T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively regulate 
antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [5] [6].
The structure of murine PD-1 has been resolved [7]. PD-1 and its family members are type 1
transmembrane glycoproteins containing an Ig variable–type domain responsible for ligand 
binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif.  
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Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to 
the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta, protein kinase C-theta, and 
zeta-chain-associated protein kinase, which are involved in the CD3 T-cell signaling cascade
[8] [9] [10] [6]. 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 [11] [12].  As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in advanced/metastatic esophageal cancer.
Preclinical and Clinical Trials
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities.  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated antitumor 
responses as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, 
melanoma, and colorectal carcinoma.  Blockade of the PD-1 pathway effectively promoted 
CD8+ T-cell infiltration into the tumor and the presence of interferon-gamma, granzyme B,
and perforin, indicating that the mechanism of action involved local infiltration and 
activation of effector T-cell function in vivo [13] [3] [4] [14] [6] [5].  Experiments have 
confirmed the in vivo efficacy of PD-1 blockade as a monotherapy as well as in combination 
with chemotherapy in syngeneic mouse tumor models (see the IB for further details).
Clinical trials have demonstrated efficacy in subjects with advanced melanoma, non-small 
cell lung cancer (NSCLC), head and neck cancer, bladder cancer, Hodgkin’s lymphoma, 
triple-negative breast cancer, and gastric adenocarcinoma.
Ongoing Clinical Trials
Ongoing clinical trials of pembrolizumab are being conducted in advanced melanoma, 
NSCLC, and a number of other advanced solid tumor indications and hematologic 
malignancies. For details on all ongoing pembrolizumab studies, refer to the IB.
4.1.3.1
Ongoing Clinical Trials in Esophageal Cancer
Two trials are currently ongoing with pembrolizumab in esophageal cancer. KEYNOTE 
(KN) 180 is a Phase II study of pembrolizumab monotherapy in third-line previously treated 
subjects with advanced/metastatic adenocarcinoma or squamous cell carcinoma of the 
esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the EGJ. 
This 
open-label trial completed enrollment 21-Mar-2017 with 121 subjects allocated to treatment.  
The second study, KN181, is a Phase III, randomized, open-label study of single-agent 
pembrolizumab versus physicians’ choice of single-agent docetaxel, paclitaxel, or irinotecan 
in subjects with advanced/metastatic adenocarcinoma and squamous cell carcinoma of the 
esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the EGJ that have 
progressed after first-line standard therapy. As of 16-Jun-2017, KN181 has completed 
enrollment of 629 subjects in the Global Cohort out of a total of approximately 600 planned.
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Information on Other Trial-related Therapy
Cisplatin is a platinum-based chemotherapy that acts by interfering with DNA replication,
and 5-FU is a fluoropyrimidine that interferes with DNA synthesis to inhibit tumor growth. 
Cisplatin and 5-FU are currently recommended by guidelines for first-line treatment of 
subjects with advanced/metastatic esophageal cancer. Refer to the respective product labels 
and Section 4.2.2.1 – Justification for Treatment Regimen for further information.
Rationale
Rationale for the Trial and Selected Subject Population
Esophageal cancer is the sixth most common cause of cancer deaths in the world and is more 
prevalent in men than in women. In developing countries; however, esophageal cancer is 
endemic and is the fourth most common cause of cancer deaths.  Globally, close to 
480,000 cases occur annually, with 53% of these cases arising in China [15] [16]. In the US, 
in 2015, an estimated 15,980 esophageal cancers were expected to be diagnosed and it is 
estimated that 15,590 people would eventually die of their disease [17]. In Japan, esophageal 
cancer is the sixth leading cause of cancer deaths, and in 2008, there were 11,746 deaths 
from esophageal carcinoma, with male patients outnumbering female patients 6:1 [18]. The 
majority of patients are diagnosed with advanced/metastatic cancer and, in this setting,
response to chemotherapeutic agents is poor.
Given the high incidence and mortality 
worldwide and lack of good therapeutic options, esophageal cancer patients represent a high 
unmet need for drug development.
The geographical distribution of esophageal cancer varies widely, with a 60-fold difference 
between high- and low-prevalence regions. High-prevalence areas include Asia, Africa, and 
France, where squamous esophageal cancers predominate [19]. A dramatic shift in the 
histology and location of upper gastrointestinal (GI) tumors has occurred over the past 
decades. In Western countries, adenocarcinoma is the more predominant histology, with the 
most common site of esophageal cancer being in the lower third of the esophagus, which 
often involves the EGJ [20] [21] [22]. 
For the purpose of this study, the Siewert 
classification will be used for adenocarcinoma of the EGJ, and thus, type 1 patients (about 
20% of the EGJ adenocarcinoma patients) will be eligible. Siewert type 1 tumors are 
adenocarcinomas of the lower esophagus with the center located within 1 to 5 centimeters 
above the anatomic EGJ. Type 2 and 3 Siewert adenocarcinomas of the EGJ are managed as 
gastric cancer patients, and therefore, would be eligible to participate in the first-line gastric 
trial, KN062.
Adenocarcinoma has been gradually increasing in men of all ethnic 
backgrounds and also in women [23]. Squamous cell carcinoma seems to be more sensitive 
to chemotherapy, chemoradiation, and radiation therapy than adenocarcinoma, but the 
long-term outcome is similar for both histologies [24] [25], thus emphasizing the need for 
improved therapies in both histologies.
Phase III trials specifically designed for metastatic esophageal cancers have not been 
performed, and there is no definitive standard of care.  Current guidelines for first-line 
treatment of advanced/metastatic esophageal cancer recommend combination treatment with 
platinum-based chemotherapy in combination with fluoropyrimidine as palliative therapy, 
with the combination of cisplatin and 5-FU being the most commonly used across regions.  
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Docetaxel, paclitaxel, and irinotecan are included as options for second-line therapy for 
patients with locally advanced or metastatic disease. 
Other regimens included in the 
guidelines for patients with locally advanced or metastatic disease are derived from the 
gastric adenocarcinoma Phase III trials that have included patients with lower esophageal 
and/or EGJ cancer.
KN028 is a nonrandomized, multicohort, Phase 1b trial of pembrolizumab for 
PD-L1-positive advanced solid tumors that includes esophageal cancer patients. 
Key 
eligibility criteria for this cohort include squamous cell carcinoma or adenocarcinoma of the 
esophagus or gastroesophageal junction, measurable disease, PD-L1 expression in ≥1% of 
cells in tumor nests or PD-L1-positive stromal bands determined centrally by IHC, failure of 
standard therapy, ECOG performance status 0 to 1, and no autoimmune disease. 
Pembrolizumab 10 mg/kg is administered every 2 weeks for up to 2 years or until confirmed 
PD. Of the 90 patients with esophageal cancer who have been screened, 37 (44.6%) have 
had PD-L1-positive tumors. Of the 23 patients treated between March and December 2014, 
83% were men, and the median age was 65 years. Histology was squamous in 18 patients 
(78.3%) and adenocarcinoma in 5 patients (21.7%). 
Eighty-seven percent of patients 
received ≥2 prior therapies for metastatic disease; all patients received ≥1 platinum-based 
therapy. As of the data cutoff (20-Feb-2017), median follow-up was 7 months (range, 1 to 
33 months). Treatment-related AEs occurred in nine patients (39%), most commonly 
decreased appetite, decreased lymphocyte count, generalized rash, and rash in two patients 
(9%) each. Grade 3 treatment-related AEs occurred in four patients (17%) and included 
decreased lymphocyte count in two patients (9%) and decreased appetite, liver disorder, and 
generalized rash in one patient (4%) each. There were no Grade 4 drug-related AEs, and no 
patients died due to a drug-related AE. Tumor shrinkage was seen in 52% of patients and 
ORR was 30% (95% confidence interval [CI], 13% to 53%) with seven responses confirmed 
partial responses (5 squamous [28%] and 2 adenocarcinoma [40%]). Stable disease was seen 
in 9% (N = 2) and PD in 59% (N = 13). Median time to initial response was 4 months 
(range, 2 to 8 months) and median duration of response was 15 months (range, 6 to 26+ 
months) for the patients in the esophageal cohort.
KN-180 is a Phase 2 open-label, interventional, single-arm study of pembrolizumab 
monotherapy in previously treated subjects with advanced/metastatic EAC or ESCC or 
advanced/metastatic Siewert type 1 adenocarcinoma of the EGJ.  This open-label trial 
completed enrollment at 57 sites in 10 countries on 21-MAR-2017 with 121 subjects 
allocated to treatment.  Patients had advanced, metastatic esophageal cancer that progressed 
after 2 or more lines of therapy and had evaluable tumor samples for biomarkers. 
Pembrolizumab 200 mg was administered intravenously every 3 weeks until disease 
progression, unacceptable toxic effects, or study withdrawal, for up to 2 years. As of 17-
AUG-2018, of 121 enrolled patients (100 males and 21 females; median age, 65 years [range, 
33-87 years]), 18 (14.9%) had undergone 3 or more prior therapies, 63 (52.1%) had ESCC, 
and 58 (47.9%) had tumors positive for programmed death-ligand-1 (PD-L1), defined as a 
combined positive score of 10 or higher assessed by immunohistochemistry. Median duration 
of follow-up was 5.8 months (range, 0.2 to 27.8 months). Objective response rate was 9.9% 
(95% CI, 5.2%-16.7%) among all patients (12 of 121), and median duration of response was 
not reached (range, 2.1 to 25.1+ months). Objective response rate was 14.3% (95% CI, 6.7%-
25.4%) among patients with ESCC (9 of 63), 5.2% (95% CI, 1.1%-14.4%) among patients 
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with adenocarcinoma (3 of 58), 13.8% (95% CI, 6.1%-25.4%) among patients with PD-L1-
positive tumors (8 of 58), and 6.3% (95% CI, 1.8%-15.5%) among patients with PD-L1-
negative tumors (4 of 63). Overall, 15 patients (12.4%) had treatment-related Grade 3 to 5 
adverse events. Seven patients (5.8%) discontinued treatment because of drug-related adverse 
events. There was 1 treatment-related death from pneumonitis.
KN-181, is a Phase 3, randomized, open-label study of single-agent pembrolizumab versus 
physicians’ choice of single-agent docetaxel, paclitaxel, or irinotecan in subjects with 
advanced/metastatic EAC and ESCC or advanced/metastatic Siewert type 1 adenocarcinoma 
of the EGJ that have progressed after first-line standard therapy.  As of Nov 6, 2018, KN-181 
has completed enrollment of 628 subjects.   In PD-L1 CPS ≥10 subjects, there was 
significant clinical benefit with a median OS for pembrolizumab of 9.3 months versus 6.7 
months for SOC. The OS rate of pembrolizumab versus SOC at 6 months was 63.6% and 
54.1% respectively; and at 12 months was 42.1% and 20.4%, respectively. The ORR was 
21.5% for pembrolizumab and 6.1% for SOC. In the ESCC subpopulation, pembrolizumab 
demonstrated a favorable OS benefit compared with SOC; the median OS for pembrolizumab 
was 8.2 months versus 7.1 months for SOC. The OS rate of pembrolizumab versus SOC at 6 
months was 61.1% and 58.8% respectively; and at 12 months was 38.9% and 24.9%, 
respectively The ORR was 16.7% for pembrolizumab and 7.4% for SOC. In the overall study 
population, the median OS for pembrolizumab and SOC was 7.1 months. The ORR in all 
subjects was 13.1% for pembrolizumab and 6.7% for SOC. Confirmed complete response 
(CR) was reported in 9 subjects in the pembrolizumab arm and 2 subjects in the SOC arm. In 
an additional analysis in ESCC subjects whose tumors expressed PD-L1 CPS ≥10, there was 
significant clinical benefit with a median OS for pembrolizumab of 10.3 months versus 6.7 
months for SOC. The OS rate of pembrolizumab versus SOC at 6 months was 65.9% and 
52.7% respectively; and at 12 months was 47.1% and 22.6%, respectively. The ORR was 
22.4% for pembrolizumab and 7.3% for SOC. These data underscore the superior OS with 
pembrolizumab monotherapy in a late line setting in esophageal cancer patients.
Thus, pembrolizumab has an acceptable safety profile and provides highly promising
antitumor activity in patients with heavily pretreated, advanced esophageal carcinoma. The
high unmet need, lack of efficacious approved therapies, and the above data with
pembrolizumab strongly support further development of this drug in first-line patients with 
advanced/metastatic esophageal carcinoma, across both the squamous cell carcinoma and 
adenocarcinoma histologies.
Rationale for Dose Selection/Regimen/Modification
4.2.2.1
Justification for Treatment Regimen
There are currently no Phase III clinical trial data or approved therapy for first-line 
advanced/metastatic esophageal cancer, and no standard chemotherapy regimen has been 
established. Various palliative chemotherapy regimens have been investigated in esophageal 
cancer studies and have been shown to have at least some activity in the first-line setting, 
with responses ranging from 20% to 48% and 5-year survival rates of approximately 15%,
with significant toxicity rates [26].
Current National Comprehensive Cancer Network
(NCCN) and European Society for Medical Oncology (ESMO) guidelines recommend the 
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combination of a fluoropyrimidine (5-FU or capecitabine) with platinum agents (cisplatin, 
oxaliplatin, or carboplatin), either alone or in combination with a third drug such as 
epirubicin or a taxane, as the most effective first-line treatment option. The most common 
regimen of 5-FU plus cisplatin has resulted in response rates of 13% to 35.9%, disease 
control rates of 57% to 63.9 %, median PFS of 3.6 months, and median survival of 5.5 to 
6.7 months in reported Phase II trials [27] [28] [29] [30].
A Phase II study of first-line squamous cell carcinoma subjects treated with cisplatin 
(100 mg/m2) plus 5-FU (1000 mg/m2/day continuous Days 1 to 5), repeated every 3 weeks
(Q3W), demonstrated a response rate of 35% for the combination arm compared with 19% 
for single-agent cisplatin. Median time to progression was 6.3 months and median OS was 
7.7 months for the combination. Toxicity was more severe in the combination arm compared 
with cisplatin alone and included Grade 4 aplasia and septicemia, meningeal hemorrhage, 
cerebrovascular event, and ischemia of lower limb [27].
A Phase II study by the Japan Esophageal Oncology Group evaluated a first-line regimen of 
20 mg/m2 cisplatin plus 5-FU at 800 mg/m2/day (continuous for Days 1 to 5), repeated every 
4 weeks (Q4W), in subjects with advanced/metastatic squamous cell carcinoma.  Overall 
response rate was 33.3%, with median response duration of 5.7 months and OS of 
6.6 months. Hematological (including Grade 3 neutropenia and thrombocytopenia) and GI
(nausea/vomiting, diarrhea, stomatitis) toxicities were the most common adverse reactions 
observed [28].
A German study of cisplatin (100 mg/m2) plus 5-FU (1000 mg/m2/day continuous Days 1 to 
5), repeated Q4W, alone or in combination with cetuximab (400 mg/m2) was performed in 
patients with advanced ESCC. 
Objective response rates were modestly higher in the 
cetuximab combination arm at 34% compared with 30% with cetuximab plus 5-FU alone, 
while confirmed response rates were lower for both, at 19% and 13%, respectively. Median 
PFS and OS were also longer in the cetuximab arm, at 5.9 and 9.5 months, respectively, 
compared with the cisplatin plus 5-FU arm at 3.6 and 5.5 months, respectively, although 
differences were not statistically different.
The most common Grade 3 to 4 AEs were 
neutropenia, diarrhea, nausea, fatigue, and thrombocytopenia [29].
In the NCCN clinical practice guideline, a combination of 5-FU (750 to 1000mg/m2/day 
continuous infusion, Days 1 to 4), and cisplatin (75 to 100 mg/m2, 29 to 35 day cycle) is 
listed as a recommended regimen for the first-line setting (Esophageal NCCN and ESMO 
guidelines). 
While cisplatin doses of 100 mg/m2 Q4W may be the preferred dose in 
Non-Asian clinical trials, doses of 60 to 80 mg/m2 are more common for Asian patients. The 
proposed doses of 80 mg/m2 cisplatin and 800 mg/m2/day (Days 1 to 5) 5-FU in combination 
with pembrolizumab Q3W have been evaluated in a cohort of first-line subjects with gastric 
cancer (KN059), in which the combination was shown to have a manageable safety profile 
with no treatment-related discontinuations or deaths. The most common treatment-related 
AEs were nausea (52%), stomatitis (52%), decreased neutrophils (48%), and decreased 
appetite (44%) [31].
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4.2.2.2
Rationale for Fixed Dose Pembrolizumab
The planned dose of pembrolizumab for this trial is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated in the pembrolizumab development program, 200 mg Q3W is 
the appropriate dose of pembrolizumab across all indications and regardless of tumor type. 
As outlined below, this dose is justified by:
• Clinical data from eight randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every two weeks (Q2W)
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically based 
pharmacokinetic [PBPK] analysis) at 200 mg Q3W
Among the eight randomized dose-comparison studies, a total of 2262 subjects 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 vs. 10 mg/kg Q3W 
(KN001 B2, KN001 D, KN002, KN010 and KN021), and three studies compared 10 mg/kg 
Q3W vs. 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 
head and neck cancer, 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.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) 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 subject 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.
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Rationale for Endpoints
4.2.3.1
Rationale for Efficacy Endpoints
4.2.3.1.1 Primary Efficacy Endpoints
Overall survival has been recognized as the gold standard for the demonstration of 
superiority of a new antineoplastic therapy in randomized clinical studies.  Achieving 
superiority in OS; however, is likely to be complicated by the availability of multiple 
post-progression therapies being available to subjects as second-line treatment. Therefore, 
this trial will use a dual endpoint of OS and PFS. Progression-free survival is an acceptable 
measure of clinical benefit for a late-stage trial that demonstrates superiority of a new 
antineoplastic therapy, especially if the magnitude of the effect is large and the therapy has 
an acceptable risk/benefit profile.
The use of a central imaging vendor and RECIST 1.1 to assess PFS is typically considered 
acceptable by regulatory authorities.  Images will be read by a central imaging vendor 
blinded to treatment assignment to minimize bias in the response assessments.  In addition, 
the final determination of radiologic progression will be based on the central assessment of 
progression, rather than a local site investigator/radiology assessment. Real-time 
determination of radiologic progression as determined by central review will be 
communicated to the site.  Standard RECIST 1.1 will be used by the local site for treatment 
decisions until the occurrence of PD that is verified by the central imaging vendor.
Following verification of PD by the central imaging vendor, treatment decision may be made 
by the adaptation of RECIST 1.1, as outlined in Section 7.1.2.5.5 – irRECIST Assessment of 
Disease and termed irRECIST.  Immunotherapeutic agents such as pembrolizumab may 
produce antitumor effects by potentiating endogenous cancer-specific immune responses,
which may be functionally anergic.  Recruitment of immune cells to tumor sites may result in 
a transient increase in the size of existing tumor lesions or the appearance of new lesions.  
Standard RECIST may not accurately capture the response to immunotherapeutic agents such 
as pembrolizumab. When feasible, subjects should not be discontinued until progression is 
confirmed by subsequent tumor imaging as assessed by the investigator.  This allowance to 
continue treatment despite initial radiologic progression takes into account the observation 
that some subjects can have a transient tumor flare in the first few months after the start of 
immunotherapy but with subsequent disease response.
Change in primary endpoint of PFS from BICR to investigator-assessed
Based on recent medical monitoring review, there was greater than anticipated discordance 
rate (~27%) between blinded independent central review (BICR) assessed PD and 
investigator-assessed PD. This has led to a higher than expected censoring of PFS events; in 
many of these instances, investigators decided to initiate next line of treatment without PD
confirmation by BICR. The investigator assessment is based on patient’s overall status 
including signs of clinical progression factored into their assessment of radiographic PD 
while BICR assessment of PD is solely based on radiographic progression.  Sponsor, 
investigators and central readers are blinded to study treatment.  Thus, the protocol is 
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amended for the PFS endpoint to be changed from BICR assessment to investigator
assessment.
4.2.3.1.2 Secondary Efficacy Endpoints
Objective response rate based on RECIST 1.1 and assessed by investigator, as well as DOR 
based on RECIST 1.1 assessed by investigator, are commonly accepted endpoints by both 
regulatory authorities and the oncology community.
Immune-related RECIST
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following the treatment of pembrolizumab. 
Immunotherapeutic agents such as 
pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific 
immune responses.  The response patterns seen with such an approach may extend beyond 
the typical time course of responses seen with cytotoxic agents, and subjects may manifest a 
clinical response after an initial increase in tumor burden or even the appearance of new 
lesions.  Standard RECIST 1.1 may, therefore, not provide an accurate response assessment 
of immunotherapeutic agents such as pembrolizumab.
Based on an analysis of subjects with melanoma enrolled in KN001, 7% of evaluable 
subjects experienced delayed or early tumor pseudo-progression.  Of note, subjects who had 
PD by RECIST 1.1, but not by irRECIST, had longer OS than subjects with PD by both 
criteria.  Additionally, the data suggest that RECIST 1.1 may underestimate the benefit of 
pembrolizumab in approximately 15% of subjects.  These findings support the need to apply 
a modification to RECIST 1.1 that takes into account the unique patterns of atypical response 
in immunotherapy and enables treatment beyond initial radiographic progression.
The irRECIST assessment is based on RECIST 1.1 and is adapted to account for the unique 
tumor response seen with immunotherapeutics as described by Nishino et al. [1].  The 
assessment of unidimensional target lesions and response categories per irRECIST are 
identical to RECIST 1.1.  However, the Sponsor has implemented an adaptation related to 
new lesions, non-target lesions, and tumor burden assessment in order to confirm 
radiographic progression.  irRECIST will be used by local site investigators to assess tumor 
response and progression and to make treatment decisions, as well as to be used by the 
central imaging vendor in support of the PFS endpoint.
For further information on irRECIST, see Section 7.1.2.5.5– irRECIST Assessment of 
Disease.
4.2.3.2
Rationale for Patient-reported Outcomes
Symptomatic improvement is considered a clinical benefit and accepted by health authorities
as additional evidence on the risk-benefit profile of any new treatment. Subjects will provide 
information regarding their health-related quality of life via the following assessment tools: 
EORTC QLQ-C30, EORTC QLQ-OES18, and EQ-5D-5L.  These measures are not pure 
efficacy or safety endpoints because they are affected by both disease progression and 
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treatment tolerability.  Details on these instruments are provided in Section 7.1.2.6.2 –
Electronic Patient-reported Outcomes.
4.2.3.3
Rationale for Safety Endpoints
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 v4.0.
4.2.3.4
Planned Biomarker Research
A PD-L1 biomarker-positive subject is defined as one whose tumor has a CPS ≥10, as 
defined in Section 4.2.3.4.1 – Biomarker Research for Primary Objectives.
4.2.3.4.1 Biomarker Research for Primary Objectives
PD-L1 Expression
PD-L1 protein level in tumor sections, assessed by IHC, correlates with response to 
pembrolizumab in patients with NSCLC, and an in vitro diagnostic device has been 
developed. Preliminary data indicate that this association between tumor PD-L1 expression 
and response to pembrolizumab may also be true in additional cancer types (eg, triple-
negative breast cancer, head and neck cancer, and gastric cancer), therefore, this relationship 
was also evaluated in esophageal cancer.  An interim database lock of a subset of KN180 
subjects (N = 105) was used as training set to evaluate the utility of a PD-L1 CPS across a 
range of cut points in identifying subjects with esophageal cancer that respond to 
pembrolizumab. Combined positive score is defined as the percentage of tumor cells and 
mononuclear inflammatory cells within the tumor nests and the adjacent supporting stroma 
expressing PD-L1 at any intensity.
For those subjects that had esophageal tumor PD-L1 scores of CPS ≥10 (approximately 45% 
of subjects), both ORR and survival were significantly improved compared with either the 
all-comers population or the population with CPS <10. This cut point also maintained good 
sensitivity to detect responders as well as prevalence across esophageal tumors, compared 
with other cut points. Programmed cell death-ligand 1 CPS ≥10 will be used in KN590 as 
part of the primary objectives outlined in section 3.1 above.
4.2.3.4.2 Biomarker Research for Exploratory Objectives
Introduction: 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 trials. 
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 
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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 analyses, whole 
exome sequencing, whole genome sequencing): This research will evaluate whether genetic 
variation within a clinical trial 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 (eg, 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 (eg, mutations, methylation status, MSI).  Key molecular changes of interest to 
immune-oncology drug development include the mutational burden of tumors and the 
clonality of T-cells in the tumor microenvironment.  Increased mutational burden (sometimes 
referred to as a ‘hyper-mutated’ state) may generate neo-antigen presentation in the tumor 
microenvironment.  To conduct this type of research, it is important to identify tumor-
specific mutations that occur across all genes in the tumor genome.  Thus, genome-wide 
approaches may be used for this effort. Note that in order to understand tumor-specific 
mutations, it is necessary to compare the tumor genome with the germline genome.  
Microsatellite instability may also be evaluated, as this is an important biomarker for some 
cancers (eg, colorectal cancer).
Tumor and blood RNA analyses: Both genome-wide and targeted mRNA expression 
profiling and sequencing in tumor tissue and in blood may be performed to define gene 
signatures that correlate to clinical response to treatment with pembrolizumab or other 
immunotherapies.  Pembrolizumab induces a response in tumors that likely reflects an 
inflamed/immune phenotype.  Specific immune-related gene sets (ie, those capturing 
interferon-gamma transcriptional pathways) may be evaluated and new signatures may be 
identified.   Individual genes related to the immune system may also be evaluated (eg, IL-10).  
MicroRNA profiling may also be pursued.
Proteomics and immunohistochemistry using blood or tumor: Tumor and blood samples from 
this study may undergo proteomic analyses.  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 
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assessing tumor biomarkers.  This research would serve to develop such assays for future 
clinical use.
Other exploratory biomarkers (eg, PD-1 expression, markers of T-cell phenotype) may also 
be evaluated.
Note that exploratory biomarkers are not applicable for China.
4.2.3.5
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 subjects. 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 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of Future Biomedical Research are presented in Section 12.2 – Collection and Management 
of Specimens for Future Biomedical Research.
Note: Future Biomedical Research is not applicable for China.
Benefit/Risk
It cannot be guaranteed that subjects in clinical trials will directly benefit from treatment 
during participation as clinical trials are designed to provide information about the safety and 
effectiveness.
Beneficial effects of pembrolizumab have been seen in several trials to date. Publications of 
a significantly positive benefit/risk ratio have been reported for melanoma both in a 
single-arm study encompassing nearly 1000 patients (KN001), which led to United States
FDA approval in September 2014, and in a randomized comparison to chemotherapy 
(KN002 – detailed in the IB).
Data from KN028, a Phase 1b study in subjects with 
esophageal cancer, also support a positive benefit/risk ratio (see Section 4.2.1 – Rationale for 
the Trial and Selected Subject Population).
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and informed consent documents.
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5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male and female subjects with locally advanced unresectable or metastatic adenocarcinoma 
or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert type 1
adenocarcinoma of the EGJ of at least 18 years of age will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial. The subject 
may also provide consent for Future Biomedical Research where approved by local 
authorities. However, the subject may participate in the trial without participating in 
Future Biomedical Research.
2. Be ≥ 18 years of age on the day of signing informed consent.
3. Have histologically or cytologically confirmed diagnosis of locally advanced 
unresectable or metastatic adenocarcinoma or squamous cell carcinoma of the 
esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the EGJ.
a.
Subjects with direct invasion into adjacent organs such as the aorta or 
trachea (T4b disease) should be closely evaluated for bleeding risk prior to 
enrollment and a Sponsor consultation before enrollment is required.
b.
Subjects with Siewert type 1 adenocarcinoma of the EGJ with known 
human epidermal growth factor receptor-2/neu (HER-2/neu)-positive 
tumors are not eligible. If HER-2/neu status is unknown, site should follow 
local standards for HER-2/neu testing.
4. Have measurable disease per RECIST 1.1 as determined by the local site 
investigator/radiology assessment.  A lesion(s) situated in a previously irradiated area 
can be considered a target lesion(s) if progression has been demonstrated and the 
lesion(s) is considered measurable per RECIST 1.1 criteria.
Note: The same image acquisition and processing parameters should be used 
throughout the study for a given subject.
5. Have an ECOG performance status of 0 to 1.
6. Provide either a newly obtained or archival tissue sample for PD-L1 by 
immunohistochemistry analysis.  Newly obtained tissue is preferred. Formalin-fixed, 
paraffin-embedded (FFPE) block specimens are preferred to slides. Repeat samples 
will be required if none of the samples submitted (archival or newly obtained) is 
adequate. For purposes of this study, newly obtained tissue refers to tissue that was 
collected between the last line of therapy and the first dose of study medication.
a.
Tumor samples that meet the minimum acceptance criteria (as defined in the 
Procedures Manual) must be submitted to the PD-L1 testing lab prior to
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subject randomization in the study.  If multiple tumor samples are submitted, 
at least one of the samples must be confirmed to be adequate by a pathologist 
(either local or from testing laboratory) prior to subject being enrolled.
b. For subjects from whom newly obtained samples cannot be obtained (eg,
inaccessible or subject safety concern), an archival specimen may be 
submitted.
c.
If newly obtained tissue is provided and an archival tissue sample is available, 
it should also be provided to support evaluation of the clinical utility of PD-L1 
analysis by immunohistochemistry in newly obtained vs. archival tissue 
samples. However, a subject will not be excluded from participating in the
study if he/she has provided newly obtained tissue and an archival tissue 
sample is not available or is otherwise insufficient for analysis.
Note: Tumor samples obtained from a lesion that received radiation therapy is 
not acceptable for biomarker analysis. If a subject has received prior radiation 
therapy, the subject is eligible if either a newly obtained sample from a tumor 
lesion not previously irradiated or an archival sample that was obtained before 
receiving radiation therapy can be provided.
7. Female subjects of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to randomization. If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required. If first 
dose is given > 72 hours post randomization, pregnancy test should be repeated 
within 72 hours of first dose.
8. Female subjects of childbearing potential must be willing to use an adequate method 
of contraception as outlined in Section 5.7.2 – Contraception, for the course of the 
study through 120 days after the last dose of study medication and up to 180 days 
after last dose of cisplatin.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject.
9. Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 5.7.2 – Contraception, starting with the first dose 
of study therapy through 120 days after the last dose of study medication and up to 
180 days after last dose of cisplatin and refrain from donating sperm during this 
period.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject.
10. Have adequate organ function as defined in Table 1.  Specimens must be collected 
within 14 days prior to the start of study treatment.
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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/La
Renal
Creatinine OR
Measured or calculatedb creatinine clearance
(glomerular filtration rate can also be used in 
place of creatinine or creatinine clearance)
≤1.5 × ULN OR
≥60 mL/min for subject with creatinine levels 
> 1.5 × institutional ULN
Cisplatin product label should be followed for 
acceptable creatinine clearance rates.
Hepatic
Total bilirubin
≤ 1.5 × ULN OR direct bilirubin ≤ ULN for 
subjects with total bilirubin levels > 1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 × ULN (≤ 5 × ULN for subjects with liver 
metastases)
Coagulation
International normalized ratio (INR) OR
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless subject 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); ULN=upper limit of 
normal
a
Criteria must be met without erythropoietin dependency and without packed red blood cell transfusion 
within last 2 weeks.
b
Creatinine clearance should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of specific 
chemotherapies.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has locally advanced esophageal carcinoma that is resectable or potentially curable 
with radiation therapy (as determined by local investigator).
2. Has had previous therapy for advanced/metastatic adenocarcinoma or squamous cell 
cancer of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the 
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EGJ. 
Subjects may have received prior neoadjuvant or adjuvant therapy in 
consideration of following:
a.
Assessment of disease progression should be confirmed by CT scan. In 
certain situations, clinical evidence of disease progression such as any new or 
worsening malignant effusion (documented by ultrasound) and confirmation 
by pathologic criteria (histology and/or cytology) may be acceptable for 
assessment. 
b. Treatment with curative intent, including neoadjuvant/adjuvant treatment, 
given as chemotherapy or chemoradiotherapy, using standard of care agents or 
definitive chemoradiation, will count as a line of therapy if disease 
progression occurs during treatment or within 6 months of cessation of 
treatment.
c.
Dose reduction and/or switching of one or more agents due to
toxicity/intolerability as deemed clinically appropriate by the investigator will 
not constitute a new line of therapy.
3. Has had major surgery, open biopsy, or significant traumatic injury within 28 days 
prior to randomization, or anticipation of the need for major surgery during the course 
of study treatment.
4. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include early-stage cancers (carcinoma in situ or Stage 1) treated with 
curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin,
in situ cervical cancer, in situ breast cancer that has undergone potentially curative 
therapy, and in situ or intramucosal pharyngeal cancer.
5. Has known active central nervous system metastases and/or carcinomatous 
meningitis. 
Subjects with previously treated brain metastases may participate 
provided they are radiologically stable (ie, without evidence of progression for at 
least 4 weeks by repeat imaging [note that the repeat imaging should be performed 
during study screening]), clinically stable and without requirement of steroid 
treatment for at least 14 days prior to first dose of trial treatment.
6. 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. Brief (ie, < 7 days) use of systemic corticosteroids 
is allowed when use is considered standard of care by investigator.
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment, or 
has a history of organ transplant, including allogeneic stem cell transplant.
8. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
9. Has an active infection requiring systemic therapy.
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10. Has a history or current evidence of any condition (eg, known deficiency of the 
enzyme dihydropyrimidine dehydrogenase, hearing impairment, etc.), therapy, or 
laboratory abnormality that might confound the results of the trial, interfere with the 
subject’s participation for the full duration of the trial, or is not in the best interest of 
the subject to participate (eg, any contraindication to the use of cisplatin or 5-FU), in 
the opinion of the treating investigator.
Note: Sites in France will perform a systematic search for dihydropyrimidine 
dehydrogenase deficiency for subjects who are naive to 5-FU. This research should 
be performed before any administration of 5-FU.
11. Has known psychiatric or substance abuse disorder that would interfere with 
cooperation with the requirements of the trial.
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of study medication and up to 180 days after last dose of cisplatin.
13. 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 (i.e., CTLA-4, OX-40, 
CD137) or has previously participated in a pembrolizumab (MK-3475) clinical trial.
14. Has severe hypersensitivity (≥Grade 3) to any study treatment (pembrolizumab, 
cisplatin, or 5-FU) and/or any of its excipients.
15. Has a known history of active tuberculosis (TB; Mycobacterium tuberculosis).
16. Has a known history of human immunodeficiency virus (HIV) infection.  No HIV 
testing is required unless mandated by local health authority.
17. Has known history of or is positive for hepatitis B (hepatitis B surface antigen 
reactive) or hepatitis C (hepatitis C virus RNA or hepatitis C antibody is detected).  
No hepatitis testing is required unless mandated by local health authority.
18. Is currently participating in or has participated in a study of an investigational agent 
or has used an investigational device within 4 weeks prior to the first dose of trial 
treatment.
Note:  Subjects who have entered the follow-up phase of an investigational trial may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
19. Has received a live vaccine within 30 days prior to the first dose of trial drug.  
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®) are live attenuated vaccines and are not allowed.
20. Has had radiotherapy within 14 days of randomization. Subjects who received 
radiotherapy >14 days prior to randomization must have completely recovered from 
any radiotherapy-related AEs/toxicities.
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Note: Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to 
this criterion and may qualify for the study.
Note: See Appendix 12.6.1 France-specific requirements for additional exclusion criterion 
related to French subjects and their eligibility to receive cisplatin.
Trial Treatment(s)
The treatments to be used in this trial are outlined below in Table 2.
Table 2
Trial Treatments
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Treatment 
Period
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each 
cycle
Experimental
Normal saline
NA
Q3W
IV infusion
Day 1 of each 
cycle
Placebo
Cisplatina
80 mg/m2
Q3W
IV infusion
Day 1b of each 
cycle 
Comparator 
regimen and 
combination 
agent
5-FU
800 mg/m2/day ×
5 days (4000 
mg/m2 total per 
cycle)
Q3W
IV infusion
Continuous 
Days 1b to 5 of 
each cyclec
Comparator 
regimen and 
combination 
agent
a Duration of cisplatin treatment will be capped at 6 doses, however treatment with 5-FU may continue per local 
standard.
b Administration of cisplatin and/or 5-FU may begin 1 to 2 days following pembrolizumab/placebo (eg, Day 2 
or Day 3) as needed per local standard of care, with end day for 5-FU adjusted accordingly.
c Or per local standard for 5-FU administration duration as long as total dose of 4000 mg/m2 per cycle Q3W is 
followed (eg, 1000 mg/m2/day on each of Days 1 to 4). 5-FU treatment is not to exceed a maximum of 35 
cycles.
Abbreviations: 5-FU=5-fluorouracil, IV=intravenous, NA=not applicable, Q3W=every 3 weeks
Trial treatment for Cycle 1 should begin within 3 days of randomization.  However, every 
effort should be made to begin trial treatment on day of randomization.
All trial treatments will be administered on an outpatient basis.
For 5-FU continuous 
infusion, use of a portable infusion pump is preferred; however, hospitalization is acceptable 
if that is the standard procedure for the local site.
All supplies indicated in Table 2 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will 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 
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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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of dose of pembrolizumab to be used in this trial is provided in 
Section 4.0 – Background & Rationale. 
Details on preparation and administration of 
pembrolizumab are provided in the Pharmacy Manual.
Preparation of cisplatin and 5-FU should follow the local product label and administration 
should follow local standard procedures. The body surface area in m2 should be calculated 
per local guidance.
5.2.1.2
Dose Modification (Escalation/Titration/Other)
If appropriate, the investigator may attribute each toxicity event to cisplatin, 5-FU, or 
pembrolizumab and use a stepwise dose reduction according to Table 3, Table 4, Table 5,
Table 6, and Table 7.  For individual subjects 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 subject (with the exception of alopecia).
Pembrolizumab/placebo dose reductions are not permitted.
Pembrolizumab/placebo 
treatment may be interrupted or discontinued due to toxicity (see Section 5.8.1 –
Discontinuation of Treatment). If a dose reduction for toxicity occurs with any agent, the 
dose may not be re-escalated. Subjects can have a maximum of 2 dose modifications (if 
applicable) to each of the components of study therapy throughout the course of the study for 
toxicities.  If a subject
experiences several toxicities and there are conflicting 
recommendations, follow the most conservative dose adjustment recommended (i.e., dose 
reduction appropriate to the most severe toxicity).  Subjects who require a third dose 
modification to any particular component will have that agent discontinued.
Reduction of one chemotherapy agent and not the other agent is appropriate if, in the opinion 
of the investigator, the toxicity is clearly related to one of the treatments. If, in the opinion of 
the investigator, the toxicity is related to the combination of both chemotherapy agents, both 
drugs should be reduced according to recommended dose modifications. If the toxicity is 
related to the combination of 3 agents, chemotherapy should be reduced, interrupted, or 
discontinued, and pembrolizumab/placebo should be interrupted or discontinued according to 
the recommended dose modifications.
The CTCAE v4.0 must be used to grade the severity of AEs. All dose modifications should 
be based on the AE requiring the greatest dose modification. Dose modifications are detailed 
in Table 3, Table 4, Table 5, Table 6, and Table 7.  Exceptional circumstances to following 
the dose modification tables below may be considered after consultation with the Sponsor.
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Table 3
Dose Modifications for Trial Medications
Dose level 0
Dose level -1
Dose level -2
Dose level -3
Cisplatin
80 mg/m2
60 mg/m2
(75% of Level 0)
40 mg/m2
(50% of Level 0)
Discontinue
5-fluorouracil
4000 mg/m2/cycle
3000 mg/m2/cycle 
(75% of Level 0)
2000 mg/m2/cycle 
(50% of Level 0)
Discontinue
Pembrolizumab/
placebo
200 mg fixed dose
Dose reductions are 
not permitted
Dose reductions are 
not permitted
Dose reductions 
are not permitted
If a toxicity is not otherwise specified, investigators should refer to the product label or local 
guidelines for cisplatin and 5-FU for dose adjustments.
5.2.1.2.1 Immune-Related 
Events 
and 
Dose 
Modification 
(Withhold, 
Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. 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 4.
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Table 4
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
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
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
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
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
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
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
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
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).
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab-associated 
infusion reaction are provided in Table 5.
Table 5
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 subject 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 hours
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 subject 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 subject
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate 
premedication 
should 
be 
permanently discontinued from further study 
treatment.
Subject may be premedicated 
1.5 hours (± 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)
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NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., 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 subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject
is permanently discontinued from 
further study treatment.
No subsequent dosing
Abbreviations: IV=intravenous, NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events,
NSAID=nonsteroidal anti-inflammatory drug, PO=per os (orally)
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration.
For further information, refer to the CTCAE v4.0 at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the 
subject’s study record.
5.2.1.2.2 Dose Modification for Cisplatin and 5-fluorouracil
Refer to criteria for cisplatin and 5-FU dose modification included in Table 6 and Table 7
respectively.
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Table 6
Dose Modification Guidelines for Cisplatin Drug-Related Adverse Events
Category
Toxicity
Hold 
Cisplatin
Treatment 
for Grade
Timing for
Restarting
Cisplatin
Treatment
Dose for
Restarting
Cisplatin
Treatment
Discontinue Cisplatin
Hematologicc
Neutropenia
3a
Neutrophil
count resolves
to
> 1,000/mm3
No Reduction
(consider
G-CSF)
Toxicity does not resolve
within 4 weeks of last 
infusion or if > 2 dose level
reductions exceeded
4a
Neutrophil
count resolves
to
> 1,000/mm3
Reduce by 1
DL
(consider
G-CSF)
Toxicity does not resolve
within 4 weeks of last 
infusion or if > 2 dose level
reductions exceeded
Febrile 
neutropenia
3a
Toxicity
resolves to
Grade 0 or 1
Reduce by 1
DL
Toxicity does not resolve
within 4 weeks of last 
infusion or if > 2 dose level
reductions exceeded
4a
NA
Discontinue
Permanently discontinue 
cisplatin
Thrombo-
cytopenia
3 or 4a
Platelet count
resolves to 
> 75,000/mm3 
or baseline
Reduce by 1
DL
Toxicity does not resolve
within 4 weeks of last 
infusion or if > 2 dose level
reductions exceeded
Non-
hematologic
Creatinine
increased
2
Toxicity
resolves to
Grade 0 or 1
Reduce by 1
DL
Toxicity does not resolve
within 4 weeks of last 
infusion or if > 2 dose level
reductions exceeded
3 or 4a
Toxicity
resolves to
Grade 0 or 1
Reduce by 1
DL
Toxicity does not resolve
within 4 weeks of last 
infusion or if > 2 dose level
reductions exceeded
Sensory 
neuropathy
3 or 4a
Toxicity
resolves to
Grade 0 or 1
Reduce by 1
DL
Toxicity does not resolve
within 4 weeks of last 
infusion or if > 2 dose level
reductions exceeded
Ototoxicityd
1 or 2b
Toxicity
resolves to
Grade 0 or 1
Reduce by 1
DL
Toxicity does not resolve 
within 4 weeks of last infusion 
or if >2 dose level reductions 
exceeded
3 or 4
NA
Discontinue
Permanently discontinue 
cisplatin
All other
non-
hematologic 
toxicitiesb
3 or 4a
Toxicity
resolves to
Grade 0 or 1
Reduce by 1
DL
Toxicity does not resolve
within 4 weeks of last 
infusion or if > 2 dose level
reductions exceeded
Laboratory
AEs
4a
Toxicity
resolves to
Grade 0 or 1
Reduce by 1
DL
Toxicity does not resolve
within 4 weeks of last 
infusion or if > 2 dose level
reductions exceeded
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Category
Toxicity
Hold 
Cisplatin
Treatment 
for Grade
Timing for
Restarting
Cisplatin
Treatment
Dose for
Restarting
Cisplatin
Treatment
Discontinue Cisplatin
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
Subjects with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion. Permanently 
discontinue from agent for persistent Grade 2 adverse reactions for which treatment has been held, and did not recover 
to Grade 0 or 1 within 12 weeks of the last dose.
c Subjects with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion.
d Cisplatin is known to cause high frequency hearing loss. Follow local product label and institutional guidelines. If 
Grade 1 or 2 hearing loss occurs, the risk of additional hearing loss versus the potential benefit of continuing cisplatin 
chemotherapy should be made. Grade 3 and 4 hearing loss is an indication to discontinue cisplatin.
Abbreviations: AE=adverse event, DL=dose level, G-CSF= granulocyte colony-stimulating factor, NA=not applicable.
Table 7
Dose Modification Guidelines for 5-fluorouracil Drug-Related Adverse Events
Category
Toxicity
Hold 5-FU
Treatment 
for Grade
Timing for
Restarting 5-FU
Treatment
Dose for
Restarting 5-FU
Treatment
Discontinue
5-FU
Hematologicc
Neutropenia
3a
Neutrophil count
resolves to
> 1,000/mm3
No Reduction
(consider G-CSF)
Toxicity does not
resolve within 4 or 5
weeks of last infusion or
if > 2 dose level
reductions exceeded
4a
Neutrophil count
resolves to
> 1,000/mm3
Reduce by 1 DL
(consider G-CSF)
Toxicity does not
resolve within 4 or 5
weeks of last infusion or
if > 2 dose level
reductions exceeded
Febrile
neutropenia
3a
Toxicity resolves
to Grade 0 or 1
Reduce by 1 DL
Toxicity does not
resolve within 4 or 5
weeks of last infusion or
if > 2 dose level
reductions exceeded
4a
NA
Discontinue
Permanently discontinue
Thrombo-
cytopenia
3 or 4a
Platelet count 
resolves to 
> 75,000/mm3
Reduce by 1 DL
Toxicity does not
resolve within 4 or 5
weeks of last infusion or
if > 2 dose level
reductions exceeded
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Category
Toxicity
Hold 5-FU
Treatment 
for Grade
Timing for
Restarting 5-FU
Treatment
Dose for
Restarting 5-FU
Treatment
Discontinue
5-FU
Non-
hematologic
Diarrhea, 
mucositis, or 
hand-foot 
syndrome
2 or 3
Toxicity resolves
to Grade 0 or 1
Reduce by 1 DL
Toxicity does not
resolve within 4 or 5
weeks of last infusion or
if > 2 dose level
reductions exceeded
4
NA
Discontinue
Permanently discontinue
All other
non-
hematologic 
toxicitiesb
3 or 4a
Toxicity resolves
to Grade 0 or 1
Reduce by 1 DL
Toxicity does not
resolve within 4 or 5
weeks of last infusion or
if > 2 dose level
reductions exceeded
Laboratory
AEs
4a
Toxicity resolves
to Grade 0 or 1
Reduce by 1 DL
Toxicity does not
resolve within 4 or 5
weeks of last infusion 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
Subjects with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion. Permanently 
discontinue from agent for persistent Grade 2 adverse reactions for which treatment has been held, and did not recover to 
Grade 0 or 1 within 12 weeks of the last dose.
c
Subjects with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion.
Abbreviations: AE=adverse event, DL=dose level, G-CSF= granulocyte colony-stimulating factor, NA=not applicable.
Timing of Dose Administration
Study treatment in both arms will begin on Day 1 of each 3-week dosing cycle after all 
procedures/assessments have been completed as detailed in Section 6.0 – Trial Flow Chart.  
Trial treatments may be administered up to 3 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons.
All trial treatments may be administered on an outpatient basis.
Treatment will be administered in the order presented below:

