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 I Adenocarcinoma of the Esophagogastric Junction (KEYNOTE-180)
Phase: PHASE2
Conditions: Esophageal Carcinoma, Esophagogastric Junction Carcinoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
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 I Adenocarcinoma of the 
Esophagogastric Junction (KEYNOTE – 180)
28-Jun-2021
NCT02559687

Product:  MK-3475 
1
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
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 I Adenocarcinoma of the Esophagogastric Junction 
(KEYNOTE – 180)
IND NUMBER:  123,482
EudraCT NUMBER:  2015-002427-26 
06DRHM
082M0Q

Product:  MK-3475 
2
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 6
28-JUN-2021
To update the criteria for early trial termination.
To clarify the concomitant use of COVID-19 vaccines.
Amendment 5
30-NOV-2017
To add guidelines for the management of myocarditis based 
upon health authority feedback.
Amendment 4
29-NOV-2017
To add guidelines for the management of myocarditis, based 
upon health authority feedback.
Amendment 3
12-JAN-2017

To indicate prespecified GEP cutoffs.

To clarify requirements for HIV, HBV, and HCV testing
for Germany.
Amendment 2
05-DEC-2016

To indicate prespecified GEP cutoffs.
Amendment 1
21-JUL-2016

To clarify the inclusion and exclusion criteria.
Original Protocol
24-AUG-2015
Not applicable.
06DRHM
082M0Q

Product:  MK-3475 
3
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.11
Clinical Criteria for Early Trial 
Termination
The criteria for early trial 
termination was updated.
To add flexibility to allow the 
study to terminate before the 
planned completion date.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.1.3, 12.8
Subject Exclusion Criteria, 
Germany-specific 
Requirements
To clarify requirements for 
HIV, HBV, and HCV testing 
for Germany.
To consolidate the Germany-
specific amendment with the 
global amendment.
1.0, 5.1.2, 5.10, 7.1.1.1.2, 
7.1.1.3, 7.1.3.2.2, 7.1.3.3, 
7.1.3.5
Trial Summary, Subject 
Inclusion Criteria, Beginning 
and End of the Trial, Consent 
and Collection of Specimens 
for Future Biomedical 
Research, Subject Identification 
Card, Whole Blood Collection 
for Correlative and Biomarker 
Studies, Tumor Tissue
Updated informed consent 
language to provide for 
documentation of consent.
To align text with legal 
requirements to obtain 
informed consent.
06DRHM
082M0Q

Product:  MK-3475 
4
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.5.2
Prohibited Concomitant 
Medications
Added a note that any COVID-
19 vaccine that is licensed in a 
given country is allowed in the 
study.
To clarify the concomitant use 
of COVID-19 vaccines.
Overall
Overall
Minor editorial changes.
For clarity.
06DRHM
082M0Q

Product:  MK-3475 
5
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
TABLE OF CONTENTS
DOCUMENT HISTORY ....................................................................................................... 2
SUMMARY OF CHANGES.................................................................................................. 3
1.0
TRIAL SUMMARY.................................................................................................. 14
2.0
TRIAL DESIGN........................................................................................................ 15
Trial Design ........................................................................................................... 15
Trial Diagram........................................................................................................ 17
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 18
Primary Objective(s) & Hypothesis(es).............................................................. 18
Secondary Objective(s) & Hypothesis(es)........................................................... 18
Exploratory Objectives......................................................................................... 18
4.0
BACKGROUND & RATIONALE.......................................................................... 18
Background ........................................................................................................... 18
Pharmaceutical and Therapeutic Background .................................................... 18
Pre-clinical and Clinical Trials ........................................................................... 19
Preclinical and Clinical Studies ................................................................... 19
Ongoing Clinical Trials....................................................................................... 20
Rationale................................................................................................................ 20
Rationale for the Trial and Selected Subject Population .................................... 20
Rationale for Evaluating Gene Expression Profile (GEP) in Esophageal 
Cancer and Implications for Future Studies........................................................ 22
Rationale for Dose Selection/Regimen............................................................... 22
Rationale for Endpoints ...................................................................................... 23
Efficacy Endpoints....................................................................................... 23
4.2.4.1.1
Primary Efficacy Endpoints.................................................................. 23
4.2.4.1.2
Secondary Efficacy Endpoints.............................................................. 24
4.2.4.1.3
Exploratory Efficacy Endpoints............................................................ 24
Immune-related RECIST (irRECIST) ......................................................... 24
Safety Endpoints.......................................................................................... 24
Biomarker Research..................................................................................... 25
06DRHM
082M0Q

Product:  MK-3475 
6
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
4.2.4.4.1
Biomarker Research for Primary Objectives........................................ 25
4.2.4.4.2
Biomarker Research for Exploratory Objectives.................................. 25
Future Biomedical Research........................................................................ 26
Benefit/Risk ........................................................................................................... 26
5.0
METHODOLOGY ................................................................................................... 27
Entry Criteria........................................................................................................ 27
Diagnosis/Condition for Entry into the Trial...................................................... 27
Subject Inclusion Criteria.................................................................................... 27
Subject Exclusion Criteria .................................................................................. 30
Trial Treatment(s) ................................................................................................ 31
Dose Selection/Modification .............................................................................. 32
Dose Selection (Preparation) ....................................................................... 32
Dose Modification and Toxicity Management Guidelines for 
Pembrolizumab............................................................................................ 32
Timing of Dose Administration.......................................................................... 37
Trial Blinding/Masking....................................................................................... 38
Randomization or Treatment Allocation............................................................ 38
Stratification.......................................................................................................... 38
Concomitant Medications/Vaccinations ............................................................. 38
Acceptable Concomitant Medications ................................................................ 38
Prohibited Concomitant Medications.................................................................. 39
Rescue Medications & Supportive Care............................................................. 39
Diet/Activity/Other Considerations..................................................................... 40
Diet...................................................................................................................... 40
Contraception...................................................................................................... 40
Use in Pregnancy ................................................................................................ 42
Use in Nursing Women....................................................................................... 42
Subject Withdrawal/Discontinuation Criteria................................................... 42
Discontinuation of Treatment ............................................................................. 42
Discontinuation of Study Therapy After Complete Response............................ 43
Withdrawal from the Trial .................................................................................. 44
Subject Replacement Strategy............................................................................. 44
06DRHM
082M0Q

Product:  MK-3475 
7
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Beginning and End of the Trial ........................................................................... 44
Clinical Criteria for Early Trial Termination ................................................... 44
6.0
TRIAL FLOW CHART ........................................................................................... 46
Initial Treatment Phase with Pembrolizumab ................................................... 46
Second Course Phase with Pembrolizumab (Retreatment).............................. 49
7.0
TRIAL PROCEDURES ........................................................................................... 51
Trial Procedures ................................................................................................... 51
Administrative Procedures.................................................................................. 51
Informed Consent......................................................................................... 51
7.1.1.1.1
General Informed Consent.................................................................... 51
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 51
Inclusion/Exclusion Criteria ........................................................................ 52
Subject Identification Card .......................................................................... 52
Medical History ........................................................................................... 52
Disease Details............................................................................................. 52
Prior and Concomitant Medications Review............................................... 52
7.1.1.6.1
Prior Medications.................................................................................. 52
Prior Treatment Details for Esophageal Carcinoma ...................... 53
7.1.1.6.2
Concomitant Medications..................................................................... 53
7.1.1.6.3
Subsequent Anti-Cancer Therapy Status .............................................. 53
Assignment of Screening Number............................................................... 53
Assignment of Treatment/Randomization Number..................................... 53
Trial Compliance ......................................................................................... 53
7.1.1.9.1
Study Medication.................................................................................. 53
Clinical Procedures/Assessments........................................................................ 54
Adverse Event Monitoring........................................................................... 54
Physical Exam.............................................................................................. 54
7.1.2.2.1
Full Physical Exam ............................................................................... 54
7.1.2.2.2
Directed Physical Exam........................................................................ 54
Height, Weight, and Vital Signs .................................................................. 54
12-Lead Electrocardiogram ......................................................................... 55
06DRHM
082M0Q

Product:  MK-3475 
8
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Eastern Cooperative Oncology Group Performance Status......................... 55
Laboratory Procedures/Assessments .................................................................. 55
Local Laboratory Assessments .................................................................... 56
7.1.3.1.1
Pregnancy Tests .................................................................................... 57
Central laboratory Assessments................................................................... 57
7.1.3.2.1
Pharmacokinetic/Pharmacodynamic Evaluations................................. 57
Blood Collection for Serum MK-3475........................................... 57
Blood Collection for Anti-pembrolizumab Antibodies.................. 57
7.1.3.2.2
Whole Blood Collection for Correlative and Biomarker Studies......... 57
Planned Genetic Analysis Sample Collection.............................................. 57
Future Biomedical Research Sample Collection ......................................... 58
Tumor Tissue ............................................................................................... 58
Efficacy Measurements....................................................................................... 58
Tumor Imaging and Assessment of Disease................................................ 58
7.1.4.1.1
Initial Tumor Imaging........................................................................... 59
7.1.4.1.2
Tumor Imaging During the Trial .......................................................... 59
7.1.4.1.3
End of Treatment and Follow-up Tumor Imaging................................ 60
7.1.4.1.4
Second Course Phase Tumor Imaging.................................................. 60
7.1.4.1.5
RECIST 1.1 Assessment of Disease..................................................... 61
7.1.4.1.6
irRECIST Assessment of Disease......................................................... 61
Other Procedures................................................................................................. 64
Withdrawal/Discontinuation........................................................................ 64
7.1.5.1.1
Withdrawal From Future Biomedical Research ................................... 65
Blinding/Unblinding .................................................................................... 65
Calibration of Critical Equipment................................................................ 65
Visit Requirements.............................................................................................. 65
Screening...................................................................................................... 66
Treatment Period.......................................................................................... 66
Post-Treatment Visits................................................................................... 67
7.1.6.3.1
Safety Follow-up Visits ........................................................................ 67
7.1.6.3.2
Follow-up visits .................................................................................... 68
7.1.6.3.3
Survival Follow-up ............................................................................... 68
06DRHM
082M0Q

Product:  MK-3475 
9
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Survival Status................................................................................ 68
Assessing and Recording Adverse Events .......................................................... 68
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 69
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 69
Immediate Reporting of Adverse Events to the Sponsor.................................... 70
Serious Adverse Events ............................................................................... 70
Events of Clinical Interest............................................................................ 71
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 72
Evaluating Adverse Events................................................................................. 72
Sponsor Responsibility for Reporting Adverse Events ...................................... 75
Trial Governance and Oversight......................................................................... 75
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 75
Statistical Analysis Plan Summary ..................................................................... 75
Responsibility for Analyses/In-House Blinding ................................................. 75
Estimation.............................................................................................................. 76
Analysis Endpoints ............................................................................................... 76
Efficacy Endpoints.............................................................................................. 76
Primary Efficacy Endpoint .......................................................................... 76
Secondary Efficacy Endpoints..................................................................... 76
Safety Endpoints ................................................................................................. 76
Analysis Populations............................................................................................. 76
Efficacy Analysis Populations ............................................................................ 76
Safety Analysis Populations ............................................................................... 77
Statistical Methods................................................................................................ 77
Statistical Methods for Efficacy Analyses.......................................................... 77
Statistical Methods for Safety Analyses ............................................................. 78
Summaries of Baseline Characteristics, Demographics, and Other Analyses.... 78
Interim Analysis.................................................................................................... 78
Multiplicity ............................................................................................................ 78
Sample Size............................................................................................................ 79
Subgroup Analyses and Effect of Baseline Factors ........................................... 80
06DRHM
082M0Q

Product:  MK-3475 
10
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Compliance (Medication Adherence).................................................................. 80
Extent of Exposure................................................................................................ 80
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 80
Investigational Product ........................................................................................ 80
Packaging and Labeling Information ................................................................. 81
Clinical Supplies Disclosure................................................................................. 81
Storage and Handling Requirements.................................................................. 81
Discard/Destruction/Returns and Reconciliation .............................................. 81
Standard Policies................................................................................................... 82
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 82
Confidentiality....................................................................................................... 82
Confidentiality of Data ....................................................................................... 82
Confidentiality of Subject Records..................................................................... 82
Confidentiality of Investigator Information........................................................ 82
Confidentiality of IRB/IEC Information............................................................. 83
Compliance with Financial Disclosure Requirements....................................... 83
Compliance with Law, Audit and Debarment ................................................... 83
Compliance with Trial Registration and Results Posting Requirements........ 85
Quality Management System............................................................................... 85
Data Management................................................................................................. 86
Publications ........................................................................................................... 86
11.0
LIST OF REFERENCES......................................................................................... 87
12.0
APPENDICES........................................................................................................... 92
Merck Code of Conduct for Clinical Trials........................................................ 92
Collection and Management of Specimens for Future Biomedical 
Research................................................................................................................. 94
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff ...................................................................................... 98
Response Evaluation Criteria in Solid Tumors ............................................... 109
ECOG Performance Status................................................................................ 110
06DRHM
082M0Q

Product:  MK-3475 
11
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Common Terminology Criteria for Adverse Events ....................................... 111
List of Abbreviations .......................................................................................... 112
Germany-specific Requirements ....................................................................... 114
13.0
SIGNATURES......................................................................................................... 115
Sponsor's Representative ................................................................................... 115
Investigator.......................................................................................................... 115
06DRHM
082M0Q

Product:  MK-3475 
12
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
LIST OF TABLES
Table 1
Adequate Organ Function Lab Values.................................................................... 29
Table 2
Trial Treatment ....................................................................................................... 31
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab.................................................................... 33
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines............................................................................................................... 36
Table 5
Laboratory Tests ..................................................................................................... 56
Table 6
Imaging and Treatment after First Radiologic Evidence of PD ............................. 63
Table 7
Evaluating Adverse Events..................................................................................... 73
Table 8
Analysis Strategy for Efficacy Variables................................................................ 78
Table 9
Two-sided 95% Confidence Interval of ORR with 100 Subjects........................... 79
Table 10 Two-sided 95% Confidence Interval for ORR with 60 Subjects............................ 79
Table 11 Two-sided 95% Confidence Interval for ORR with 40 Subjects............................ 79
Table 12 Product Descriptions............................................................................................... 81
06DRHM
082M0Q

Product:  MK-3475 
13
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
LIST OF FIGURES
Figure 1 Trial Diagram.......................................................................................................... 17
Figure 2 Imaging and Treatment for Clinically Stable Subjects after First Radiologic 
Evidence of PD Assessed by the Site..................................................................... 64
06DRHM
082M0Q

Product:  MK-3475 
14
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
1.0 TRIAL SUMMARY
Abbreviated Title
A Phase II study of Pembrolizumab in Third Line Previously Treated 
Subjects with Advanced/Metastatic Adenocarcinoma or Squamous 
Cell Carcinoma of the Esophagus
Trial Phase
Phase II
Clinical Indication
Advanced/metastatic adenocarcinoma or squamous cell carcinoma of 
the esophagus or advanced/metastatic Siewert type I adenocarcinoma 
of the esophagogastric junction.
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous (IV)
Trial Blinding
Unblinded Open-label
Treatment Groups
Pembrolizumab (MK-3475) 200 mg IV every 3 weeks
Number of trial subjects
Approximately 100 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 24
months from the time the first subject provides documented informed 
consent until the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial from the time the subject 
provides the documented Informed Consent Form (ICF) through the 
final contact. After a screening phase of up to 28 days, each subject 
will receive pembrolizumab beginning on Day 1 of each 3-week 
dosing cycle. Treatment will continue until progressive disease, 
unacceptable adverse events, 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; subject 
receives 35 treatments (approximately 2 years) of pembrolizumab, or 
administrative reasons requiring cessation of treatment. Subjects who 
stop pembrolizumab as a result of obtaining a centrally confirmed 
complete response (CR) or those subjects who stop after receiving 35 
trial treatments may be eligible, at the discretion of the investigator, 
for an additional 17 trial treatments (approximately 1 year) after 
experiencing progressive disease if they meet the criteria for re-
treatment (Second Course Phase) and the study is ongoing. Subjects 
who discontinue for reasons other than progressive disease will have 
post-treatment follow-up for disease status until progressive disease, 
initiating a non-study cancer treatment, withdrawing consent, or 
becoming lost to follow-up. All subjects will be followed (example; 
by telephone) for overall survival until death, withdrawal of consent, 
or the end of the study. After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring. Serious adverse 
events will be collected for 90 days after the end of treatment or for 30 
days after the end of treatment if the subject initiates new anticancer 
therapy, whichever is earlier.  
A list of abbreviations used in this document can be found in Section 12.6.
Randomization Ratio
N/A
06DRHM
082M0Q

