Conditions: Esophageal Carcinoma Esophagogastric Junction Carcinoma
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1) Programmed Death-Ligand 2 (PDL2, PD-L2) Gene expression profiling (GEP)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 628
Healthy volunteers: no

Brief summary:
In this study, participants with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the esophagogastric junction (EGJ) that had progressed after first-line standard therapy were randomized to receive either pembrolizumab (MK-3475) OR the Investigator's choice of standard chemotherapy with paclitaxel, docetaxel, or irinotecan.

The primary study hypothesis was that treatment with pembrolizumab would prolong overall survival (OS) as compared to treatment with standard chemotherapy.

Detailed description:

Arms:
arm 1: Participants received pembrolizumab 200 mg, intravenously (IV) on Day 1 of every 21-day (3-week) cycle for up to 35 administrations (up to approximately 25 months). arm 2: Participants received Investigator's choice of paclitaxel 80-100 mg/m\^2 IV on Days 1, 8, and 15 of every 28-day (4-week) cycle, OR docetaxel 75 mg/m\^2 IV on Day 1 of every 21-day (3-week) cycle, OR irinotecan 180 mg/m\^2 IV on Day 1 of every 14-day (2-week) cycle (up to approximately 19 months).

Interventions: intervention 1: pembrolizumab intervention 2: paclitaxel intervention 3: docetaxel intervention 4: irinotecan
Intervention descriptions: intervention 1: 200 mg administered as IV infusion on Day 1 of every 21-day cycle intervention 2: 80-100 mg/m\^2 administered as IV infusion on Days 1, 8, and 15 of each 28-day cycle intervention 3: 75 mg/m\^2 administered as IV infusion on Day 1 of every 21-day cycle intervention 4: 180 mg/m\^2 administered as IV infusion on Day 1 of every 14-day cycle

Protocol document:
SAP_002.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase III Randomized Open-Label Study of Single Agent 
Pembrolizumab vs. Physicians’ Choice of Single Agent Docetaxel, 
Paclitaxel, or Irinotecan in Subjects with Advanced/Metastatic 
Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus that 
have Progressed after First-Line Standard Therapy (KEYNOTE-181)
28-Feb-2018
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Supplemental SAP
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Supplemental Statistical Analysis Plan (sSAP)
TABLE OF CONTENTS
1. INTRODUCTION .....................................................................................................................3
2. SUMMARY OF CHANGES.....................................................................................................3
3. ANALYTICAL AND METHODOLOGICAL DETAILS........................................................5
3.1
Statistical Analysis Plan Summary.......................................................................5
3.2
Responsibility for Analyses/In-House Blinding...................................................7
3.3
Hypotheses/Estimation .........................................................................................7
3.4
Analysis Endpoints ...............................................................................................7
3.4.1
Efficacy Endpoints................................................................................................7
3.4.2
Safety Endpoints...................................................................................................8
3.5
Analysis Populations.............................................................................................8
3.5.1
Efficacy Analysis Populations ..............................................................................8
3.5.2
Safety Analysis Populations .................................................................................9
3.6
Statistical Methods................................................................................................9
3.6.1
Statistical Methods for Efficacy Analyses............................................................9
3.6.2
Statistical Methods for Safety Analyses .............................................................14
3.6.3
Statistical Methods for the Exploratory Analyses ..............................................15
3.6.4
Summaries of Demographic and Baseline Characteristics .................................16
3.6.5
Statistical methods for patient-reported outcomes (PRO) 
endpoints.............................................................................................................16
3.6.5.1
Statistical methods for PRO endpoints .........................................................16
3.6.5.2
Treatment effect on PRO ..............................................................................19
3.6.5.3
Analysis of the Proportions of 
Deterioration/Stable/Improvement ...............................................................20
3.6.5.4
Analysis of the Time to Deterioration ..........................................................20
3.7
Interim Analyses.................................................................................................21
3.8
Multiplicity .........................................................................................................23
3.9
Sample Size and Power Calculations..................................................................24
3.10
Subgroup Analyses and Effect of Baseline Factors............................................25
3.11
Compliance (Medication Adherence).................................................................26
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3.12
Extent of Exposure..............................................................................................26
4. Statistical Analysis Plan for China Cohort ..............................................................................26
4.1
Introduction.........................................................................................................26
4.2
Responsibility for Analyses/In-House Blinding.................................................26
4.3
Hypotheses/Estimation .......................................................................................27
4.4
The Analysis Endpoints......................................................................................27
4.4.1
Efficacy Endpoints..............................................................................................27
4.4.2
Safety Endpoints.................................................................................................27
4.5
Analysis Populations...........................................................................................27
4.5.1
Efficacy Analysis Populations............................................................................27
4.5.2
Safety Analysis Populations ...............................................................................27
4.6
Statistical Methods..............................................................................................27
4.6.1
Statistical Methods for Efficacy Analyses..........................................................28
4.6.2
Statistical Methods for Safety Analyses .............................................................28
4.6.3
Summaries of Baseline Characteristics, Demographics, and 
Other Analyses....................................................................................................29
4.7
Interim Analysis..................................................................................................29
4.8
Multiplicity .........................................................................................................29
4.9
Sample Size and Power Calculations..................................................................29
5. REFERENCES ........................................................................................................................30
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1. INTRODUCTION
This 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 sSAP 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. There will be a separate 
pharmacokinetic data analysis plan as well as a biomarker analysis plan.   
2. SUMMARY OF CHANGES 
Section Number (s)
Section Title(s)
Description 
of 
Change (s)
Rationale
3.6.1
Statistical 
Methods 
for Efficacy Analyses
Note that in addition 
to a positive test for 
the 
treatment 
difference for OS in 
all subjects using the 
stratified max-combo 
test, the upper bound 
of the stratified Cox 
HR should be <1.1.
To allow for a robust 
assessment 
of 
the 
significance of a positive 
assessment 
of 
the 
treatment effect on OS 
based 
only 
on 
the 
stratified 
max-combo 
test. 
3.6.1
Statistical 
Methods 
for Efficacy Analyses
‘A sensitivity  
analysis, which tests 
the hypothesis of 
treatment difference 
for OS in all subjects
using 
the 
stratified 
log-rank test, will be 
conducted.’ 
was 
replaced by ‘Due to 
historical 
precedent, 
the log-rank test as an 
alternative to the max 
combo test for the 
overall 
population 
will also be evaluated, 
including applying the 
log-rank 
in 
the 
multiplicity scheme in 
the same fashion as if 
it were the primary 
testing method.’ In 
Overall Survival and 
Progression-Free 
Due to the historical 
precedent for the log-
rank test, it will be 
evaluated along with the 
as max combo test in the 
same fashion. 
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Section Number (s)
Section Title(s)
Description 
of 
Change (s)
Rationale
analysis.
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3. ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
Statistical Analysis Plan Summary
The key elements of the statistical analysis plan that are summarized below are applicable to the 
Global Cohort; the comprehensive plan is provided in Sections 3.2 through 3.12. Statistical 
analysis plan for the China Cohort is provided in Section 4.
Table 1
Statistical Analysis Plan
Study Design Overview
A Phase III Randomized Open-Label Study of Single Agent Pembrolizumab 
vs. Physicians’ Choice of Single Agent Docetaxel, Paclitaxel, or Irinotecan in 
Subjects with Advanced/Metastatic Adenocarcinoma and Squamous Cell 
Carcinoma of the Esophagus that have Progressed after First-Line Standard 
Therapy (KEYNOTE-181)
Treatment Assignment
Subjects will be randomized in a 1:1 ratio to receive pembrolizumab or 
investigator’s choice of paclitaxel, docetaxel, or irinotecan (Control Arm).
Stratification factors are in Section 5.4. This is an open-label study. 
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary
Endpoints/Hypotheses
1. Overall Survival (OS) in subjects with squamous cell carcinoma of the 
Esophagus.
2. Overall Survival (OS) in subjects with PD-L1 CPS≥10
3. Overall Survival (OS) in all subjects.
Statistical Methods for
Key
Efficacy Analyses
The primary hypotheses will be evaluated by comparing pembrolizumab to the 
control on OS in subjects with squamous cell carcinoma of the esophagus and 
OS in subjects in ESCC subjects and with PD-L1 CPS≥ 10 using a stratified 
Log-rank test. The primary hypotheses on OS in all subjects will be evaluated 
using a stratified maximum weighted log-rank test (max-combo test) [9] [10].
Estimation of the hazard ratio will be done using a stratified Cox regression 
model. Event rates over time will be estimated within each treatment group
using the Kaplan-Meier method.
Statistical Methods for
Key Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers differ 
with respect to the analyses that will be performed. “Tier 1” safety endpoints 
will be subject to inferential testing for statistical significance with p-values
and 95% confidence intervals provided for between-group comparisons. Other 
safety parameters will be considered Tier 2 or Tier 3. Tier 2 parameters will be 
assessed via point estimates with 95% confidence intervals provided for 
between-group comparisons; only point estimates by treatment group are 
provided for Tier 3 safety parameters. There are no Tier 1 events in this trial. 
The between-treatment difference will be analyzed using the Miettinen and 
Nurminen method [1].
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Interim Analyses
One interim efficacy analysis will be performed in this study. Results will be 
reviewed by an external data monitoring committee. Details are provided in
Section 8.7.

Interim Efficacy Analysis
o Timing: To be performed after (1) enrollment is completed, (2) 
approximately 251 OS events and 385 OS events have been 
observed among subjects with squamous cell carcinoma of the 
esophagus and all subjects, respectively, and (3) 8 months after last 
subject randomized. In addition, if there are fewer than 172 OS 
events among subjects with PD-L1 CPS≥10 at the time, the interim 
efficacy analysis may be delayed for up to 2 months or when the 
target number of OS events in subjects with PD-L1 CPS≥10 is 
reached, whichever occurs first.  
o Primary Purpose: Interim efficacy analysis for OS