Pembrolizumab or placebo infusion is administered first, followed by the cisplatin 
and 5-FU infusions.
Administration of chemotherapy (ie, cisplatin and/or 5-FU) may follow 1 to 2 days after 
pembrolizumab/placebo (eg, Day 2 or Day 3) as needed per local standard of care.
Treatment may continue with pembrolizumab + chemotherapy or placebo + chemotherapy 
until documented confirmed PD, unacceptable AE(s), intercurrent illness that prevents 
further administration of treatment, investigator’s decision to discontinue treatment, subject 
withdraws consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, subject receives 35 administrations (approximately 2 years) of study 
medication, or administrative reasons requiring cessation of treatment.
Note: Dosing interruptions are permitted in the case of medical/surgical events or logistical 
reasons (i.e., elective surgery, unrelated medical events, subject vacation, and holidays) not 
related to study therapy. Subjects should be placed back on study therapy as soon as 
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clinically appropriate per the investigator, and not exceeding 3 weeks from the interrupted 
dosing. Day 1 of subsequent cycles should be adjusted accordingly to adhere to every 
3-week dosing schedule. Discuss with the Sponsor if subject cannot restart study medication 
within 3 weeks. The reason for interruption should be documented in the subject’s study 
record.
5.2.2.1
Pembrolizumab
Regardless of clinical benefit, subjects may only receive 35 administrations (approximately 
2 years) with pembrolizumab.  Pembrolizumab 200-mg fixed dose will be administered as a 
30-minute IV infusion Q3W.  Sites should make every effort to target infusion timing to be 
as close to 30 minutes as possible. However, given the variability of infusion pumps from 
site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 
between 25 and 40 minutes). Note that infusion time may be adjusted as needed if subject 
has experienced an infusion reaction (see Table 5).
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution.  Pembrolizumab will 
be prepared by unblinded qualified site personnel and administered by blinded qualified site 
personnel.
5.2.2.2
Placebo
Placebo will be normal saline solution prepared by the local pharmacist. Placebo will be 
dosed and administered by blinded qualified trial site personnel in the same manner as the 
investigational product (pembrolizumab).
5.2.2.3
Cisplatin
Cisplatin 80 mg/m2 will be administered as a 60- or 120-minute IV infusion (or per site’s 
standard practice) Q3W on Day 1 of each treatment cycle after all procedures and 
assessments are completed according to Section 6.0 – Trial Flow Chart and after 
pembrolizumab/placebo administration. Duration of cisplatin treatment will be capped at 
6 doses. Treatment with cisplatin may follow 1 to 2 days after pembrolizumab/placebo (eg,
Day 2 or Day 3) as needed per local standard of care.
5.2.2.4
5-fluorouracil
5-fluorouracil will be administered as a continuous IV infusion of 800 mg/m2/day on each of 
Days 1 to 5 Q3W or per local standard for 5-FU administration duration as long as total dose 
of 4000 mg/m2 per 3-week cycle is followed (eg, 1000 mg/m2/day on Days 1 to 4 Q3W is 
also acceptable). 5-FU will be administered after completion of all procedures and 
assessments according to Section 6.0 – Trial Flow Chart and after pembrolizumab/placebo 
administration. Treatment with 5-FU may follow 1 to 2 days after pembrolizumab/placebo 
(eg, Day 2 or Day 3) as needed per local standard of care.  Duration of 5-FU treatment will 
not exceed 35 cycles.
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Investigators are advised to counsel subjects assigned to receive 5-FU about risk of 
photosensitivity and to take sun protection measures accordingly.
Trial Blinding 
A double-blinding technique will be used.  Pembrolizumab and placebo will be prepared 
and/or dispensed in a blinded fashion by an unblinded pharmacist or qualified trial site 
personnel. The subject and the investigator who is involved in the treatment or clinical 
evaluation of the subjects are unaware of the group assignments.
Pembrolizumab or placebo treatment is blinded to the subject, study site personnel, and 
Sponsor personnel.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization
Treatment randomization will occur centrally using an interactive voice response system / 
integrated web response system (IVRS/IWRS). There are 2 treatment arms.  Subjects will be 
assigned randomly in a 1:1 ratio to pembrolizumab + cisplatin + 5-FU (Arm 1) or placebo + 
cisplatin + 5-FU (Arm 2).
Stratification
Treatment randomization will be stratified according to the following factors:
1. Geographic region (Asia versus Rest of World)
2. Histology (adenocarcinoma versus squamous cell carcinoma)
3. ECOG performance status (0 versus 1)
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination 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 subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’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 (OTC) products, herbal supplements, and 
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IV medications and fluids. If changes occur during the trial period, documentation of drug 
dosage, frequency, route, and date should also be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of trial treatment 
and up to 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered 30 days after the last dose of trial treatment should be recorded for 
SAEs and events of clinical interest (ECIs) as defined in Section 7.2 – Assessing and 
Recording Adverse Events.
Prohibited Concomitant Medication
Subjects are prohibited from receiving the following therapies during screening to the end of 
treatment of this trial:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy
Note: radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed following consultation with Sponsor.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, 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®) are live attenuated vaccines and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
AE that is suspected to have an immunologic etiology or for cisplatin or 5-FU
supportive care.  The use of physiologic doses of corticosteroids may be approved 
after consultation with the Sponsor.