Product:  MK-3475 
15
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
2.0 TRIAL DESIGN
Trial Design
This is a single arm, open-label, multi-site trial of pembrolizumab (MK-3475) in subjects 
with previously treated, advanced/metastatic adenocarcinoma or squamous cell carcinoma of 
the esophagus or advanced/metastatic Siewert type I adenocarcinoma of the esophagogastric 
junction (EGJ). Siewert type I tumors are adenocarcinomas of the lower esophagus with the 
center located within 1cm to 5cm above the anatomic EGJ.
Subjects will be required to have an Eastern Cooperative Oncology Group (ECOG) 
Performance Status (PS) of 0 or 1, life expectancy greater than 3 months, have at least one 
measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for 
response assessment, and had to have been previously treated with two lines of therapy. 
Subjects will be required to provide a tumor sample for retrospective analysis of biomarkers 
which may predict response to pembrolizumab. Biomarkers assessed include an intratumoral 
immune-related gene expression profile (GEP) and
PD-L1
expression assayed by 
immunohistochemistry (IHC). Approximately 100 subjects will be allocated to receive single 
agent pembrolizumab 200 mg IV every 3 weeks (Q3W). Additionally, to ensure that an 
adequate number of adenocarcinoma subjects are included in the study, there will be a cap on 
enrollment of subjects residing in the Asia Pacific region at approximately 25% of the total
number of enrolled subjects.
The primary objective of this trial is to determine the objective response rate (ORR) of 
pembrolizumab given as monotherapy. Beginning with screening, all imaging assessments 
will be submitted for central imaging vendor review and will be evaluated using RECIST 1.1 
for determining eligibility and assessment of response. On study imaging assessments will be 
performed every 9 weeks (Q9W) calculated from the date of allocation and independent of 
treatment delays. RECIST 1.1 will be used by the site for treatment decisions until the first 
radiologic evidence of progressive disease (PD). Following the first radiologic evidence of
PD by RECIST 1.1, treatment decisions may be made by the adaption of RECIST 1.1, as 
described in Section 7.1.4.1.6 termed immune-related RECIST (irRECIST) to account for the 
tumor response pattern observed with pembrolizumab treatment (eg, tumor flare). This was 
first described by Nishino, et al. 2013 [1], but is further modified for the PD1 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 pembrolizumab 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.
Subjects will continue to be treated with pembrolizumab until PD is confirmed by irRECIST, 
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, 
administrative reasons, or the subject has received 35 trial treatments (approximately 2 years) 
with pembrolizumab. Subjects who discontinue treatment for reasons other than PD will have 
06DRHM
082M0Q

Product:  MK-3475 
16
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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 overall survival (OS) until death, withdrawal of consent or the end of 
the study, whichever comes first.
Subjects who attain centrally confirmed complete response (CR) by 2 tumor imaging 
assessments at least 4 weeks apart and who have received at least 8 treatments 
(approximately 6 months) with pembrolizumab may discontinue treatment at the discretion 
of the investigator after receiving at least 2 treatments beyond the initial determination of a 
CR. Subjects who stop pembrolizumab after receiving 35 trial treatments for reasons other 
than PD or intolerability or who stopped after attaining a CR may be eligible for retreatment 
with up to an additional 17 treatments (approximately 1 year) after they have experienced 
radiographic PD. The decision to retreat will be at the discretion of the investigator only if no 
other cancer treatment was administered since the last dose of pembrolizumab, the subject 
still meets the parameters listed in the Inclusion and Exclusion Criteria, and the trial remains 
open. 
Adverse events 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 (Section 12.6)  After the end of treatment, each subject 
will be followed for 30 days for AE monitoring. Serious adverse events (SAEs) will be 
collected for 90 days after the end of treatment or 30 days after the end of treatment if the 
subject initiates new anticancer therapy, whichever is earlier.  
This study will be conducted in conformance with Good Clinical Practices (GCP).
The relationship between clinical outcome and an intratumoral immune-related Gene 
Expression Profile (GEP) and PD-L1 expression assayed by IHC will be assessed
retrospectively in this study. 
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.
06DRHM
082M0Q

Product:  MK-3475 
17
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Trial Diagram
Figure 1
Trial Diagram
06DRHM
082M0Q

Product:  MK-3475 
18
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
For subjects previously treated with 2
lines of standard therapy; and
with 
advanced/metastatic adenocarcinoma or squamous cell carcinoma of the esophagus, or 
advanced/metastatic Siewert type I adenocarcinoma of the EGJ.
Primary Objective(s) & Hypothesis(es)
Objective:  To evaluate the Objective Response Rate (ORR) per RECIST 1.1 assessed by 
central imaging vendor in all subjects and in subjects whose tumors are classified as GEP 
intermediate or high and in subjects whose tumors are classified as GEP high. 
Secondary Objective(s) & Hypothesis(es)
(1) Objective:  To evaluate safety and tolerability of pembrolizumab. 
(2) Objective:  To evaluate Duration of Response (DOR), and Progression-free Survival 
(PFS) per RECIST 1.1 assessed by central imaging vendor and Overall Survival (OS).
(3) Objective: To evaluate PD-L1 IHC in esophageal cancer for its utility to predict 
pembrolizumab efficacy.
Exploratory Objectives
(1) Objective:  To explore the relationship between genetic variation and response to the 
treatment administered. Variation across the human genome will be analyzed for 
association with clinical data collected in this study.  
(2) Objective: To evaluate ORR, DOR, and PFS per irRECIST assessed by central 
imaging vendor.
4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
Pharmaceutical and Therapeutic Background
Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal antibody 
(mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 
and its ligands, PD-L1 and PD-L2. KEYTRUDA® (pembrolizumab) has recently been 
approved in the United States for the treatment of patients with unresectable or metastatic 
melanoma and disease progression following treatment with ipilumumab, a BRAF inhibitor,
if BRAF V600 mutation positive.
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [2]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [3] [4] [5] [6] [7]. In particular, the presence of CD8+ T-cells and the 
06DRHM
082M0Q

Product:  MK-3475 
19
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [8] 
[9]. The structure of murine PD-1 has been resolved [10]. PD-1 and family members are type 
I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail, which is 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 (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade [8] [11] [12] [13]. The mechanism by which 
PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both 
molecules regulate an overlapping set of signaling proteins [14] [15]. PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs and Natural Killer cells [16] [17]. Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells, as well as subsets of macrophages and 
dendritic cells [18]. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or 
can be induced in a variety of cell types, including non-hematopoietic tissues, as well as in 
various tumors [19] [20] [21] [14]. Both ligands are type I transmembrane receptors 
containing both IgV- and IgC-like domains in the extracellular region and contain short 
cytoplasmic regions with no known signaling motifs. Binding of either PD-1 ligand to PD-1 
inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at low 
levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas 
PD-L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid 
tissue or chronic inflammatory environments. PD-L2 is thought to control immune T-cell 
activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function 
in peripheral tissues [14]. Although healthy organs express little (if any) PD-L1, a variety of 
cancers were demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL) 
[22].
Pre-clinical and Clinical Trials
Preclinical and Clinical Studies
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 mono-therapy or in combination with other 
treatment modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as a mono-therapy in models of squamous cell carcinoma, pancreatic 
carcinoma, MEL and colorectal carcinoma. Blockade of the PD-1 pathway effectively 
06DRHM
082M0Q

Product:  MK-3475 
20
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-γ, granzyme B and 
perforin, indicating that the mechanism of action involved local infiltration and activation of 
effector T-cell function in vivo [23] [24] [25] [26] [27] [28]. Experiments have confirmed the 
in vivo efficacy of PD-1 blockade as a mono-therapy as well as in combination with 
chemotherapy in syngeneic mouse tumor models (see the Investigator’s Brochure [IB]).
Clinical trials have demonstrated efficacy in subjects with advanced melanoma, non-small 
cell lung cancer, head and neck cancer, bladder cancer, Hodgkin’s lymphoma, triple-negative 
breast cancer, and gastric adenocarcinoma. In addition, recent data demonstrates emerging 
evidence of single agent activity in additional tumor types such as mesothelioma, urothelial 
cancer, ovarian cancer, neuroendocrine carcinoma, and small cell lung cancer.
Ongoing Clinical Trials
Ongoing clinical trials of pembrolizumab are being conducted in advanced melanoma, 
non-small cell lung cancer, and a number of other advanced solid tumor indications and 
hematologic malignancies. For study details please refer to the IB.
Rationale
Rationale for the Trial and Selected Subject Population
Esophageal cancer is the sixth most common cancer in the world and is more prevalent in 
men than women. However, in the developing countries 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 [29] [30]. In the United States, in 2015, an 
estimated 15,980 esophageal cancers will be diagnosed and it is estimated that 15,590 people 
will eventually die of their disease [31]. 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 [32]. Majority of the 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 incidence of esophageal cancer represents one of the widest variations with a 60-fold 
difference between high and low prevalence regions. High prevalence areas include Asia, 
Africa, and France where squamous esophageal cancers predominate [33]. A dramatic shift 
in the histology and location of upper gastrointestinal (GI) tumors has occurred over the past 
decades. In Western countries, the most common site of esophageal cancer is in the lower 
third of the esophagus, which often involves the EGJ [34] [35] [36]. Adenocarcinoma has 
been gradually increasing in men of all ethnic backgrounds and also in women. Squamous 
cell carcinoma (SCC) seems to be more sensitive to chemotherapy, chemoradiation, and
radiation therapy (RT) than adenocarcinoma, but the long-term outcome is the same for both 
histologies [37] [38], thus emphasizing the need for better improved therapies in both 
histologies. 
Phase III trials specifically designed for metastatic esophageal cancers have not been 
performed. The survival benefit of second-line chemotherapy compared to best supportive 
06DRHM
082M0Q

Product:  MK-3475 
21
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
care has been demonstrated in a small cohort of patients with lower esophageal or EGJ 
adenocarcinoma included in gastric adenocarcinoma phase III trials [39] [40]. In a 
randomized phase III study, second-line chemotherapy with irinotecan significantly 
prolonged OS compared to best supportive in patients with metastatic or locally advanced 
gastric or EGJ adenocarcinoma (n = 40) [39]. The study was closed prematurely due to poor 
accrual. Median survival was 4 months in the irinotecan arm compared to 2.4 months in the 
best supportive care only arm.
In a recent open-label, multicenter, phase III, randomized trial, the addition of docetaxel for
active symptom control was associated with a survival benefit for patients with advanced, 
histologically confirmed adenocarcinoma of the esophagus, EGJ junction, or stomach that 
had progressed on or within 6 months of treatment with combination chemotherapy with 
platinum and fluoropyrimidine [40]. In this study, patients (n = 168) with an ECOG PS score 
of 0-2 were randomly assigned to receive docetaxel plus active symptom control or active 
symptom control alone. After a median follow-up of 12 months, the median OS was 5.2 
months for patients with the docetaxel group compared to 3.6 months for those in the active 
symptom control group (P = .01). Docetaxel was associated with higher incidence of 
Grade 3-4 neutropenia, infection, and febrile neutropenia. However, disease-specific, health-
related quality of life measures also showed benefits for docetaxel in reducing dysphagia and 
abdominal pain. 
In a phase II study by Ilson et al. [41], one hundred and two patients with advanced 
esophageal cancer were treated with paclitaxel 80 mg/m2 weekly. Sixty-six patients had 
adenocarcinoma (66%) and 65 patients (68%) had no prior chemotherapy. In terms of 
responses, in patients without prior chemotherapy, partial responses (PR) were seen in 
10 patients (15%, 95% confidence interval [CI] 6% to 24%), with comparable response in 
adenocarcinoma (8/50, 16%) and squamous carcinoma (2/15, 13%). Limited response was 
seen in patients with prior chemotherapy, in the second line setting (1/21, 5%). Therapy was 
well tolerated with minimal hematologic or Grade 3 or 4 toxicity.
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. The use of gefitinib as a second-line treatment for unselected patients 
does not improve overall survival [42]. There are no standard guidelines for third-line 
treatment of patients with esophageal cancer as the efficacy of chemotherapy is expected to 
be very poor in this setting (<5%). In addition, patient PS frequently declines at this stage 
and patients are managed by addressing symptoms from tumor burden.
KEYNOTE-028, a nonrandomized, multicohort, Phase 1b trial of pembrolizumab for PD-L1+
advanced solid tumors includes esophageal cancer patients. Key eligibility criteria for this 
cohort included SCC or adenocarcinoma of the esophagus or EGJ junction, measurable 
disease, PD-L1 expression in ≥1% of cells in tumor nests or PD-L1+ stromal bands 
determined centrally by IHC, failure of standard therapy, ECOG PS 0-1, and no autoimmune 
disease. Pembrolizumab 10 mg/kg is being given every 2 weeks for up to 2 years or until 
confirmed progression. Of the 90 pts with esophageal cancer who were screened, 37 (44.6%) 
06DRHM
082M0Q

Product:  MK-3475 
22
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
had PD-L1+ tumors. Of the 23 patients treated between Mar and Dec 2014, 83% were men 
and median age was 65 years. Histology was squamous in 17 pts (73.9%), adenocarcinoma in 
5 pts (21.7%), and mucoepidermoid in 1 patient (4.3%). Eighty-seven percent of pts received 
≥2 prior therapies for metastatic disease; all pts received ≥1 platinum-based therapy. Nine
patients (39.1%) experienced drug-related adverse events (DRAEs), including 4 (17.4%) who 
experienced Grade 3 DRAEs. There were no Grade 4 DRAEs, and no pts died or 
discontinued due to a DRAE. Tumor shrinkage was seen in 52% of patients and ORR was
30.4% (n = 7; 5 squamous (29.4%) and 2 adenocarcinoma (40.0%)); best response was stable 
disease (SD) in 13% (n = 3; 2 squamous and 1 adenocarcinoma) and progressive disease in 
59% (n = 13). Six patients still remain on therapy. Median time to response is 16 weeks 
(Range: 7.9-36.0 weeks) and median duration of response is 40.0 weeks (Range: 0.1+ to 40.0 
weeks) for the patients in the esophageal cohort.
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 patients with esophageal
squamous and adenocarcinoma.
Rationale for Evaluating Gene Expression Profile (GEP) in Esophageal Cancer 
and Implications for Future Studies
Gene expression signatures measuring mRNA for key immune-related genes have been 
confirmed to be associated with clinical benefit to pembrolizumab treatment in melanoma, 
head & neck, and gastric cancers [43] [44] [45], as well as in the esophageal cancer cohort in 
KN028. The predominant pattern indicates that tumors with relatively low expression of 
these genes have a low probability of response to pembrolizumab. Using data from KN012 
and KN028, a GEP combining expression levels of 18 genes into a scalar score has been 
developed and 2 cut-offs on that score which divide tumors into “low,” “intermediate,” and 
“high,” were determined using data from KN028, KN012, and KN052. The lower cut-off 
was defined to favor sensitivity in capturing responders by centrally reviewed RECIST and 
the higher cut-off was selected to enrich for higher response rates at potentially some cost in 
sensitivity. In this study, in addition to estimating ORR in all subjects, ORR will be estimated 
in 2 additional patient subgroups, defined by the GEP categories:  (1) subjects whose tumors 
are classified as “intermediate or high” and (2) subjects whose tumors are classified as 
“high.”
Rationale for Dose Selection/Regimen
The planned dose of pembrolizumab for this trial is 200 mg Q3W. Based on the totality of
data generated in the KEYTRUDA® development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab across all indications, regardless of tumor type. As outlined below, 
this dose is justified by: 

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W)

Clinical data showing meaningful improvement in benefit-risk, including overall 
survival at 200 mg Q3W across multiple indications
06DRHM
082M0Q