Final analysis
o
Timing: after approximately 310 OS events and 473 OS 
events have been observed among subjects with squamous cell 
carcinoma of the esophagus and all subjects, respectively , and 
16 months after last subject randomized
Multiplicity
The multiplicity strategy specified in this section will be applied to the three 
primary hypotheses (superiority of pembrolizumab on OS in subjects with 
squamous cell carcinoma of the esophagus, or subjects with PD-L1 CPS≥10%
or in all subjects) and two secondary hypotheses (superiority of pembrolizumab 
on PFS in all subjects or ORR in all subjects). 
The overall Type-I error is strongly controlled at 2.5% (one-sided), with 
initially 0.8% allocated to OS hypothesis in subjects with squamous cell 
carcinoma of the esophagus, 0.9% allocated to OS hypothesis in subjects with 
PD-L1 CPS≥10 and 0.8% allocated to the OS hypotheses in all subjects, and 
0% to the PFS and ORR hypotheses. By using the graphical approach of 
Maurer and Bretz [2], if OS hypothesis in subjects with squamous cell 
carcinoma of the esophagus is rejected, the corresponding alpha level can be 
shifted to OS hypothesis in all subjects. If OS hypothesis in subjects with PD-
L1 CPS≥10 is rejected, the corresponding alpha level can also be shifted to OS 
hypotheses in all subjects. 
The secondary hypotheses of PFS and ORR will be tested only if 
pembrolizumab arm is superior to the control in OS in all subjects. If OS 
hypothesis in all subjects is rejected, the corresponding alpha level can be 
shifted by half to PFS in all subjects and by half to ORR in all subjects,
respectively. 
Sample Size and Power
For the hypotheses in all subjects, the sample size is approximately 600.
Among all subjects, it is expected about 400 subjects with squamous cell 
carcinoma of the esophagus will be enrolled. For the hypotheses in subjects 
with PD-L1 CPS≥10, the sample size is approximately 280 (based on an 
observed prevalence rate of ~47% from KN180). 
For the primary endpoint, OS in subjects with squamous cell carcinoma of the 
esophagus, with 310 OS events, the trial has 91.3% power to demonstrate that 
pembrolizumab is superior to the control at a one-sided 0.8% alpha-level, if the 
underlying hazard ratio of OS is 0.65.
For the primary endpoint, OS in subjects with PD-L1 CPS≥10, with 213 OS 
events, the trial has 90.9% power to demonstrate that pembrolizumab is 
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superior to the control at a one-sided 0.9% alpha-level, if the underlying hazard 
ratio of OS is 0.6.
For the primary endpoint, OS in all subjects, with 473 OS events, the trial has
92.6% power to demonstrate that pembrolizumab is superior to the control at a 
one-sided 0.8% alpha-level, if the underlying hazard ratio of OS is 0.7.
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.
The SPONSOR will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IVRS/IWRS. 
Although the trial is open label, analyses or summaries generated by randomized treatment 
assignment, actual treatment received will be limited and documented. In addition, the central 
imaging vendor will perform the central imaging review without knowledge of treatment group 
assignment.
The eDMC will serve as the primary reviewer of the unblinded results of the interim analyses 
and will make recommendations for discontinuation of the study or modification to an executive 
oversight committee of the Sponsor.
Depending on the recommendation of the eDMC, the 
Sponsor may prepare a regulatory submission. If the eDMC recommends modifications to the 
design of the protocol or discontinuation of the study, this executive oversight committee and 
limited additional Sponsor personnel may be unblinded to results at the treatment level in order 
to act on these recommendations. The extent to which individuals are unblinded with respect to 
results of interim analyses will be documented. Additional logistical details, revisions to the 
above plan and data monitoring guidance will be provided in the eDMC Charter. 
3.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Protocol Section 3.0.
3.4
Analysis Endpoints
3.4.1
Efficacy Endpoints
Primary
Overall Survival
Overall Survival (OS) is defined as the time from randomization to death due to any cause. 
Subjects without documented death at the time of the final analysis will be censored at the date
of the last follow-up.
Secondary
Progression-free survival (PFS) – RECIST 1.1 by central imaging vendor review in all subjects;
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Progression-free-survival (PFS) is defined as the time from randomization to the first 
documented disease progression per RECIST 1.1 based on central imaging vendor review or
death due to any cause, whichever occurs first. See Section 8.6.1 for definition of censoring;
Objective Response Rate (ORR) – RECIST 1.1 by central imaging vendor review in all 
subjects;
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).
Exploratory
Progression-free survival (PFS) – RECIST 1.1 by investigator assessment and irRECIST
assessed by central imaging vendor
Progression-free-survival (PFS) is defined as the time from randomization to the first confirmed 
disease progression or death due to any cause, whichever occurs first. See Section 3.6.1 for 
definition of censoring.
Objective Response Rate (ORR) – RECIST 1.1 by investigator assessment
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).
3.4.2
Safety Endpoints
Safety measurements are described in Protocol Section 7.
3.5
Analysis Populations
3.5.1
Efficacy Analysis Populations
The Intention-to-Treat (ITT) population will serve as the population for primary efficacy 
analysis. All randomized subjects will be included in this population. Subjects will be included in 
the treatment group to which they are randomized.
Details on the approach to handling missing data are provided in Section 3.6 Statistical Methods.
The China Cohort
After the sample size required for the Global Cohort is reached, the study will continue to 
randomize subjects in China until the sample size for the Chinese subjects meets the required 
target for China. The Chinese subjects randomized after the enrollment of the Global Cohort is 
closed will not be included in the above primary efficacy analysis population which is based on 
the Global Cohort. The China Cohort will also be analyzed separately per local regulatory 
requirement.
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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 randomized subjects who received at least one dose 
of study treatment. Subjects will be included in the treatment group corresponding to the study 
treatment they actually received for the analysis of safety data using the ASaT population.  For 
most subjects this will be the treatment group to which they are randomized.  Subjects who take 
incorrect study treatment for the entire treatment period will be included in the treatment group 
corresponding to the study treatment actually received. Any subject who receives the incorrect 
study medication for one cycle but receives the correct treatment for all other cycles will be 
analyzed according to the correct treatment group and a narrative will be provided for any events 
that occur during the cycle for which the subject is incorrectly dosed. 
At least 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.
The China Cohort
The Chinese subjects randomized and treated in the China extension enrollment period will not 
be included in the above primary safety analysis population. The China Cohort will also be 
analyzed separately per local regulatory requirement. 
3.6
Statistical Methods
3.6.1
Statistical Methods for Efficacy Analyses
Efficacy results that will be deemed to be statistically significant after consideration of the Type 
I error control strategy are described in Section 3.8, Multiplicity. Nominal p-values may be 
computed for other efficacy analyses, but should be interpreted with caution due to potential 
issues of multiplicity.
Overall Survival (OS)
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. A 
stratified Cox proportional hazard model with Efron's method of tie handling will be used to 
estimate the magnitude of the treatment difference (i.e., the hazard ratio). The hazard ratio and its 
95% confidence interval from the stratified Cox model with a single treatment covariate will be 
reported. The hypotheses of treatment difference for OS in subjects with squamous cell 
carcinoma of the esophagus and OS in subjects with PD-L1 CPS≥10 will be tested using the 
stratified log-rank test. The hypotheses of treatment difference for OS in all subjects will be 
tested using the stratified max-combo test. The stratification factors used for randomization will 
be applied to both the stratified log-rank test, stratified max-combo test and the stratified Cox 
model if applicable. Note that in addition to a positive test for the treatment difference for OS in 
all subjects using the stratified max-combo test, the upper bound of the stratified Cox HR should 
be <1.1.
The max-combo test statistic is the maximum of the log-rank test statistic and a weighted log-
rank variation of the Fleming-Harrington test statistic; Zm = max (Z1, Z2), where Z1 and Z2 are 
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the test statistics from the FH (0, 0) and FH (0, 1) family of test statistics, respectively. FH (0, 0) 
corresponds to the log-rank test, while FH (0, 1) is more sensitive to late-difference alternatives. 
Due to historical precedent, the log-rank test as an alternative to the max combo test for the 
overall population will also be evaluated, including applying the log-rank in the multiplicity 
scheme in the same fashion as if it were the primary testing method.
Subjects in the control arm are expected to discontinue treatment earlier compared to subjects in 
the pembrolizumab arm, and may switch to another anti PD-1 treatment. Exploratory analyses to 
adjust for the effect of crossover to other PD-1 therapies on OS may be performed based on 
recognized methods, e.g. the Rank Preserving Structural Failure Time (RPSFT) model proposed 
by Robins and Tsiatis (1989) [6] or a two stage model [7], based on an examination of the 
appropriateness of the data to the assumptions required by the methods.
The RPSFT model assumes:

Given two subjects i and j, if i failed before j when both were on one treatment, then i 
would also fail before j if both subjects took the same alternative treatment. 

An equal treatment effect for subjects after switching to a treatment as for those initially 
allocated to receive it.
The RPSFT method uses the Accelerated Failure Time (AFT) model to link the observed 
survival time (T) and the counterfactual survival time (S) that would be observed if no treatment 
were received. Patients randomized to the control arm who never switch to treatment with an 
anti-PD-1 or anti-PD-L1 therapy don’t need any adjustment. Patients randomized to the control 
arm who switch to treatment with an anti-PD-1 or anti-PD-L1 agent need the adjustment for their 
survival time after crossover using the Acceleration Factor. To identify the acceleration factor,
patients who are randomized to treatment arm need to be adjusted by acceleration factor
(unresolved) first for all their observed survival time to counterfactual survival time. Then a grid 
search method is used to get the best estimate of the Acceleration Factor such that the 
counterfactual survival life of treatment arm and control arm would be as close as possible. More 
detailed steps to implement the RPSFT method will be provided in the Programming 
Requirement Specification (PRS) for the macro implementing the RPSFT method.
The two stage method is based on a modified iterative parametric estimation [7]. It assumes:

There are no unmeasured confounders at the secondary baseline time-point (disease 
progression), 