Brivudine, sorivudine analogs, and other inhibitors of the enzyme dihydropyrimidine 
dehydrogenase should not be administered with 5-FU therapy.
Subjects who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.
Concomitant Medications to Be Used with Caution

Cimetidine, metronidazole, and interferons may increase levels of 5-FU.

Phenytoin should not be started with cisplatin therapy. Follow label and local 
guidelines for usage and dose adjustments.
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
Subjects who are taking phenytoin in conjunction with 5-FU should be examined 
regularly due to a potential elevation in phenytoin plasma levels. 

Hepatotoxic effects (i.e., rise in alkaline phosphatase, transaminase, or bilirubin 
levels) are commonly observed under the treatment with 5-FU and levamisole.

For 5-FU and cisplatin, refer to the product labels or local standards of care for 
further information regarding concomitant medications to be used with caution.
Rescue Medications & Supportive Care
Supportive Care Guidelines for Pembrolizumab
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Table 4 of Section 5.2.1.2.1. 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, bacterial infection, or viral infection, which might require additional supportive care. 
The treatment guidelines are intended to be applied when the investigator determines the 
events to be related to pembrolizumab.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 4 in 
Section 5.2.1.2.1
–
Dose Modification and Toxicity Management Guidelines for 
Pembrolizumab/Placebo for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Supportive Care Guidelines for Cisplatin
Refer to the product label or local standards of care for additional cisplatin supportive 
measures.
Supportive Care Guidelines for 5-fluorouracil
Refer to the product label or local standards of care for 5-FU supportive measures.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
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Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).

Female subjects will be considered of non-reproductive potential if they meet one of 
the following criteria:
o
She is postmenopausal, defined as at least 12 months with no menses without 
an alternative medical cause. In women < 45 years of age who are not using 
hormonal contraception or hormonal replacement therapy, a high 
follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state. In the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.
o
She 
had 
a 
hysterectomy 
and/or 
bilateral 
oophorectomy, 
bilateral 
salpingectomy, or bilateral tubal ligation/occlusion, at least 6 weeks prior to 
screening.
o
She has a congenital or an acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study medication and up to 180 days after last dose of cisplatin by complying 
with one of the following:

Practice abstinence from heterosexual activity
Note: Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and Ethics Review 
Committees (ERCs)/Institutional Review Boards (IRBs).  Periodic abstinence (eg, 
calendar, ovulation, symptothermal, post-ovulation methods, etc.) and withdrawal are 
not acceptable methods of contraception.