Product:  MK-3475 
23
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential

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 8 randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment-naïve, previously treated, PD-L1 enriched and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 
2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 B2, KN001 D, KN002, KN010 and KN021), 
and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 B3, KN001 F2 and 
KN006). All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied representing an approximate 5 to 7.5 fold difference in exposure. 
The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses 
studied. Subsequently, flat dose-/exposure-response relationships were also observed in other 
tumor types including 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 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.
Rationale for Endpoints
Efficacy Endpoints
4.2.4.1.1 Primary Efficacy Endpoints
The primary efficacy objective of this study is to evaluate ORR of pembrolizumab in subjects 
with previously treated advanced/metastatic adenocarcinoma or squamous cell carcinoma of
the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the EGJ. Objective
response rate (ORR) will be evaluated per RECIST 1.1 assessed by the central imaging 
vendor.
06DRHM
082M0Q

Product:  MK-3475 
24
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
4.2.4.1.2 Secondary Efficacy Endpoints
The secondary efficacy objectives of this study are to evaluate DOR, and PFS per 
RECIST 1.1 assessed by central imaging vendor and OS. 
4.2.4.1.3 Exploratory Efficacy Endpoints
Exploratory efficacy objectives of this study are to evaluate ORR, DOR, and PFS per 
irRECIST assessed by the central imaging vendor and OS. Intratumoral immune-related GEP 
and PD-L1 IHC in esophageal cancer will also be evaluated for their utility to predict 
pembrolizumab efficacy.
Immune-related RECIST (irRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with 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 can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions. Standard RECIST 1.1 may, 
thus, not provide an accurate response assessment of immunotherapeutic agents such as 
pembrolizumab. 
Based on an analysis of patients with melanoma enrolled in Keynote-001, 7 % of evaluable 
patients experienced delayed or early tumor pseudoprogression. Of note, patients who had 
progressive disease by RECIST 1.1 but not by immune related Response Criteria had longer 
OS than patients with progressive disease by both criteria. Additionally, the data suggest that 
RECIST 1.1 may underestimate the benefit of pembrolizumab in approximately 15% of 
patients. 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 enable treatment 
beyond initial radiographic progression. 
Immune-related RECIST (irRECIST) is RECIST 1.1 adapted to account for the unique tumor 
response seen with immuno-therapeutics as described in Nishino et al., CCR 2013 [1]. The 
assessment of unidimensional target lesions and response categories per irRECIST are 
identical to RECIST 1.1. However, Merck has implemented an adaptation related to new 
lesions, non-target 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 make treatment decisions, as well as by central imaging vendor in support 
of  exploratory efficacy endpoints.  
Safety Endpoints
The safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in subjects with advanced/metastatic adenocarcinoma or squamous cell 
carcinoma of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the 
EGJ who have progressed on 2 lines of previous therapy. The primary safety analysis will be 
based on subjects who experienced toxicities as defined by CTCAE, v4.0 (Section 12.6). 
06DRHM
082M0Q

Product:  MK-3475 
25
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
The attribution to drug, time-of-onset, duration of the event, its resolution, and any 
concomitant medications administered will be recorded. Adverse event will be analyzed,
including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes. Furthermore, 
specific events will be collected and designated as events of clinical interest (ECIs), as 
described in Section 7.2.3.2.
Biomarker Research
4.2.4.4.1 Biomarker Research for Primary Objectives
Immune-related Gene Expression Profile (GEP)
Intratumoral expression levels of 18 genes will be analyzed and the GEP score determined 
using the NanoString nCounter Analysis System. Two pre-specified, analytically validated, 
cut-offs on the GEP will be used to divide tumors into “low,” “intermediate,” and “high” for 
the GEP. ORR will be estimated in the set of subjects whose tumors are “intermediate or 
high” and in the set of subjects whose tumors are “high,” and these ORRs will be compared
to the All-comers Population. 
Tumor PD-L1 Expression
In the pembrolizumab PN001 and PN012 studies, PD-L1 immunohistochemistry (IHC) has 
successfully been used as a biomarker in the NSCLC and head and neck cancer cohort, 
respectively, to enrich for a subpopulation with high response to pembrolizumab [46]. 
Therefore, the relationship between PD-L1 expression in esophageal tumor tissue and 
response to treatment with pembrolizumab will be evaluated. PD-L1 expression in tumor 
cells and inflammatory cells within pre-treatment tumor tissue samples will be characterized 
by immunohistochemistry (IHC) using a combined positive score and a cut-off of 1% (1% 
CPS) and retrospectively tested for association with response to pembrolizumab.
4.2.4.4.2 Biomarker Research for Exploratory Objectives
Additional biomarker research to identify factors important for pembrolizumab (MK-3475) 
therapy may also be pursued. For example, tumor and blood samples (including serum and 
plasma) from this study may undergo proteomic, genomic, metabolomic and transcriptional 
analyses. Additional research may evaluate factors important for predicting responsiveness or 
resistance to pembrolizumab therapy and other immunologic targets.
Assays may include but are not be limited to:
Transcriptional Analyses
In addition to examining an immune-related GEP described above, global messenger RNA 
profiling will also be pursued. Expression of individual genes related to the immune system 
may also be evaluated such as immune signatures and critical cytokines (eg, IL-10). 
MicroRNA profiling may also be pursued in serum samples.
Proteomic analysis
In addition to expression on the tumor tissue, PD-L1 can be shed from tumor and released 
into the blood. Enzyme-linked immunoassay can measure PD-L1 in serum and correlate this 
expression with response to pembrolizumab (MK-3475) therapy, as well as levels of PD-L1 
06DRHM
082M0Q

Product:  MK-3475 
26
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
IHC or protein in the tumor. Blood would be a less invasive compartment compared to tumor 
from which to measure PD-L1 protein biomarker. In addition to this specific protein 
biomarker, both tissue and blood derivatives can be subjected to proteomic profiling studies 
using a variety of platforms that could include and are not limited to immunoassay, liquid 
chromatography/mass spectrometry. This approach could identify novel protein biomarkers 
that could aid in patient selection for pembrolizumab (MK-3475) therapy.
Gene Analyses
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to define certain tumor types at the genetic level as being 
‘hypermutated’ or it can detect the presence of specific T-cell clones within the tumor 
microenvironment. There is a potential that this hypermutated state and the detection of 
increased T-cell clonality may correlate with response to pembrolizumab therapy, and/or that 
the converse, “hypomutated” state or lack of T-cells clones may correlate with non-response.  
Planned Genetic Analysis 
Understanding genetic determinants of drug response is an important endeavor during 
medical research. 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 adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study. 
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected 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.
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 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 this Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
06DRHM
082M0Q

Product:  MK-3475 
27
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and Informed Consent (ICF) documents.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with advanced/metastatic adenocarcinoma or squamous cell carcinoma 
of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the EGJ 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 documented informed consent for the trial. The subject 
may also provide consent for Future Biomedical Research. However, the subject may 
participate in the main trial without participating in Future Biomedical Research.
2. Be ≥ 18 years of age on the day of providing documented informed consent. 
3. Have an ECOG performance status of 0 or 1.
4. Have a life expectancy greater than 3 months.
5. Have histologically proven advanced/metastatic adenocarcinoma or squamous cell 
carcinoma of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of 
the EGJ (defined as adenocarcinomas of the lower esophagus with the center located 
within 1cm to 5cm above the anatomic EGJ).
a.
Subjects with advanced/metastatic Siewert type 1 adenocarcinoma of the EGJ 
with HER-2/neu negative tumors are eligible. Subjects with HER2/neu 
positive tumors or those with an unknown tumor status, need to match the 
following:
i. If HER2/neu positive, subject must have documentation of disease 
progression on treatment containing trastuzumab. 
ii. Subjects with unknown status must have their HER2/neu status 
determined locally. If HER2/neu negative, the subject will be eligible. 
If HER2/neu positive, the subject must have documentation of disease 
progression on treatment containing trastuzumab.
6. Have 
experienced documented objective radiographic
or clinical disease 
progression on 2 previous lines of standard therapy. This study will only include 
third-line subjects. Third-line subjects are defined as those who have progressed 
during or after receiving at least 1 dose of standard therapy given in a second-line 
setting.
a.
Disease progression should be confirmed by CT scan. In certain situations, 
clinical evidence of disease progression such as any new or worsening 
06DRHM
082M0Q

Product:  MK-3475 
28
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
malignant effusion (documented by ultrasound) and confirmation by 
pathologic criteria (histology and/or cytology) is acceptable.
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 first or second line agents due 
to toxicity/intolerability as deemed clinically appropriate by the investigator 
will not constitute a new line of therapy.
7. Have measurable disease based on RECIST 1.1, as determined by central imaging 
vendor 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.
8. Provide either a newly obtained or archival tissue sample for intratumoral immune-
related GEP and 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 a newly-obtained tissue sample 
is not adequate and archival tissue is not provided or if a newly obtained tissue 
sample is not provided and an archival sample is also not 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.
Central laboratory confirmation of tumor tissue sample adequacy is required 
prior to subject enrollment in the study. If multiple tumor samples are 
submitted, at least one of the samples must be confirmed to be adequate by the 
central laboratory prior to subject being enrolled.
b. Subjects from whom newly-obtained samples cannot be obtained (eg,
inaccessible or subject safety concern) an archived specimen may be 
submitted. 
c.  If newly obtained tissue is provided and an archived tissue sample is available, 
it should also be provided to support evaluation of the clinical utility of 
immune-related 
GEP 
assessment 
and 
PD-L1 
analysis 
by 
immunohistochemistry analysis in newly obtained versus archived tissue 
samples; however, a subject will not be excluded from participating if he/she 
has provided newly obtained tissue and an archived tissue sample is not 
available or is insufficient for analysis.
9. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.
06DRHM
082M0Q

Product:  MK-3475 
29
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
10. Female subjects of childbearing potential (Section 5.7.2) 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.  
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
11. Male subjects of childbearing potential (Section 5.7.2) must agree to use an adequate 
method of contraception, as outlined in Section 5.7.2 – Contraception and not to 
donate sperm starting with the first dose of study therapy through 120 days after the 
last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
12. Demonstrated adequate organ function as defined in Table 1. All screening labs 
should be performed within 10 days of treatment initiation.
Table 1
Adequate Organ Function Lab Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /µL
Platelets
≥100,000 / µL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO 
dependency within 7 days.
Renal
Creatinine OR
Measured or calculateda  creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > 1.5 ×
institutional ULN
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 OR
≤ 5 × ULN for subjects with liver metastases
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
≤1.5 × ULN unless subject is receiving anticoagulant 
therapy
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants
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
a Creatinine clearance should be calculated per institutional standard.
06DRHM
082M0Q

Product:  MK-3475 
30
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1.
Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.
Note: Subjects who have entered the follow-up phase of an investigational study 
may participate as long as it has been 4 weeks since the last dose of the previous 
investigational agent or device.
2. Has an active autoimmune disease that has required systemic treatment within the 
2 years prior to the first dose of study treatment (i.e. 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, etc.) is not considered a form of systemic treatment. 
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. The use of physiologic doses of corticosteroids may be approved after 
consultation with the Sponsor.
4. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate 
provided they have stable brain metastases for at least four weeks prior to the first 
dose of trial treatment; also, any neurologic symptoms must have returned to baseline
See Section 7.1.4.1.1 for additional details.
5. Has received prior anti-cancer mAb, chemotherapy, targeted small molecule therapy, 
or radiation therapy within 2 weeks prior to first dose of trial treatment or who has not 
recovered (ie, ≥Grade 1 at baseline) from adverse events due to a previously 
administered agent. The specified 2-week period between last dose of prior therapy 
and first dose of pembrolizumab is the minimum amount of time allowed. Subjects 
may not receive pembrolizumab within less than 2 weeks from the last dose of a prior 
therapy. However, a period of more than 2 weeks may be used if indicated both 
clinically and due to concern between possible negative interactions between prior 
therapy and pembrolizumab therapy.
Note:  Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception 
to this criterion and may qualify for the study
Note:  If subject received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting 
therapy.
6. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or 
has previously participated in Merck pembrolizumab (MK-3475) clinical trials. 
7. Has a known additional malignancy that progressed or required active treatment 
within the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous 
06DRHM
082M0Q

Product:  MK-3475 
31
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
cell carcinoma of the skin that has undergone potentially curative therapy, in situ 
cervical cancer, and in situ or intramucosal pharyngeal cancer.
8. Has received a live vaccine within 30 days of the first dose of trial treatment.
Note: The killed virus vaccines used for seasonal influenza vaccines for injection 
are allowed; however intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines, and are not allowed.
9. Has a history or current evidence of any condition, 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, in the opinion of the treating investigator.
10. Has a known history of Human Immunodeficiency Virus (HIV) infection. See 
Germany-specific requirements in Appendix 12.8
11. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). See Germany-specific requirements in Appendix 12.8
12. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
13. Has an active infection requiring systemic therapy.
14. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
15. 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 trial treatment.  
Trial Treatment(s)
The treatment to be used in this trial is outlined below in Table 2.
Table 2
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route 
of 
Administration
Regimen
Use
Pembrolizumab
(MK-3475)
200 mg
Q3W
IV Infusion
Day 1 of each 21-
day cycle
Experimental
Trial treatment for Cycle 1 should begin within 3 days of allocation. However, every effort 
should be made to begin trial treatment on the day of allocation
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.
06DRHM
082M0Q

Product:  MK-3475 
32
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Dose Selection/Modification
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
Dose Modification and Toxicity Management Guidelines for Pembrolizumab
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
Adverse events associated with pembrolizumab exposure may represent an immunologic 
etiology. These immune-related AEs (irAEs) may occur shortly after the first dose or several 
months after the last dose of pembrolizumab treatment and may affect more than 1 body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical to 
reduce complications. Based on existing clinical trial 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 are provided in Table 3. 
06DRHM
082M0Q

Product:  MK-3475 
33
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab
General instructions:
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has 
been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up
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
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer 
corticosteroids 
(initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (ie, peritoneal signs and ileus).
Participants with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids. 
If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion.
Grade 4
Permanently 
discontinue
06DRHM
082M0Q

Product:  MK-3475 
34
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up
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
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly 
onset 
T1DM or 
Grade 
3 
or 
4 
hyperglycemia 
associated 
with 
evidence of -cell 
failure
Withhold
Initiate insulin replacement therapy 
for participants with T1DM 
Administer 
anti-hyperglycemic 
in 
participants with hyperglycemia 
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold
Administer corticosteroids and initiate 
hormonal replacements, as clinically 
indicated.  
Monitor for signs and symptoms of hypophysitis 
(including 
hypopituitarism 
and 
adrenal 
insufficiency)
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue1
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 
discontinue1
Hypothyroidism
Grade 2-4
Continue 
Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyroinine) 
per standard of care
Monitor for signs and symptoms of thyroid 
disorders. 
06DRHM
082M0Q

Product:  MK-3475 
35
Protocol/Amendment No.: 180-06
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up
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 or 2
Withhold
Based on severity of AE administer 
corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All 
other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold
Based on type and severity of AE 
administer corticosteroids 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 3
Withhold 
or 
discontinue based 
on the type of 
event. Events that 
require 
discontinuation 
include and are not 
limited 
to:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 
4 
or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).
06DRHM
082M0Q

Product:  MK-3475 
36
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab-associated 
infusion reaction are provided in Table 4. 
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption 
not 
indicated; 
intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the 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 h
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the 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/h to 50 mL/h). 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 drug treatment
Subject may be premedicated 
1.5 h (± 30 minutes) prior to 
infusion with:
Diphenhydramine 50 mg po 
(or 
equivalent 
dose 
of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
06DRHM
082M0Q

Product:  MK-3475 
37
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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 
(e.g., 
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 drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 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 patient's 
study record.
Timing of Dose Administration
Cycle 1 Day 1 treatment with pembrolizumab should begin on the day of allocation, but no 
later than 3 days from the date the subject is allocated to study treatment. However, every 
effort should be made to begin trial treatment on the day of allocation.
For all additional cycles of pembrolizumab, treatment may be administered up to 3 days 
before or 3 days after the scheduled Day 1 of each cycle due to administrative reasons per the 
investigator’s judgment.  
06DRHM
082M0Q

Product:  MK-3475 
38
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
All study treatments will begin on Day 1 of each cycle after all pre-dose study procedures 
and assessments have been completed as detailed on the Trial Flow Chart –Section 6.0.
Pembrolizumab will be administered as a 30-minute IV infusion every 3 weeks. Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 
minutes is permitted (ie, infusion time is 30 minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution.
All trial treatments will be administered on an outpatient basis.
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
Treatment allocation will occur centrally using an interactive voice response 
system/integrated web response system (IVRS/IWRS). All enrolled subjects will be allocated 
to receive pembrolizumab 200 mg IV Q3W as monotherapy in an unblinded fashion.
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations
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 case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids. If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF.
All medications received within 30 days before the first dose of trial treatment and within 
30 days after the last dose of trial treatment should be recorded. Medications administered 
more than 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs, as defined in Section 7.2.3.2.
06DRHM
082M0Q

Product:  MK-3475 
39
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol

Immunotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy for tumor control 
Note: Radiation therapy to a symptomatic solitary lesion may be allowed 
after 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, chickenpox, yellow fever, rabies, BCG, 
and typhoid (oral) vaccine. The killed virus vaccines used for seasonal influenza 
vaccines for injection are allowed; however live attenuated intranasal influenza 
vaccines (eg, FluMist®) are not allowed.
Note: Any licensed COVID 19 vaccine (including for Emergency use) in a 
particular country is allowed in the study as long as they are mRNA vaccines, 
adenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as 
any other concomitant therapy.
Investigational vaccines (i.e., those not licensed or approved for Emergency Use) 
are not allowed.