Treatment switching only happens after progression, and happens soon after progression. 
At Stage 1, the date of disease progression is used as a secondary baseline for subjects who have 
a documented progression in the standard of care treatment arm and data from these subjects 
beyond this time-point are considered as an observational dataset.  An accelerated failure time 
(AFT) model including covariates for crossover and other prognostic covariates measured at the 
secondary baseline will be applied to this observational dataset to estimate an acceleration factor.  
At Stage 2, a counterfactual survival dataset will be constructed such that survival time of 
subjects with treatment switching will be shrunk by the inverse of the acceleration factor in order 
to approximate their event time had they not switched treatment, while no shrinkage is 
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performed for the survival time of subjects in the control group without treatment switching or 
subjects in the experimental arm.  A Cox model will then be applied to the counterfactual 
survival dataset to estimate the HR from this two-stage method. More detailed steps to 
implement the two-stage method will be provided in the Programming Requirement 
Specification (PRS) for the macro of two-stage method.
It is very important to assess trial data, crossover mechanism, and treatment effect to determine 
which method is likely to be most appropriate to evaluate the cross-over effect.  
A supportive analysis, which includes PD-L1 status (CPS≥10 vs. CPS<10) and the stratification 
factors used for randomization as the factors in the stratified log-rank test and Cox model, may 
be performed for the all comer population analysis.
Progression-Free Survival (PFS)
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. A stratified Cox proportional hazard model with Efron's method of tie handling 
will be used to estimate the magnitude of the treatment difference (i.e., hazard ratio) between the 
treatment arms. The hazard ratio and its 95% confidence interval from the stratified Cox model 
with Efron's method of tie handling and with a single treatment covariate will be reported. The 
hypotheses of treatment difference for PFS in subjects with squamous cell carcinoma of the 
esophagus and PFS in subjects with PD-L1 CPS≥10 will be tested using the stratified log-rank 
test. The hypotheses of treatment difference for PFS in all subjects will be tested using the 
stratified max-combo test. The stratification factors used for randomization will be applied to 
both the stratified log-rank test, stratified max-combo test and the stratified Cox model if 
applicable.
Due to historical precedent, the log-rank test as an alternative to the max combo test for the 
overall population will also be evaluated, including applying the log-rank in the multiplicity 
scheme in the same fashion as if it were the primary testing method.
Since disease progression is assessed periodically, progressive disease (PD) can occur any time 
in the time interval between the last assessment where PD was not documented and the 
assessment when PD is documented. For the primary analysis, for the subjects who have PD, the 
true date of disease progression will be approximated by the date of the first assessment at which 
PD is objectively documented per RECIST 1.1 by central imaging vendor review, regardless of 
discontinuation of study drug. Death is always considered as a confirmed PD event. Sensitivity 
analyses will be performed for comparison of PFS based on investigator's assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by central imaging 
vendor  review,  we  will  perform  two  sensitivity  analyses  with  a  different  set  of censoring 
rules. The first sensitivity analysis is the same as the primary analysis except that it censors at the 
last disease assessment without PD when PD or death is documented after more than one missed 
disease assessment. The second sensitivity analysis is the same as the primary analysis except 
that it considers discontinuation of treatment or initiation of an anticancer treatment subsequent 
to discontinuation of study-specified treatments, whichever occurs later, to be a PD event for 
subjects without documented PD or death. If a subject meets multiple criteria for censoring, the 
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censoring criterion that occurs earliest will be applied. The censoring rules for primary and 
sensitivity analyses are summarized in Table 2.  If there is an imbalance between the treatment 
groups on disease assessment schedules or censoring patterns, we will also perform additional 
PFS sensitivity analysis: a PFS analysis using scheduled tumor assessment time.
Table 2
Censoring rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and no death; 
new anticancer 
treatment is not 
initiated
Censored at last disease 
assessment 
Censored at last disease 
assessment 
Censored at last disease 
assessment if still on study 
therapy; progressed at 
treatment discontinuation 
No PD and no death; 
new anticancer 
treatment is initiated
Censored at last disease 
assessment before new 
anticancer treatment
Censored at last disease 
assessment before new 
anticancer treatment
Progressed at date of new 
anticancer treatment
No PD and no death; ≥ 
2 consecutive missed 
disease assessments
Censored at last disease 
assessment
Censored at last disease 
assessment prior to ≥2 
consecutive missed 
visits
Censored at last disease 
assessment
PD or death 
documented after ≤ 1 
missed disease 
assessment
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
PD or death 
documented at any 
time after ≥ 2 
consecutive missed 
Progressed at date of 
documented PD or death
Censored at last disease 
assessment prior to 
the ≥ 2 consecutive 
missed disease 
Progressed at date of 
documented PD or death
The proportional hazards assumption on PFS will be examined using both graphical and 
analytical methods if warranted. The log[ -log] of the survival function vs. time to PFS  will be 
plotted for the comparison between pembrolizumab and the control arm. If the curves are not 
parallel, indicating that hazards are not proportional, supportive analyses may be conducted to 
account for the possible non-proportional hazards effect associated with immunotherapies: for 
example, using the Restricted Mean Survival Time (RMST) method [3] or a parametric 
method [4].
The RMST is simply the population average of the amount of event-free survival time 
experienced during the study follow up time. This quantity can be estimated for a treatment 
group by the area under the KM curve up to a specified follow up time. The difference of two 
RMSTs between the two treatment groups will be estimated along with its 95% confidence 
interval. A series of different cutoff time (8 months, 12 months etc.) will be pre-specified prior 
to unblinding of the study by a Merck team who are blinded to the treatment group assignment.
For the parametric method, accelerated failure time model and negative binomial cure rate 
model [8] using an underlying Weibull distribution (using gamlss.cens package in R) may be 
conducted.
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One assumption for the stratified Cox proportional hazard model is that, the treatment hazard 
ratio (HR) is constant across the strata. If strong departures from the assumption of the HR 
being the same for all the strata observed (which can result in a notably biased and/or less 
powerful analysis), a sensitivity analysis may be performed based on a two-step weighted Cox 
model approach by Mehrotra 2012 [5], in which the treatment effect is first estimated for each 
stratum and then the stratum specific estimates are combined for overall inference using sample 
size weights.
A supportive analysis, which includes PD-L1 status (CPS≥10 vs. CPS<10) and the stratification 
factors used for randomization as the factors in the stratified log-rank test and Cox model, may 
be conducted in all subjects for the primary analysis of all comer population only.
Objective Response Rate (ORR)
Stratified Miettinen and Nurminen’s method [1] will be used for comparison of the objective
response rates between the treatment arms. The difference in ORR and its 95% confidence 
interval from the stratified Miettinen and Nurminen’s method with strata weighting by sample 
size will be reported. The stratification factors used for randomization will be applied to the 
analysis if applicable.
Table 3 summarizes the primary analysis approach for primary and secondary efficacy 
endpoints. Sensitivity analysis methods are described above for each endpoint.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, multiple 
populations, and interim analyses is described in Section 3.7 Interim Analyses and in Section 3.8 
Multiplicity.
Table 3
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
†
Statistical Method
Analysis Population
Missing Data
Approach
Primary Hypothesis #1
OS in subjects with squamous 
cell carcinoma of the Esophagus.
Test: Stratified Log-rank 
test Estimation: Stratified 
Cox model with Efron’s 
tie handling method
ITT in subjects with 
squamous cell carcinoma 
of the Esophagus.
Censored at last known
alive date
Primary Hypothesis #2
OS
in subjects with PD-L1 
CPS≥10.
Test: Stratified Log-rank 
test Estimation: Stratified 
Cox model with Efron’s 
tie handling method
ITT in subjects with PD-
L1 CPS≥10
Censored at last known
alive date
Primary Hypothesis #3
OS in all subjects
Test: 
Stratified Max-
combo
Estimation: 
Stratified 
Cox 
model 
with Efron’s tie handling 
method
ITT in all subjects
Censored at last known
alive date
Key Secondary Endpoints
PFS per RECIST 1.1 by central 
imaging vendor
review in all 
subjects
Test: 
Stratified 
Max-
combo
Estimation:
Stratified Cox model with
Efron’s 
tie 
handling
ITT 
in 
all 
subjects
Primary censoring 
rule
Sensitivity analysis 1
Sensitivity analysis 2 
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Endpoint/Variable
(Description, Time Point)
†
Statistical Method
Analysis Population
Missing Data
Approach
method
(More details are in
Table 2)
  ORR per RECIST 1.1 by central 
imaging vendor review in all subjects
Test: Stratified M & N
method‡
ITT in all subjects
Subjects 
with 
missing 
data are considered non-
responders
† Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for
randomization (See Section 5.4) will be applied to the analysis modelif applicable.
‡  Miettinen and Nurminen method [1]
3.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, vital signs, etc.
Tiered Approach
The analysis of safety results will follow a tiered approach (Table 4).  The tiers differ with 
respect to the analyses that will be performed. “Tier 1” safety endpoints that will be subject to 
inferential testing for statistical significance with p-values and 95% confidence intervals 
provided for between-group comparisons. Other safety parameters will be considered Tier 2 or
Tier 3. Tier 2 parameters will be assessed via point estimates with 95% confidence  intervals 
provided for between-group comparisons; only point estimates by treatment group are provided 
for Tier 3 safety parameters.
AEs (specific terms as well as system organ class terms) that are not pre-specified as Tier 1 
endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on the number of events 
observed. Membership in Tier 2 requires that at least 4 subjects in any treatment group exhibit 
the event; all other AEs and predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment groups 
of equal size each have less than 4 events and thus would add little to the interpretation of 
potentially meaningful differences. Because many 95% confidence intervals may be provided 
without adjustment for multiplicity, the confidence intervals should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences in AEs and predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, that are not pre-
specified as Tier-1 endpoints will be considered Tier 3 safety parameters.  Summary statistics for 
baseline, on-treatment, and change from baseline values will be provided by treatment group in 
table format.
Based on the mechanism of action of pembrolizumab and safety data observed in historic 
pembrolizumab trials to date, there are no events of interest that warrant classification as Tier I 
events for this protocol. In addition, the broad clinical and laboratory AE categories consisting of 
the percentage of subjects with any AE, any drug related AE, any Grade 3-5 AE, any serious AE, 
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any AE which is both drug-related and Grade 3-5, any AE which is both serious and drug-
related, dose modification due to AE, and who discontinued due to an AE, and death will be 
considered Tier 2 endpoints. 95% confidence intervals (Tier 2) will be provided for between-
treatment differences in the percentage of subjects with events; these analyses will be performed 
using the Miettinen and Nurminen method (1985) [1], an unconditional, asymptotic method.
Detailed kinetics and characteristics of immune mediated AEs will be summarized in this study.
Table 4
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Serious AE 
X
X
Any Grade 3-5 AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade 3-5 and Drug-Related AE
X
X 
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
Specific AEs, SOCs, or PDLCs‡ (incidence ≥4 of 
subjects in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <4 of 
subjects in all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, Vital 
Signs)
X
Time to Grade 3-5 AE
In addition to the tiered approach, an exploratory analysis may be performed for time to first 
Grade 3-5 AE. Time to first Grade 3-5 AE is defined as the time from the first day of study drug 
to the first event of Grade 3-5 AE. For patients without a Grade 3-5 AE, the time to first Grade 3-
5 AE is censored at 30 days post last study dose. The Kaplan-Meier method will be used to 
estimate the curve of time to first Grade 3-5 AE.  
3.6.3
Statistical Methods for the Exploratory Analyses 
PFS per RECIST 1.1 by investigator assessment and per irRECIST by central imaging 
vendor review
The primary analysis and censoring rule for PFS per RECIST 1.1 by central imaging vendor 
review will also be applied to the analysis for PFS per RECIST 1.1 by investigator assessment, 
and PFS per irRECIST by central imaging vendor review. For PFS per irRECIST by central 
imaging vendor review, 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.
Objective Response Rate (ORR) per RECIST 1.1 by investigator assessment
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The analysis for ORR per RECIST 1.1 by central imaging vendor review will also be applied to 
the analysis for ORR per RECIST 1.1 by investigator assessment.
3.6.4
Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by the 
use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed. 
Demographic variables (e.g., age), baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
3.6.5
Statistical methods for patient-reported outcomes (PRO) endpoints 
3.6.5.1 Statistical methods for PRO endpoints 
The patient-reported outcomes are exploratory objectives in KN181, and thus no formal 
hypotheses were formulated. Nominal p-values to compare the pembrolizumab arm to the 
control arm may be provided as appropriate. 
The PRO instruments are EORTC QLQ-C30, EORTC QLQ-OES18 and EuroQol-5D (EQ-5D).
PRO Endpoints:

The mean score changes from baseline to Week 9 as measured by the EORTC QLQ-C30 
global health status/quality of life scale. 

The mean score change from baseline to Week 9 for all QLQ-C30 sub-scales/items. The 
QLQ-C30 includes five functional dimensions (physical, role, emotional, cognitive, and 
social), three symptom scales (fatigue, nausea/vomiting, and pain), and six single item 
measures (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial 
difficulties). 

The mean score change from baseline to Week 9 for all QLQ-OES18 sub-scales/items. 
The QLQ-OES18 contains 22 items with symptoms of dysphagia (three items), pain (four 
items), reflux symptoms (three items), eating restrictions (four items), anxiety (three 
items), dry mouth, taste, body image, and hair loss.

The mean score change from baseline to Week 9 for EQ-5D VAS and utility score.

The number and proportions of deterioration/ stable/improvement from baseline to Week 
9 for all QLQ-C30 sub-scales/items.