Use (or have their partner use) acceptable contraception during heterosexual activity
Note: Acceptable methods of contraception are‡:

Single method (one of the following is acceptable):
o
Intrauterine device
o
Vasectomy of a female subject’s male partner
o
Contraceptive rod implanted into the skin
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
Combination method (requires use of 2 of the following):
o
Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
o
Cervical cap with spermicide (nulliparous women only)
o
Contraceptive sponge (nulliparous women only)
o
Male condom or female condom (cannot be used together)
o
Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, 
or subcutaneous contraceptive injection
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for subjects participating at 
sites in this country/region.
Subjects 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, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 
120 days after the last dose of study medication and up to 180 days after last dose of 
cisplatin.  If there is any question that a subject of childbearing potential will not reliably 
comply with the requirements for contraception, that subject should not be entered into the 
study.
Pregnancy
If a subject inadvertently becomes pregnant while on study treatment, the subject will be 
immediately discontinued from trial treatment.  The site will contact the subject at least 
monthly and document the subject’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 subject impregnates his female partner, the trial personnel at the site must be informed 
immediately and the pregnancy must be reported to the Sponsor and followed as described in 
Section 7.2 – Assessing and Recording Adverse Events.
Use in Nursing Women
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, subjects who are breastfeeding are not eligible for 
enrollment.  Specific additional information follows for individual agents used in this trial.
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5.7.4.1
Pembrolizumab Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk.
5.7.4.2
Cisplatin Use in Nursing Women
Cisplatin has been reported to be found in human milk; subjects receiving cisplatin should 
not breastfeed.
5.7.4.3
5-fluorouracil Use in Nursing Women
It is not known whether 5-FU is excreted in human milk. Because 5-FU inhibits DNA, RNA,
and protein synthesis, mothers should not nurse while receiving this drug.
Subject Withdrawal/Discontinuation Criteria
Discontinuation of Treatment
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment will still continue to participate in the trial as specified in 
Section 6.0 – Trial Flow Chart and Section 7.1.6.3 – Post-Treatment Visits.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
○
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
Confirmed radiographic PD as outlined in Section 7.1.2.5 – Tumor Imaging and 
Assessment of Disease (exception if the Sponsor approves treatment continuation)
o
Unacceptable adverse experiences as described in Section 7.2 – Assessing and Recording 
Adverse Events
o
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
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o
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment
o
Recurrent Grade 2 pneumonitis
o
A confirmed positive serum pregnancy test
o
Investigator decision to discontinue treatment
o
Completion of 35 treatments (approximately 2 years) with pembrolizumab/placebo
o
Note: The number of treatments is calculated starting with the first dose
o
Administrative reasons
Discontinuation of Trial Treatment after CR:
o
Discontinuation of treatment may be considered for subjects who have attained a 
confirmed CR and have been treated for at least 8 cycles (at least 24 weeks), receiving at 
least 2 cycles of study treatment beyond the date when the initial CR was declared.
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
all visits and procedures, as outlined in the trial flowchart, should be completed.
Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
Withdrawal from the Trial
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.4 
– Other Procedures.
Lost to Follow-up
If a subject fails to return to the clinic for a required trial visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:
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
The site must attempt to contact the subject and reschedule the missed visit. If the 
subject is contacted, the subject 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 subject 
at each missed visit (eg, telephone calls and/or a certified letter to the subject’s last 
known mailing address or locally equivalent methods). These contact attempts should 
be documented in the subject’s medical record.
Note:  A subject is not considered lost to follow-up until the last scheduled visit for 
the individual subject. The missing data for the subject will be managed via the 
prespecified statistical data handling and analysis guidelines.
Subject Replacement Strategy
A subject who discontinues from trial treatment will not be replaced.
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit, withdraws 
from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the 
investigator).
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
The clinical trial 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 trial population as 
a whole is unacceptable, or for any medical, safety, regulatory, administrative, or other 
reasons consistent with applicable laws, regulations, and GCP.
The trial may also be 
terminated early at time of efficacy IA in case of positive OS based on decision of the DMC.  
In addition, further recruitment in the trial or at particular trial 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.
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6.0 TRIAL FLOW CHART
Trial Period
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 and 
Beyond
Discon
Safety 
Follow-up
Follow-Up 
Visits
Survival 
Follow-Upa
At time of 
Discon
30 Days
post Last 
Dose
Every 9 
Weeks Post-
discon
Every 12 
Weeks
Scheduling Window (Days)b
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Administrative Procedures
Informed Consent
X
Informed Consent for Future Biomedical 
Research (optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
Survival Statusa
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Xc
Full Physical Examinationd
X
X
Directed Physical Examinationd
X
X
X
X
X
X
X
X
Heighte, Weight, and Vital Signs (T,P,RR,BP)
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram (Local)
X
ECOG Performance Status
Xf
X
X
X
X
X
X
X
X
X
PROs (HRQoL Measures)g
X
X
X
X
X
X
X
Xg
X
X
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Trial Period
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 and 
Beyond
Discon
Safety 
Follow-up
Follow-Up 
Visits
Survival 
Follow-Upa
At time of 
Discon
30 Days
post Last 
Dose
Every 9 
Weeks Post-
discon
Every 12 
Weeks
Scheduling Window (Days)b
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Trial Treatment Administration
Pembrolizumab/Placebo Administrationh,i
X
X
X
X
X
X
X
X
Cisplatin Administrationh,j
X
X
X
X
X
X
5-FU Administrationh
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: 
Analysis Performed by LOCAL
Laboratory
Pregnancy Testk
X
PT/INR and aPTT
Xf
CBC with Differentiall
Xf
X
X
X
X
X
X
X
X
X
Chemistry Panell
Xf
X
X
X
X
X
X
X
X
X
Urinalysisl
Xf
X
X
X
X
X
T3, FT4, and TSHl
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: 
Analysis Performed by CENTRAL
Laboratory (not applicable for China)
Pembrolizumab Pharmacokineticsm
X
X
X
Pembrolizumab Anti-Drug Antibodiesm
X
X
X
Blood for Genetic Analysisn
X
Blood for RNA Analyseso
X
X
X
X
Blood for Plasma Biomarker Analyseso
X
X
X
X
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Trial Period
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 and 
Beyond
Discon
Safety 
Follow-up
Follow-Up 
Visits
Survival 
Follow-Upa
At time of 
Discon
30 Days
post Last 
Dose
Every 9 
Weeks Post-
discon
Every 12 
Weeks
Scheduling Window (Days)b
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Blood for Serum Biomarker Analyseso
X
X
X
X
Tumor Tissue Collection
Newly Obtained or Archival Tumor Tissue
Xp
Efficacy Measurements
Tumor Imaging
Xq
<----------------  X (every 9 weeks)r ---------------->
Xs
X
a.
In subjects that experience site-assessed PD or start a new anticancer therapy, contact should be made (eg, by telephone) approximately every 12 weeks to assess for survival 
status. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects 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 subjects that have a death event previously 
recorded).
b.
Cycle 1 treatment must be given within 3 days of allocation. The window for each visit is ± 3 days unless otherwise noted.
c.
SAEs will be followed through 90 days following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier.
d.
Refer to local regulations or local standard of practice for patient management regarding 5-FU and cisplatin treatment (eg, requirements for baseline and periodic audiograms 
for cisplatin).
e.
Height will be measured at Visit 1 only.
f.
ECOG performance status and laboratory tests for screening are to be performed within 14 days prior to the first dose of trial treatment.
g.
See Section 7.1.2.6.2 – Electronic Patient-reported Outcomes for details regarding administration of PROs.  All PROs are to be performed at Cycles 1 to 9. After 
Cycle 9 (Week 24), PROs are to be performed every 3 cycles (eg, Week 33, Week 42, Week 51).  PROs are to be performed for up to 1 year or end of treatment, whichever 
comes first, at time of discontinuation, and at the 30-day post-treatment discontinuation follow-up visit.  A visit window of ± 7 days will apply to PRO visit assessments.
h.
Pembrolizumab or placebo infusion is administered first, followed by the cisplatin and 5-FU infusions. Treatment with cisplatin and/or 5-FU may follow 1 to 2 days after 
pembrolizumab/placebo (eg, Day 2 or Day 3) as needed per local standard of care.
i.
Pembrolizumab/placebo should be administered on Day 1 of each 3-week cycle after all procedures/assessments have been completed. Pembrolizumab 200-mg fixed dose or 
placebo should be administered as a 30-minute IV infusion Q3W. Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. Given the 
variability of infusion pumps from site to site; however, a window of -5 minutes and +10 minutes is permitted (ie, infusion time between 25 and 40 minutes). 
Pembrolizumab/placebo treatment is discontinued after completion of 35 administrations (approximately 2 years).
j.
Cisplatin will be capped at total of 6 doses; cisplatin dosing may occur after cycle 6 if cisplatin was withheld for one or more cycles during Cycles 2 to 6.
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k.
For women of reproductive potential, a urine or serum pregnancy test must be performed within 72 hours prior to randomization. If first dose of study treatment occurs 
> 72 hours after randomization, pregnancy test must be repeated to be within 72 hours of first dose of study treatment. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required. Monthly pregnancy testing should be conducted as per local regulations where applicable.
Subjects must be 
excluded/discontinued in the event of a positive test result.
l.
Urinalysis and thyroid function tests to be performed every other cycle. CBC (hematology) and chemistry to be performed every cycle. After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.
m.
Both PK and anti-pembrolizumab antibody samples: pre-dose (trough) PK and anti-pembrolizumab antibody samples will be collected within 24 hours before infusion at 
Cycles 1, 2 and 4 for the first approximately 100 randomized subjects. No samples should be collected for any subject randomized after 31-Jan-2018, including all subjects 
from China.
n.
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 if the subject signs the Future Biomedical Research (FBR) consent. 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. Note that this sample is not applicable for China.
o.
Whole blood samples should be collected pre-dose on Day 1 of Cycle 1, Cycle 2, and Cycle 5, and again at treatment discontinuation. Leftover samples will be stored for 
FBR if the subject signs the FBR consent. Note that these samples are not applicable for China.
p.
At screening, either a newly obtained tumor tissue specimen (no intervening treatment [local or systemic] involving the site of tissue biopsy once tissue biopsy is obtained 
and time of study enrollment; preferred option) or an archival tumor specimen is required prior to randomization. If submitting a newly obtained specimen, an archival 
tumor sample is also requested (where available) to assess the clinical utility of PD-L1 analysis in newly obtained versus archived tissue samples. Formalin-fixed, paraffin-
embedded block specimens are preferred to slides.
q.
Screening tumor imaging will be performed within 21 days prior to randomization. At sites where the local regulatory body and/or IRB/ERC will not permit a second tumor 
imaging within a 21-day period, an already available imaging scan obtained within 28 days prior to first dose may be used with the approval of the Sponsor Clinical Director.  
For all subjects, already available imaging scans performed as part of routine clinical management are acceptable if they are of diagnostic quality and performed within the 
acceptable timeframe.
r.
The first on-study imaging time point will be performed at 9 weeks (63 days ± 7 days) calculated from the date of allocation and will continue to be performed Q9W (63 days 
± 7 days), or earlier if clinically indicated. Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts.
s.
In order to follow irRECIST criteria, if a subject is discontinued from study therapy prior to PD being confirmed at the site, then that subject should have tumor imaging 
performed at the time of treatment discontinuation. If previous tumor imaging was obtained within 4 weeks prior to the date of discontinuation, then additional tumor 
imaging at treatment discontinuation is not required.
Abbreviations: 5-FU=5-fluorouracil, aPTT=activated partial thromboplastin time, BP=blood pressure, CBC=complete blood count, DNA=deoxyribonucleic acid, ECI=event of 
clinical interest, ECOG=Eastern Cooperative Oncology Group, FBR=Future Biomedical Research, FT4=free thyroxine, HRQoL=health-related quality of life, IEC=Independent 
Ethics Committee, INR=international normalized ratio, IRB=Institutional Review Board, irRECIST=immune-related Response Evaluation Criteria in Solid Tumors,
IV=intravenous, P=pulse, PD=progressive disease, PD-L1=programmed cell death-ligand 1, PK=pharmacokinetics, PRO=patient-reported outcome, PT=prothrombin time, 
Q3W=every 3 weeks, Q9W=every 9 weeks, RNA=ribonucleic acid, RR=respiratory rate, SAE=serious adverse event, T=temperature, T3=triiodothyronine, TSH=thyroid-
stimulating hormone.
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, 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.
Administrative Procedures
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  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 subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements.
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to Future Biomedical Research.  A copy of the informed 
consent will be given to the subject.
Note that Future Biomedical Research is not applicable for China.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. 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 subject with a Subject Identification Card immediately after the subject 
provides written informed consent. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.  The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically significant. Details regarding the 
subject’s esophageal cancer will be recorded separately and not listed as medical history.
7.1.1.5
Disease Details
The investigator or qualified designee will obtain prior and current details regarding the 
subject’s esophageal cancer.
7.1.1.6
Prior and Concomitant Medications Review
7.1.1.6.1 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 subject 
within 28 days before starting the trial. Treatment for the subject’s esophageal cancer will be 
recorded separately and not listed as a prior medication.
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7.1.1.6.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial through the Safety Follow-up Visit.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7.2 – Assessing and Recording Adverse Events.
Subsequent Anticancer Therapy Status
The investigator or qualified designee will review all new anticancer therapy initiated after 
the last dose of trial treatment. If a subject initiates a new anticancer therapy within 30 days 
after the last dose of trial treatment, the 30-day Safety Follow-up Visit must occur before the 
first dose of the new therapy.
Once new anticancer therapy has been initiated, the subject will move into survival 
follow-up. Details regarding survival status follow-up are outlined in Section 7.1.6.3.3 –
Survival Follow-up.
7.1.1.7
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization.  Each subject will be 
assigned only one screening number.  Screening numbers must not be re-used for different 
subjects.
7.1.1.8
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after randomization.  Once a treatment/randomization number is assigned to a 
subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between
pembrolizumab/placebo
doses
for nondrug-related or administrative reasons
require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on subject management.
Administration of trial medications will be witnessed by the investigator and/or trial staff.
The total volume of trial medication infused will be compared with the total volume prepared 
to determine compliance with each dose administered. The instructions for preparing and 
administering pembrolizumab/placebo are provided in the Pharmacy Manual.
Preparation and administration of 5-FU and cisplatin should be completed per the approved 
product label or per institutional guidelines.
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Clinical Procedures/Assessments
7.1.2.1
Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Section 6 – Trial Flow Chart and more frequently if 
clinically indicated.
Adverse events will be graded and recorded throughout the trial and 
during the follow-up period according to NCI CTCAE v4.0 (see Section 7.2.4 – Evaluating 
Adverse Events). Toxicities will be characterized in terms including seriousness, causality, 
toxicity grading, and action taken with regard to trial treatment.
Refer to Section 7.2 – Assessing and Recording Adverse Events for detailed information 
regarding the assessment and recording of AEs.
7.1.2.2
Physical Exam
7.1.2.2.1 Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 6 – Trial Flow 
Chart. After the first dose of trial treatment, new clinically significant abnormal findings 
should be recorded as AEs.
A complete physical examination is a comprehensive inspection of a subject’s general 
appearance, HEENT, neck, chest and lungs, cardiovascular system, abdomen, genitourinary 
system, musculoskeletal system, lymph nodes, extremities, and neurological system by 
reviewing history, palpation, percussion, and auscultation.
Refer to local regulations or local standard of practice for patient management regarding 5-
FU and cisplatin treatment (eg, requirements for baseline audiograms for cisplatin).
7.1.2.2.2 Directed Physical Exam
For cycles that do not require a full physical examination as defined in Section 6.0 – Trial 
Flow Chart, the investigator or qualified designee will perform a directed physical 
examination as clinically indicated prior to the administration of the trial treatment. New 
clinically significant abnormal findings should be recorded as AEs.
Refer to local regulations or local standard of practice for patient management regarding 5-
FU and cisplatin treatment (eg, requirements for periodic audiograms for cisplatin).
7.1.2.3
Vital Signs
Vital signs include temperature, pulse, respiratory rate, weight and blood pressure. The 
investigator or qualified designee will take vital signs at screening, prior to the administration 
of each dose of trial treatment, and at treatment discontinuation as specified in the Section 6
– Trial Flow Chart. Height will be measured at Visit 1 only.
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7.1.2.4
12-Lead Electrocardiogram
A standard 12-lead electrocardiogram will be performed using local standard procedures 
once at screening. Clinically significant abnormal findings should be recorded in the medical 
history. Additional time points may be performed as clinically necessary.
7.1.2.5
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual. Tumor imaging is strongly preferred to be acquired by 
CT. Magnetic resonance imaging should be used only when CT is contraindicated or for 
imaging of the brain.
The same imaging technique regarding modality and the use of 
contrast should be used in a subject throughout the trial to optimize the visualization of 
existing and new tumor burden.
Subject eligibility will be determined using local assessment (investigator assessment) based 
on RECIST 1.1.  Although RECIST 1.1 references a maximum of 5 target lesions in total and 
2 per organ, the Sponsor allows a maximum of 10 target lesions in total and 5 per organ.  All 
scheduled images for all trial subjects from the sites will be submitted to the central imaging 
vendor. 
In addition, images (including via other modalities) that are obtained at an 
unscheduled time point to determine PD, as well as imaging obtained for other reasons, but 
captures radiologic progression, should also be submitted to the central imaging vendor.
The central imaging vendor will verify PD following the first radiologic evidence of PD 
(based on local investigator assessment).  Expedited verification of radiologic PD by the 
central imaging vendor will be communicated to the trial site and Sponsor (see 
Section 7.1.2.5.2 – Tumor Imaging During the Trial).
7.1.2.5.1 Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 21 days prior to the date of 
randomization.  The site trial team must review screening images to confirm the subject has 
measurable disease per RECIST 1.1.
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 21 days prior to the 
date of randomization and can be assessed by the central imaging vendor. At sites where the 
local regulatory body and/or IRB/ERC will not permit a second tumor imaging within a 
21-day period, an already available imaging scan obtained within 28 days prior to first dose 
may be used with the approval of the Sponsor Clinical Director.
Subjects with previously treated brain metastases may participate provided they have stable 
brain metastases (ie, without evidence of progression by imaging as confirmed by MRI if 
MRI was used at prior imaging or confirmed by CT imaging if CT was used at prior imaging 
for at least 4 weeks prior to the first dose of trial treatment).  Any neurologic symptoms must 
have returned to baseline and subjects must have no evidence of new or enlarging brain 
metastases and have not used steroids for brain metastases for at least 14 days prior to trial 
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initiation per local site assessment.  This exception does not include carcinomatous 
meningitis, as subjects with carcinomatous meningitis are excluded regardless of clinical 
stability.
7.1.2.5.2 Tumor Imaging During the Trial
The first on-trial imaging assessment should be performed at 9 weeks (63 days ± 7 days) 
from the date of randomization.  Subsequent tumor imaging should be performed every 
9 weeks (63 days ± 7 days) or more frequently if clinically indicated.  Imaging timing should 
follow calendar days and should not be adjusted for delays in cycle starts.  Imaging should 
continue to be performed until PD is verified by the central imaging vendor (unless the site 
principal investigator elects to continue treatment and follow irRECIST), the start of new 
anticancer treatment, withdrawal of consent, or death, whichever occurs first.  All 
supplemental imaging must be submitted to the central imaging vendor.
Per RECIST 1.1, partial response (PR) and CR should be confirmed by a repeat tumor 
imaging assessment obtained 4 weeks or longer from the date the response was first 
documented.  The tumor imaging performed to confirm a response may be performed, at the 
earliest, 4 weeks after the first indication of a response, or at the next scheduled scan [i.e., 
9 weeks later (63 days ± 7 days)], whichever is clinically indicated.  Subjects will then return 
to regular scheduled imaging every 9 weeks (63 days ± 7 days), starting with the next 
scheduled imaging time point.  Subjects who obtain a confirmation scan do not need to 
undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may 
resume at the subsequent scheduled imaging time point.
Per irRECIST, PD should be confirmed by the site at least 4 weeks after central verification 
of site-assessed first radiologic evidence of PD in clinically stable subjects.  Subjects who 
have unconfirmed PD may continue on treatment at the discretion of the site investigator 
until progression is confirmed by the site as long as they have met the conditions detailed in 
Section 7.1.2.5.5 – irRECIST Assessment of Disease.  Subjects who obtain a confirmation 
scan do not need to undergo the next scheduled tumor imaging if it is less than 4 weeks later; 
tumor imaging may resume at the subsequent scheduled imaging time point if clinically 
stable. Subjects who have confirmed PD, as assessed by the site, will discontinue trial 
treatment.  Exceptions are detailed in Section 7.1.2.5.5 – irRECIST Assessment of Disease.
7.1.2.5.3 End of Treatment and Follow-up Tumor Imaging
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (± 4 week window).  If a previous scan was obtained within 
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not 
mandatory.  In subjects who discontinue trial treatment due to documented PD, this is the 
final required tumor imaging.
In subjects who discontinue trial treatment without documented PD, every effort should be 
made to continue monitoring their disease status by tumor imaging using the same imaging 
schedule used while on treatment [every 9 weeks (63 days ± 7 days)] to monitor disease 
status until the start of a new anticancer treatment, PD, death, or the end of the trial, 
whichever occurs first.
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7.1.2.5.4 RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by the central imaging vendor as the primary measure for 
assessment of tumor response, date of PD, and as a basis for all protocol guidelines related to 
disease status (eg, discontinuation of trial therapy). 
Initial tumor imaging showing 
site-assessed PD should be submitted to the central imaging vendor immediately.  The site 
will be notified if the central imaging vendor verifies PD using RECIST 1.1.  Figure 2
illustrates the imaging flow involving verification of PD for clinically stable subjects.
7.1.2.5.5 irRECIST Assessment of Disease
Immune-related RECIST is RECIST 1.1 adapted as described below to account for the 
unique tumor response seen with immunotherapeutic drugs. Immune-related RECIST will be 
used by the site investigator/local radiology reviewers to assess tumor response and 
progression, and make treatment decisions.  This data will be collected in the clinical 
database.
When feasible, subjects should not be discontinued until progression is confirmed by the 
local site investigator/radiology assessment.  This allowance to continue treatment despite 
initial radiologic PD takes into account the observation that some subjects can have a 
transient tumor flare in the first few months after the start of immunotherapy, and then 
experience subsequent disease response.  Subjects that are deemed clinically unstable are not 
required to have repeat tumor imaging for confirmation of PD.  Tumor flare includes any of 
the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing non-target lesion(s)