Glucocorticoids (inhaled steroids as part of a stable regimen for the treatment of 
asthma/chronic obstructive pulmonary disease [COPD] or topical steroids for skin 
conditions are permitted) for any purpose other than to modulate symptoms from 
an adverse event. The use of physiologic doses of corticosteroids may be 
approved after consultation with the Sponsor.
o
Note:  Use of prophylactic corticosteroids to avoid allergic reactions (eg,
IV contrast dye) is permitted.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be discontinued from study 
treatment. Subjects may receive other medications that the investigator deems to be 
medically necessary.
The Exclusion Criteria describe other medications that are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Rescue Medications & Supportive Care
No rescue or supportive medications are specified to be used in this trial.
06DRHM
082M0Q

Product:  MK-3475 
40
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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.
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 are either:
1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
3) has a congenital or 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 drug by complying with one of the following:  
1) practice abstinence† from heterosexual activity; 
OR 
2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):
•
intrauterine device (IUD)
•
vasectomy of a female subject’s male partner 
•
contraceptive rod implanted into the skin
06DRHM
082M0Q

Product:  MK-3475 
41
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Combination method (requires use of two of the following):
•
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
•
cervical cap with spermicide (nulliparous women only)  
•
contraceptive sponge (nulliparous women only) 
•
male condom or female condom (cannot be used together)
•
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection
†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 ERCs/IRBs. Periodic abstinence 
(eg, calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are 
not acceptable methods of contraception. 
‡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 trial therapy. 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.
Below are the required contraceptions for countries where the health authority requests 
compliance with the Clinical Trial Facilitation Group (CTFG) Guidance:
Subjects should use birth control methods that can achieve a failure rate of less than 1% per 
year when used consistently and correctly and are considered as highly effective birth control 
methods. Such methods include:

Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:
o
Oral
o
Intravaginal
o
Transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
Oral
o
Injectable
06DRHM
082M0Q

Product:  MK-3475 
42
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
o
Implantable
o
Intrauterine device (IUD)
o
Intrauterine hormone-releasing system (IUS)
o
Bilateral tubal occlusion
o
Vasectomised partner
o
Sexual abstinence
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study 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 study personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
followed as described in Section 7.2.2 (Reporting of Pregnancy and Lactation to the 
Sponsor).
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment
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 
Withdrawal/Discontinuation.
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 7.1.5 – Other Procedures.
06DRHM
082M0Q

Product:  MK-3475 
43
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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 (irPD) as outlined in Section 7.1.4.1.2 (except if Sponsor 
approves treatment continuation). 
o
Unacceptable adverse events as described in Section 7.2.
o
Investigator’s decision to withdraw the subject
o
The subject has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or sponsor, placed the subject at unnecessary risk from continued 
administration of study drug.
o
Non-compliance with trial treatment or procedure requirements.
o
The subject has a confirmed positive pregnancy test
o
Administrative reasons.
o
Completed 35 cycles of pembrolizumab.
o
Note: 35 treatments (approx. 2 years) are calculated from the first dose.
Subjects who stop pembrolizumab after receiving 35 treatments may be
eligible for retreatment if they progress after stopping study treatment
provided they meet the requirements detailed in Section 7.1.6.2.1. Subjects
may be retreated in the Second Course Phase with up to 17 (approx. 1 year)
additional trial treatments.
The End of Treatment and Follow-up visit procedures are listed in Section 7.1.6.3 and the
Trial Flow Charts in Section 6.0. After the end of treatment, each subject will be followed for 
a minimum of 30 days for adverse event monitoring (serious adverse events will be collected 
for up to 90 days after the end of treatment as described in Section 7.2.3). Subjects who 
discontinue 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. After documented PD each subject will be followed (e.g. by telephone) for OS 
until death, withdrawal of consent, or the end of the study, whichever occurs.
Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she shall 
not be allowed to restart treatment unless the conditions in Section 5.8.2 – Discontinuation of 
Study Therapy after CR are met.
Discontinuation of Study Therapy After Complete Response
Discontinuation of treatment may be considered for subjects who have attained a centrally 
confirmed CR, and who have received at least 8 cycles (approx. 6 months) of 
pembrolizumab, and who received at least 2 cycles of pembrolizumab beyond the date when 
initial CR was declared. Subjects who discontinue pembrolizumab therapy due to CR and 
06DRHM
082M0Q

Product:  MK-3475 
44
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
then experience radiographic disease progression may be eligible for up to 17 additional 
cycles (approx. 1 year) of pembrolizumab in the Second Course Phase, at the discretion of 
the investigator if:
•
No cancer treatment was administered since the last dose of pembrolizumab
•
The subject meets the parameters listed in the Inclusion/Exclusion criteria
•
The trial is ongoing
Subjects will resume pembrolizumab therapy at the same dose level and on the same 
schedule as those at the time of initial discontinuation. Additional details are provided in 
Section 7.1.6.2. Response or progression in this Second Course Phase will not count towards 
the primary endpoint in this trial.
Withdrawal from the Trial
Subjects may withdraw from the trial at any time for any reason.  If a subject withdraws from 
the trial, they will no longer receive treatment or be followed at scheduled protocol visits.
A subject must be withdrawn from the trial if:
○
The subject or subject’s legally acceptable representative withdraws consent from the 
trial.
○
The subject is lost to follow-up.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including specific details regarding withdrawal from Future Biomedical Research are 
outlined in Section 7.1.5 – Other Procedures.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The overall trial begins when the first subject provides the documented informed consent 
form.  The overall trial ends when the last subject completes the last study-related phone-call 
or visit, discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be 
contacted by the investigator).
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete.
2. Poor adherence to protocol and regulatory requirements.
3. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects.
4. Plans to modify or discontinue the development of the study drug. 
06DRHM
082M0Q

Product:  MK-3475 
45
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
In the event of Sponsor decision to no longer supply study drug, ample notification 
will be provided so that appropriate adjustments to subject treatment can be made.
5. Any medical, safety, regulatory, administrative, or other reasons consistent with 
applicable laws, regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor 
will promptly notify that study site’s IRB/IEC.
06DRHM
082M0Q

Product:  MK-3475 
46
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
6.0 TRIAL FLOW CHART
Initial Treatment Phase with Pembrolizumab
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-discon
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 Status
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Xq
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
X
X
Height, Weight, and Vital Signs (T,P,RR,BP)c
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
ECOG Performance Status
Xr
X
X
X
X
X
X
X
X
X
Pembrolizumab Administration
Xb
X
X
X
X
X
X
X
LOCAL Laboratory Assessments
Pregnancy Testd
Xd
X
X
X
X
X
X
X
X
PT/INR and aPTT
Xe
CBC with Differentialf
Xe
X
X
X
X
X
Xf
X
X
Chemistry Panelf
Xe
X
X
X
X
X
Xf
X
X
Urinalysisg
Xe
X
X
X
X
X
T3, FT4, and TSHg
Xe
X
X
X
X
X
X
06DRHM
082M0Q

Product:  MK-3475 
47
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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-discon
Every 9 Weeks 
Post-discon
Every 
12 Weeks
CENTRAL Laboratory Assessments
Pembrolizumab Pharmacokineticsh, i
Xi
X
X
X
Xh,i
Pembrolizumab Anti-Drug Antibodies (ADA)h
X
X
X
X
Xh
Blood for Geneticsj
X
Whole Blood for Biomarker Studies (serum and 
plasma)k
X
Whole Blood for Correlative Studies (RNA and 
DNA)k
X
X
X
X
Tumor Tissue Collection
Newly Obtained Tumor Tissuem
X
Archival Tumor Tissuen
X
Efficacy Measurements
Tumor Imagingo
Xl
Xo
Xp
X
06DRHM
082M0Q

Product:  MK-3475 
48
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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-discon
Every 9 Weeks 
Post-discon
Every 
12 Weeks
a.
After subjects who experience confirmed site-assessed PD or who start a new anti-cancer therapy, each subject will be contacted by telephone for survival approximately every 12 weeks until 
the subject withdraws consent, is lost to follow-up, death, or the trial ends. In addition, upon Sponsor request, subjects may be contacted for survival status at any time during the course of the 
trial.
b.
Cycle 1 treatment must be given within 3 days of allocation. The window for each visit is ± 3 days unless otherwise noted.  
c.
Height will be measured at Visit 1 only.
d.
For women of reproductive potential, a urine or serum pregnancy test should be performed within 72 hours prior to Day 1 of each treatment cycle and 30 days post treatment. A serum test can be 
done if urine is not appropriate. Additionally, if urine test is positive or is not evaluable, a serum test is required. Subjects must be excluded/discontinued in the event of a positive test results. 
Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
e.
Laboratory tests for screening and determining eligibility are to be performed within10 days prior to the first dose of trial treatment.
f.
CBC (Hematology) with diff and Chemistry to be performed every cycle.
g.
UA and thyroid function tests will be performed every other cycle. T3 is preferred; if not available free T3 may be tested.
h.
Both PK and Anti-pembrolizumab Samples: pre-dose (trough) PK and anti-pembrolizumab antibody samples will be collected at within 24 hours before infusion at Cycles 1, 2, 4, 6, 8 and every 
4 cycles thereafter.
i.
PK Samples:  additional post-dose (peak) PK samples will be drawn within 30 minutes after end of pembrolizumab infusion at Cycles 1 and 8. An additional single PK sample should be drawn 
at; 24 hours (Day 2), between 72 and 168 hours (Day 4-8) and 336 hours (Day 15) after Cycle 1 dosing. 
j.
Details for collection can be found in Section 7.1.3 Laboratory Procedure/Assessments
k.
Whole blood samples for correlative studies (DNA and RNA) should be collected pre-dose on Day 1 of Cycle 1, Cycle 2, and Cycle 3, and at treatment discontinuation if subject discontinues 
prior to Cycle 3. Whole blood for Biomarker Samples (plasma and serum) to be collected pre-dose on Day 1 of Cycle 1 only.  
l.
Screening tumor imaging will be performed within 28 days prior to allocation. Confirmation of baseline measurable disease per RECIST 1.1 by the central imaging vendor is required prior to 
subject allocation. . Confirmation of baseline measurable disease per RECIST 1.1 by the central imaging vendor is required prior to subject allocation. 
m.
Newly-obtained tissue is preferred; FFPE block specimens are preferred to slides. Newly obtained tissue is defined as no intervening treatment (local or systemic) involving the site of tissue 
biopsy once tissue biopsy is obtained and time of study enrollment. 
n.
Archival tumor tissue will also be requested (where available) to assess the clinical utility of PD-L1 and immune-related GEP assessment in newly obtained vs. archived tissue samples.
o.
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. 
p.
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.
q.
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
06DRHM
082M0Q

Product:  MK-3475 
49
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Second Course Phase with Pembrolizumab (Retreatment)
Trial Period:
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
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-
discon
Every 9 Weeks 
Post-discon
Every 12 Weeks
Scheduling Window (Days)b
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Administrative Procedures
Eligibility Criteria
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
Xh
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
X
Weight, and Vital Signs (T,P,RR,BP)
X
X
X
X
X
X
X
X
X
ECOG Performance Status
Xd
X
X
X
X
X
X
X
X
Post-study anticancer Therapy Status
X
X
Survival Status
X
Trial Treatment Administration
Pembrolizumab
X
X
X
X
X
X
X
X
LOCAL Laboratory Assessments
Pregnancy Testc
X
X
X
X
X
X
X
X
PT/INR and aPTT
Xd
CBC with Differentiale
Xd
X
X
X
X
X
X
X
X
Chemistry Panele
Xd
X
X
X
X
X
X
X
X
Urinalysise
Xd
X
X
X
X
X
X
T3, FT4, and TSH e
Xd
X
X
X
X
X
06DRHM
082M0Q

Product:  MK-3475 
50
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Trial Period:
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
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-
discon
Every 9 Weeks 
Post-discon
Every 12 Weeks
Efficacy Measurements
Tumor Imaging
Xf
Xf
Xg
X
a.
After the start of new anti-cancer treatment or PD, each subject will be contacted by telephone for survival approximately every 12 weeks until the subject withdraws
consent, is lost to follow-up, death, or the retreatment phase ends. In addition, upon Sponsor request, subjects may be contacted for survival status at any time during the 
course of the trial.
b.
In general, the window for each visit is ± 3 days unless otherwise noted.  
c.
For women of reproductive potential, a urine or serum pregnancy test should be performed within 72 hours prior to Day 1 of each treatment cycle and 30 days post treatment. 
A serum test can be done if urine is not appropriate. Additionally, if urine test is positive or is not evaluable, a serum test is required. Subjects must be excluded/discontinued 
in the event of a positive test results. Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
d.
Laboratory tests and ECOG PS for determining eligibility are to be performed within 10 days prior to the first retreatment dose of pembrolizumab  
e.
After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point. CBC (Hematology) and Chemistry, to be performed every cycle. UA and 
Thyroid function tests to be performed every other cycle. T3 is preferred; if not available free T3 may be tested.
f.
Tumor imaging should be performed within 28 days prior to restarting treatment with pembrolizumab and continue to be performed every 9 weeks (63 ± 7 days)  after the 
first dose of retreatment, or more frequently if clinically indicated. At sites where the local regulatory body and/or IRB/ERC will not permit a second tumor imaging within a 
28-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.
g.
Tumor imaging should be performed at the time of treatment discontinuation (ie, date of discontinuation ± 4 week window). If previous tumor imaging was obtained within 4 
weeks prior to the date of discontinuation, then additional tumor imaging at treatment discontinuation isn’t mandatory.
h.
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.
06DRHM
082M0Q

Product:  MK-3475 
51
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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
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.
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/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
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 documented informed consent 
06DRHM
082M0Q

Product:  MK-3475 
52
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
before performing any procedure related to the Future Biomedical Research sub-trial.  A 
copy of the informed consent will be given to the subject.
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.
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 documented informed consent.
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.
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the investigator. Disease details regarding the 
subject’s esophageal cancer will be recorded separately and not listed as medical history.
If the subject has lost at least 15 lbs. (6.8 kg) over the 3 months prior to screening, “weight 
loss” should be entered as an active condition on the Medical History. As well, any 
autoimmune disorders, regardless of onset date, should be recorded.
Disease details regarding the subject’s esophageal carcinoma will be recorded separately and 
not listed as medical history.
Disease Details
The investigator or qualified designee will obtain prior and current details regarding the 
subject’s esophageal carcinoma.
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 30 days of the first dose of trial treatment. 
Prior treatment for esophageal carcinoma will be recorded separately and not listed as a prior 
medication.
06DRHM
082M0Q