The time to deterioration (TTD) for QLQ-OES18 dysphagia (three items), pain (four 
items) and reflux symptoms (three items).
For multi-item scale(s), the analysis will focus on the subscale score rather than each single 
item.
Scoring Algorithm:
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QLQ-C30 Scoring: For each scale or item, a linear transformation will be applied to standardize 
the score as between 0 and 100, according to the corresponding scoring standard. For functioning 
and global health status/quality-of-life scales, a higher value indicates a better level of function; 
for symptom scales and items, a higher value indicates increased severity of symptoms. 
According to the QLQ-C30 Manuals, if items I1, I2,…,In are included in a scale, the linear 
transformation procedure is as follows:
1. Compute the raw score:
2. Linear transformation to obtain the score S:
Function scales: 
Symptom scales/items: 
Global health status/QoL: 
100
1

Range
RS
S
Range is the difference between the maximum possible value of RS and the minimum possible 
value. If more than half of the items within one scale are missing, then the scale is considered 
missing, otherwise, the score will be calculated as the average score of those available items 
[13].
QLQ-OES18 scoring: QLQ-OES18 contains 18 items with symptoms of dysphagia (three items), 
pain (four items), reflux symptoms (three items), eating restrictions (four items), anxiety (three 
items), dry mouth, taste, body image, and hair loss [14]. 
EQ-5D scoring: EQ-5D utility score will be calculated based on the European algorithm [15]. 
The five health state dimensions in this instrument include the following: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. 
The schedule for PRO data collection: 
Table 5 provides the schedule for PRO data collection.
n
I
I
I
RS
n /)
...
(
2
1




100
1
1










Range
RS
S
100
1 

Range
RS
S
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Table 5  PRO Data Collection Schedule
Treatment 
Week
Disconti
nuation
Visit
Follow-
up
Visit 
0
2/3/
4
6
9
12
18
27
36
45
MK-3475 
C1
C2
C3
C4
C5
C7
C10 
C13
C16
X
X
Paclitaxel 
C1D1
C2D
1
C2D1
5
C3D8
C4D1
C5D15
C7D22
C10D1
C12D8
X
X
Docetaxel
C1
C2
C3
C4
C5
C7
C10 
C13
C16
X
X
Irinotecan
C1D1
C2
D1
C4D1
C5D8
C7D1
C10D1
C14D8
C19D1
C23D8
X
X
C: Cycle; D: Day
Each cycle is 3 weeks for MK-3475.
Each cycle is 4 weeks for Paclitaxel. 
Each cycle is 3 weeks for Docetaxel.
Each cycle is 4 weeks for Irinotecan.
The general rule of mapping relative day to analysis visit is provided in Table 6.
Table 6  Mapping Relative Day to Analysis Visit
Week
0
2/3/4
6
9
12
18
27
36
45
Day
1
21
42
63
84
126
189
252
315
Range
-7-1
2-31
32-52
53- 73
74-105
106-157
158 -220
221-283
284-
At each scheduled visit, three instruments, EORTC QLQ-C30, EORTC QLQ-OES18 and EQ-
5D, will be collected. If a patient does not complete the PRO instruments, the site staff will 
record the reason for missingness from pre-defined choices. If there are multiple PRO collections 
within any of the stated time windows, we use the closest collection to the target day. 
Analysis Populations
The primary analysis approach for the pre-specified exploratory PRO endpoints will be based on 
a quality of life related full analysis set (FAS) population following the intention-to-treat (ITT) 
principle and ICH E9 guidelines. This population consists of all randomized patients who have 
received at least one dose of study medication, and have completed at least one PRO assessment.
Statistical Methods
This section describes the planned analyses for the PRO endpoints. Descriptive statistics (mean, 
SE) of observed data with no imputation for missing data on global HRQoL score and/or key 
functional and symptom scales of the EORTC QLQ-C30 and EORTC QLQ-OES18 will be 
plotted.
Table 7 gives an overview of the analyses planned for all PRO endpoints. 
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Table 7
Planned Statistical Analysis
Endpoint
Analysis
Primary Statistical 
Method
Report
Score change 
from baseline
Treatment effect 
estimation/comp
arison
Mixed effect model 
based on the missing 
at random (MAR) 
assumption.
lsmean score (95% CI) by 
treatment group and visit,  
lsmean score change (95% CI) 
from baseline by treatment 
group and visit, between-
group difference in score 
change from baseline (95% 
CI, nominal p-value).
Proportion of 
deterioration/
stable/improv
ement
Treatment effect 
estimation/comp
arison
Summary with 
multiple imputation 
based on the MAR 
assumption
Proportion (95% CI) by 
treatment group at Week 9
Time to 
deterioration
Treatment effect 
estimation/comp
arison
Stratified log rank 
test
Stratified Cox 
proportional hazard 
model
Kaplan-Meier plot
Hazard Ratio (95% CI, p-
value)
3.6.5.2   Treatment effect on PRO
To assess the treatment effects based on the PRO, for each continuous endpoint defined, a 
constrained longitudinal data analysis (cLDA) model will be used as the primary analysis 
method, with the PRO score as the response variable, and treatment by study visit interaction, 
and stratification factors as covariates. 
The cLDA model is specified as follows:
,...
3,2,1,0
    
,2
,1
    
,
)
0
(
)
(
0






t
j
X
t
I
Y
E
i
it
jt
ijt



, where Yijt is the PRO score for 
subject i, with treatment assignment j, at visit t, 
0

is the baseline mean for both treatment 
groups,
jt

is the mean change from baseline for treatment group j at time t, 
i
X is the 
stratification factor vector for this patient, and 
it
is the coefficient vector for stratification factor 
at time t.
Treatment effect on PRO score change from baseline will be evaluated at Week 9. Treatment 
comparison will be performed and the differences in the lsmean change from baseline will be 
reported, together with 95% C.I. and nominal p-value at the primary analysis time points. 
Most of the patients without disease progression are expected to have complete data up to 9
weeks. Patients with disease progression confirmed or feeling worse due to drug-related AE may 
have missing PRO assessments. The missing data must be handled accordingly to obtain valid 
statistical inference. The cLDA model implicitly treats missing data as missing at random 
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(MAR), i.e. missingness may depend on observed outcomes. Sensitivity analyses may be 
conducted in case the robustness of MAR assumption is questionable.
3.6.5.3   Analysis of the Proportions of Deterioration/Stable/Improvement
Patient’s post-baseline PRO score will be classified as “improved” “stable” or “deteriorated” 
according to a change from baseline ≥10 points for each of the instrument/scale, as this 
magnitude of change is perceived by patients as being clinically significant [12]. 
The number and proportion of patients who were “improved”, “stable”, or “deteriorated”, from 
baseline will be summarized by treatment group at 9 weeks based on MAR imputation (i.e. 
model based) of missing data. 
3.6.5.4   Analysis of the Time to Deterioration
The true time-to-deterioration is defined as the time to first onset of a decrease of ≥10 points 
from baseline with confirmation under right-censoring rule (the last observation). The non-
parametric Kaplan-Meier method will be used to estimate the deterioration curve in each group. 
A stratified Cox proportional hazard model with Efron’s method of tie handling will be used to 
assess the magnitude of the treatment difference (hazard ratio) between treatment arms. 
Compliance Summary
Completion and compliance of QLQ-C30, QLQ-OES18 and EQ-5D by visit and by treatment 
will be described based on PRO FAS population. Numbers and percentages of complete and 
missing data at each visit will be summarized for each of the treatment groups. 
Completion rate in the FAS population is defined as the percentage of number of subjects who 
complete at least one item over the number of subjects in the FAS population at each time points.
ܥ݋݉݌݈݁ݐ݅݋݊ ܴܽݐ݁ൌ ܰݑܾ݉݁ݎ ݋݂ ܵݑܾ݆݁ܿݐݏ ݓ݄݋ ܥ݋݉݌݈݁ݐ݁ ܽݐ ݈݁ܽݏݐ ݋݊݁ ܫݐ݁݉
ܰݑܾ݉݁ݎ ݋݂ ܴܽ݊݀݋݉݅ݖ݁݀ ܵݑܾ݆݁ܿݐݏ
The completion rate is expected to shrink in the later visit during study period due to the subjects 
who discontinued early. Therefore, another measurement, Compliance Rate, defined as the 
percentage of observed visit over number of eligible subjects who are expected to complete the 
PRO assessment (not including the subjects missing by design (such as death, discontinuation, 
translation not available)) will be employed as the support for completion rate.
ܥ݋݉݌݈݅ܽ݊ܿ݁ ܴܽݐ݁ൌ 
ܰݑܾ݉݁ݎ ݋݂ ܵݑܾ݆݁ܿݐݏ ݓ݄݋ ܥ݋݉݌݈݁ݐ݁ ܽݐ ݈݁ܽݏݐ ݋݊݁ ܫݐ݁݉
ܰݑܾ݉݁ݎ ݋݂ ܧ݈ܾ݈݅݃݅݁ ܵݑܾ݆݁ܿݐݏ ݓ݄݋ ܽݎ݁ ܧݔ݌݁ܿݐ݁݀ ݐ݋ ܥ݋݉݌݈݁ݐ݁
Reason for non-completion will be summarized. An instrument is considered complete as at least 
one valid score available according to the missing item rules outlined in the EORTC QLQ-C30 
Manual for each functional and symptoms scale.
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3.7
Interim Analyses
There is one planned interim efficacy analysis in this trial. Results will be reviewed by an 
external data monitoring committee (eDMC).
The primary purpose of the interim efficacy analysis is to evaluate superiority of pembrolizumab 
in OS. In order to account for potential delayed treatment effects that have been observed with 