Development of new lesion(s)
In subjects who have shown initial evidence of radiological PD by RECIST 1.1 as verified by 
the central imaging vendor, it is at the discretion of the principal investigator whether to 
continue a subject on trial medication until repeat imaging is obtained (using irRECIST for 
subject management (see Table 8 and Figure 2).  This clinical judgment decision by the site 
investigator should be based on the subject’s overall clinical condition, including 
performance status, clinical symptoms, and laboratory data.  Subjects may receive trial 
medication and the tumor assessment should be repeated ≥4 weeks later in order to confirm 
PD by irRECIST per site assessment. Clinical stability is defined as the following:

Absence of symptoms and signs indicating clinically significant progression of 
disease, including worsening of laboratory values

No decline in ECOG performance status

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention)
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Any subject deemed clinically unstable should be discontinued from trial treatment at central 
verification of site-assessed first radiologic evidence of PD and is not required to have repeat 
imaging for PD confirmation.
In determining whether or not the tumor burden has increased or decreased per irRECIST, 
the local site investigator should consider all target and non-target lesions, as well as any 
incremental new lesion(s).
Disease progression will be considered to be “not confirmed” at repeat imaging if ALL of the 
following occur (as assessed by irRECIST):

Target lesion sum of diameters is < 20% or < 5 mm absolute increase compared to 
nadir

Non-target disease resulting in initial PD is stable or qualitatively improved

New lesion resulting in initial PD is stable or qualitatively improved

No incremental new lesion(s) since last evaluation

No incremental new non-target lesion progression since last evaluation
If repeat imaging does not confirm PD per irRECIST as assessed by the local site 
investigator and the subject continues to be clinically stable, treatment may continue and 
follow the regular imaging schedule.
Disease progression will be considered to be “confirmed” at repeat imaging if ANY of the 
following occur (as assessed by irRECIST):

Target lesion sum of diameters remains ≥20% and at least 5 mm absolute increase 
compared to nadir

Non-target disease resulting in initial PD is qualitatively worse

New lesion resulting in initial PD is qualitatively worse

Additional new lesion(s) since last evaluation

Additional new non-target lesion progression since last evaluation
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
discontinued from trial therapy.
NOTE: If a subject has confirmed radiographic progression (i.e., 2 scans at least 4 weeks 
apart demonstrating PD) per irRECIST, but the subject is achieving a clinically meaningful 
benefit, and there is no further increase in the tumor burden at the confirmatory tumor 
imaging, an exception to continue treatment may be considered following consultation with 
the Sponsor.  In this case, if treatment is continued, tumor imaging should continue to be 
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performed following the intervals as outlined in Section 6.0 – Trial Flow Chart and be 
submitted to the central imaging vendor.
Additional details about irRECIST are provided in MSD TIP Sheet for RECIST 1.1 and 
irRECIST.
Table 8
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 which 
has been verified 
by the central 
imaging vendor
Repeat imaging 
at ≥4 weeks at 
site to confirm 
PD
May continue trial 
treatment at the local 
site investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
irRECIST.
Repeat imaging 
at ≥4 weeks to 
confirm PD per 
investigator’s
discretion only
Discontinue treatment
Repeat tumor 
imaging confirms 
PD by irRECIST 
at the local site
No additional 
imaging required
Discontinue 
treatment (exception 
is possible upon 
consultation with 
Sponsor)
No additional 
imaging required
Not applicable
Repeat tumor 
imaging shows 
SD, PR or CR by 
irRECIST at the 
local site
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue trial 
treatment at the local 
site investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart trial 
treatment if condition 
has improved and/or 
clinically stable per 
investigator’s 
discretion. Next tumor 
image should occur 
according to the regular 
imaging schedule
CR=complete response, irRECIST=immune-related Response Evaluation Criteria in Solid Tumors, PD=progressive disease,
PFS=progression-free survival, PR=partial response, SD=stable disease
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Abbreviations: CIV=central imaging vendor; PD=progressive disease; SFU=safety follow-up; RECIST= 
Response Evaluation Criteria in Solid Tumors; irRECIST=immune-related RECIST; PI=principle investigator
Figure 2
Imaging and Treatment for Clinically Stable Subjects After First Radiologic 
Evidence of PD Assessed by the Site
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7.1.2.6
Performance and Quality of Life Assessments
7.1.2.6.1 Eastern Cooperative Oncology Group Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 12.3 – ECOG 
Performance Status) at screening, prior to the administration of each dose of trial treatment, 
and at treatment discontinuation as specified in Section 6 – Trial Flow Chart.
7.1.2.6.2 Electronic Patient-reported Outcomes
The following health-related quality of life assessment tools will be administered by trained 
study site personnel and completed electronically by subjects. It is strongly recommended 
that electronic patient-reported outcomes (ePROs)
are administered prior to drug 
administration, AE evaluation, and disease status notification; an exception to this 
recommendation may occur at the treatment discontinuation visit. 
Electronic 
patient-reported outcome will be administrated in the following order: the EQ-5D-5L first, 
followed by EORTC QLQ-C30, and lastly the EORTC QLQ-OES18 at the time points
specified in Section 6 – Trial Flow Chart. If the subject does not complete a given ePRO
assessment, the MISS_MODE form must be completed to capture the reason the assessment 
was not performed.  A visit window of ± 7 days will apply to ePRO visit assessments.
If at the time of enrollment of a subject, the translated version of the EORTC QLQ-OES18 is 
not available for that language/country, and therefore cannot be completed by the subject at 
Cycle 1 Day 1, then the EORTC QLQ-OES18 will not be required for this subject at any 
point during the study.  The other study patient-reported outcomes (PRO) measures must be 
completed as scheduled. NOTE: For some sites, the translated EORTC QLQ-OES18 might 
become available after study startup and should be administered to subjects at their time of 
enrollment; for some sites, the EORTC QLQ-OES18 translation might not be available for 
the entire duration of the study.
EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data for use in economic models and analyses including developing health utilities or 
quality-adjusted life-years.  The 5 health state dimensions in this instrument 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 (extreme problem).  The 
EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the subject 
rates his or her general state of health at the time of the assessment.  The EQ-5D-5L will 
always be completed electronically by subjects first, prior to completing any other ePRO.
EORTC QLQ-C30
The EORTC QLQ-C30 was developed to assess the quality of life of patients with cancer. It 
has been translated and validated into 81 languages and used in more than 3000 studies 
worldwide. It consists of 5 functioning scales (physical, role, cognitive, emotional, and 
social), 3 symptom scales (fatigue, nausea, pain), and additional single-symptom items [32].
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It is scored on a 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). The 
EORTC QLQ-C30 instrument also contains 2 global scales that use a 7-point scale scoring 
with anchors (the scores range from 1=very poor to 7=excellent).
EORTC QLQ-OES18
The EORTC QLQ-OES18 is a disease-specific questionnaire developed and validated to 
address measurements specific to esophageal cancer [33].  It is one of multiple disease-
specific modules developed by the EORTC Quality of Life Group designed for use in clinical 
trials, to be administered in addition to the QLQ-C30 to assess disease-specific treatment 
measurements.  It contains 18 items with symptoms of dysphagia, pain, reflux, eating, 
difficulty with swallowing saliva, choking, dry mouth, taste, cough, and speech.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Trial Procedures 
Manual. Refer to Section 6 – Trial Flow Chart for the timing of laboratory assessments.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Table 9.
Table 9
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or 
urine)a
Hemoglobin
Alkaline phosphatase
Glucose
Prothrombin Time (PT) or 
International Normalized 
Ratio (INR)
Platelet count
ALT (SGPT)
Protein
Activated Partial 
Thromboplastin Time (aPTT)
White blood cell 
(WBC) (total and 
differential)b
AST (SGOT)
Specific gravity 
Total triiodothyronine (T3) or 
Free T3c,d 
Red blood cell 
(RBC) count
Bicarbonate (or carbon 
dioxide [CO2])e
Microscopic exam, if 
abnormal results are noted
Free thyroxine (FT4)d
Absolute lymphocyte 
count
Calcium
Thyroid-stimulating hormone 
(TSH)d
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Hematology
Chemistry
Urinalysis
Other
Absolute neutrophil 
count (ANC)
Chloride
Creatinine or creatinine 
clearancef
Glucose
Phosphorus
Potassium
Sodium
Total bilirubin
Direct bilirubin, if total 
bilirubin is elevated above 
the upper limit of normal
Total protein
Blood urea nitrogen
(BUN)/ureag
a. For women of reproductive potential, a urine or serum pregnancy test must be performed within 72 hours prior to 
randomization. If first dose of study treatment occurs > 72 hours after randomization, pregnancy test must be repeated to 
be within 72 hours of first dose of study treatment. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required. 
Monthly pregnancy testing should be conducted as per local regulations where 
applicable.
b. Report % or absolute results for differential per standard of practice. Report the results in the same manner throughout 
the trial.
c. Total T3 is preferred; if not available, free T3 may be tested.
d. If the local laboratory is unable to perform these tests, the site should submit the sample to the central laboratory for 
testing. Details are provided in the Procedures Manual. Note, there may be instances when sites are unable to obtain the 
thyroid function testing results prior to scheduled dosing.  After Cycle 1, review of thyroid function tests (FT3, FT4 and 
TSH) results after dosing is acceptable.
e. If these tests are not done as part of standard of care in your region, then these tests do not need to be performed.
f. Glomerular filtration rate can also be used in place of creatinine or creatinine clearance.
g. BUN is preferred; if not available, urea may be tested.
Abbreviations: ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase)
Laboratory tests for screening should be performed within 14 days prior to the first dose of 
trial treatment.  An exception is hepatitis (if required per local regulations) and thyroid 
function testing, which may be performed within 28 days prior to first dose.  Pre-dose 
laboratory procedures can be conducted up to 72 hours prior to dosing.
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each dose of trial treatment. Note, there may be 
instances when sites are unable to obtain the thyroid function testing results prior to 
scheduled dosing.  After Cycle 1, review of thyroid function tests (T3 or FT3, FT4, and TSH) 
results after dosing is acceptable. Unresolved abnormal laboratory values that are 
drug-related AEs should be followed until resolution.  Laboratory tests do not need to be 
repeated after the end of treatment if laboratory results are within the normal range.
7.1.3.2
Pregnancy Test
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal, must be tested for pregnancy within 72 hours of randomization.
If first dose of study treatment occurs > 72 hours after randomization, pregnancy test must be 
repeated to be within 72 hours of first dose of study treatment. Monthly pregnancy testing 
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(serum and/or urine) should be conducted per local regulations where applicable.  If a urine 
test is positive or not evaluable, a serum test will be required.  Subjects must be 
excluded/discontinued from the trial in the event of a positive or borderline-positive test 
result.
7.1.3.3
HIV, Hepatitis B Virus, and Hepatitis C Virus Testing
Testing for HIV, hepatitis B virus, and hepatitis C virus will be conducted at screening only 
where required per local regulations using site standard operating procedures. 
Active 
hepatitis B is defined as a known positive hepatitis B surface antigen result. Active hepatitis 
C is defined by a known positive hepatitis C antibody result or known quantitative hepatitis 
C virus RNA results greater than the lower limits of detection of the assay.
7.1.3.4
Pharmacokinetic/Pharmacodynamic Evaluations
The accumulation of robust PK and ADA data has allowed for the adequate characterization 
the clinical pharmacology of 
pembrolizumab across 
indications, 
including for 
pembrolizumab monotherapy in esophageal cancer subjects and for subjects treated with 
pembrolizumab in combination with chemotherapy in other indications. Therefore, PK and 
ADA samples for this study will be limited to the first approximately 100 randomized 
subjects at Cycles 1, 2 and 4 only. Analysis will be performed only if required.
7.1.3.4.1 Blood Collection for Serum Pembrolizumab
Pre-dose PK samples will be collected at Cycles 1, 2 and 4 for the first approximately 100 
randomized subjects. All pre-dose trough samples should be drawn within 24 hours before 
infusion of pembrolizumab/placebo. Sample collection, storage, and shipment instructions 
for serum samples will be provided in the Procedures Manual.
Note that no samples should be collected from subjects randomized after 31-Jan-2018, 
including all subjects from China.
7.1.3.4.2 Blood Collection for Anti-pembrolizumab Antibodies
Pre-dose anti-pembrolizumab antibodies samples will be collected at Cycles 1, 2 and 4 for 
the first approximately 100 randomized subjects. All pre-dose trough samples should be 
drawn within 24 hours before infusion of pembrolizumab/placebo. 
Sample collection, 
storage, and shipment instructions for serum samples will be provided in the Procedures 
Manual.
Note that no samples should be collected from subjects randomized after 31-Jan-2018, 
including all subjects from China.
7.1.3.4.3 Blood Collection for RNA Analysis and Plasma and Serum Biomarker 
Analyses
Blood should be collected pre-dose for Cycles 1, 2, 5 and at the time of discontinuation.  
Leftover RNA, plasma, and serum will be stored at the end of the trial for Future Biomedical 
Research (FBR) if the subject has consented (see Section 4.2.3.5 – Future Biomedical 
Research).
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Further details are provided in the Procedures Manual.
Note that these samples are not applicable to China.
7.1.3.5
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual. Samples should be collected for planned analysis 
of associations between genetic variants in germline/tumor DNA and drug response.  If a 
documented law or regulation prohibits (or local IRB/ERC does not approve) sample 
collection for these purposes, then such samples should not be collected at the corresponding 
sites.  Leftover DNA extracted from planned genetic analysis samples will be stored for 
future biomedical research only if subject signs the FBR consent. Note that this is not 
applicable to China.
7.1.3.6
Future Biomedical Research Samples
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research

Leftover RNA

Leftover plasma and serum from biomarker analyses

Leftover main study tumor tissue
7.1.3.7
Tumor Tissue
Eligibility for this study is dependent upon supplying tumor tissue for biomarker analysis as 
described under eligibility criteria. Repeat samples may be required if adequate tissue is not 
provided.  If the subject signs the FBR consent, any leftover tissue that would ordinarily be 
discarded at the end of the main study will be retained for FBR.
Newly obtained tissue is preferred (no intervening treatment [local or systemic] involving the 
site of tissue biopsy once tissue biopsy is obtained and time of study enrollment). 
Formalin-fixed, paraffin-embedded block specimens are preferred to slides. 
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual.
Other Procedures
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue treatment prior to completion of the treatment regimen should be 
encouraged to continue to be followed for all remaining study visits.
When a subject withdraws from participation in the trial, all applicable activities scheduled 
for the end of treatment visit should be performed at the time of withdrawal.  Any adverse 
events which are present at the time of withdrawal should be followed in accordance with the 
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safety requirements outlined in Section 7.2 - Assessing and Recording Adverse Events. 
After discontinuing treatment following assessment of CR or 35 administrations 
(approximately 2 years) of treatment, these subjects should return to the site for a Safety 
Follow-up Visit (described in Section 7.1.6.3.1 – Safety Follow-up Visit) and then proceed to 
the Follow-up Period of the study (described in Section 7.1.6.3.2 – Follow-up Visits).
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research.  Subjects 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 subject’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 subject 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 (e.g., 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 
subject’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
Note that Future Biomedical Research is not applicable for China.
7.1.4.1.2 Lost to Follow-up
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit.  If the 
subject is contacted, the subject 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 subject 
at each missed visit (eg, phone calls and/or a certified letter to the subject’s last 
known mailing address or locally equivalent methods). 
These contact attempts 
should be documented in the subject’s medical record.
Note:  A subject is not considered lost to follow-up until the last scheduled visit for 
the individual subject.  The amount of missing data for the subject will be managed 
via the pre-specified data handling and analysis guidelines.
7.1.4.2
Subject Blinding/Unblinding
STUDY TREATMENT IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND THE PARTICIPANT UNLESS 
NECESSARY.
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For emergency situations where the investigator or delegate needs to identify the drug used 
by a subject and the dosage administered, he/she will contact the emergency unblinding call 
center by telephone and make a request for emergency unblinding.  As requested by the 
investigator or delegate, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor.  Prior to contacting the emergency 
unblinding call center to request unblinding of a subject’s treatment assignment, the 
investigator or delegate must enter the toxicity grade of the adverse events observed, the 
relation to study drug, the reason thereof, etc., in the medical chart etc.
Subjects whose treatment assignment has been unblinded by the investigator/delegate and/or 
non-study treating physician must be discontinued from study drug, but should continue to be 
monitored in the trial.
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
Treatment/Vaccine identification information is to be unmasked ONLY if necessary for the 
welfare of the subject.  Every effort should be made not to unblind the subject unless 
necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. Once an emergency unblinding has 
taken place, the principal investigator, site personnel, and Sponsor personnel may be
unblinded so that the appropriate follow-up medical care can be provided to the participant.
7.1.4.3
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 trial 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 
trial site.