Product:  MK-3475 
53
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Prior Treatment Details for Esophageal Carcinoma
The investigator or qualified designee will review all prior anti-cancer treatments, including 
systemic treatments, radiation and surgeries.
7.1.1.6.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial from the time of signing the informed consent form until the Safety 
Follow-up Visit. In addition, new medications started during the Second Course Phase 
through the Second Course Safety Follow-up Visit should be recorded. 
All medications related to reportable SAEs and ECIs should be recorded, as defined in 
Section 7.2.
7.1.1.6.3 Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-cancer therapy initiated after 
the last dose of trial treatment. If a subject initiates a new anti-cancer 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 anti-cancer therapy has been initiated the subject will move into survival 
follow-up. Details regarding survival status follow-up are outlined in 7.1.6.3.3 – Survival 
Follow-Up.
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 or treatment allocation.  Each
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Assignment of Treatment/Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive an 
allocation number. The allocation number identifies the subject for all procedures occurring 
after treatment allocation. Once an allocation number is assigned to a subject, it can never be 
re-assigned to another subject. 
A single subject cannot be assigned more than 1 allocation number.
Trial Compliance
7.1.1.9.1 Study Medication
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
pembrolizumab doses for non-drug-related or administrative reasons require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
06DRHM
082M0Q

Product:  MK-3475 
54
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
The total volume of pembrolizumab infused will be compared to the total volume prepared to 
determine compliance with each dose of pembrolizumab administered. The instructions for 
preparing and administering pembrolizumab are provided in the Pharmacy Manual.
Administration of trial medication will be witnessed by the investigator and/or trial staff.
Clinical Procedures/Assessments
Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the 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 Version 4.0 (see Section 12.6). Toxicities will 
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated 
to determine if it is possibly an event of a potentially immunologic etiology; see Section
5.6.1.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
Physical Exam
7.1.2.2.1 Full Physical Exam
The investigator or clinical designee will perform a complete physical examination during 
the screening period. A complete physical examination is a comprehensive inspection of a 
patient’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. Clinically 
significant abnormal findings should be recorded as medical history. Additional full physical 
examinations should be performed as specified in the Trial Flow Chart-Section 6.0. After the 
first dose of trial treatment new clinically significant abnormal findings should be recorded 
as AEs.
7.1.2.2.2 Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart-Section 6.0, the 
investigator or qualified designee will perform a directed physical examination, as clinically 
indicated prior to dosing on Day 1 of each treatment cycle. New clinically significant 
abnormal findings should be recorded as AEs.
Height, Weight, and Vital Signs
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 Trial Flow Chart- Section 6.0. Height will be measured at Visit 1 only.
06DRHM
082M0Q

Product:  MK-3475 
55
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Vital signs should include temperature, pulse, respiratory rate, blood pressure, height, and 
weight.
12-Lead Electrocardiogram
A standard 12-lead electrocardiogram (ECG) will be performed one time during screening
using local standard procedures. Clinically significant abnormal findings should be recorded 
as medical history. Additional time points may be performed, as clinically necessary.
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG Performance Status (see
Section 12.5) at screening, prior to dosing on Day 1 of each treatment cycle, and at 
discontinuation of trial treatment as specified in the Trial Flow Chart – Section 6.0.
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 Procedures 
Manual.
Refer to the Trial Flow Chart – Section 6.0 for the schedule of laboratory assessments.
06DRHM
082M0Q

Product:  MK-3475 
56
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Local Laboratory Assessments
Local laboratory tests are specified in Table 5.
Table 5
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Alkaline phosphatase
Specific gravity
TSH
Hemoglobin
Blood urea nitrogen/Ureab
Microscopic exam, if 
abnormal results are 
noted
Pregnancy testa
Platelet count
Lactate dehydrogenase 
(LDH)
Urine pregnancy testa
Free thyroxine (FT4)
Red blood count
Alanine aminotransferase 
(ALT)
Protein
Total triiodothyronine (T3) 
or Free T3d
White blood cell count 
(total and differential)e
Aspartate aminotransferase 
(AST)
Glucose
aPTT
Absolute neutrophil 
countf
Bicarbonate or Carbon 
dioxidec
Blood
PT(INR)
Absolute lymphocyte 
countf
Calcium
Chloride
Creatinine
Glucose
Potassium
Sodium
Total bilirubin  
Direct bilirubin, if total 
bilirubin is elevated above 
the upper limit of normal
Total protein
a. Perform on women of childbearing potential only 72 hours prior to Day 1 of each cycle and 30 days post treatment.
b. Blood Urea Nitrogen is preferred; if not available urea may be tested.
c. If these tests are not done as part of standard of care in your region then these tests do not need to be performed.
d. T3 is preferred; if not available free T3 may be tested. If the local laboratory is unable to perform either of these tests the 
site should submit the sample to the central laboratory for testing; details are provided in the procedure manual. 
e. Report % or absolute results per standard of practice. Report the results in the same manner throughout the study.
f. Results should be calculated per local standard of practice.
Laboratory tests for screening should be performed within 10 days prior to the first dose of 
trial treatment. Subjects eligible for retreatment with pembrolizumab should have lab test 
performed within 10 days prior to the first dose of trial treatment in the Second Course 
Phase. After Cycle 1, in both the Initial Treatment Phase and the Second Course Phase, 
pre-dose laboratory safety tests 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. Unresolved abnormal 
labs that are drug related AEs should be followed until resolution. Laboratory tests do not 
need to be repeated after the end of treatment if lab results are within normal range.
06DRHM
082M0Q

Product:  MK-3475 
57
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
7.1.3.1.1 Pregnancy Tests
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 each cycle of 
trial treatment and 30 days post treatment. If a urine test is positive or not evaluable a serum 
test will be required. Subjects must be excluded/discontinued from the study in the event of a 
positive or borderline-positive test result. 
Central laboratory Assessments
Sample collection timing, storage, and shipment instructions for the central laboratory 
assessments will be provided in the central laboratory manual.
7.1.3.2.1 Pharmacokinetic/Pharmacodynamic Evaluations
To evaluate the immunogenicity and exposure of pembrolizumab in this indication, sample 
collections for analysis of anti-pembrolizumab antibodies (ADA) and PK are currently 
planned as shown in the Trial Flowchart (Section 6.1). Blood samples for PK and ADA 
collected may be stored only at this time. Further sample analysis may be performed, if 
required. If ongoing PK and/or ADA sampling is deemed to be unnecessary by the Sponsor, 
it may be reduced or discontinued. 
Blood Collection for Serum MK-3475
PK samples should be drawn according to the PK collection schedule. 
Blood Collection for Anti-pembrolizumab Antibodies
Anti-pembrolizumab antibody samples should be drawn according to the ADA collection 
schedule. Simultaneous PK sampling is required for interpretation of ADA analysis. 
7.1.3.2.2 Whole Blood Collection for Correlative and Biomarker Studies
Additional biomarker research to identify factors important for pembrolizumab therapy may 
also be pursued. Analysis to be inclusive of all testing is in Section 4.2.4.4.
Any leftover samples from the correlative and biomarker studies will be stored for future 
biomedical research if the subject provides documented informed consent for FBR.
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the central laboratory manual. This sample should be drawn for planned 
analysis of the association between genetic variants in DNA and drug response. If there is 
either a documented law or regulation prohibiting collection, or if the IRB/IEC does not 
approve the collection of the sample for these purposes, then this sample will not be collected 
at that site. If the sample is collected, leftover extracted DNA will be stored for future 
biomedical research if the subject provides the informed consent for FBR. If the planned 
genetic analysis is not approved, but FBR is approved and consent is given, this sample will 
be collected for the purpose of FBR.
06DRHM
082M0Q

Product:  MK-3475 
58
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA for future research

Leftover main study tumor tissue

Leftover DNA and RNA from correlative studies

Leftover plasma and serum from biomarker studies
Tumor Tissue
Eligibility for this study is dependent upon supplying adequate tumor tissue for biomarker 
analysis as described under eligibility criteria. Repeat samples may be required if adequate 
tissue is not provided. If the subject provides informed consent for FBR, any leftover tissue 
what 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 (FFPE) block specimens are preferred to slides. 
Detailed instructions for tissue collection, processing and shipment are provided in the 
central laboratory manual.
Efficacy Measurements
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 (SIM). Tumor imaging should be acquired by computed 
tomography (CT, strongly preferred). Magnetic resonance imaging (MRI) should be used 
when CT is contraindicated or for imaging in the brain. The same imaging technique 
regarding modality and use of contrast should be used in a subject throughout the trial to 
optimize the visualization of existing and new tumor burden. Imaging should include the 
chest, abdomen, and pelvis at baseline and all subsequent follow up time points; additional 
details are in the SIM. 
Expedited determination of measurable disease based on RECIST 1.1 by central imaging 
vendor at screening will be used to determine subject eligibility. Confirmation of measurable 
disease by the central imaging vendor per RECIST 1.1 is required prior to subject enrollment. 
Although RECIST 1.1 references to maximum of 5 target lesions in total and 2 per organ, 
Merck allows maximum of 10 target lesions in total and 5 per organ.
All scheduled images for all study subjects from the sites will be submitted to the central 
imaging vendor. In addition, imaging (including other modalities) that are obtained at an 
unscheduled time point to determine disease progression, as well as imaging obtained for 
other reasons but captures radiologic progression, should be submitted to the central imaging 
vendor, as well.
06DRHM
082M0Q

Product:  MK-3475 
59
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
7.1.4.1.1 Initial Tumor Imaging
Initial tumor imaging (baseline scans) of the chest abdomen and pelvis at screening must be 
performed within 28 days prior to the date of allocation. The site study team must review 
baseline images to confirm the subject has measurable disease per RECIST 1.1. The baseline
images must be submitted to the central imaging vendor for confirmation of measurable 
disease per RECIST 1.1; as part of the eligibility determination, prior to allocation.
Scans performed as part of routine clinical management are acceptable for use as baseline
tumor imaging if they are of diagnostic quality, performed within 14 days prior to the date of 
allocation, and can be assessed by the central imaging vendor. 
Subjects with previously treated brain metastases may participate provided they have stable 
brain metastases, i.e. without evidence of progression by imaging [confirmed by magnetic 
resonance imaging (MRI) if MRI was used at prior imaging, or confirmed by computed 
tomography (CT) imaging if CT 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 7 days prior to trial initiation as per local site 
assessment. This exception does not include carcinomatous meningitis, as subjects with 
carcinomatous meningitis are excluded regardless of clinical stability.
7.1.4.1.2 Tumor Imaging During the Trial
The first on study imaging assessment should be performed at 9 weeks (63 days ±7 days) 
from the date of allocation. Subsequent tumor imaging should be performed Q9W (63 days 
±7 days) or more frequently if clinically indicated. Imaging timing should follow calendar 
days should not be adjusted for delays in cycle starts. Imaging should continue to be 
performed until disease progression (unless site investigator elects to continue treatment and 
follow irRECIST), the start of new anti-cancer treatment, withdrawal of consent, death, or 
notification by the SPONSOR, whichever occurs first. All supplemental imaging must be 
submitted to the central imaging vendor. 
Per RECIST 1.1, partial or complete response should be confirmed by a repeat tumor 
imaging assessment not less than 4 weeks from the date the response was first documented. 
The tumor imaging for confirmation of response may be performed at the earliest 4 weeks 
after the first indication of response, or at the next scheduled tumor imaging (ie, 9 weeks 
later), whichever is clinically indicated. Subjects will then return to regular scheduled 
imaging Q9W, starting with the next scheduled imaging time point. Subjects who obtain a 
confirmation imaging scan do not need to undergo the next scheduled tumor imaging if it is < 
4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point.
Per irRECIST (Section 7.1.4.1.6) disease progression should be confirmed by the site at least 
4 weeks after site-assessed 1st radiologic evidence of PD in clinically stable subjects. 
Subjects who have unconfirmed disease progression may continue on treatment at the 
discretion of the site investigator until progression is confirmed by the site provided they 
have met the conditions detailed in Section 7.1.4.1.6. Subjects who obtain a confirmation 
scan do not need to undergo the next scheduled tumor imaging if it is < 4 weeks later; tumor 
imaging may resume at the subsequent scheduled imaging time point if clinically stable. 
06DRHM
082M0Q

Product:  MK-3475 
60
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Subjects who have confirmed disease progression as assessed by the site will discontinue the 
treatment. Exception is detailed in Section 7.1.4.1.6.
7.1.4.1.3 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 isn’t 
mandatory. In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by tumor imaging using the 
same imaging schedule used while on treatment (every 9 weeks) to monitor disease status 
until (1) the start of new anti-cancer treatment, (2) disease progression, (3) death, or (4) the 
end of the study, whichever occurs first.
7.1.4.1.4 Second Course Phase Tumor Imaging
A scan must be performed within 28 days prior to restarting treatment with pembrolizumab. 
Local reading (investigator assessment with site radiology reading) will be used to determine 
eligibility. Imaging should be submitted to the central imaging vendor for retrospective 
review.
The first on study imaging assessment should be performed at 9 (63 days ±7 days) after the 
restart of treatment. Subsequent tumor imaging should be performed Q9W (63 days ±7 days) 
or more frequently if clinically indicated.
Per irRECIST (Section 7.1.4.1.6), if tumor imaging shows initial PD, tumor assessment 
should be repeated ≥ 4 weeks later in order to confirm PD with the option of continuing 
treatment while awaiting radiologic confirmation of progression. Subjects who obtain a 
confirmation scan do not need to undergo scheduled tumor imaging if it is < 4 weeks later 
and may wait until the next scheduled imaging time point, if clinically stable.
Imaging should continue to be performed until disease progression, the start of new anti-
cancer treatment, withdrawal of consent, death, or notification by the Sponsor, whichever 
occurs first. Disease progression may be confirmed at least 4 weeks after the first tumor 
imaging indicating progressive disease in clinically stable subjects.
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 isn’t 
mandatory. In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by radiologic imaging every 
9 weeks (63 days ± 7 days) until (1) the start of new anti-cancer treatment, (2) disease 
progression, (3) death, or (4) the end of the study, whichever occurs first.
06DRHM
082M0Q

Product:  MK-3475 
61
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
7.1.4.1.5 RECIST 1.1 Assessment of Disease
RECIST 1.1 will be applied by the central imaging vendor as the primary measure for 
assessment of tumor response, date of disease progression, and as a basis for all protocol 
guidelines related to disease status (eg, discontinuation of study therapy).
7.1.4.1.6 irRECIST Assessment of Disease
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic drugs. irRECIST will be used by site 
investigator/local radiology review to assess tumor response and progression, and make 
treatment decisions. This data will be collected in the clinical database. Treatment efficacy 
based on irRECIST as assessed by central imaging vendor review will be evaluated 
retrospectively. 
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 progressive disease (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 
determined by the site, it is at the discretion of the PI whether to continue a subject on study 
treatment until repeat imaging is obtained (using irRECIST for subject management, see 
Table 6 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 study treatment and 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: 
1) Absence of symptoms and signs indicating clinically significant progression of 
disease, including worsening of laboratory values
2) No decline in ECOG performance status 
3) Absence of rapid progression of disease 
4) Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention  
Any subject deemed clinically unstable should be discontinued from trial treatment at site-
assessed 1st radiologic evidence of PD and is not required to have repeat imaging for PD 
confirmation.
06DRHM
082M0Q

Product:  MK-3475 
62
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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).
Scenarios where PD is not confirmed at repeat imaging if ALL of the following occur 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 qualitatively stable or improved
•
New lesion resulting in initial PD is qualitatively stable or 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 by 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. 
Scenarios where PD is confirmed at repeat imaging if ANY of the following occur 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 study therapy.
NOTE: If a subject has confirmed radiographic progression (i.e. 2 scans at least 4 weeks 
apart demonstrating progressive disease) 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 performed following the intervals as outlined in Section 6.0 
Study Flowchart and be submitted to the central imaging vendor.
Additional details about irRECIST are referenced in Merck TIP Sheet for RECIST 1 1 and 
irRECIST
06DRHM
082M0Q