immunotherapy, the interim efficacy analysis will be performed after: (1) enrollment is 
completed,  (2) approximately 251 OS events and 385 OS events have been observed among 
subjects with squamous cell carcinoma of the Esophagus and all subjects, respectively, and (3) 8 
months after last subject randomized. In addition, if there are fewer than 172 OS events among 
subjects with PD-L1 CPS≥10 at the time, the interim efficacy analysis may be delayed for up to 
2 months or when the target number of OS events in subjects with PD-L1 CPS≥10 is reached, 
whichever occurs first. Thus, adequate follow-up time is incorporated into the trial to ensure that 
the interim efficacy analysis is conducted at an appropriate time to characterize the potential 
benefit of immunotherapy. The boundary for the final analysis will be adjusted according to the 
actual alpha spent at IA and the actual number of events at IA and FA.
For the OS hypothesis, Lan-DeMets O'Brien-Fleming alpha spending function with specified
calendar time fraction (0.76) [11] will be used to construct group sequential boundaries to 
control the Type-I error. 
The actual boundaries for interim analysis will be determined from the number of OS events 
observed at the time of the interim efficacy analysis using the alpha-spending function. The 
actual boundaries for final analysis will be determined from the number of OS events observed at 
the time of the interim efficacy analysis and final analysis using the alpha-spending function. 
Table 8 summarizes the timing, sample size and decision guidance of the interim analysis and 
final analysis. Bounds are based on estimated number of events and will be updated at times of 
analyses using spending functions as noted above.
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Table 8 Summary of Timing, Sample Size and Decision Guidance of Interim Analysis and 
Final analysis
Analysis
Criteria for Conduct of Analysis
Endpoint
Value
Efficacy
Interim Efficacy Analysis
~ 25  months after first subject
randomized
Approximately 251 OS events and 385 
OS events have been observed among 
subjects with squamous cell carcinoma 
of the esophagus and all subjects, 
respectively, and 8 months after last 
subject randomized. 
If there are fewer than 172 OS events 
among subjects with PD-L1 CPS≥10 
at the time, the interim efficacy 
analysis may be delayed for up to 2 
months or when the target number of 
OS events in subjects with PD-L1 
CPS≥10 is reached, whichever occurs 
first. OS events among subjects with 
squamous cell carcinoma of the 
esophagus: ~251
OS events among subjects with PD-L1 
CPS≥10: ~172
OS events among all subjects: 385
OS
in
subjects 
with squamous cell 
carcinoma 
of 
the 
esophagus
p value (1-sided)
at boundary
~ HR at boundary
≤0.0023
0.70
OS
in
subjects
with PD-L1 CPS≥10
p value (1-sided)
at boundary
~ HR at boundary
≤0.0027
0.65
OS
in
all subjects p value (1-sided)
at boundary
~ HR at boundary
≤0.0023
0.75
Final Analysis
~
33
months 
after 
first 
subject
randomized 
Approximately 310 OS events and 473 
OS events have been observed among 
subjects with squamous cell carcinoma 
of the esophagus and all subjects, 
respectively, and 16 months after last 
subject randomized. 
OS
events among subjects with 
squamous cell carcinoma of the 
esophagus: ~310
OS events among subjects with PD-L1 
CPS≥10: ~213
OS events among all subjects: 473
OS
in subjects with 
squamous 
cell 
carcinoma 
of 
the 
esophagus
p value (1-sided)
at boundary
~ HR at boundary
≤0.0075
0.76
OS
in
subjects
with PD-L1 CPS≥10
p value (1-sided)
at boundary
~ HR at boundary
≤0.0084
0.72
OS
in
all subjects p value (1-sided)
at boundary
~ HR at boundary
≤0.0075
0.80
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3.8
Multiplicity
The multiplicity strategy specified in this section will be applied to the three primary hypotheses 
(superiority of pembrolizumab on OS in subjects with squamous cell carcinoma of the esophagus 
or  subjects with PD-L1 CPS≥10 or all subjects) and two secondary hypotheses (superiority of 
pembrolizumab on PFS in all subjects and ORR in all subjects). 
The overall Type-I error is strongly controlled at 2.5% (one-sided), with initially 0.8% allocated 
to OS hypothesis in subjects with squamous cell carcinoma of the esophagus, 0.9% allocated to 
OS hypothesis in subjects with PD-L1 CPS≥10 and 0.8% allocated to OS hypothesis in all 
subjects, and 0% to PFS and ORR hypotheses.
Within each hypothesis, the Type-I error rate for the interim efficacy analysis and final analysis 
is controlled through alpha-spending functions as described in Section 8.7 Interim Analyses.
By using the graphical approach of Maurer and Bretz [2], if OS hypothesis in subjects with 
squamous cell carcinoma of the esophagus is rejected, the corresponding alpha level can be 
shifted to OS hypothesis in all subjects. If the OS hypothesis in subjects with PD-L1 CPS≥10is 
rejected, the corresponding alpha level can also be shifted to the OS hypothesis in all subjects.
The secondary hypotheses of PFS and ORR will be tested only if pembrolizumab arm is superior 
to the control on OS in all subjects. If the OS hypothesis in all subjects is rejected, the 
corresponding alpha level can be shifted by half to PFS in all subjects and half to ORR in all 
subjects. The cumulative alpha spending for PFS hypothesis is determined by the same alpha 
spending function (with calendar fraction=0.76) defined for OS hypotheses. If OS in all subjects 
is not statistically significant at the interim analysis, then ORR at the IA will be considered 
without any data updates if the step-down criteria allow formal testing based on FA of OS in all 
subjects.
See Figure 1 for the multiplicity strategy diagram of the study.
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Figure 1
Multiplicity Strategy
3.9
Sample Size and Power Calculations
The study will randomize subjects in a 1:1 ratio into pembrolizumab arm and the control arm. 
The enrollment is driven by all subjects. The total sample size in the Global Cohort is 
approximately 600. It is expected that approximately 400 subjects with squamous cell carcinoma 
of the esophagus will be enrolled. Based on the observed preliminary prevalence of PD-L1 
CPS≥10 in subjects with esophageal carcinoma of ~47% from MK3475 KN180, for the 
hypotheses in subjects with PD-L1 CPS≥10, the sample size is approximately 280.
The final analysis of the study will complete after approximately 310 OS events and 473 OS 
events have been observed among subjects with squamous cell carcinoma of the esophagus and 
all subjects, respectively, and 16 months after last subject randomized.
OS analysis 
The sample size and power calculations are based on the following assumptions: 1) Overall 
survival follows an exponential distribution with a median of 8 months in the control arm; 2) an 
enrollment period of 17 months and a minimum of 16 months follow-up after enrollment 
completion; 3) a yearly dropout rate of 2%.
The final OS analysis will be carried out after approximately 310 OS events and 473 OS events 
have been observed among subjects with squamous cell carcinoma of the esophagus and all 
subjects,
respectively, and 16 months after last subject randomized. It is expected that 
approximately 213 OS events would have been observed in subjects with PD-L1 CPS≥10. With 
310/213/473 OS events in subjects with squamous cell carcinoma of the esophagus/subjects with 
PD-L1 CPS≥10/all subjects, respectively, the trial has at least 91.3%/90.9%/92.6% power to 
demonstrate that pembrolizumab is superior to the control at a one-sided 0.8%/0.9%/0.8% alpha-
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level, if the underlying hazard ratio of OS is 0.65/0.6/0.7. Success for OS at the final analysis 
approximately corresponds to an observed hazard ratio of < 0.76 for subjects with squamous cell 
carcinoma of the esophagus, 0.72 for subjects with PD-L1 CPS≥10, and < 0.80 for all subjects.
To further investigate the impact of the delayed separation of OS curve on the actual power in all 
subjects, a simulation was carried out using the current study design parameters described above 
but with a piece-wise time varying hazard ratio: the hazard ratio was specified as 1 and 0.6 at the 
beginning of time intervals of Month 0 and 5 since randomization respectively. With 1,000 
simulations the overall study power with 473 events at the final analysis given the hazard ratio 
assumption above is approximately 74.7% using log-rank test statistics and 86% using max-
combo test statistics.
The China Cohort
After the enrollment for the Global Cohort has completed, the study will continue to randomize 
subjects in a 1:1 ratio into the pembrolizumab arm and the SOC arm in China until the sample 
size for the Chinese subjects overall reaches approximately 120. Chinese subjects randomized 
after completion of enrollment in the Global Cohort will not be included in the analyses of the 
Global Cohort.
3.10
Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the estimate of 
the between-group treatment effect (with a nominal 95% CI) for the three primary endpoints 
(OS) will be estimated and plotted within each category of the following classification variables:

Age category (<65 vs. ≥65 years)

Sex (Female vs. Male)

Geographic region (Asia vs. Rest of the World)

ECOG Performance Scale (0 vs. 1)

Histological subtype (Squamous cell carcinoma vs. adenocarcinoma/Siewert type 1 
adenocarcinoma of the EGJ)
For OS, the stratified Cox model will be used. The consistency of the treatment effect will be 
assessed descriptively via summary statistics by category for the classification variables listed 
above. If any level of a subgroup variable has fewer than 10% of the ITT population, above 
analysis will not be performed for this level of the subgroup variable. If a subgroup variable has 
two levels and one level of the subgroup variable has fewer than 10% of the ITT population, then 
this subgroup will not be displayed in the forest plot. 
Asia includes China, Japan, Korea, Hong Kong, Taiwan, Malaysia, Thailand, and Singapore.
In addition to the subgroup based on Asia vs. Rest of the World, US vs. ex-US and EU vs. ex-
EU will also be assessed. 
The EU region includes countries from both EU member states (2016) and EFTA members.
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Country specific population (e.g. Chinese, Japanese, etc.) may also be analyzed per local 
regulatory requirements.
3.11
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported. 
3.12
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
4. STATISTICAL ANALYSIS PLAN FOR CHINA COHORT
4.1
Introduction
Approximately 120 subjects from China will be enrolled in the China Cohort; this will include 
subjects enrolled in China during the global enrollment period as well as during the China 
extension enrollment period. After the enrollment in the Global Cohort is closed, subjects from 
China will continue to be enrolled in the China extension period designed to meet local 
regulatory needs. The China Cohort will be identical to the Global Cohort (e.g., inclusion and 
exclusion criteria, study endpoints, primary and secondary objectives, study procedures) in 
general, with additional statistical analyses for the China Cohort.
The purpose of the China Cohort is to evaluate the consistency of efficacy and safety in the 
Chinese subpopulation and the global population. Country-specific analysis may also be 
conducted per local regulatory requirement.
After the enrollment in the Global Cohort is completed, subjects in China will continue to be 
enrolled in a 1:1 ratio into the pembrolizumab arm and the SOC arm until the sample size in this 
subpopulation reaches approximately 120. 
After the cut-off date for the primary analyses based on the Global Cohort (including interim and 
final analyses), all Chinese subjects, including subjects enrolled in the Global Cohort and those 
enrolled during the China extension period, will continue their randomized treatment and 
continue to be followed up for OS events for China registration purpose. The China Cohort will 
be completed after the target number of OS events has been observed between the two arms in 
all Chinese subjects and 8 months after last Chinese subject randomized. The expected timing of 
the analysis for the China Cohort is about 23 months from when the first Chinese subject is 
randomized in the Global Cohort. Additional analyses may be considered for China Cohort based 
on Sponsor’s discretion and/or consultation with regulatory if global final analysis shows 
positive results and leads to filing.  
4.2
Responsibility for Analyses/In-House Blinding
Although the trial is open-label, analyses or summaries generated by randomized treatment 
assignment and actual treatment received will be limited and documented. Subjects randomized 
in the China extension period will not be included in the data base locked for the analysis of the 
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global Cohort. For all Chinese subjects, including subjects randomized in the Global Cohort and 
the extension period, patient level treatment randomization information, will be in-house blinded 
in the analysis team for statistician(s)/programmer(s) responsible for the China analysis until the 
data base lock for China.
4.3
Hypotheses/Estimation
No hypothesis testing is planned for the China Cohort.
After succeeding in the global trial, the consistency of efficacy and safety in the Chinese 
subpopulation to the global population will be evaluated. Consistency of efficacy will be 
evaluated using the percentage of risk reduction preserved in the Chinese subpopulation from the 
empirical risk reduction based on the global primary efficacy analyses (based on point 
estimates). The planned sample size for the China Cohort is estimated to provide about 80% 
chance of that the observed point estimate in the Chinese subpopulation preserves at least 
approximately 50% of the empirical risk reduction based on the global primary efficacy analysis 
assuming the same hazard ratio used in the sample size and power calculation for the Global 
Cohort.  
4.4
The Analysis Endpoints
4.4.1
Efficacy Endpoints
Efficacy endpoints are the same as described in section 3.4.1.
4.4.2
Safety Endpoints
Safety endpoints are the same as described in Section 3.4.2.
4.5
Analysis Populations
4.5.1
Efficacy Analysis Populations
The efficacy analysis population will include subjects based on the intention-to-treat (ITT) 
principle, i.e., subjects will be included in the treatment group to which they are randomized.  
For the China Cohort this population will include all Chinese subjects by their assigned treatment 
groups in this population. 
4.5.2
Safety Analysis Populations
Safety analysis will be carried out in the All Subjects as Treated (ASaT) population which 
consists of all randomized subjects who received at least 1 dose of study treatment.  The China 
Cohort will include all Chinese subjects in this population. 
4.6
Statistical Methods
No formal testing of hypotheses is planned. Nominal p-values will be computed as noted below. 
However, the focus of analyses will be estimation of treatment effects, including confidence 
intervals and a comparison of these estimates between the China and global Cohorts.
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4.6.1
Statistical Methods for Efficacy Analyses
Overall Survival (OS)
Analysis of OS is the same as that for the Global Cohort as applicable. 
In detail, the Kaplan-Meier method will be used to estimate the survival curves. For the whole 
population, stratified log-rank will be used to assess the treatment difference and stratified Cox 
proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (i.e., the hazard ratio). The hazard ratio and its 95% 
confidence interval from the stratified Cox model with a single treatment covariate will be 
reported. The same stratification factors used in the global Cohort will be used. For the Chinese 
subgroup analysis, the stratified method will only be used if applicable. The factor of Geographic 
region (Asia vs. Rest of World) will not be included in the stratified analysis for Chinese 
subgroup analysis. 
Consistency in OS between the China and Global Cohorts will be evaluated.
In addition, supportive analyses on the entire ITT population will be provided with the data 
pooled the global Cohort (prior to data cutoff for the primary analysis) and Chinese subjects 
together. Accordingly, non-Chinese subjects will be censored at the data cut off for the primary 
analysis in the global study if subjects are still alive at that time.
Progression-Free Survival (PFS)
Analysis of PFS is the same as that for the global Cohort if applicable. 
In detail, the Kaplan-Meier method will be used to estimate the survival curves. For the Global 
Cohort, stratified log-rank test will be used to assess the treatment difference and stratified Cox 
proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (i.e., the hazard ratio). The hazard ratio and its 95% 
confidence interval from the stratified Cox model with a single treatment covariate will be 
reported. For the Chinese subgroup analysis, the stratified method will only be used if applicable. 
The factor of Geography (Asia vs. Rest of World) will not be included in the stratified analysis 
for Chinese subgroup analysis. 
Objective Response Rate (ORR)
Analysis of ORR is the same as that for the global Cohort if applicable. 
Exploratory Analyses
Exploratory analyses are the same to that for the global study (if applicable).
4.6.2
Statistical Methods for Safety Analyses
Safety analyses are the same to that for the main study as described in Section 3.6.2.  
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4.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
They are the same to that for the global study as described in Section 3.6.4. 
4.7
Interim Analysis 
No interim analysis is planned. 
4.8
Multiplicity
No multiplicity adjustment will be applied. 
4.9
Sample Size and Power Calculations
After the sample size for the Global Cohort reaches approximately 600, global enrollment period 
will finish and the study will continue to randomize subjects in a 1:1 ratio into the 
Pembrolizumab arm and the SOC arm in China extension period until the sample size for the 
Chinese subpopulation reaches approximately 120. All Chinese subjects will be included in the 
China primary analysis.  Whereas, the Chinese subjects enrolled in extension period, i.e., those 
Chinese subjects randomized after the global LPI, will not be included in the global primary 
analysis. 
The extension study will complete after approximately 75 deaths have been observed between 
the two arms in the China Cohort and 8 months after last subject randomized assuming the 
underlying hazard ratio is 0.70. With 75 deaths and a true hazard ratio of 0.70, the extension 
study has >90% chance to observe a hazard ratio on OS <1 and ~80%  chance to observe a point 
estimate that preserves approximately at least 50% of the empirical risk reduction from the
global analysis in the Chinese subpopulation assuming the underlying hazard ratio is 0.70 
respectively. The above calculations for the consistency evaluation are based on the same 
assumptions on the median OS and the true hazard ratio.
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5. REFERENCES 
1.
Miettinen O, Nurminen M. Comparative analysis of two rates. Statistics in Medicine 
1985; 4:213-226.
2.
Maurer W, Bretz F. Multiple Testing in Group Sequential Trials using Graphical 
Approaches. Statistics in Biopharmaceutical Research 2013; 5(4): 311-320.
3.
Uno, H., et al. Moving Beyond the Hazard Ratio in Quantifying the Between-Group 
Difference in Survival Analysis. J Clin Oncol. 2014; 32 (22): 2380-2385.
4.
Odell P.M., Anderson K.M., Kannel B.W. New models for predicting cardiovascular 
events. Journal of Clinical Epidemiology 1994; 47(6): 583-592.
5.
Mehrotra D., Su S.C., Li X.  An efficient alternative to the stratified Cox model analysis. 
Statist. Med. 2012, 31 1849–1856.
6.
Robins, J.M., Tsiatis, A.A. Correcting for non-compliance in randomized trials using 
rank preserving structural failure time models. Communications in Statistics-Theory and 
Methods, 1991;20 (8): 2609-2631.
7.
Latimer, N.R., Abrams, K.R., Lambert, P.C., Crowther, M.J., Wailoo, A.J., Morden,J.P. 
et al. Adjusting Survival Time Estimates to Account for Treatment Switching in
Randomized controlled Trials - an Economic Evaluation Context: Methods,Limitations, 
and Recommendations. Medical Decision Making 2013.
8.
De Castro, M., V.G. Cancho and J. Rodrigues, 2010. A hands-on approach for fitting 
long-term survival models under the GAMLSS framework. Comput. Methods Programs 
Biomed., 97: 168-177.
9.
Lee, S.-H. 2007. On the versatility of the combination of the weighted log-rank statistics.
Computational Statistics and Data Analysis 51: 6557–6564.
10.
Karrison T.G, 2016. Versatile tests for comparing survival curves based on weighted log-
rank statistics. The Stata Journal (2016).
11.
Lan KKG, DeMets DL.  Group sequential procedures: calendar versus information time: 
biostatics technical report. Madison (WI): University of Wisconsin Clinical Cancer 
Center (US); 1988 May. 16 p. Report No.:44.
12.
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes 
in health-related quality-of-life scores. J Clin Oncol 1998; 16:139-44.
13.
The EORTC QLQ-C30 Manuals, Reference Values and Bibliography.
14.
Blazeby JM, Conroy T, Hammerlid E, Fayers P, Sezer O, Koller M, et al. Clinical and 
psychometric validation of an EORTC questionnaire module, the EORTC QLQ-OES18, 
to assess quality of life in patients with oesophageal cancer. Eur J Cancer. 2003 
Jul;39(10):1384-94.
15.
EQ-5D-3L User Guide, Oct 2013.
085M9Z

Prot_001.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase III Randomized Open-Label Study of Single Agent 
Pembrolizumab vs. Physicians’ Choice of Single Agent Docetaxel, 
Paclitaxel, or Irinotecan in Subjects with Advanced/Metastatic 
Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus that 
have Progressed after First-Line Standard Therapy (KEYNOTE-181)
25-Jun-2021
NCT02564263