Laboratory equipment – as required for inclusion labs and trial assessments

Imaging equipment – as required for study objectives
See protocol-specified guidance in the Administrative Binder, Procedures Manual, and Site 
Imaging Manual.
Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency room visits must be reported in the eCRF, from the 
time of treatment allocation/randomization through 90 days following cessation of study 
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treatment, or 30 days following cessation of study treatment, if the subject initiates new 
anticancer therapy, whichever is earlier.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.6.1
Screening Visit
Within 28 days prior to treatment randomization, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1 – Entry Criteria.  
Visit requirements are outlined in the Section 6 – Trial Flow Chart.  Screening procedures 
may be repeated.
Written consent must be obtained prior to performing any protocol-specific procedure.  
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame.  Screening procedures are to be completed within 28 days prior to the first dose of 
trial treatment except for the following:

Laboratory tests are to be performed within 14 days prior to the first dose of trial 
treatment. Exceptions are thyroid function and hepatitis testing, which may be done 
up to 28 days prior to the first dose of trial treatment.

Evaluation of ECOG is to be performed within 14 days prior to the first dose of trial 
treatment.

For women of reproductive potential, a urine or serum pregnancy test will be 
performed within 72 hours prior to randomization. If first dose of study treatment 
occurs > 72 hours after randomization, pregnancy test must be repeated to be within 
72 hours of the first dose of trial treatment.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test will be required (performed by the 
local trial site laboratory).

Initial tumor imaging at Screening must be performed within 21 days prior to the date 
of randomization. 
Subjects may be not be rescreened after failing to meet the inclusion/exclusion criteria during 
the initial 28-day screening period.
7.1.6.2
Treatment Period Visits
Visit requirements are outlined in the Section 6 – Trial Flow Chart.  Specific 
procedure related details are provided in Section 7.1 – Trial Procedures.
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7.1.6.3
Post-Treatment Visits
7.1.6.3.1 Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anticancer treatment, whichever 
comes first.
7.1.6.3.2 Follow-up Visits
Subjects who discontinue trial treatment for a reason other than PD will move into the 
Follow-up Phase and should be assessed by radiologic evaluation every 9 weeks (63 days 
± 7 days) to monitor disease status.  Every effort should be made to collect information 
regarding disease status until the start of new anticancer therapy, PD, death, or end of trial.  
Information regarding post-trial anticancer treatment will be collected if new treatment is 
initiated.
7.1.6.3.3 Survival Follow-up
Subjects who experience confirmed PD or start a new anticancer therapy will move into the 
Survival Follow-up Phase and should be contacted by telephone approximately every 
12 weeks (84 days ± 7 days) to assess for survival status until death, withdrawal of consent, 
or the end of the trial, whichever occurs first.
7.1.6.4
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor.  For 
example, updated survival status may be requested prior to, but not limited to, an external 
DMC review, interim and/or final analysis.  Upon Sponsor notification, all subjects 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 subjects that have a previously 
recorded death event in the collection tool).
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
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Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for cisplatin or 5-FU by ≥20% and as ≥1000 mg (5 times the dose) of pembrolizumab
in a 3-week period. No specific information is available on the treatment of overdose of 
pembrolizumab. In the event of overdose, study treatment should be discontinued and the 
subject should be observed closely for signs of toxicity.  Appropriate supportive treatment 
should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
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reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of trial treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  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.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
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●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: 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.
Refer to Table 10 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject 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, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of trial treatment, or 30 days following cessation of trial treatment if the 
subject initiates new anticancer therapy, whichever is earlier, any serious adverse event, or 
follow up to a serious adverse event, including death due to any cause other than progression 
of the cancer under study (reference Section 7.2.3.3 for additional details), whether or not 
related to the Sponsor's product, must be reported within 24 hours to the Sponsor either by 
electronic media or paper. Electronic reporting procedures can be found in the EDC data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
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reported within 24 hours to the Sponsor if it causes the subject 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, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, 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).
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3 – Immediate Reporting of Adverse Events.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The external DMC will monitor unblinded aggregated efficacy endpoint events and safety 
data to ensure the safety of the subjects in the trial.  Any suspected endpoint that, upon 
review, is not progression of the cancer under study will be forwarded to global safety as an 
SAE within 24 hours of determination that the event is not progression of the cancer under 
study.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events 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.
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All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
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 (i.e., 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.
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Table 10
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
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
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient 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 an MSD product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product 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 drug and the adverse event based upon the 
available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Sponsor’s product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of the 
Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
Sponsor’s product(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 SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS 
PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology or 
toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's product 
is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
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.
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 
DMC 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 
be involved with the trial in any other way (e.g., 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 subject 
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 8.7 - 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 Sponsor 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.
The DMC will monitor the trial at an appropriate frequency, as described in the detailed 
DMC charter. Treatment-level results of the IA will be provided by the unblinded statistician 
to the DMC. Key enrollment metrics and study data will also be monitored by the external 
unblinded statistician to inform the timing of the first PFS and OS analyses as needed.  The 
DMC will serve as the primary reviewer of the results of the main PFS analysis and will 
make recommendations for discontinuation of the study or modification to an EOC of the 
Sponsor.
If the DMC recommends modifications to the design of the protocol or 
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discontinuation of the study, this EOC may be unblinded to results at the treatment level in 
order to act on these recommendations. If the EOC is unblinded to the results, they may 
consult with Sponsor Senior Management to determine if further actions need to be taken.  
Additional Sponsor personnel may be unblinded to the treatment-level results of the main
PFS analyses, if required, in order to act on the recommendations of the DMC or facilitate 
regulatory filing after the first PFS analysis. The extent to which individuals are unblinded 
with respect to the results of the IA will be documented by the unblinded statistician
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, changes 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 E9).  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. There will be a separate PK analysis plan as well as 
biomarker analysis plan. Post hoc exploratory analyses will be clearly identified in the CSR. 
The PRO analysis plan will be included in the sSAP.
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan that are summarized below are applicable to the 
Global Study population (all enrolled subjects N=749). The comprehensive plan is provided 
in Section 8.2 – Responsibility for Analyses/In-house Blinding through Section 8.12 – Extent 
of Exposure. Additional details for the statistical analysis of the China Cohort (N=106) are
described in the supplemental SAP.
Study Design Overview
A Randomized, Double-Blind, Placebo-Controlled Phase III Clinical Trial of 
Pembrolizumab (MK-3475) in Combination with Cisplatin and 5-Fluorouracil 
versus Placebo in Combination with Cisplatin and 5-Fluorouracil as First-Line 
Treatment 
in 
Subjects 
with 
Advanced/Metastatic 
Esophageal 
Carcinoma 
(KEYNOTE-590)
Treatment Assignment
Subjects will be randomized in a 1:1 ratio to receive pembrolizumab with 
5-fluorouracil (5-FU) and cisplatin combination therapy or placebo with 5-FU and 
cisplatin. Stratification factors are in Section 5.4 – Stratification.
Analysis Populations
Global Study Population N=749
Efficacy: Intention-to-Treat
Safety: All Subjects as Treated
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Primary
Endpoints/Hypotheses
1.
OS in subjects with ESCC whose tumors are PD-L1 biomarker-positive (CPS 
≥10).
2.
OS in subjects with ESCC.
3.
OS in subjects whose tumors are PD-L1 biomarker-positive (CPS ≥10).
4.
OS in all subjects.
5.
PFS based on RECIST 1.1 as assessed by investigator in subjects with ESCC.
6.
PFS based on RECIST 1.1 as assessed by investigator in subjects whose tumors 
are PD-L1 biomarker-positive (CPS ≥10).
7.
PFS based on RECIST 1.1 as assessed by investigator in all subjects.
Key Secondary 
Endpoints/Hypotheses
1.
Objective response rate (ORR) based on RECIST 1.1 as assessed by 
investigator in all subjects.
Statistical Methods for
Key Efficacy Analyses
The primary hypotheses will be evaluated by comparing pembrolizumab + 
chemotherapy arm to placebo + chemotherapy arm on PFS and OS using a
stratified Log-rank test. Estimation of the hazard ratio (HR) will be done using a
stratified Cox regression model.
Event rates over time will be estimated within 
each treatment group using the Kaplan-Meier method.
Statistical Methods for
Key Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers differ with 
respect to the analyses that will be performed. There are no Tier I events in this 
study. Tier 2 parameters will be assessed via point estimates with 95% CI provided 
for between-group comparisons; only point estimates by treatment group are 
provided for Tier 3 safety parameters.   The between-treatment difference will be 
analyzed using the Miettinen and Nurminen method [34].
Interim Analyses
One efficacy interim analysis will be performed in this study. Results will be 
reviewed by an external Data Monitoring Committee. Details are provided in
Section 8.7 – Interim Analyses.
Interim Analysis (IA):

Timing: (1) Enrollment is complete with a minimum follow-up of 13 
months and (2) ~460 investigator-assessed PFS events have been observed 
in ESCC and (3) ~391 deaths have occurred in ESCC

Primary purpose: Final PFS analysis and Interim OS analysis
FA:

Timing: (1) A minimum follow-up of 9 months after IA and (2) ~233 
deaths have occurred in ESCC with PD-L1 CPS ≥10 and (3) ~455 deaths 
have occurred in ESCC