Product:  MK-3475 
63
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Table 6
Imaging and Treatment after First Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st 
radiologic 
evidence of PD by 
RECIST 1.1 
Repeat imaging 
at > 4 weeks at 
site to confirm 
PD
May 
continue 
study 
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 physician 
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
N/A
Repeat 
tumor 
imaging shows SD, 
PR 
or 
CR 
by 
irRECIST 
at 
the 
local site
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue study treatment 
at 
the 
local 
site 
Investigator’s discretion
Continue 
regularly 
scheduled 
imaging 
assessments 
May 
restart 
study 
treatment if condition 
has 
improved 
and/or 
clinically 
stable 
per 
Investigator’s discretion. 
Next 
tumor 
image 
should occur according 
to the regular imaging 
schedule outlined in the 
protocol
06DRHM
082M0Q

Product:  MK-3475 
64
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Figure 2
Imaging and Treatment for Clinically Stable Subjects after First Radiologic 
Evidence of PD Assessed by the Site
Other Procedures
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the end of treatment visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events. Subjects who attain a CR or complete 35 trial treatments 
(approximately 2 years) may discontinue treatment with the option of restarting treatment if 
they meet the criteria specified in Section 7.1.6.2. After discontinuing treatment following 
assessment of a CR or the 35 trial treatments, subjects should return to the site for a Safety 
Follow-up visit (Section 7.1.6.3.1) and then proceed to the Follow-up Period of the study 
(Section 7.1.6.3.2).
06DRHM
082M0Q

Product:  MK-3475 
65
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
7.1.5.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   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@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for 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 
specimen destruction cannot be processed.
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and 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.
Critical Equipment for this trial includes:

Laboratory equipment – as required for inclusion labs and trial assessments

Imaging equipment – as required for study objectives
See protocol-specified guidance in the Trial Administrative Binder, Procedures Manual, and 
Site Imaging Manual.
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.
06DRHM
082M0Q

Product:  MK-3475 
66
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Screening
Approximately 28 days prior to treatment allocation, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. Screening 
procedures may be repeated.
Subjects may not be rescreened in this study.  
Screening procedures are to be completed within 28 days prior to the first dose of trial 
treatment except for the following:
•
Laboratory tests and ECOG PS are to be performed within 10 days prior to the 
first dose of trial treatment.
•
For women of reproductive potential, a pregnancy test will be performed within 
72 hours prior to the first dose of trial treatment. A urine test may be considered if 
serum test is not appropriate.
Treatment Period
Visit requirements are outlined in the Trial Flow Chart (Section 6.0). Specific procedure-
related details are provided above in the Trial Procedures.
Subjects who stop pembrolizumab with SD or better may be eligible for up to 17 additional 
trial treatments (approximately 1 year) if they progress after stopping study treatments. 
Retreatment with pembrolizumab is termed the Second Course Phase and is only available if 
the trial remains open and the subject meets the following conditions:

Either 
o
Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1

Was treated with at least 8 trial treatments (approximately 6 months) 
with pembrolizumab before discontinuing therapy

Received at least 2 treatments with pembrolizumab beyond the date 
when the initial CR was declared
OR
o
Had SD, PR or CR and stopped pembrolizumab after 35 trial treatments 
(approximately 2 years) for reasons other than disease progression or 
intolerability

AND
o
Experienced an investigator-determined confirmed radiographic disease 
progression after stopping their initial treatment with pembrolizumab
o
Did not receive any anti-cancer treatment since the last dose of 
pembrolizumab
o
Has a performance status of 0 or 1 on the ECOG Performance Scale
o
Demonstrates adequate organ function as detailed in Section 5.1.2
06DRHM
082M0Q

Product:  MK-3475 
67
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
o
Female subject of childbearing potential should have a negative serum or 
urine pregnancy test within 72 hours prior to receiving retreatment with study 
medication.  
o
Female subjects of childbearing potential (Section 5.7.2) 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.  

Note: Abstinence is acceptable if this is the usual lifestyle and 
preferred contraception for the subject.
o
Male subjects of childbearing potential (Section 5.7.2) must agree to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception
and not to donate sperm starting with the first dose of study therapy through 
120 days after the last dose of study therapy.

Note: Abstinence is acceptable if this is the usual lifestyle and 
preferred contraception for the subject.
o
Does not have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might 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, in the opinion of the treating investigator.
Subjects who enter the Second Course Phase will be retreated at the same dose frequency as 
when they last received pembrolizumab. Pembrolizumab will be administered for up to an 
additional 17 trial treatments (approximately 1 year).
Visit requirements for the second course phase are outlined in the Second Course Phase Trial 
Flow Chart (Section 6.2).
Post-Treatment Visits
7.1.6.3.1 Safety Follow-up Visits
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 anti-cancer treatment, whichever 
comes first.
All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Subjects with an 
AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the 
beginning of a new anti-cancer therapy, whichever occurs first. SAEs that occur within 
90 days of the end of treatment or before initiation of a new anti-cancer treatment should also 
be followed and recorded.  
Subjects who are eligible for retreatment with pembrolizumab may have up to 2 safety 
follow-up visits, one after the Initial Treatment Period and one after the Second Course 
Treatment Phase.
06DRHM
082M0Q

Product:  MK-3475 
68
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
7.1.6.3.2 Follow-up visits
Subjects who discontinue trial treatment for reasons other than disease progression will move
into the Follow-up Phase and should be assessed Q9W by radiologic imaging to monitor 
disease status. The Sponsor may request survival status to be assessed at additional time 
points during the course of the study (not to exceed approximately 12 weeks). Every effort 
should be made to collect information regarding disease status until the start of a new anti-
cancer therapy, disease progression, death, or the end of the study. 
Information regarding post-study anti-cancer treatment will be collected if new treatment is 
initiated.  
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.6.2 will move from the Follow-up Phase to the Second Course Phase when 
they experience disease progression.
7.1.6.3.3 Survival Follow-up
Subjects, who experience disease progression (by site assessment) or start a new anti-cancer 
therapy, will move into the Survival Follow-Up Phase. Subjects should be contacted by 
telephone approximately every 12 weeks to assess for survival status until death, withdrawal 
of consent, or the end of the study, whichever occurs first.
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 Data 
Monitoring Committee (eDMC) review, interim and/or final analysis. Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact 
during the Sponsor defined time period will be contacted for their survival status (excluding 
participants 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.  
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.
06DRHM
082M0Q

Product:  MK-3475 
69
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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 EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
In this trial, an overdose is any dose higher than ≥1000 mg (5 times the protocol-defined 
dose) of pembrolizumab. 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 
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.
06DRHM
082M0Q

Product:  MK-3475 
70
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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 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
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;
●
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 7 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.
06DRHM
082M0Q

Product:  MK-3475 
71
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of 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.
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 
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 
06DRHM
082M0Q

Product:  MK-3475 
72
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined will not be reported to the Sponsor, as described in 
Section 7.2.3. - Immediate Reporting of Adverse Events to the Sponsor. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor safety data to ensure the safety of the subjects in the trial. Any 
suspected endpoint which upon review is not progression of the cancer under study will be 
forwarded to global safety as a SAE within 24 hours of determination that the event is not 
progression of the cancer under study.
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.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
06DRHM
082M0Q

Product:  MK-3475 
73
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Table 7
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 a Merck 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
06DRHM
082M0Q

Product:  MK-3475 
74
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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.)
06DRHM
082M0Q

Product:  MK-3475 
75
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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
This trial was developed in collaboration with both Sponsor and non-Sponsor scientific 
experts who provide input with respect to the trial design, interpretation of trial results and 
subsequent peer-reviewed scientific publications.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any final database lock, 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 E-9). Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to final 
database lock, will be documented in a supplemental SAP (sSAP) and referenced in the 
Clinical Study Report (CSR) for the study. There will be a separate PK analysis plan. Post 
hoc exploratory analyses will be clearly identified in the CSR.  
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below. The comprehensive plan 
is provided in Sections 8.2 through 8.12.
Study Design Overview
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 I Adenocarcinoma of the 
Esophagogastric Junction (KEYNOTE – 180)
Treatment Assignment
This is a single-arm open-label study. 
Analysis Populations
All Subjects as Treated (ASaT)
Primary Endpoint(s)
ORR based on RECIST 1.1 assessed by central imaging vendor 
Statistical Methods for Key 
Efficacy Analyses
95% CI for ORR will be calculated using the exact binomial 
distribution.
Statistical Methods for Key 
Safety Analyses
Count and percentage of AE will be provided. 
Multiplicity
Not applicable since this is an estimation study.
Sample Size 
The planned sample size is approximately 100 subjects. The primary 
objective of the study is to estimate ORR in all subjects and in subjects 
whose tumors are classified as GEP intermediate or high and subjects 
whose tumors are classified as GEP high. Section 8.7 provides the 
precision of the ORR estimates. 
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.
06DRHM
082M0Q

Product:  MK-3475 
76
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
This trial is being conducted as an open-label study, ie, subjects, investigators, and 
SPONSOR personnel will be aware of subject treatment.
The Clinical Biostatistics department will generate the allocation schedule.
Estimation
Objectives and estimations of the study are stated in Section 3.0.
Analysis Endpoints
Efficacy Endpoints
Primary Efficacy Endpoint

Objective response rate (ORR) - RECIST 1.1 assessed by central imaging vendor
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a complete response (CR) or partial response (PR). Responses are based upon 
central imaging vendor assessments per RECIST 1.1.
Secondary Efficacy Endpoints

Duration of Response (DOR) - RECIST 1.1 assessed by central imaging vendor
For subjects who demonstrated CR or PR, response duration is defined as the time from the 
date of first response (CR or PR) until the date of disease progression or death.

Progression-free Survival (PFS) - RECIST 1.1 assessed by central imaging 
vendor
PFS is defined as the time from first day of study treatment to the first documented disease 
progression or death due to any cause, whichever occurs first.

Overall survival (OS)
OS is defined as the time from first day of study treatment 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.
Safety Endpoints
Safety measurements are described in Section 7.0 Trial Procedures.
Analysis Populations
Efficacy Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of ORR, PFS, 
and OS. The ASaT population consists of all allocated subjects who received at least 1 dose 
of study treatment.
The analysis population for DOR consists of responders.
06DRHM
082M0Q

Product:  MK-3475 
77
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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 allocated subjects who received at least 
1 dose of study treatment. 
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.
For the primary efficacy endpoint of ORR, the point estimate and 95% confidence interval
will be provided using exact binomial method proposed by Clopper and Pearson (1934)[47]. 
Subjects in the primary analysis population (ASaT) without ORR data will be counted as 
non-responder.
For PFS, DOR and OS endpoints, Kaplan-Meier (KM) curves and median estimates from the 
KM curves will be provided as appropriate. The efficacy analysis is summarized in Table 8.
06DRHM
082M0Q

Product:  MK-3475 
78
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Table 8
Analysis Strategy for Efficacy Variables
Endpoint/Variable‡
(Description, Time Point)
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Endpoint and Hypothesis 
ORR

RECIST 
1.1, 
Central 
imaging 
vendor assessment
Exact method based
on binomial
distribution
ASaT

All subjects

Subjects 
whose 
tumors
are 
classified as 
GEP 
intermediate 
or high 

Subjects 
whose 
tumors
are 
classified as 
GEP high
Subjects with missing data 
are 
considered 
non-
responders
Secondary Endpoints
DOR

RECIST 
1.1, 
Central 
imaging 
vendor assessment
Summary 
statistics 
using Kaplan-Meier 
method
All responders
Non-responders 
are 
excluded from analysis
PFS

RECIST 
1.1, 
Central 
imaging 
vendor assessment
Summary 
statistics 
using Kaplan-Meier 
method
ASaT
Censored at last assessment
OS
Summary 
statistics 
using Kaplan-Meier 
method
ASaT
Censored at last known 
alive date
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including
AEs, laboratory tests, and vital signs. Count and percentage of AEs will be provided.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The number and percentage of subjects screened, enrolled, the primary reasons for screening 
failure, and the primary reason for discontinuation will be displayed. Demographic variables 
(eg, age, gender), baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized either by descriptive statistics or categorical tables
for all enrolled subjects.
Interim Analysis
No interim analysis is planned in this study. 
Multiplicity
Multiplicity adjustment is not applicable since this is an estimation study.
06DRHM
082M0Q

Product:  MK-3475 
79
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Sample Size 
In this study, approximately 100 subjects with previously treated, advanced/metastatic 
adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic
Siewert type 1 adenocarcinoma of the EGJ will be enrolled.
Table 9 shows the two-sided 95% confidence interval of ORR with 100 subjects for different 
observed response rates.
Table 9
Two-sided 95% Confidence Interval of ORR with 100 Subjects
Number of Observed Responders
ORR Estimates
95% CI of ORR (%)
17
17%
(10.2, 25.8)
25
25%
(16.9, 34.7)
30
30%
(21.2, 40.0)
35
35%
(25.7, 45.2)
For the subjects with tumors classified as GEP intermediate or high, if the prevalence of
about 60%, there will be approximately 60 such subjects.  Table 10 shows the two-sided 95% 
CI of ORR with 60 subjects for different response rates. For example, if the observed ORR is 
35% in this group, the 95% CI of this estimate of ORR is (23.1%, 48.4%).
Table 10
Two-sided 95% Confidence Interval for ORR with 60 Subjects
Number of Observed
Responders
ORR Estimates
95% CI of ORR (%)
15
25%
(14.7, 37.9)
18
30%
(18.8, 43.2)
21
35%
(23.1, 48.4)
24
40%
(27.6, 53.5)
For the subjects with tumors classified as GEP high, if the prevalence of this group is about 
40%, there will be approximately 40 such subjects. Table 11 shows the two-sided 95% CI of 
ORR with 40 subjects for different response rates. For example, if the observed ORR is 35% 
in this group, the 95% CI of this estimate of ORR is (20.6%, 51.7%).
Table 11
Two-sided 95% Confidence Interval for ORR with 40 Subjects
Number of Observed 
Responders
ORR Estimates
95% CI of ORR (%)
12
30%
(16.6, 46.5)
14
35%
(20.6, 51.7)
16
40%
(24.9, 56.7)
06DRHM
082M0Q

Product:  MK-3475 
80
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Subgroup Analyses and Effect of Baseline Factors
The estimate of the treatment effect for the primary endpoint will be estimated and/or plotted 
within each category of the following classification variables: 

Age category (≤65 vs. >65 years)

Sex (Female vs. Male)

Race (Asian vs. non-Asian)

Histology (Adenocarcinoma vs. Squamous Cell Carcinoma vs. Siewert type 1 
adenocarcinoma of the EGJ)
Compliance (Medication Adherence)
Drug accountability data for MK-3475 will be collected during the study. Any deviation from
protocol-directed administration will be reported.
Extent of Exposure
Extent of Exposure for a subject is defined as number of cycles in which the subject receives 
the study medication infusion. Summary statistics will be provided on Extent of Exposure for 
ASaT population.
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 12.
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.
06DRHM
082M0Q

Product:  MK-3475 
81
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Table 12
Product Descriptions
Product Name & Potency
Dosage Form
MK-3475 50 mg/vial
Lyophilized Powder for Injection
All other supplies not indicated in Table 12 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 to record 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.
Subjects will receive open label vials for each treatment cycle. The MK-3475 will not be 
kitted.
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
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.
06DRHM
082M0Q

Product:  MK-3475 
82
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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.
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.
06DRHM
082M0Q

Product:  MK-3475 
83
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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.
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 member 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 Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
06DRHM
082M0Q

Product:  MK-3475 
84
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
The investigator also agrees to allow monitoring, audits, IRB/ERC 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.
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.
06DRHM
082M0Q

Product:  MK-3475 
85
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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.
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, Merck, 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 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 Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA 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 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
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.
06DRHM
082M0Q

Product:  MK-3475 
86
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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.
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. Merck 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.
06DRHM
082M0Q