Product:  MK-3475 
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Protocol/Amendment No.: 181-06 
MK-3475-181-06 Final Protocol
25-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 III Randomized Open-Label Study of Single Agent Pembrolizumab vs. Physicians’ 
Choice of Single Agent Docetaxel, Paclitaxel, or Irinotecan in Subjects with 
Advanced/Metastatic Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus that 
have Progressed after First-Line Standard Therapy (KEYNOTE-181)
IND NUMBER:  123,482
EudraCT NUMBER:  2015-002782-32
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Confidential
TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 13
1.0
TRIAL SUMMARY.................................................................................................. 15
2.0
TRIAL DESIGN........................................................................................................ 16
Trial Design ........................................................................................................... 16
Trial Diagram........................................................................................................ 19
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 20
Primary Objective(s) & Hypothesis(es).............................................................. 20
Secondary Objective(s) & Hypothesis(es)........................................................... 21
Exploratory Objectives......................................................................................... 21
4.0
BACKGROUND & RATIONALE.......................................................................... 22
Background ........................................................................................................... 22
Pharmaceutical and Therapeutic Background .................................................... 22
Pre-clinical and Clinical Trials ........................................................................... 23
Preclinical Studies........................................................................................ 23
Ongoing Clinical Trials....................................................................................... 23
Rationale................................................................................................................ 24
Rationale for the Trial and Selected Subject Population .................................... 24
Rationale for Dose Selection/Regimen/Modification......................................... 25
Rationale for the Use of Pembrolizumab..................................................... 25
Rationale for the Use of Comparator........................................................... 26
Rationale for using the Intratumoral Immune-related Gene Expression 
Profile (GEP) in Esophageal Cancer ........................................................... 28
Rationale for Endpoints ...................................................................................... 28
Primary Efficacy Endpoints......................................................................... 28
Secondary Efficacy Endpoints..................................................................... 28
Safety Endpoints.......................................................................................... 29
Exploratory Endpoints ................................................................................. 29
4.2.3.4.1
Immune-related RECIST (irRECIST) .................................................. 29
4.2.3.4.2
Patient Reported Outcomes .................................................................. 30
Biomarker Research..................................................................................... 31
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4.2.3.5.1
Biomarker Research for Primary Objectives........................................ 31
4.2.3.5.2
Biomarker Research for Exploratory Objectives.................................. 31
Future Biomedical Research........................................................................ 32
Benefit/Risk ........................................................................................................... 33
5.0
METHODOLOGY ................................................................................................... 33
Entry Criteria........................................................................................................ 33
Diagnosis/Condition for Entry into the Trial...................................................... 33
Subject Inclusion Criteria.................................................................................... 33
Subject Exclusion Criteria .................................................................................. 36
Trial Treatment(s) ................................................................................................ 38
Dose Selection/Modification .............................................................................. 39
Dose Selection (Preparation) ....................................................................... 39
Dose Modification (Escalation/Titration/Other).......................................... 39
5.2.1.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).......................................................................................... 39
5.2.1.2.2
Dose Modification for Paclitaxel, Docetaxel and Irinotecan................ 44
Timing of Dose Administration.......................................................................... 44
Pembrolizumab ............................................................................................ 44
Paclitaxel...................................................................................................... 45
Docetaxel ..................................................................................................... 45
Irinotecan ..................................................................................................... 46
Trial Blinding/Masking....................................................................................... 46
Randomization or Treatment Allocation............................................................ 47
Stratification.......................................................................................................... 47
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 47
Acceptable Concomitant Medications ................................................................ 47
Prohibited Concomitant Medication................................................................... 48
Rescue Medications & Supportive Care............................................................. 49
Supportive Care Guidelines for Pembrolizumab ................................................ 49
Supportive Care Guidelines for Paclitaxel, Docetaxel and Irinotecan................ 49
Diet/Activity/Other Considerations..................................................................... 50
Diet...................................................................................................................... 50
Contraception...................................................................................................... 50
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Use in Pregnancy ................................................................................................ 53
Use in Nursing Women....................................................................................... 53
Subject Withdrawal/Discontinuation Criteria................................................... 53
Discontinuation of Treatment ............................................................................. 53
Discontinuation of Study Therapy after Complete Response............................. 54
Withdrawal from the Trial .................................................................................. 55
Subject Replacement Strategy............................................................................. 55
Beginning and End of the Trial ........................................................................... 55
Clinical Criteria for Early Trial Termination ................................................... 55
6.0
TRIAL FLOW CHART ........................................................................................... 57
Trial Flow Chart – Initial Treatment Phase for Pembrolizumab Arm........... 57
Trial Flow Chart –Treatment Phase for Paclitaxel ........................................... 61
Trial Flow Chart –Treatment Phase for Docetaxel ........................................... 65
Trial Flow Chart –Treatment Phase for Irinotecan.......................................... 68
Second Course Phase (Retreatment with Pembrolizumab).............................. 72
7.0
TRIAL PROCEDURES ........................................................................................... 74
Trial Procedures ................................................................................................... 74
Administrative Procedures.................................................................................. 74
Informed Consent......................................................................................... 74
7.1.1.1.1
General Informed Consent.................................................................... 74
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 75
Inclusion/Exclusion Criteria ........................................................................ 75
Subject Identification Card .......................................................................... 75
Medical History ........................................................................................... 75
Disease Details............................................................................................. 75
Prior and Concomitant Medications Review............................................... 75
7.1.1.6.1
Prior Medications.................................................................................. 75
Prior Treatment Details for Esophageal or EGJ Carcinoma .......... 76
7.1.1.6.2
Concomitant Medications..................................................................... 76
7.1.1.6.3
Subsequent Anti-Cancer Therapy Status .............................................. 76
Assignment of Screening Number............................................................... 76
Assignment of Treatment/Randomization Number..................................... 76
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Trial Compliance (Medication/Diet/Activity/Other)................................... 77
Clinical Procedures/Assessments........................................................................ 77
Adverse Event Monitoring........................................................................... 77
Physical Exam.............................................................................................. 77
7.1.2.2.1
Full Physical Exam ............................................................................... 77
7.1.2.2.2
Directed Physical Exam........................................................................ 78
Height, Weight, and Vital Signs .................................................................. 78
12-Lead Electrocardiogram ......................................................................... 78
Eastern Cooperative Oncology Group Performance Status......................... 78
Patient Reported Outcome........................................................................... 78
Laboratory Procedures/Assessments .................................................................. 79
Laboratory Safety Evaluations..................................................................... 79
7.1.3.1.1
Pregnancy Tests .................................................................................... 80
Central Laboratory Assessments.................................................................. 80
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 80
7.1.3.3.1
Blood Collection for Serum MK-3475 ................................................. 80
7.1.3.3.2
Blood Collection for Anti-pembrolizumab (MK-3475) Antibodies..... 80
7.1.3.3.3
Correlative and Biomarker Blood Samples .......................................... 81
Planned Genetic Analysis Sample Collection.............................................. 81
Future Biomedical Research Sample Collection ......................................... 81
Tumor Tissue ............................................................................................... 81
Efficacy Measurements....................................................................................... 81
Tumor Imaging and Assessment of Disease................................................ 81
7.1.4.1.1
Initial Tumor Imaging........................................................................... 82
7.1.4.1.2
Tumor Imaging During the Trial .......................................................... 82
7.1.4.1.3
End of Treatment and Follow-up Tumor Imaging................................ 83
7.1.4.1.4
Second Course (Retreatment) Tumor Imaging..................................... 83
7.1.4.1.5
RECIST 1.1 Assessment of Disease..................................................... 84
7.1.4.1.6
irRECIST Assessment of Disease......................................................... 84
Other Procedures................................................................................................. 87
Withdrawal/Discontinuation........................................................................ 87
7.1.5.1.1
Withdrawal From Future Biomedical Research ................................... 88
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7.1.5.1.2
Lost to Follow-up.................................................................................. 88
7.1.5.2
Blinding/Unblinding .................................................................................... 89
Calibration of Equipment............................................................................. 89
Visit Requirements.............................................................................................. 89
Screening...................................................................................................... 89
Treatment Period.......................................................................................... 90
Post-Trial Visits ........................................................................................... 91
7.1.6.3.1
Safety Follow-up Visits ........................................................................ 91
7.1.6.3.2
Follow-up Visits ................................................................................... 91
7.1.6.3.3
Survival Follow-up ............................................................................... 92
Survival Status................................................................................ 92
Assessing and Recording Adverse Events .......................................................... 92
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 93
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 93
Immediate Reporting of Adverse Events to the Sponsor.................................... 94
Serious Adverse Events ............................................................................... 94
Events of Clinical Interest............................................................................ 95
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 96
Evaluating Adverse Events................................................................................. 96
Sponsor Responsibility for Reporting Adverse Events ...................................... 99
TRIAL GOVERNANCE AND OVERSIGHT................................................... 99
Scientific Advisory Committee........................................................................... 99
Executive Oversight Committee......................................................................... 99
Data Monitoring Committee............................................................................... 99
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 100
Statistical Analysis Plan Summary ................................................................... 100
Responsibility for Analyses/In-House Blinding ............................................... 102
Hypotheses/Estimation....................................................................................... 102
Analysis Endpoints ............................................................................................. 102
Efficacy Endpoints............................................................................................ 102
Safety Endpoints ............................................................................................... 103
Analysis Populations........................................................................................... 103
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Efficacy Analysis Populations .......................................................................... 103
Safety Analysis Populations ............................................................................. 103
Statistical Methods.............................................................................................. 104
Statistical Methods for Efficacy Analyses........................................................ 104
Overall Survival (OS) ................................................................................ 104
Progression-Free Survival (PFS)................................................................ 105
Objective Response Rate (ORR) ............................................................... 106
Statistical Methods for Safety Analyses ........................................................... 107
Summaries of Demographic and Baseline Characteristics ............................... 109
Interim Analyses ................................................................................................. 109
Multiplicity .......................................................................................................... 112
Sample Size and Power Calculations ................................................................ 113
Subgroup Analyses and Effect of Baseline Factors.......................................... 114
Compliance (Medication Adherence)................................................................ 114
Extent of Exposure.............................................................................................. 114
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 115
Investigational Product ...................................................................................... 115
Packaging and Labeling Information ............................................................... 115
Clinical Supplies Disclosure............................................................................... 116
Storage and Handling Requirements................................................................ 116
Discard/Destruction/Returns and Reconciliation ............................................ 116
Standard Policies................................................................................................. 116
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 117
Confidentiality..................................................................................................... 117
Confidentiality of Data ..................................................................................... 117
Confidentiality of Subject Records................................................................... 117
Confidentiality of Investigator Information...................................................... 117
Confidentiality of IRB/IEC Information........................................................... 118
Compliance with Financial Disclosure Requirements..................................... 118
Compliance with Law, Audit and Debarment ................................................. 118
Compliance with Trial Registration and Results Posting Requirements...... 120
Quality Management System............................................................................. 120
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Data Management............................................................................................... 121
Publications ......................................................................................................... 121
11.0
LIST OF REFERENCES....................................................................................... 123
12.0
APPENDICES......................................................................................................... 128
Merck Code of Conduct for Clinical Trials...................................................... 128
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 130
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 134
Response Evaluation Criteria in Solid Tumors ............................................... 145
ECOG Performance Status................................................................................ 146
Common Terminology Criteria for Adverse Events ....................................... 147
List of Abbreviations .......................................................................................... 148
13.0
SIGNATURES......................................................................................................... 151
Sponsor's Representative ................................................................................... 151
Investigator.......................................................................................................... 151
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LIST OF TABLES
    
Table 1
Adequate Organ Function Laboratory Values...................................................... 35
Table 2
Trial Treatment ..................................................................................................... 38
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse 
Events 
Associated 
with 
Pembrolizumab 
Monotherapy, 
Coformulations or IO Combinations .................................................................... 40
Table 4
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines ............................................................................................................. 43
Table 5
Laboratory Tests ................................................................................................... 79
Table 6
Imaging and Treatment after First Radiologic Evidence of PD ........................... 86
Table 7
Evaluating Adverse Events................................................................................... 97
Table 8
Statistical Plan Analysis Summary..................................................................... 100
Table 9
Censoring rules for Primary and Sensitivity Analyses of PFS ........................... 106
Table 10
Analysis Strategy for Key Efficacy Endpoints................................................... 107
Table 11
Analysis Strategy for Safety Parameters............................................................. 109
Table 12
Summary of Timing, Sample Size and Decision Guidance of Interim Efficacy  
Analysis and Final Analysis................................................................................ 111
Table 13
Product Descriptions........................................................................................... 115
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LIST OF FIGURES
          