Primary purpose: Final OS analysis
Multiplicity
The overall Type I error is strongly controlled at 2.5% (1-sided), with 1.2% initially 
allocated to OS in ESCC with PD-L1 CPS ≥10, 1.1% to OS in ESCC, 0 to OS in 
PD-L1 CPS ≥10, 0 to OS in all subjects, 0.2% to PFS in ESCC, 0 to PFS in PD-L1 
CPS ≥10, and 0 to PFS in all subjects.
Reallocation of Type I error will use the graphical approach of Maurer and Bretz
[35].
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Sample Size and Power
The sample size is 749 subjects. As per preliminary baseline characteristics, the 
prevalence of ESCC with PD-L1 CPS ≥10 is 38%, PD-L1 CPS ≥10 is 51%, and 
ESCC is 73%.
A total of ~233 deaths are expected in ESCC with PD-L1 CPS ≥10 at the OS final 
analysis. With 233 deaths, the study has ~85% power for detecting an HR of 0.65 at 
an initially assigned 0.012 (1-sided) significance level.
A total of ~455 deaths are expected in ESCC at the OS final analysis. With 455
deaths, the study has ~88% power for detecting an HR of 0.72 at an initially 
assigned 0.011 (1-sided) significance level.
A total of ~ 460 investigator-assessed PFS events are expected in ESCC at the 
interim analysis (IA). With ~460 PFS events, the study has ~82.8% power for 
detecting a HR of 0.7 at an initially assigned 0.002 (1-sided) significance level.
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.
The investigators, other study site staff, and subjects will be blinded to subject-level 
biomarker status. Analysis or summaries generated by biomarker status will be limited and 
documented.
The study will be conducted as a double-blind, Phase III study under in-house blinding 
procedures. The official, final database will not be unblinded until medical/scientific review 
has been performed, protocol deviations have been identified, and data have been declared 
final and complete. In addition, the independent radiologist(s) will perform the central 
imaging review without knowledge of treatment group assignment. 
Additional details 
regarding trial blinding/unblinding including unblinding required for operational purposes 
(eg, unblinded pharmacist) are described in Section 5.2.3 – Trial Blinding.
The planned efficacy IA is described in Section 8.7 – Interim Analyses. Blinding to 
treatment assignment will be maintained at all investigational sites. Treatment-level results of 
the efficacy IA will be provided by an external unblinded statistician to the DMC (see 
Section 7.3.3 – Data Monitoring Committee). 
Prior to final study unblinding, the unblinded statistician will not be involved in any 
discussions regarding modifications to the protocol, statistical methods, identification of 
protocol deviations, or data validation efforts.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0 – Objective(s) & 
Hypothesis(es).
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Analysis Endpoints
Efficacy Endpoints
8.4.1.1
Primary Efficacy Endpoints
Progression-free Survival – RECIST 1.1 by investigator assessment
Progression-free survival is defined as the time from randomization to the first documented 
disease progression per RECIST 1.1 based on investigator assessment or death due to any 
cause, whichever occurs first.  See Section 8.6.1.1 – Progression-free Survival for the 
definition of censoring.
Overall Survival
Overall survival is defined as the time from randomization to death due to any cause. 
Subjects without documented death at the time of the final analysis will be censored at the 
date of the last follow-up.
8.4.1.2
Secondary Efficacy Endpoints
Objective Response Rate – RECIST 1.1 by investigator assessment
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a CR or PR.
Duration of Response – RECIST 1.1 by investigator assessment
For subjects who demonstrate CR or PR, DOR is defined as the time from first documented 
evidence of CR or PR until disease progression per RECIST 1.1 based on assessments by 
investigator or death due to any cause, whichever occurs first. See Section 8.6.1.4 – Duration 
of Response for the definition of censoring.
Safety Endpoints
Safety measurements are described in Section 7 – Trial Procedures.
Patient-reported Outcome Endpoints
Assessment of PRO will be based on the EORTC QLQ-C30 and 3 pre-specified disease-
related symptom scores (dysphagia, reflux, and pain) from the EORTC QLQ-OES18.
Time to deterioration (10 points worse than baseline) and rate of improvement (10 points 
better than baseline) in EORTC QLQ-C30 global health status, and the 3 pre-specified 
disease-related symptom scores from the EORTC QLQ-OES18 will be analyzed.
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Analysis Populations
Efficacy Analysis Populations
The Intention-to-Treat population will serve as the population for primary efficacy analysis.
All randomized subjects will be included in this population. Subjects will be included in the 
treatment group to which they are randomized.
The ITT population for the primary analyses is the Global Study population (N=749) which 
includes all subjects randomized in the Global Study.  Details on the approach to handling 
missing data are provided in Section 8.6 – Statistical Methods.
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be included in the treatment group corresponding 
to the study treatment they actually received for the analysis of safety data using the ASaT 
population. For most subjects, this will be the treatment group to which they are randomized. 
Subjects who take incorrect study treatment for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received. Any subject who 
receives the incorrect study medication for one cycle, but receives the correct treatment for 
all other cycles, will be analyzed according to the correct treatment group and a narrative will 
be provided for any events that occur during the cycle for which the subject is incorrectly 
dosed.
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 each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in 
Section 8.6 – Statistical Methods.
Statistical Methods
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.
Note that a sensitivity analysis for efficacy endpoints described in Sections 8.6.1.1 through 
8.6.1.4 below will also be conducted for the Global Cohort (N=711).
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 8.8 – Multiplicity. Nominal p-values 
will be computed for other efficacy analyses but should be interpreted with caution due to 
potential issues of multiplicity.
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8.6.1.1
Progression-free Survival
The non-parametric Kaplan-Meier method will be used to estimate the PFS rate over time in 
each treatment group. The hypotheses of treatment difference in PFS will be tested by the 
stratified log-rank test. A stratified Cox proportional hazard model with Efron’s method of 
tie handling will be used to estimate the magnitude of the treatment difference (ie, hazard 
ratio [HR]) between the treatment arms. The HR and its 95% confidence interval (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 5.4
– Stratification) will be applied to both the stratified log-rank test and the stratified Cox 
model.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. For the primary analysis, for the subjects who have PD, the true date of PD will 
be approximated by the date of the first assessment at which PD is objectively documented 
per RECIST 1.1 by investigator assessment, regardless of discontinuation of study drug or 
missed study visits. Death is always considered as a confirmed PD event. Subjects who do 
not experience a PFS event will be censored at the last disease assessment.
For the primary analysis, any subject who experiences an event (PD or death) immediately 
after 2 or more missed disease assessments will be censored at the last disease assessment 
prior to the missed visits.  In addition, any subject who initiates new anticancer therapy will 
be censored at the last disease assessment prior to the initiation of new anticancer therapy. 
Subjects who do not start new anticancer therapy and who do not experience an event will be 
censored at the last disease assessment.   If a subject meets multiple criteria for censoring, the 
censoring criterion that occurs earliest will be applied. 
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by investigator
assessment, 2 sensitivity analyses with different sets of censoring rules will be performed. 
The first sensitivity analysis follows the intention-to-treat principle. That is, PDs/deaths are 
counted as events regardless of missed study visits or initiation of new anticancer therapy. 
The second sensitivity analysis considers discontinuation of treatment due to reasons other 
than complete response or initiation of new anticancer treatment, whichever occurs later, to 
be a PD event for subjects without documented PD or death.  If a subject meets multiple 
criteria for censoring, the censoring criterion that occurs earliest will be applied.   The 
censoring rules for the primary and sensitivity analyses are summarized in Table 11.
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Table 11
Censoring Rules for Primary and Sensitivity Analyses of Progression-free 
Survival
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death documented 
after ≤1 missed disease 
assessment, and before 
new anticancer therapy, if 
any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
Death or progression after 
≥2 consecutive missed 
disease assessments 
without further valid non-
PD disease assessments, or 
after new anticancer
therapy
Censored at last 
disease assessment 
prior to the earlier date 
of ≥2 consecutive 
missed disease 
assessment and new 
anticancer therapy, if 
any
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
No PD and no death; and 
new anticancer treatment is 
not initiated
Censored at last 
disease assessment 
Censored at last disease 
assessment 
Progressed at treatment 
discontinuation due to 
reasons other than complete 
response; otherwise 
censored at last disease 
assessment if still on study 
treatment or completed 
study treatment
No PD and no death; new 
anticancer treatment is 
initiated
Censored at last 
disease assessment 
before new anticancer 
treatment 
Censored at last disease 
assessment
Progressed at date of new 
anticancer treatment
Abbreviations: PD = progressive disease
The proportional hazards assumption on PFS will be examined using both graphical and 
analytical methods if warranted. The log[-log] of the survival function versus time for PFS 
will be plotted for the comparison between the pembrolizumab + chemotherapy arm and the 
placebo + chemotherapy arm. If the curves are not parallel, indicating that hazards are not 
proportional, supportive analyses may be conducted to account for the possible 
non-proportional hazards effect associated with immunotherapies: for example, using 
Restricted Mean Survival Time method [36], parametric method [37], etc. Further details of 
sensitivity analyses will be described in the sSAP as needed.
The primary approach for PFS will be based on RECIST 1.1 by investigator assessment. A 
sensitivity analysis using RECIST 1.1 by BICR will also be conducted.
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8.6.1.2
Overall Survival
The non-parametric Kaplan-Meier method will be used to estimate the survival rates over 
time. The hypotheses of treatment difference in survival will be tested by the stratified 
log-rank test. A stratified Cox proportional hazard model with Efron’s method of tie 
handling will be used to estimate the magnitude of the treatment difference (ie, the HR). The 
HR and its 95% CI from the stratified Cox model with a single treatment covariate will be 
reported. The stratification factors used for randomization will be applied to both the 
stratified log-rank test and the stratified Cox model.
Subjects in the placebo + chemotherapy arm are expected to discontinue treatment earlier 
compared with subjects in the pembrolizumab + chemotherapy arm and may switch to 
another anti-PD-1 treatment following the verification of PD by the central imaging vendor. 
Exploratory analyses to adjust for the effect of crossover to other PD-1 therapies on OS may 
be performed based on recognized methods (eg, the Rank Preserving Structural Failure Time 
model proposed by Robins and Tsiatis [38], 2-stage model, etc., based on an examination of 
the appropriateness of the data to the assumptions required by the methods).
8.6.1.3
Objective Response Rate
Stratified Miettinen and Nurminen method [34] will be used for comparison of the ORR
between the treatment arms. The difference in ORR and its 95% CI from the stratified 
Miettinen and Nurminen method with strata weighting by sample size will be reported. The 
stratification factors used for randomization will be applied to the analysis.
The ORR hypotheses will be tested according to the hypotheses-testing plan as described in 
Section 8.8 – Multiplicity.
The primary approach for ORR will be based on RECIST 1.1 by investigator assessment. A 
sensitivity analysis using RECIST 1.1 by BICR will also be conducted. 
8.6.1.4
Duration of Response
If sample size permits, DOR will be summarized descriptively using the non-parametric 
Kaplan-Meier method.  Only the subset of subjects who achieved CR or PR will be included 
in this analysis.
Censoring rules for DOR are summarized in Table 12.
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Table 12
Censoring Rules for Duration of Response
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anticancer therapy initiated
Last adequate disease assessment
Censor
(Non-event)
No progression nor death, new 
anticancer therapy initiated
Last adequate disease assessment 
before new anticancer therapy 
initiated
Censor
(Non-event)
≥2 consecutive missed disease 
assessments at any time prior to 
progression or death
Last adequate disease assessment 
prior to ≥2 missed adequate disease 
assessments
Censor
(Non-event)
Death or progression after 
≤1 missed disease assessment
PD or death
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
Subjects are considered to have an ongoing response if censored, alive, have not progressed, have not started a 
new anticancer therapy, have not had ≥2 consecutive missed disease assessments, and have not been 
determined to be lost to follow-up.
Abbreviations: PD=progressive disease
The primary approach for DOR will be based on RECIST 1.1 by investigator assessment. A 
sensitivity analysis using RECIST 1.1 by BICR will also be conducted. 
Table 13 summarizes the primary analysis approach for primary and key secondary efficacy 
endpoints. Sensitivity analysis methods are described above for each endpoint.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, 
multiple populations, and the IA is described in Section 8.7 – Interim Analyses and in 
Section 8.8 – Multiplicity.
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Table 13
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses
PFS per RECIST 
1.1 by investigator
Testing: stratified log-rank test
Estimation: Stratified Cox model 
with Efron’s tie handling method 
ITT
Censored according to rules in 
Table 11
OS
Testing: stratified log-rank test
Estimation: Stratified Cox model 
with Efron’s tie handling method
ITT
Censored at subject’s last known 
alive date
Key Secondary Analyses
ORR per RECIST 
1.1 by investigator
Testing and estimation:
stratified Miettinen and 
Nurminen method
ITT
Subjects with missing data are 
considered nonresponders
Abbreviations: ITT = intent-to-treat; ORR = objective response rate; OS = overall survival; PFS = progression-
free survival; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors.
Patient-reported Outcome Analyses: EORTC QLQ-C30 and QLQ-OES18
The PRO secondary objective is to compare the change from baseline on global health status
quality of life scores in subjects treated with pembrolizumab in combination with 
chemotherapy versus placebo in combination with chemotherapy, based on the EORTC 
QLQ-C30 and 3 pre-specified disease-related symptom scores (dysphagia, reflux and pain) 
from the EORTC QLQ-OES18.
Additional PRO analyses will be described in the sSAP.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, etc.
Tiered Approach
The analysis of safety results will follow a tiered approach (Table 14).  The tiers differ with 
respect to the analyses that will be performed. “Tier 1” safety endpoints will be subject to 
inferential testing for statistical significance with p-values and 95% CI provided for between-
group comparisons. Other safety parameters will be considered Tier 2 or Tier 3. Based on 
the safety data observed in historic pembrolizumab trials to date, there are no events of 
interest that warrant classification as Tier I events. Therefore, there are no events of interest 
that will be analyzed as Tier 1 safety endpoints in this study.
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Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method, an 
unconditional, asymptotic method [34].
Membership in Tier 2 requires that at least 5% of participants in any treatment group exhibit 
the event; all other AEs and predefined limits of change will belong to Tier 3. The threshold 
of at least 5% of participants was chosen for Tier 2 events 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 5% of participants would 
obscure the assessment of the overall safety profile and add little to the interpretation of 
potentially meaningful treatment differences. In addition, Grade 3 to 5 AEs (≥5% of 
participants in 1 of the treatment groups) and SAEs (≥2% of participants in 1 of the treatment 
groups) will be considered Tier 2 endpoints. Because many 95% CIs may be provided 
without adjustment for multiplicity, the CIs should be regarded as a helpful descriptive 
measure to be used in safety review, not as a formal method for assessing the statistical 
significance of the between-group differences.
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. The broad AE 
categories consisting of the proportion of participants with any AE, a drug-related AE, a 
serious AE, an AE which is both drug-related and serious, a Grade 3-5 AE, a drug-related 
Grade 3-5 AE, and discontinuation due to an AE will be considered Tier 3 endpoints. Only 
point estimates by treatment group are provided for Tier 3 safety parameters.
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Table 14
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Grade 3-5 AE (incidence ≥5% of participants in one of 
the treatment groups)
X
X
Serious AE (incidence ≥2% of participants in one of the 
treatment groups)
X
X
AEs (incidence ≥5% of participants in one of the 
treatment groups)
X
X
Tier 3
Any AE
X
Any Grade 3-5 AE
X
Any Serious AE 
X
Any Drug-Related AE
X
Any Serious and Drug-Related AE
X
Any Grade 3-5 and Drug-Related AE
X
Discontinuation due to AE
X
Death
X
Specific AEs, SOCs (incidence ≥0% of participants 
in 1 of the treatment groups)
X
Change from Baseline Results (lab toxicity shift, 
vital signs)
X
Abbreviations: AE = adverse event; CI = confidence interval; SOC = system organ class.
Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant 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 subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed. 
Demographic variables (eg, age), baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
Interim Analyses
Safety Interim Analyses
As noted in Section 7.3.3 – Data Monitoring Committee, the DMC will be responsible for 
periodic interim safety reviews as specified in the DMC charter.
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Efficacy Interim Analyses
One interim analysis is planned in addition to the final analysis for this study. For the interim 
and final analyses, all randomized subjects will be included. Results of the interim analysis
will be reviewed by the DMC. Details of the boundaries for establishing statistical 
significance with regard to efficacy are discussed further in Section 8.8.
The analyses planned, endpoints evaluated, and drivers of timing are summarized in 
Table 15.
Table 15
Summary of Interim and Final Analyses Strategy
Analyses 
Key Endpoints 
Timing
Estimated Time 
after First 
Subject
Randomized 
Primary Purpose 
of Analysis
IA
PFS in ESCC;
PFS in PD-L1 CPS≥10;
PFS in All subjects;
OS in ESCC with PD-L1 
CPS≥10;
OS in ESCC;
OS in PD-L1 CPS≥10;
OS in All subjects
(1) Enrollment is 
complete with a 
minimum follow-up of 
13 months and
(2) ~ 460 investigator-
assessed PFS events 
have been observed in 
ESCC and
(3) ~391 deaths have 
occurred in ESCC
At this time ~200
deaths are expected to 
have occurred in ESCC 
with PD-L1 CPS≥10 
and ~ 267 deaths are 
expected to have 
occurred in PD-L1 
CPS≥10 
~35 months
Final PFS 
analysis
Interim OS 
analysis
FA
OS in ESCC with PD-L1 
CPS≥10;
OS in PD-L1 CPS≥10;
OS in ESCC;
OS in All subjects
(1) A minimum follow-
up of 9 months after IA 
and
(2) ~233 deaths have 
occurred in ESCC with 
PD-L1 CPS≥10 and
(3) ~ 455 deaths have 
occurred in ESCC.
At this time ~311 
deaths are expected to 
have occurred in PD-
L1 CPS≥10 
~44 months
Final OS 
analysis
Abbreviations: FA = final analysis; IA = interim analysis; OS = overall survival; PFS = progression-free 
survival.
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Multiplicity
Multiplicity Control for Efficacy Analyses
The study uses the graphical method of Maurer and Bretz [39] to provide strong multiplicity 
control for multiple hypotheses as well as interim analysis. According to this approach, study 
hypotheses may be tested more than once, and when a particular null hypothesis is rejected, 
the α allocated to that hypothesis can be reallocated to other hypothesis tests. Figure 3 shows
the initial 1-sided α allocation for each hypothesis in the ellipse representing the hypothesis. 
The weights for reallocation from each hypothesis to the others are shown in the boxes on the 
lines connecting hypotheses.
Abbreviations: ORR = objective response rate; OS = overall survival; PFS = progression-free survival.
Figure 3
Multiplicity Diagram for Type I Error Control
8.8.1.1
Progression-free Survival
The study will test the PFS hypothesis once, at IA which will represent FA for PFS as 
assessed by the investigator. The initial α assigned to PFS in ESCC will be 0.002. If PFS 
hypothesis in ESCC subjects is rejected, the α will be reallocated to PFS in subjects with PD-
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L1 CPS ≥10. If PFS hypothesis in subjects with PD-L1 CPS ≥10 is also rejected, the α will 
be reallocated to PFS in all subjects. If all the OS null hypotheses are rejected, 0.99 of the
initially allocated α i.e. 0.023 to OS hypotheses will be reallocated to test the PFS hypothesis 
in all subjects. Thus, if the PFS null hypotheses in the ESCC and the PDL1 CPS ≥10 
populations are rejected and the OS hypothesis in all subjects is not rejected the PFS null 
hypothesis in all subjects may be tested at α=0.002. If the PFS null hypotheses in the ESCC 
and the PDL1 CPS ≥10 populations are rejected and all the OS hypotheses are rejected, the 
PFS null hypothesis in all subjects may be tested at α=0.025.
Table 16 shows the boundary properties for PFS at the IA for each of these α levels, 
assuming the estimated numbers of events are analyzed. IA will be the final analysis for PFS. 
Note that the final row indicates the total power to reject the null hypothesis for PFS at each 
α level. Also, note that if the OS null hypothesis in all subjects is rejected at the final 
analysis, PFS in all subjects may be tested again at the time of the final analysis using the 
interim data with its updated bounds, considering the α reallocation from the OS hypothesis.
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Table 16
Efficacy Boundaries and Properties for Progression-free Survival Analyses
Analysis for ESCC
Value
=0.002
IA (Final):100%*
N = 547
Events: 460
Month: 35
Z
2.878
p (1-sided) a
0.002
HR at boundb
0.765
P(Cross) if HR=1c
0.002
P(Cross) if HR=0.7d
0.828
Analysis for PD-L1 
CPS ≥10
Value
=0.002
IA (Final):100%*
N = 381
Events: 320
Month: 35
Z
2.878
p (1-sided) a
0.002
HR at boundb
0.725
P(Cross) if HR=1c
0.002
P(Cross) if HR=0.7d
0.622
Analysis for All 
Subjects
Value
=0.002
=0.025
IA (Final):100%*
N = 749
Events: 630
Month: 35
Z
2.878
1.960
p (1-sided) a
0.002
0.025
HR at boundb
0.795
0.855
P(Cross) if HR=1c
0.002
0.025
P(Cross) if HR=0.75d
0.768
0.951
Abbreviations: HR = hazard ratio; IA = interim OS analysis; PD-L1 = programmed cell death-ligand 1.
The number of events and timings are estimated approximately.
*Percentage of the target number of events at final analysis anticipated at interim analysis.
ap (1-sided) is the nominal α for testing.
bHR at bound is the approximate HR required to reach an efficacy bound.
cP (Cross if HR=1) is the probability of crossing a bound under the null hypothesis.
dP(Cross if HR=0.xx) is the probability of crossing a bound under the alternative hypothesis.
8.8.1.2
Overall Survival
The initial α assigned to the OS hypothesis in ESCC with PD-L1 CPS ≥10 will be 0.012; the 
initial α assigned to OS in ESCC will be 0.011; and the initial α assigned to OS in PD-L1 
CPS ≥10 and OS in all subjects will be 0. If the OS hypothesis in ESCC with PD-L1 CPS
≥10 is rejected, half of the α will be reallocated to OS in ESCC and half will be reallocated to 
OS in PD-L1 CPS ≥10. If OS hypothesis in ESCC is rejected, that α will be reallocated to OS 
in PD-L1 CPS ≥10. Thus, the OS null hypothesis in ESCC may be tested at α=0.011 if the 
OS null hypothesis in ESCC with PD-L1 CPS ≥10 is not rejected, or at α=0.017 if the OS 
null hypothesis in ESCC with PD-L1 CPS ≥10 is rejected; the OS null hypothesis in PD-L1 
CPS ≥10 may be tested at α=0.006 if the OS null hypothesis in ESCC with PD-L1 CPS ≥10 
is rejected and the OS null hypothesis in ESCC is not rejected, or at α=0.011 if the OS null 
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hypothesis in ESCC with PD-L1 CPS ≥10 is not rejected and the OS null hypothesis in 
ESCC is rejected, or at α=0.023 if the OS null hypotheses in ESCC with PD-L1 CPS ≥10 and 
in ESCC are both rejected. If OS hypothesis in PD-L1 CPS ≥10 is rejected, the α will be 
reallocated to OS hypothesis in all subjects. If all PFS null hypotheses are rejected, 0.99 of 
the α initially allocated to PFS hypotheses (α=0.002) will be reallocated to OS hypothesis in 
all subjects. Thus, the OS null hypothesis in all subjects may be tested at α=0.023 if the OS 
null hypotheses in all populations are rejected and any PFS null hypotheses are not rejected, 
or at α=0.025 if the OS null hypotheses in all populations and all PFS null hypotheses are 
rejected.
Table 17 shows the bounds and boundary properties for OS hypothesis testing derived using 
a Lan-DeMets O’Brien-Fleming spending function.
Table 17
Efficacy Boundaries and Properties for Overall Survival Analyses
Analysis in 
ESCC with PD-
L1 CPS≥10
Value
=0.012
IA : 86%*
N = 285
Events: 200
Month: 35
Z 
2.473
p (1-sided)a
0.007
HR at boundb
0.705
P(Cross) if HR=1c
0.007
P(Cross) if HR=0.65d
0.721
Final: 100%*
N = 285
Events: 233
Month: 44
Z 
2.324
p (1-sided)a
0.010
HR at boundb
0.737
P(Cross) if HR=1c
0.012
P(Cross) if HR=0.65d
0.845
Analysis in 
ESCC
Value
=0.011
=0.017
IA : 86%*
N = 547
Events: 391
Month: 35
Z 
2.507
2.325
p (1-sided)a
0.006
0.010
HR at boundb
0.776
0.790
P(Cross) if HR=1c
0.006
0.010
P(Cross) if HR=0.72d
0.773
0.824
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Analysis in 
ESCC with PD-
L1 CPS≥10
Value
=0.012
Final: 100%*
N = 547
Events: 455
Month: 44
Z 
2.356
2.194
p (1-sided)a
0.009
0.014
HR at boundb
0.802
0.814
P(Cross) if HR=1c
0.011
0.017
P(Cross) if HR=0.72d
0.883
0.913
Analysis in PD-L1 
CPS≥10
Value
=0.006
=0.011
=0.023
IA : 86%*
N = 381
Events: 267
Month: 35
Z 
2.745
2.508
2.193
p (1-sided)a
0.003
0.006
0.014
HR at boundb
0.715
0.736
0.765
P(Cross) if HR=1c
0.003
0.006
0.014
P(Cross) if HR=0.65d
0.784
0.847
0.909
Final: 100%*
N = 381
Events: 311
Month: 44
Z 
2.568
2.356
2.075
p (1-sided)a
0.005
0.009
0.019
HR at boundb
0.747
0.766
0.790
P(Cross) if HR=1c
0.006
0.011
0.023
P(Cross) if HR=0.65d
0.899
0.932
0.962
Analysis in All 
Subjects
Value
=0.023
=0.025
IA : 86%*
N = 749
Events:  539
Month: 35
Z 
2.192
2.154
p (1-sided)a
0.014
0.016
HR at boundb
0.828
0.831
P(Cross) if HR=1c
0.014
0.016
P(Cross) if HR=0.75d
0.875
0.883
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Analysis in 
ESCC with PD-
L1 CPS≥10
Value
=0.012
Final: 100%*
N = 749
Events: 627
Month: 44
Z 
2.075
2.042
p (1-sided)a
0.019
0.021
HR at boundb
0.847
0.850
P(Cross) if HR=1c
0.023
0.025
P(Cross) if HR=0.75d
0.942
0.946
Abbreviations: HR = hazard ratio; IA = interim analysis.
The number of events is estimated approximately. The timing is estimated based on minimal follow-up 
requirement.
*Percentage of the target number of events at final analysis anticipated at interim analysis.
ap (1-sided) is the nominal α for testing.
bHR at bound is the approximate HR required to reach an efficacy bound.
cP(Cross if HR=1) is the probability of crossing a bound under the null hypothesis.
dP(Cross if HR=0.xx) is the probability of crossing a bound under the alternative hypothesis.
The bounds provided in the table above are based on the assumption that the expected 
number of events at IA and FA are 200 and 233 in ESCC with PD-L1 CPS ≥10, 391 and 455 
in ESCC, 267 and 311 in PD-L1 CPS ≥10, 539 and 627 in all subjects, respectively.  At the 
time of an analysis, the observed number of events may differ substantially from the 
expected.  To avoid overspending at the interim analysis and leave reasonable alpha for the 
final analysis, the minimum alpha spending strategy will be adopted.  At the IA, the 
information fraction used in Lan-DeMets spending function to determine the alpha spending 
at the IA will be based on the minimum of the expected information fraction and the actual 
information fraction at each analysis.  Specifically,