Product:  MK-3475 
87
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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 
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.
11.0 LIST OF REFERENCES
[1]
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. 
Developing a common language for tumor response to immunotherapy: immune-
related response criteria using unidimensional measurements. Clin Cancer Res. 
2013 Jul 15;19(14):3936-43.
[2]
Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8.
[3]
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune 
evasion. Nat Med 2002;8(8):793-800.
[4]
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol 
2002;2(2):116-26.
[5]
Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. 
Blockade of programmed death-1 ligands on dendritic cells enhances T cell 
activation and cytokine production. J Immunol 2003;170(3):1257-66.
[6]
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010;236:219-42.
[7]
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. 
PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor 
outcome for patients with renal cell carcinoma. Clin Cancer Res 2007;13(6):1757-
61.
[8]
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: 
Jekyll or Hyde. Cancer Metastasis Rev 2007;26(3-4):373-400.
06DRHM
082M0Q

Product:  MK-3475 
88
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
[9]
Usubütün A, Ayhan A, Uygur MC, Özen H, Toklu C, Ruacan S. Prognostic 
factors in renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.
[10]
Al-Shibli K, Al-Saad S, Andersen S, Donnem T, Bremnes RM, Busund L-T. The 
prognistic value of intraepithelial and stromal CD3-, CD117- and CD138-positive 
cells in non-small cell lung carcinoma. APMIS 2010;118:371-82.
[11]
Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen P, Lardon F, et 
al. Tumor infiltrating lymphocytes: an intriguing player in the survival of 
colorectal cancer patients. BMC Immunol 2010;11:19.
[12]
Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18(1B):689-94.
[13]
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, 
et al. Type, density, and location of immune cells within human colorectal tumors 
predict clinical outcome. Science 2006;313(5795):1960-4.
[14]
Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: 
molecular biology. Int J Clin Oncol 2010;15(6):544-51.
[15]
Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive 
lymphocyte and dendritic cell infiltration after interleukin-2 immunotherapy. 
Report of a case. Tumori 2008;94(3):426-30.
[16]
Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 
associate with immunoreceptor tyrosine-based switch motif of programmed death 
1 upon primary human T cell stimulation, but only receptor ligation prevents T 
cell activation. J Immunol 2004;173:945-54.
[17]
Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
Oncol. 2009 Sep;10(9):840-1.
[18]
Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are 
parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol 
Immunother 2008;57(1):97-106.
[19]
Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic 
implications of type and density of tumour-infiltrating lymphocytes in gastric 
cancer. Br J Cancer 2008;99(10):1704-11.
06DRHM
082M0Q

Product:  MK-3475 
89
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
[20]
Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema 
H, et al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary 
and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol 
Immunother 2009;58(3):449-59.
[21]
Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification 
of positive selection in the thymus of PD-1-deficient mice. J Exp Med. 2000 Mar 
6;191(5):891-8.
[22]
Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes 
correlates with poor prognosis in renal cell carcinoma. BJU Int 2011;107(9):1500-
6.
[23]
Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic 
value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 
1997;182(3):318-24.
[24]
Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J 
Clin Oncol 2005;23(10):2346-57.
[25]
Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. 
Treatment of metastatic melanoma with autologous CD4+ T cells against NY-
ESO-1. N Engl J Med 2008;358(25):2698-703.
[26]
Pölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. 
Foxp3(+) cell infiltration and granzyme B(+)/Foxp3(+) cell ratio are associated 
with outcome in neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer 
Immunol Immunother 2010;59(6):909-19.
[27]
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 
2001;98(24):13866-71.
[28]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48.
[29]
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer
statistics. CA Cancer J Clin 2011;61:69-90.
[30]
Bosetti C, Levi F, Ferlay J, Garavello W, Lucchini F, Bertuccio P, et al. Trends in 
oesophageal cancer incidence and mortality in Europe. Int J Cancer. 2008 Mar 
1;122(5):1118-29.
06DRHM
082M0Q

Product:  MK-3475 
90
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
[31]
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015 
Jan;65(1):5-29.
[32]
Kuwano H, Nishimura Y, Oyama T, Kato H, Kitagawa Y, Kusano M, et al. 
Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus April 
2012 edited by the Japan Esophageal Society. Esophagus. 2015;12:1-30.
[33]
Corley DA, Buffler PA. Oesophageal and gastric cardia adenocarcinomas: 
analysis of regional variation using the Cancer Incidence in Five Continents 
database. Int J Epidemiol. 2001 Dec;30(6):1415-25.
[34]
Brown LM, Devesa SS, Chow WH. Incidence of adenocarcinoma of the 
esophagus among white Americans by sex, stage, and age. J Natl Cancer Inst. 
2008 Aug 20;100(16):1184-7.
[35]
Trivers KF, Sabatino SA, Stewart SL. Trends in esophageal cancer incidence by 
histology, United States, 1998-2003. Int J Cancer. 2008 Sep 15;123(6):1422-8.
[36]
Pickens A, Orringer MB. Geographical distribution and racial disparity in 
esophageal cancer. Ann Thorac Surg. 2003 Oct;76(4):S1367-9.
[37]
Siewert JR, Ott K. Are squamous and adenocarcinomas of the esophagus the same 
disease? Semin Radiat Oncol. 2007 Jan;17(1):38-44.
[38]
Siewert JR, Stein HJ, Feith M, Bruecher BL, Bartels H, Fink U. Histologic tumor 
type is an independent prognostic parameter in esophageal cancer: lessons from 
more than 1,000 consecutive resections at a single center in the Western world. 
Ann Surg. 2001 Sep;234(3):360-7; discussion 368-9.
[39]
Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, et 
al. Survival advantage for irinotecan versus best supportive care as second-line 
chemotherapy in gastric cancer--a randomised phase III study of the 
Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011 
Oct;47(15):2306-14.
[40]
Ford HER, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, et al. 
Docetaxel versus active symptom control for refractory oesophagogastric 
adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled 
trial. Lancet Oncol. 2014 Jan;15(1):78-86.
[41]
Ilson DH, Wadleigh RG, Leichman LP, Kelsen DP. Paclitaxel given by a weekly 
1-h infusion in advanced esophageal cancer. Ann Oncol. 2007 May;18(5):898-
902.
06DRHM
082M0Q

Product:  MK-3475 
91
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
[42]
Dutton SJ, Ferry DR, Blazeby JM, Abbas H, Dahle-Smith A, Mansoor W, et al. 
Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 
3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol. 
2014 Jul;15(8):894-904.
[43]
Ribas A, Robert C, Hodi FS, Wolchok JD, Joshua AM, Hwu WJ, et al. 
Association of response to programmed death receptor 1 (PD-1) blockade with 
pembrolizumab (MK-3475) with an interferon-inflammatory immune gene 
signature. 2015 ASCO (American Society of Clinical Oncology) Annual Meeting; 
2015 May 29-June 2; Chicago, IL.
[44]
Seiwert TY, Burtness B, Weiss J, Eder JP, Yearley J, Murphy E, et al. Inflamed-
phenotype gene expression signatures to predict benefit from the anti-PD-1 
antibody pembrolizumab in PD-L1+ head and neck cancer patients. 2015 ASCO 
(American Society of Clinical Oncology) Annual Meeting; 2015 May 29-June 2; 
Chicago, IL.
[45]
Shankaran V, Muro K, Bang YJ, Geva R, Catenacci DV, et al. Correlation of gene 
expression signatures and clinical outcomes in patients with advanced gastric 
cancer treated with pembrolizumab (MK-3475). 2015 ASCO (American Society 
of Clinical Oncology) Annual Meeting; 2015 May 29-June 2; Chicago, IL.
[46]
Johnson DB, Rioth MJ, Horn L. Immune checkpoint inhibitors in NSCLC. Curr 
Treat Options Oncol. 2014 Dec;15(4):658-69.
[47]
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the 
case of binomial. Biometrika 1934;26(4):404-13.
06DRHM
082M0Q

Product:  MK-3475 
92
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, 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 subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck 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 which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
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 Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  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 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. 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.  Merck funding of a trial will be acknowledged in publications. 
06DRHM
082M0Q

Product:  MK-3475 
93
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects 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.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck 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
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck 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 including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
06DRHM
082M0Q

Product:  MK-3475 
94
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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 collected in this trial as outlined in Section 7.1.3.4 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects 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 the 
Future Biomedical Research sub-trial.
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 Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
06DRHM
082M0Q

Product:  MK-3475 
95
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of patient 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 Collections
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 for transfer to the storage facility.  This first 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 first 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 Merck Biorepository 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 this sub-trial. 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 have their 
specimens and all derivatives destroyed.   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 
06DRHM
082M0Q

Product:  MK-3475 
96
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for 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 specimen destruction can not 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 (e.g., ISO17799) 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 any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
06DRHM
082M0Q

Product:  MK-3475 
97
Protocol/Amendment No.:  180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study 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 future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (ie, only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address 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@merck.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
06DRHM
082M0Q

Product:  MK-3475 
98
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
06DRHM
082M0Q

Product:  MK-3475 
99
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
06DRHM
082M0Q

Product:  MK-3475 
100
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
06DRHM
082M0Q

Product:  MK-3475 
101
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
06DRHM
082M0Q

Product:  MK-3475 
102
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
06DRHM
082M0Q

Product:  MK-3475 
103
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
06DRHM
082M0Q

Product:  MK-3475 
104
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
06DRHM
082M0Q

Product:  MK-3475 
105
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
06DRHM
082M0Q

Product:  MK-3475 
106
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
06DRHM
082M0Q

Product:  MK-3475 
107
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
06DRHM
082M0Q

Product:  MK-3475 
108
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
06DRHM
082M0Q

Product:  MK-3475 
109
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Response Evaluation Criteria in Solid Tumors
RECIST 1.1* will be used in this study for assessment of tumor response. While either CT or 
MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study.
* As published in the European Journal of Cancer
06DRHM
082M0Q

Product:  MK-3475 
110
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
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.
06DRHM
082M0Q

Product:  MK-3475 
111
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Common Terminology Criteria for Adverse Events
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).
06DRHM
082M0Q

Product:  MK-3475 
112
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
List of Abbreviations
Abbreviation/Term
Definition
1L
First Line
2L
Second Line
AE
Adverse Event
ADA
Anti-Drug Antibodies
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AP
Alkaline Phosphatase
APaT
All Patients as Treated
aPTT
Activated Partial Thromboplastin Time
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
bid
Twice a Day
ß-HCG
Beta Human Chorionic Gonadotropin
BSA
Body Surface Area
CBC
Complete Blood Count
CI
Confidence Interval
CIMP
CPG Island Methylator Phenotype
CIN
Chromosomal Instability
COPD
Chronic Obstructive Pulmonary Disease
CNS
Central Nervous System
CR
Complete Response
CRC
Colorectal Carcinoma
CrCl
Calculated Creatinine Clearance
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4
dMMR
Deficient Mismatch Repair
DNA
Deoxyribonucleic acid
DOR
Duration of Response
DR
Drug Related
ECI
Events of Clinical Interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EGJ
Esophagogastric Junction
eDMC
external Data Monitoring Committee
EOC
Executive Oversight Committee
EORTC
European Organisation for Research and Treatment 
of Cancer
ePRO
Electronic Patient Reported Outcomes
ERC
Ethics Review Committee
ESMO
European Society for Medical Oncology
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FNA
Fine Needle Aspirate
06DRHM
082M0Q

Product:  MK-3475 
113
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Abbreviation/Term
Definition
GCP
Good Clinical Practice
GEP
Gene Expression Profile
GI
Gastrointestinal
GFR
Glomerular Filtration Rate
GFR
Glomerular Filtration Rate
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HEA
Health Economic Assessment
HIV
Human Immunodeficiency Virus
HNSCC
Head and Neck Squamous Cell Carcinoma
HPV
Human Papillomavirus
HR
Hazard Ratio
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
INR
International Normalized Ratio
irAE
immune-related adverse event
irRECIST
Immune related RECIST (Modification of RECIST 
1.1)
irRC
Immune related Response Criteria
IRB
Institutional Review Board
ITIM
Immunoreceptor Tyrosine-based Inhibition Motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
ITT
Intention To Treat
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
Kg
Kilogram
LDH
Lactate Dehydrogenase
mAb
Monoclonal Antibody
mCRC
Metastatic Colorectal Carcinoma
mcL
Microliters
MEL
Melanoma 
Mg
Milligram
Mg/kg
Milligram per Kilogram
mL
milliliter
MRI
Magnetic Resonance Imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of 
Merck & Co., Inc.
MSI-H
Microsatellite Instability High
MTD
Maximum Tolerated Dose
NA or N/A
Not Applicable
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSAID
Non-Steroidal Anti-inflammatory Drug
NSCLC
Non-Small Cell Lung Cancer
ORR
Objective Response Rate
OS
Overall Survival
OTC
Over-the-counter
PBPK
Physiologically based pharmacokinetic
PD
Progressive Disease
06DRHM
082M0Q

Product:  MK-3475 
114
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
Confidential
Abbreviation/Term
Definition
PFS
Progression Free Survival
PGt
Pharmacogenetic
PIN
Personal Identification Number
PK
Pharmacokinetic
PK/PD
Pharmacokinetic/Pharmacodynamic
PO
Oral Administration
PR
Partial Response
PRO
Patient Reported Outcomes
PT
Prothrombin Time
PS
Performance Status
QoL
Quality of Life
R/M
Recurrent or Metastatic
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
RR
Response Rate
QoL
Quality of Life
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
Q9W
Every 9 Weeks
RT
Radiation Therapy
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SCC
Squamous Cell Carcinoma
SD
Stable Disease
SFU
Survival Follow-Up
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SIM
Site Imaging Manual
SOP
Standard Operating Procedures
TIL
Tumor Infiltrating Lymphocytes
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
WBC
White Blood Cell
Germany-specific Requirements
Section 5.1.3 Exclusion Criteria
Exclusion Criterion: HIV 1/2 antibodies testing is required for participants when the 
investigator has reason to suspect the patient has Human Immunodeficiency Virus infection 
or is otherwise mandated per local guidance.
Exclusion Criterion: Hepatitis B surface Antigen reactive and HCV RNA [qualitative] testing 
is only required when the investigator has reason to suspect the patient has an Hepatitis B, 
Hepatitis C infection or testing is mandated per local guidance.
06DRHM
082M0Q

Product:  MK-3475 
115
Protocol/Amendment No.: 180-06 
MK-3475-180-06 Final Protocol
28-Jun-2021
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 – 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
06DRHM
082M0Q

MK-3475
PAGE 1
P180-01
SUPPLEMENTAL STATISTICAL ANALYSIS PLAN
Supplemental Statistical Analysis Plan (sSAP)
 
 
04HW4T
04HW4T
082M0X

MK-3475
PAGE 2
P180-01
SUPPLEMENTAL STATISTICAL ANALYSIS PLAN
Table of Contents
Table of Contents............................................................................................................................ 2
List of Tables .................................................................................................................................. 3
1
INTRODUCTION................................................................................................................... 4
2
SUMMARY OF CHANGES................................................................................................... 4
3
ANALYTICAL AND METHODOLOGICAL DETAILS...................................................... 5
3.1
Statistical Analysis Plan Summary .................................................................................. 5
3.2
Responsibility for Analyses/In-House Blinding .............................................................. 6
3.3
Estimation......................................................................................................................... 6
3.4
Analysis Endpoints........................................................................................................... 6
3.4.1 Efficacy Endpoints ......................................................................................................... 6
3.4.1.1 Primary Efficacy Endpoint ...................................................................................... 6
3.4.1.2 Secondary Efficacy Endpoints................................................................................. 6
3.4.1.3 Exploratory Efficacy Endpoints............................................................................... 7
3.4.2 Safety Endpoints............................................................................................................. 7
3.5 Analysis Populations............................................................................................................. 7
3.5.1 Efficacy Analysis Populations........................................................................................ 7
3.5.2 Safety Analysis Populations........................................................................................... 7
3.6 Statistical Methods................................................................................................................ 8
3.6.1 Statistical Methods for Efficacy Analyses...................................................................... 8
3.6.2 Statistical Methods for Safety Analyses....................................................................... 11
3.6.3 Summaries of Baseline Characteristics, Demographics, and Other Analyses ............. 11
3.6.4 Sample Size .................................................................................................................. 11
3.7 Subgroup Analyses and Effect of Baseline Factors ............................................................ 13
3.8 Compliance (Medication Adherence) ................................................................................. 13
3.9 Extent of Exposure.............................................................................................................. 13
LIST OF REFERENCES.............................................................................................................. 13
 
 
04HW4T
04HW4T
082M0X

MK-3475
PAGE 3
P180-01
SUPPLEMENTAL STATISTICAL ANALYSIS PLAN
List of Tables
Table 1. Censoring Rules for DOR................................................................................................. 8
Table 2 Censoring rules for PFS analysis....................................................................................... 9
Table 3 Analysis Strategy for Efficacy Variables........................................................................... 9
Table 4 Two-sided 95% Confidence Interval of ORR with 100 Subjects.................................... 12
Table 5 Two-sided 95% Confidence Interval for ORR with 60 Subjects..................................... 12
Table 6 Two-sided 95% Confidence Interval for ORR with 40 Subjects..................................... 12
 
 
04HW4T
04HW4T
082M0X

MK-3475
PAGE 4
P180-01
SUPPLEMENTAL STATISTICAL ANALYSIS PLAN
1
INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of confirmatory 
analyses for this trial, this supplemental SAP provides additional statistical analysis details/data 
derivations and documents modifications or additions to the analysis plan that are not “principal” 
in nature and result from information that was not available at the time of protocol finalization.     
2
SUMMARY OF CHANGES
Section Number (s)
Section Title(s)
Description 
of 
Change (s)
Rationale
3.4.1.1
Primary 
Efficacy 
Endpoint
DOR 
definition
updated
Using the most up to 
date DOR definition in 
oncology 
SAP 
template. 
3.6.1
Statistical Methods for 
Efficacy Analyses
The 
Table 
1:
censoring rules for 
DOR; and Table 2:
Censoring rules for 
PFS 
analysis 
are 
updated.
Updates are based on 
the
changes 
of
censoring rules in the 
latest SAP template. 
3.6.1
Statistical Methods for 
Efficacy Analyses
Added the sentence:
“The secondary and 
exploratory endpoints 
may be analyzed by 
populations 
as 
appropriate.” 
The 
secondary 
and 
exploratory endpoints 
may also be analyzed 
by 
all 
three 
populations. 
3.6.3
Summaries of Baseline 
Characteristics, 
Demographics, and 
Other Analyses
Paragraphs related to
biomarker analysis are 
deleted.
The cutoffs of GEP 
“low”, “intermediate” 
and “high” have been 
pre-specified at -1.540 
and -0.945. 
3.6.4
Sample size
The 
sample 
size 
descriptions based on 
the 
different 
assumptions of “GEP 
intermediate or high” 
The cutoffs of GEP 
“low”, “intermediate”
and “high” have been 
pre-specified at -1.540 
 
 
04HW4T
04HW4T
082M0X

MK-3475
PAGE 5
P180-01
SUPPLEMENTAL STATISTICAL ANALYSIS PLAN
Section Number (s)
Section Title(s)
Description 
of 
Change (s)
Rationale
and 
“GEP 
high”, 
respectively, 
are 
added. 
and -0.945.
3
ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan is 
provided in Sections 3.2 to Section 3.9. There will be a separate PK analysis plan. Post hoc 
exploratory analyses will be clearly identified in the CSR.
Study Design Overview
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 I Adenocarcinoma of the 
Esophagogastric Junction (KEYNOTE – 180)
Treatment Assignment
This is a single arm open-label study. 
Analysis Populations
All Subjects as Treated (ASaT)
Primary Endpoint(s)
ORR based on RECIST 1.1 assessed by central imaging vendor 
Statistical Methods for Key 
Efficacy Analyses
95% CI for ORR will be calculated using the exact binomial 
distribution.
Statistical Methods for Key 
Safety Analyses
Count and percentage of AE will be provided. 
Multiplicity
Not applicable since this is an estimation study.
Sample Size 
The planned sample size is approximately 100 subjects. The 
primary objective of the study is to estimate ORR in all subjects, 
in subjects whose tumors classified as “GEP intermediate or high”
(GEP ≥ -1.540) and subjects whose tumors classified as “GEP 
high” (GEP ≥-0.945). 
 
 
04HW4T
04HW4T
082M0X

MK-3475
PAGE 6
P180-01
SUPPLEMENTAL STATISTICAL ANALYSIS PLAN
3.2
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This trial is being conducted as an open-label study, i.e., subjects, investigators, and SPONSOR 
personnel will be aware of subject treatment.
The Clinical Biostatistics department will generate the allocation schedule.
3.3
Estimation
Objectives of the study and estimation to be performed are stated in Section 3.0 in the protocol.
3.4
Analysis Endpoints
3.4.1 Efficacy Endpoints
3.4.1.1 Primary Efficacy Endpoint

Objective response rate (ORR) - RECIST 1.1 assessed by central imaging vendor
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a complete response (CR) or partial response (PR). Responses are based upon blinded 
central imaging vendor assessments per RECIST 1.1.
3.4.1.2 Secondary Efficacy Endpoints

Disease Control Rate (DCR) - RECIST 1.1 assessed by central imaging vendor
Disease control rate (DCR) is defined as the percentage of subjects who have achieved 
confirmed CR or PR or have demonstrated SD prior to any evidence of progression.

Duration of Response (DOR) - RECIST 1.1 assessed by central imaging vendor
For subjects who demonstrate CR or PR, duration of response is defined as the time from first 
documented evidence of CR or PR until disease progression or death due to any cause, 
whichever occurs first.  

Progression-free Survival (PFS) - RECIST 1.1 assessed by central imaging vendor
PFS is defined as the time from first day of study treatment to the first documented disease 
progression or death due to any cause, whichever occurs first.
 
 
04HW4T
04HW4T
082M0X

MK-3475
PAGE 7
P180-01
SUPPLEMENTAL STATISTICAL ANALYSIS PLAN

Overall survival (OS)
OS is defined as the time from first day of study treatment 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.
3.4.1.3 Exploratory Efficacy Endpoints

Progression-free Survival (PFS) - irRECIST assessed by central imaging vendor
Progression-free-survival (PFS) is defined as the time from first day of study treatment to the 
first confirmed disease progression or death due to any cause, whichever occurs first.   

ORR – - irRECIST assessed by central imaging vendor
Overall response rate is defined as the proportion of the subjects in the analysis population who 
have a complete response (CR) or partial response (PR). Responses are based upon blinded 
central imaging vendor assessments per irRECIST.

Duration of Response (DOR) - irRECIST assessed by central imaging vendor 
For subjects who demonstrated CR or PR, response duration is defined as the time from the date 
of first response (CR or PR) until the date of confirmed disease progression or death.
3.4.2 Safety Endpoints
Safety measurements are described in Section 7 Trial Procedures in the protocol.
3.5 Analysis Populations
3.5.1 Efficacy Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of ORR, DCR, PFS, 
and OS. The ASaT population consists of all allocated subjects who received at least one dose of 
study treatment.
The analysis population for DOR consists of responders.
Details on the approach to handling missing data are provided in Section 3.6 Statistical Methods.
3.5.2 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 allocated subjects who received at least one dose of 
study treatment. 
 
 
04HW4T
04HW4T
082M0X

MK-3475
PAGE 8
P180-01
SUPPLEMENTAL STATISTICAL ANALYSIS PLAN
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 3.6
Statistical Methods.
3.6 Statistical Methods
3.6.1 Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary objectives.
For the primary efficacy endpoint of ORR, the point estimate and 95% confidence interval  will 
be 
provided 
using 
exact 
binomial 
method 
proposed 
by 
Clopper 
and 
Pearson
(1934)[Ref. 5.4: 03RMKM]. Subjects in the primary analysis population (ASaT) without ORR 
data will be counted as non-responders.
For DCR, the point estimate, 95% confidence interval will be provided using the exact binomial 
method proposed by Clopper and Pearson (1934)[Ref. 5.4: 03RMKM]. Subjects in the analysis 
population (ASaT) with missing DCR data are considered as disease not under control.
For DOR, Kaplan-Meier (KM) curves and median estimates from the KM curves will be
provided, as appropriate. Subjects who are alive, have not progressed, have not initiated new 
anti-cancer treatment, and have not been determined to be lost to follow-up are considered 
ongoing responders at the time of analysis. Censoring rules for DOR are summarized in Table 1.  
Table 1. Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new anti-
cancer therapy initiated
Last adequate disease assessment
Censored
(non-event)
No progression nor death, new anti-cancer 
therapy initiated
Last adequate disease assessment before 
new anti-cancer therapy initiated
Censored
(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
Censored
(non-event)
Death or progression after ≤ 1 missed 
adequate disease assessments
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 anti-cancer 
therapy, have not had ≥ 2 consecutive missed disease assessments, and have not been determined to be lost to follow-up.
 
 
04HW4T
04HW4T
082M0X

MK-3475
PAGE 9
P180-01
SUPPLEMENTAL STATISTICAL ANALYSIS PLAN
For PFS and OS endpoints, Kaplan-Meier (KM) curves and median estimates from the KM 
curves will be provided, as appropriate. The censoring rules for PFS are summarized in Table 2.
The efficacy analysis is summarized in Table 3. The secondary and exploratory endpoints may
be analyzed by populations as appropriate. 
Table 2 Censoring rules for PFS analysis
Situation
Primary Analysis
No PD and no death; new anticancer treatment is not initiated
Censored at last disease assessment 
No PD and no death; new anticancer treatment is initiated
Censored at last disease assessment 
before new anticancer treatment
Table 3 Analysis Strategy for Efficacy Variables
Endpoint/Variable‡
(Description, Time Point)
Statistical Method
Analysis Population
Missing 
Data 
Approach
Primary Endpoint and Hypothesis 
ORR

RECIST 1.1, Central imaging vendor 
assessment
Exact method based
on binomial
distribution
ASaT

All subjects

Subjects 
whose 
tumors 
classified as 
“GEP 
intermediate 
or 
high” 
(GEP 
≥ 
-
1.540)

Subjects 
whose 
tumors 
classified as 
“GEP high”
(GEP 
≥ 
-
0.945)
Subjects with missing 
data 
are 
considered 
non-responders
 
 
04HW4T
04HW4T
082M0X

MK-3475
PAGE 10
P180-01
SUPPLEMENTAL STATISTICAL ANALYSIS PLAN
Endpoint/Variable‡
(Description, Time Point)
Statistical Method
Analysis Population
Missing 
Data 
Approach
Secondary Endpoints
DCR

RECIST 
1.1, 
Central 
imaging 
vendor 
assessment
Exact method based
on binomial
distribution
ASaT
Subjects with missing
data are considered as
disease not under
control
DOR

RECIST 
1.1, 
Central 
imaging 
vendor 
assessment
Summary 
statistics 
using Kaplan-Meier 
method
All responders
Non-responders 
are 
excluded from analysis
PFS

RECIST 
1.1, 
Central 
imaging 
vendor 
assessment
Summary 
statistics 
using Kaplan-Meier 
method
ASaT
Censoring rules follow 
Table 2.
OS
Summary 
statistics 
using Kaplan-Meier 
method
ASaT
Censored 
at 
last 
known alive date
Exploratory Endpoints
ORR

irRECIST, 
Central 
imaging 
vendor 
assessment
Exact method based
on binomial
distribution
ASaT

All subjects

Subjects 
whose 
tumors 
classified as 
“GEP 
intermediate 
or 
high” 
(GEP 
≥ 
-
1.540)

Subjects 
whose 
tumors 
classified as 
“GEP high”
(GEP 
≥ 
-
0.945)
Subjects with missing 
data 
are 
considered 
non-responders
 
 
04HW4T
04HW4T
082M0X

MK-3475
PAGE 11
P180-01
SUPPLEMENTAL STATISTICAL ANALYSIS PLAN
Endpoint/Variable‡
(Description, Time Point)
Statistical Method
Analysis Population
Missing 
Data 
Approach
PFS

irRECIST, 
Central 
imaging 
vendor 
assessment
Summary 
statistics 
using Kaplan-Meier 
method
ASaT
Censoring rules per 
irRECIST also follow 
Table 2.
If 
there 
is 
no 
confirmation 
scan 
available 
after 
the 
initial PD scan, then it 
is considered as a PFS 
event at the initial PD 
scan time point. 
DOR

irRECIST, 
Central 
imaging 
vendor 
assessment
Summary 
statistics 
using Kaplan-Meier 
method
All responders
Non-responders 
are 
excluded 
from 
analysis;
If 
there 
is 
no 
confirmation 
scan 
available 
after 
the 
initial PD scan, then it 
is considered as a PFS 
event at the initial PD 
scan time point.
3.6.2 Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including
AEs, laboratory tests, and vital signs. Count and percentage of AEs will be provided.
3.6.3 Summaries of Baseline Characteristics, Demographics, and Other Analyses
The number and percentage of subjects screened, enrolled, the primary reasons for screening 
failure, and the primary reason for discontinuation will be displayed.  Demographic variables 
(e.g., age, gender), baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized either by descriptive statistics or categorical tables for 
all enrolled subjects.
3.6.4 Sample Size 
In this study, approximately 100 subjects with previously treated, advanced/metastatic 
adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert 
type 1 adenocarcinoma of the EGJ will be enrolled.
Table 4 shows the two-sided 95% confidence interval of ORR with 100 subjects for different 
observed response rates. 
 
 
04HW4T
04HW4T
082M0X

MK-3475
PAGE 12
P180-01
SUPPLEMENTAL STATISTICAL ANALYSIS PLAN
Table 4 Two-sided 95% Confidence Interval of ORR with 100 Subjects
Number of Observed Responders
ORR Estimates
95% CI of ORR (%)
17
17%
(10.2, 25.8)
25
25%
(16.9, 34.7)
30
30%
(21.2, 40.0)
35
35%
(25.7, 45.2)
For the subjects with tumors classified as “GEP intermediate or high” (GEP ≥-1.540), if the 
prevalence is about 60%, there will be approximately 60 such subjects.  Table 5 shows the two-
sided 95% CI of ORR with 60 subjects for different response rates. For example, if the observed 
ORR is 35% in this group, the 95% CI of this estimate of ORR is (23.1%, 48.4%). 
Table 5 Two-sided 95% Confidence Interval for ORR with 60 Subjects
Number of Observed
Responders
ORR Estimates
95% CI of ORR (%)
15
25%
(14.7, 37.9)
18
30%
(18.8, 43.2)
21
35%
(23.1, 48.4)
24
40%
(27.6, 53.5)
For the subjects whose tumors classified as “GEP high” (GEP ≥-0.945), if the prevalence of this 
group is about 40%, there will be approximately 40 such subjects. Table 6 shows the two-sided 
95% CI of ORR with 40 subjects for different response rates. For example, if the observed ORR 
is 35% in this group, the 95% CI of this estimate of ORR is (20.6%, 51.7%).
Table 6 Two-sided 95% Confidence Interval for ORR with 40 Subjects
Number of Observed 
Responders
ORR Estimates
95% CI of ORR (%)
12
30%
(16.6, 46.5)
14
35%
(20.6, 51.7)
16
40%
(24.9, 56.7)
 
 
04HW4T
04HW4T
082M0X

MK-3475
PAGE 13
P180-01
SUPPLEMENTAL STATISTICAL ANALYSIS PLAN
3.7 Subgroup Analyses and Effect of Baseline Factors
The estimate of the treatment effect for the primary endpoint will be estimated and/or plotted 
within each category of the following classification variables: 

Age category (≤65 vs. >65 years)

Sex (Female vs. Male)

Race (Asian vs. non-Asian)

Histology (Adenocarcinoma vs. Squamous Cell Carcinoma vs. Siewert type 1 
adenocarcinoma of the EGJ) 
3.8 Compliance (Medication Adherence)
Drug accountability data for MK-3475 will be collected during the study. Any deviation from
protocol-directed administration will be reported.
3.9 Extent of Exposure
Extent of Exposure for a subject is defined as number of cycles in which the subject receives the 
study medication infusion. Summary statistics will be provided on Extent of Exposure for ASaT 
population.
LIST OF REFERENCES
[Ref. 5.4: 03RMKM]
Clopper CJ, Pearson ES. The use of confidence 
or fiducial limits illustrated in the case of 
binomial. Biometrika 1934;26(4):404-13.
 
 
04HW4T
04HW4T
082M0X