In the scenario that the events accrue faster than expected and the observed number of 
events exceeds the expected number of events at a given analysis, then the information 
fraction will be calculated as the expected number of events at the interim analysis over 
the target number of events at FA.
The final analysis will use the remaining Type I error that has not been spent at the earlier 
analyses.  The boundary calculation will be based on the correlation between IA and FA test 
statistics, which is determined by the actual number of events observed at IA and FA.
8.8.1.3
Objective Response Rate
The study will test ORR only once at the interim analysis (IA), at an α level of 0.025 if all 
OS and PFS hypotheses are rejected. Note that if superiority for all PFS and OS hypotheses 
is declared at a future planned analysis, then the test statistics previously computed at IA for 
the ORR hypothesis will be used for inferential testing at an α level of 0.025.
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Based on the 749 randomized subjects with at least 10 months of follow-up, power at 
α=0.025 as well as the approximate treatment difference required to reach the bound (ΔORR) 
are shown in Table 18, assuming underlying 35% and 50% response rates in the control and 
experimental groups, respectively.
Table 18
Possible α Levels and Approximate Objective Response Rate Difference Required 
to Demonstrate Efficacy for Objective Response at Interim Analysis
α
Approximate treatment difference in ORR
Power (ΔORR=0.15)
0.025
0.070
0.987
Multiplicity Control for Safety Analyses
To account for any multiplicity concerns raised by the DMC review of unplanned efficacy 
data when prompted by safety concerns, a sensitivity analysis for PFS by investigator and OS 
will be pre-specified in the sSAP. This analysis will be performed if requested by the DMC.
However, DMC review of PFS by investigator and OS data beyond the planned efficacy 
analysis to assess the overall risk:benefit to trial subjects will not require multiplicity 
assessment typically associated with a planned efficacy IA, because these analyses are not to 
declare a positive efficacy finding based on these results.
Sample Size and Power Calculations
The sample size and power calculations for PFS and OS assume the following:

PFS follows an exponential distribution with a median of 6 months for the control 
group

OS follows an exponential distribution with a median of 12 months for the control 
group

Enrollment period of 22 months

An annual dropout rate of 5% for both PFS and OS
The sample size and power calculations were performed using R (“gsDesign” package).
Note, at the time of this amendment, the study enrollment has been completed. The study has 
enrolled 749 subjects in a 1:1 ratio into the pembrolizumab + chemotherapy and the placebo 
+ chemotherapy arms. PFS and OS are primary endpoints for the study, with ORR as the key 
secondary endpoint. It is expected that the prevalence of ESCC with PD-L1 CPS ≥10 is 
38%, PD-L1 CPS ≥10 is 51% (all subjects), and ESCC is 73%.
For the PFS endpoint, based on a target number of 460 investigator-assessed events in ESCC 
at IA (final for PFS), the study has approximately 82.8% power to detect an HR of 0.7 at an 
overall α level of 0.002 (1-sided).
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In the scenario that the PFS hypothesis is rejected in ESCC, the PFS test has 62.2% power to 
detect an HR of 0.7 at an α level of 0.002 in subjects with PD-L1 CPS ≥10. In the scenario 
that both of PFS hypotheses in ESCC and in PD-L1 CPS ≥10 are rejected, the PFS test has 
76.8% power to detect an HR of 0.75 at an α level of 0.002 in all subjects. In the scenario 
that the PFS null hypotheses in all populations and all OS null hypotheses are rejected, the 
PFS test has 95.1% power to detect an HR of 0.75 at an α level of 0.025 in all subjects.
For the OS endpoint, based on a target number of 233 events and 1 interim analysis at 
approximately 86% of the target number of events, the study has approximately 84.5% power
at FA to detect an HR of 0.65 at an overall α level of 0.012 (1-sided) in ESCC subjects with 
PD-L1 CPS ≥10; and based on a target number of 455 events, the study has approximately 
88.3% power at FA to detect an HR of 0.72 at an overall α level of 0.011 (1-sided) in ESCC 
subjects.
In the scenario that the OS hypothesis is rejected in ESCC with PD-L1 CPS ≥10 but is not 
rejected in ESCC, the OS test has approximately 89.9% power at FA to detect an HR of 0.65
at an overall α level of 0.006 (1-sided) in PD-L1 CPS ≥10. In the scenario that the OS 
hypothesis is rejected in ESCC but is not rejected in ESCC with PD-L1 CPS ≥10, the OS test 
has approximately 93.2% power at FA to detect an HR of 0.65 at an overall α level of 0.011
(1-sided) in PD-L1 CPS ≥10. In the scenario that the OS hypotheses in ESCC with PD-L1 
CPS ≥10 and in ESCC are both rejected, the OS test has approximately 96.2% power at FA
to detect an HR of 0.65 at an overall α level of 0.023 (1-sided) in PD-L1 CPS ≥10. In the 
scenario that OS hypotheses in ESCC with PD-L1 CPS ≥10, in ESCC, and in PD-L1 CPS 
≥10 are all rejected, the OS test has approximately 94.2% power at FA to detect an HR of 
0.75 at an overall α level of 0.023 (1-sided) in all subjects. In the scenario that OS hypotheses 
in all populations and all PFS null hypotheses are rejected, the OS test has approximately 
94.6% power at FA to detect an HR of 0.75 at an overall α level of 0.025 (1-sided) in all 
subjects.
Based on 749 subjects with at least 10 months of follow-up, the power of the ORR testing at 
the allocated α=0.025 is approximately 98.7% to detect a 15-percentage point difference 
between an underlying 35% response rate in the control arm and a 50% response rate in the 
experimental arm.
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, as 
applicable, the estimate of the between-group treatment effect (with a nominal 95% CI) for 
the primary endpoints in subjects with esophageal squamous cell carcinoma (ESCC) whose 
tumors are PD-L1 biomarker-positive (CPS ≥10), in subjects with ESCC, in subjects whose 
tumors are PD-L1 biomarker-positive (CPS ≥10) and in all subjects will be estimated and 
plotted within each category of the following classification variables:

Stratification factor: geographic region (Asia versus Rest of World)

Stratification factor: histology (adenocarcinoma versus squamous cell carcinoma)

Stratification factor: ECOG performance scale (0 versus 1)
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
Age category (<65 versus ≥65 years)

Sex (female versus male)

Disease status (locally advanced versus metastatic)
Country-specific population (eg, Chinese, Japanese, EU, etc.) may also be analyzed per local 
regulatory requirements.
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
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 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 19
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
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Table 19
Product Descriptions
Product Name & 
Potency
Dosage 
Form
Source/Additional Information
MK-3475 25 mg/mL
(pembrolizumab)
Injection
Provided centrally by the Sponsor
5-Fluorouracil 50 mg/mL
Injection
Rest of World
Provided centrally by the Sponsor or locally by 
the trial site, subsidiary, or designee
5-Fluorouracil 25 mg/mL
Injection
China only
Provided centrally by the Sponsor or locally by 
the trial site, subsidiary, or designee
Cisplatin 1 mg/mL*
Injection
Rest of World
Provided centrally by the Sponsor or locally by 
the trial site, subsidiary, or designee
Cisplatin 20 mg/vial
Injection
China only
Provided centrally by the Sponsor or locally by 
the trial site, subsidiary, or designee
*Note: concentration may be different for products sourced in Japan
All supplies indicated in Table 19 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 19 will be provided by the trial 
site, subsidiary or designee. 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.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Site pharmacies will receive open-label kits.  Each MK-3475 kit will contain 2 vials.  Each 
5-FU kit and each cisplatin kit will contain 1 vial.
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Clinical Supplies Disclosure
This trial is blinded but supplies are provided open label; therefore, an unblinded pharmacist 
or qualified trial site personnel will be used to blind supplies. Treatment identity (name, 
strength or potency) is included in the label text; random code/disclosure envelopes or lists 
are not provided.
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind subjects and to unmask study treatment identity. The emergency unblinding 
call center should only be used in cases of emergency (see Section 7.1.4.2).  In the event that 
the emergency unblinding call center is not available for a given site in this trial, the central 
electronic treatment allocation/randomization system (IVRS/IWRS) should be used in order 
to unblind subjects and to unmask treatment/vaccine identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. 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.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
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/ERC) 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 Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, 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 subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
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If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
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.
Compliance with Financial Disclosure Requirements
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.
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 (e.g., 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 Section 12.1 -
Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/IEC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
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The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
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 as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The Sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
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.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
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According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, MSD, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the Protocol/CSR 
CI during the anticipated review process, thorough understanding of clinical trial methods, 
appropriate enrollment of subject cohort, timely achievement of trial milestones).  The 
Protocol CI must be a participating trial investigator.
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 subjects 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.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, 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.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
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Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. MSD will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
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the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
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[31]
Fuchs CS, Ohtsu A, Tabernero J, Van Cutsem E , Wang JD, Lam B, et al. 
Preliminary safety data from KEYNOTE-059: pembrolizumab plus 5-
fluorouracil (5-FU) and cisplatin for first-line treatment of advanced gastric 
cancer [abstract]. J Clin Oncol. 2016;34. Abstract no. 4037.
[32]
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.
[33]
Blazeby JM, Conroy T, Hammerlid E, Fayers P, Sezer O, Koller M, et al. 
Clinical and psychometric validation of an EORTC questionnaire module, the 
EORTC QLQ-OES18, to assess quality of life in patients with oesophageal 
cancer. Eur J Cancer. 2003 Jul;39(10):1384-94.
[34]
Miettinen O and Nurminen M. Comparative analysis of two rates. Stat Med 
1985;4:213-26.
[35]
Maurer W and Bretz F. Multiple testing in group sequential trials using 
graphical approaches. Stat Biopharm Res 2013;5(4):311-20.
[36]
Uno H, Claggett B, Tian L, Inoue E, Gallo P, Miyata T, et al. Moving beyond 
the hazard ratio in quantifying the between-group difference in survival 
analysis. J Clin Oncol. 2014 Aug 1;32(22):2380-5.
[37]
Odell PM, Anderson KM, Kannel WB. New models for predicting 
cardiovascular events. J Clin Epidemiol. 1994 Jun;47(6):583-92.
[38]
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials 
using rank preserving structural failure time models. Commun Stat-Theor M 
1991;20(8):2609-31.
[39]
Maurer W, Glimm E, Bretz F. Multiple and repeated testing of primary, 
coprimary, and secondary hypotheses. Stat Biopharm Res. 2011;3(2):336-52.
[40]
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
Am J Clin Oncol 1982;5:649-55.
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12.0 APPENDICES
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), 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.
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3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
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.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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.
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Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this trial as outlined in Section 7.1.3.6 –
Future Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
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 Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in Future 
Biomedical Research.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects 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 subjects on the visit designated in the 
trial flow chart.  If delayed, present consent at next possible Subject Visit.  Consent 
forms signed by the subject will be kept at the clinical trial site under secure storage 
for regulatory reasons.  
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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 subject 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 trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' 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 subject 
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 subject identifiers 
and this unique code will be held at the trial site.  No personal identifiers will appear on 
the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in future biomedical research 
protocol and consent. Future Biomedical Research specimens remaining with the third 
party after specific analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and ask that their 
biospecimens not be used for Future Biomedical Research.  Subjects 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). 
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Subsequently, the subject'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 
subject 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 (e.g., 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 subject’s personal information and their specimens. In this situation, the 
request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
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 Security
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.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject 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 subjects.  Subjects will not be identified by 
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name in any published reports about this study or in any other scientific publication or 
presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For FBR, risks to the subject have been minimized. No additional risks to the subject 
have been identified as no additional specimens are being collected for FBR (i.e., only 
leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address subject 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/
Note that Future Biomedical Research is not applicable for China.
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ECOG Performance Status
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of light or sedentary nature, e.g., light housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., 
Group Chair. [40]
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Understanding the Intent, Scope and Public Health Benefits of Exploratory 
Biomarker Research: A Guide for IRBs/IECs and Investigational Site Staff
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Note that Future Biomedical Research is not applicable for China.
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List of Abbreviations
Abbreviation/Term
Definition
5-FU
5-fluorouracil
ADA
anti-drug antibody
ADL
activities of daily living
AE
adverse event
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
ASaT
all subjects as treated
AST
aspartate aminotransferase
BICR
blinded independent central review
BP
blood pressure
BUN
blood urea nitrogen
CBC
complete blood count
CI
confidence interval
CPS
Combined positive score
CR
complete response
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated protein-4
DL
dose level
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
ePRO
electronic patient-reported outcome
EGJ
esophagogastric junction
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EORTC
European Organization for the Research and Treatment of Cancer
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Abbreviation/Term
Definition
ERC
Ethics Review Committee
ESCC
esophageal squamous cell carcinoma
ESMO
European Society for Medical Oncology
EU
European Union
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone
FT4
free thyroxine
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GEP
gene expression profile
GI
gastrointestinal
HEENT
head, eyes, ears, nose, and throat
HER-2/neu
human epidermal growth factor receptor-2
HGRAC
Human Genetics Resources Administration of China
HIV
human immunodeficiency virus
HR
hazard ratio
HRQoL
health-related quality of life
IA
interim analysis
IA
interim analysis
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IHC
immunohistochemistry
irAE
immune-related adverse event
INR
international normalized ratio
IRB
Institutional Review Board
irRECIST
immune-related Response Evaluation Criteria in Solid Tumors
ITT
intent-to-treat
IV
intravenous
IVRS
interactive voice response system
IWRS
integrated web response system
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Abbreviation/Term
Definition
KN
KEYNOTE
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MSI
microsatellite instability
NA or N/A
not applicable
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
P
pulse
PBPK
physiologically based pharmacokinetic
PD
progressive disease
PD-1
programmed cell death-1
PD-L1
programmed cell death-ligand 1
PD-L2
programmed cell death-ligand 2
PDLC
predefined limit of change
PFS
progression-free survival
PIN
Personal Identification Number
PK
pharmacokinetic
PO
per os (orally)
PR
partial response
PRO
patient-reported outcomes
PT
prothrombin time
Q3W
every 3 weeks
Q4W
every 4 weeks
Q9W
every 9 weeks
QLQ-C30
Quality of Life Questionnaire C30
QLQ-OES18
Quality of Life Questionnaire Oesophageal module
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
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Abbreviation/Term
Definition
RR
respiratory rate
SAC
Scientific Advisory Committee
SAE
serious adverse event
SAP
statistical analysis plan
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOC
system organ class
SOP
Standard Operating Procedures
sSAP
supplemental statistical analysis plan
T
temperature
T3
triiodothyronine
T1DM
type 1 diabetes mellitus
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
WBC
white blood cell
WES
Whole exome sequencing
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Country-specific Appendix
France-specific Requirements

Exclusion Criterion #10: Note: Sites in France will perform a systematic search for 
dihydropyrimidine dehydrogenase deficiency for subjects who are naive to 5-FU. 
This research should be performed before any administration of 5-FU.

Additional Exclusion Criterion # 21: Has active, clinically significant cardiac disease 
or a history of myocardial infarction in the last 6 months or cardiorespiratory 
pathology which precludes hyperhydration for cisplatin therapy.

Additional Exclusion Criterion # 22:  Subjects with Grade ≥2 audiometric hearing 
loss (25 decibels in 2 consecutive wave ranges) are not eligible for treatment with 
cisplatin.

Section 5.6.1:  Pembrolizumab is to be permanently discontinued in cases of 
confirmed Stephens-Johnson Syndrome, toxic epidermal necrolysis/Lyell syndrome, 
recurrent Grade 3 colitis, and Grade 4 skin rash.

Section 5.6.2 and Section 5.6.3: For subjects receiving cisplatin and 5-FU: Please 
refer to the updated SmPC for these marketed products or the website http://base-
donnees-publique.medicaments.gouv.fr/, which presents the updated version of the 
SmPC of the medicines.
Section 7.1.2.2.1 and Section 7.1.2.2.2:  Audiometry testing must be performed before 
each cisplatin treatment cycle.
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Product:  MK-3475 
149
Protocol/Amendment No.:  590-11
MK-3475-590-11 Final Protocol
17-Oct-2022
Confidential
13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
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 (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
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