Figure 1
China Enrollment Strategy.................................................................................... 19
Figure 2
Trial Design Schematic......................................................................................... 20
Figure 3
Imaging and Treatment for Clinically Stable Subjects after First Radiologic 
Evidence of PD Assessed by the Site ................................................................... 87
Figure 4
Multiplicity Strategy........................................................................................... 112
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-181-06
25-JUN-2021
To update the dose modification and toxicity management guidelines for irAEs.
To clarify the concomitant use of COVID-19 vaccines.
3475-181-05
08-MAR-2018
The alpha spending function to control the Type-I error based on information fraction 
was replaced with one based on specified calendar time fraction (0.76). Due to 
potential delayed treatment effects that have been observed with immunotherapy, the 
stratified log-rank test was replaced by a stratified max-combo test for testing the OS 
and PFS hypotheses in all subjects. Max-combo test statistic is the maximum of test 
statistics based on the log-rank test and a test that down-weights the early events, and 
hence, is sensitive to the non-proportional hazards assumption.
3475-181-04
03-AUG-2017
The primary objectives were changed from dual endpoints of OS and PFS to a single 
endpoint of OS, based on recommendations from emerging data in MK-3475-
KEYNOTE-180. The timing of the interim and final analyses was updated in order to 
wait for more mature OS data and account for a potential delayed separation in 
survival curves observed in immuno-oncology studies.
3475-181-03
29-MAR-2017
To extend the enrollment period beyond the Global Cohort to achieve the required 
sample size of the China Cohort and the number of events to investigate efficacy and 
safety in Chinese 2L EC subjects.
3475-181-02
09-DEC-2016
Sections were revised to identify GEP low, intermediate, and high tumors; to describe 
the development of GEP cut-off “GEP intermediate or high” and/or to describe how 
the primary, secondary, and exploratory objectives and endpoints will be met and 
analyzed, respectively, based on these tumor designations
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Document
Date of Issue
Overall Rationale
3475-181-01
20-JUL-2016
All sections were revised to describe the development of 2 GEP cutpoints to identify 
GEP low, intermediate, and high tumors; and/or to describe how the primary, 
secondary, and exploratory objectives and endpoints will be met and analyzed, 
respectively, based on these tumor designations.
3475-181-00
25-AUG-2015
Original protocol.
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SUMMARY OF CHANGES
PRIMARY REASON FOR THIS AMENDMENT:
Section Number
Section Title
Description of Change
Rationale
5.2.1.2.1
Immune-Related Events and 
Dose Modification (Withhold, 
Treat, Discontinue)
The dose modification and toxicity 
management 
guidelines 
for 
immune-related 
adverse 
events 
(irAEs) and table were updated.
The dose modification and toxicity 
management guidelines for irAEs and 
table were updated as requested by the 
U.S. Food and Drug Administration
(FDA) in an effort to harmonize the 
presentation of safety information 
across all FDA-approved programmed 
cell death 1/ligand 1 (PD-1/L1)
antibody prescribing information.
ADDITIONAL CHANGE 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.
5.10
Beginning and End of the 
Trial
Added language to state that upon 
study completion, subjects may be 
enrolled 
in 
a 
pembrolizumab 
extension study, if available.
Subjects may be enrolled in a 
pembrolizumab extension study upon 
study completion.
5.5.2
Prohibited 
Concomitant 
Medication
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.
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.1.8
Assignment 
of 
Treatment/Randomization 
Number
Added language to state that if 
subjects are rerandomized, each 
subject will retain his/her original 
treatment/randomization number.
To clarify that each subjects’ original 
treatment/randomization 
will 
be 
retained if subjects are enrolled in an 
extension study.
1.0, 5.1.2, 5.10, 
7.1.1.1.2, 7.1.1.3
Trial 
Summary, 
Subject 
Inclusion Criteria, Beginning 
and End of the Trial, Consent 
and Collection of Specimens 
for 
Future 
Biomedical 
Research, 
Subject 
Identification Card
Updated 
informed 
consent 
language 
to 
provide 
for 
documentation of consent.
To align text with legal requirements 
to obtain informed consent.
Overall
Overall
Minor editorial changes.
For clarity.
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1.0 TRIAL SUMMARY
Abbreviated Title
A Phase III study of Pembrolizumab vs. Physicians’ choice of Docetaxel, 
Paclitaxel or Irinotecan in 2L Subjects with Advanced/Metastatic 
Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus
Trial Phase
Phase III
Clinical Indication
Advanced/metastatic adenocarcinoma and squamous cell carcinoma of 
the esophagus and advanced/metastatic Siewert type I adenocarcinoma
of the esophagogastric junction (EGJ)
Trial Type
Interventional
Type of control
Active control without placebo
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
Arm 1: Pembrolizumab (MK-3475) 200 mg IV every 3-weeks
Arm 2: Investigator’s choice of:
- Paclitaxel 80-100 mg/m2 on Days 1, 8, and 15 of every 28-day 
(4-week) cycle, OR
- Docetaxel 75 mg/m2 on Day 1 of every 21-day (3-week) cycle, OR
- Irinotecan 180 mg/m2 on Day 1 of every 14-day (2-week) cycle
Number of trial subjects
The Global Cohort: Approximately 600 subjects will be enrolled.
The China Cohort: Approximately 120 Chinese subjects overall will be 
enrolled in the China Cohort.
The China Cohort will enroll 120 subjects in two enrollment periods: 1) 
The Global enrollment period: part of enrollment in the China cohort 
will contribute towards enrollment in the Global Cohort until the Global 
Cohort completes enrollment of approximately 600 subjects.  2) The 
China extension enrollment period: Remaining enrollment in China 
cohort will occur in the China extension period until approximately 120 
total subjects are enrolled in the China cohort.
Estimated duration of trial
The Global Cohort: The Sponsor estimates that the cohort will require 
approximately 36 months from the time the first subject provides
informed consent until the last subject’s last study-related phone call or 
visit.
The China Cohort: The Sponsor estimates that the cohort will require 
approximately 2 additional years from the time the first subject provides
informed consent until the last subject’s last visit.
Duration of Participation
Each subject will participate in the trial from the time the subject 
provides documented informed consent through the final contact. After a 
screening phase of up to 28 days, eligible subjects will receive treatment 
beginning on Day 1 of each 3-week dosing cycle for pembrolizumab or 
investigator’s choice of paclitaxel (Days 1, 8, and 15 of every 28-day 
cycle), docetaxel (Day 1, every 21-day cycle), or irinotecan (Day 1, 
every 14-day cycle).  
Treatment with pembrolizumab or paclitaxel/docetaxel/irinotecan will 
continue until documented disease progression, unacceptable adverse 
event(s), intercurrent illness that prevents further administration of 
treatment, Investigator’s decision to discontinue the subject, subject 
withdraws consent, pregnancy of the subject, noncompliance with trial 
treatment or procedure requirements, subject receives 35 administrations 
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(approximately 2 years) of pembrolizumab, or administrative reasons 
requiring cessation of treatment. After the end of treatment, each subject 
will be followed for 30 days for adverse event (AE) monitoring. Serious 
adverse events (SAE) 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. 
Subjects who discontinue pembrolizumab as a result of obtaining an 
investigator-determined confirmed complete response (CR) or those 
subjects who stop after receiving 35 trial treatments (approximately 
2 years) may be eligible, at the discretion of the investigator, for an 
additional 17 trial treatments (approximately 1 year) after experiencing 
radiographic 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 disease progression will have post-
treatment follow-up for disease status until disease progression, initiating 
a non-study cancer treatment, withdrawing consent, or becoming lost to 
follow-up. All subjects will be followed (e.g. by telephone) for overall 
survival until death, withdrawal of consent, or the end of the study.
A list of abbreviations used in this document can be found in Section 12.7.
2.0 TRIAL DESIGN
Trial Design
This is a randomized, multi-center, open-label trial of pembrolizumab (MK-3475) versus the 
investigator’s
choice
of 
paclitaxel,
docetaxel,
or 
irinotecan
in 
subjects 
with 
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 of 0 or 1, and to have been 
previously treated with one prior line of standard therapy per local/global guidelines. 
Subjects will be required to provide a tumor sample, to be evaluated at a central laboratory, 
for analysis of PD-L1 and immune-related gene expression profile (GEP), both for response 
prediction for pembrolizumab efficacy. An adequate tumor specimen for both PD-L1 and 
GEP biomarker status must be available and confirmed evaluable prior to randomization. 
Subjects will be randomized in a 1:1 ratio to receive pembrolizumab or investigator’s choice 
of paclitaxel, docetaxel, or irinotecan. Investigator’s choice of paclitaxel, docetaxel, or 
irinotecan should be determined prior to randomization and should not be in conflict with 
local regulations or guidance. Subjects will be stratified by tumor histology and by 
geographic region (See Section 5.4 for stratification).   
The study will be enrolling into two cohorts: Global and China Cohorts. The enrollment 
period is divided into two periods: Global and China extension enrollment (Figure 1). 
Randomization Ratio
1:1
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The Global Cohort
The Global Cohort will enroll approximately 600 patients without regard to GEP biomarker 
status. This cohort will include any subject enrolled in China during the global enrollment 
period. Subjects enrolled during the China extension enrollment period are not part of the 
Global Cohort. 
Prior to starting this study, the estimated prevalence of GEP intermediate or high grade 
tumors was around 60%. The prevalence of subjects with GEP intermediate or high tumors is 
42.6% based on 357 randomized subjects’ sample results from Keynote 181. The prevalence 
of subjects with GEP intermediate or high tumors at the end of enrollment is expected to be 
between 40%-45%, and it is estimated that approximately 240-270 subjects with GEP 
intermediate or high tumors will be enrolled. The prevalence of subjects with PD-L1 CPS≥10
is 47.6% in esophageal cancer subjects based on emerging results from 105 subjects enrolled 
in MK-3475 KN180. It is expected PD-L1 CPS≥10 prevalence rate will be around 40%-48% 
in KN181. Beginning with screening, all imaging assessments will be submitted for central 
imaging vendor review and will be evaluated using Response Evaluation Criteria in Solid 
Tumors (RECIST 1.1) for determining eligibility and assessment of response. On study 
imaging assessments will be performed every 9 weeks (+/- 7 days) following the date of 
randomization until progression of disease is documented with radiologic imaging (computed 
tomography or magnetic resonance imaging). Imaging timing should follow calendar days 
and should not be adjusted for delays in cycle starts.
The primary efficacy endpoint is overall survival (OS). Progression free survival (PFS) and 
Objective response rate (ORR) are secondary efficacy endpoints. The PFS analysis will be 
based on RECIST 1.1 by central imaging vendor review. Images read by central imaging 
vendor will be blinded to treatment assignment to minimize bias in the response assessments. 
RECIST 1.1 will be used by the site for treatment decisions until verification of progressive 
disease (PD) by the central imaging vendor. Following verification of PD by the central 
imaging vendor, treatment decisions may be made by the adaption of RECIST 1.1 as 
described in Section 7.1.4.1.5 termed immune-related RECIST (irRECIST) to accommodate 
for the tumor response patterns seen with pembrolizumab treatment (e.g., tumor flare). This 
was first described by Nishino, et al. 2013 [1], but is further modified for the PD-1 program. 
For a clinically stable subject with first radiologic evidence of PD, it is at the discretion of the 
site investigator to continue treating the subject with 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.  
Adverse events will be monitored throughout the trial and graded in severity according to the 
guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0.  
Except as noted above, treatment with pembrolizumab, paclitaxel, docetaxel, or irinotecan
will continue until documented disease progression, unacceptable adverse event(s), 
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intercurrent illness that prevents further administration of treatment, Investigator’s decision 
to discontinue
the subject, subject withdraws consent, pregnancy of the subject, 
noncompliance with trial treatment or procedure requirements or administrative reasons 
requiring the cessation of treatment. For subjects in the pembrolizumab arm, treatment may 
be continued until the subject has received 35 trial treatments (approximately 2 years) with 
pembrolizumab.  
Subjects on the pembrolizumab arm who attain an investigator-determined confirmed 
complete response (CR) may consider stopping trial treatment after receiving at least 8 trial 
treatments (approx. 6 months) of pembrolizumab and had at least 2 treatments with 
pembrolizumab beyond the date when the initial CR was declared. Subjects who discontinue 
after 35 administrations (approximately 2 years) of pembrolizumab for reasons other than
disease progression or intolerability or who discontinue after attaining a CR may be eligible 
for up to one year (17 trial treatments) of retreatment after they have experienced 
radiographic disease progression. The decision to retreat will be at the discretion of the 
Investigator only if no cancer treatment was administered since the last dose of 
pembrolizumab, the subject still meets the safety parameters listed in the Inclusion/Exclusion 
criteria and the trial remains open. Subjects within the paclitaxel/docetaxel/irinotecan arm 
will continue on treatment until disease progression or unacceptable toxicity. A cross-over of 
treatment groups after documented disease progression on the study treatment will not be 
allowed. 
After the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring. Serious adverse events (SAE) 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. Subjects who discontinue treatment for reasons other than 
disease progression will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost 
to follow-up. All subjects will be followed (e.g. by telephone contact) for OS until death, 
withdrawal of consent or the end of the study, whichever comes first.
This study will be conducted in conformance with Good Clinical Practices.
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.
This trial will use a group sequential design, using an independent, external Data Monitoring 
Committee (eDMC) to monitor safety and efficacy. The role of the eDMC will be clearly 
elucidated in the eDMC Charter. There will be one formal interim efficacy analysis. See 
Section 8.7 for more details. 
The China Cohort
Approximately 120 subjects from China will be enrolled in the China Cohort, this will 
include subjects enrolled in China during the global enrollment period as well as the China 
extension enrollment period (see Figure 1). After the enrollment of the Global Cohort is 
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closed, subjects from China will continue to be enrolled in the China cohort designed to meet 
local regulatory needs. The China Cohort will be identical to the Global Cohort (e.g., 
inclusion and exclusion criteria, study endpoints, primary and secondary objectives, study 
procedures). The details of the analysis will be provided in supplemental SAP.
Figure 1
China Enrollment Strategy
Trial Diagram
The trial design is depicted in Figure 2.
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*Stratification by 1: Tumor histology 2. Geographic region
Figure 2
Trial Design Schematic
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
For subjects with advanced/metastatic adenocarcinoma or squamous cell carcinoma of the 
esophagus or advanced/metastatic Siewert type I adenocarcinoma of the EGJ who have 
progressed on one previous line of standard therapy.
1) Objective: to compare OS in subjects with squamous cell carcinoma of the 
esophagus.
Hypothesis (H1):  Pembrolizumab 200 mg every 3 weeks (Q3W) prolongs OS in 
subjects with squamous cell carcinoma of the esophagus compared to investigator’s 
choice of paclitaxel, docetaxel, or irinotecan.
2) Objective: To compare OS in subjects with PD-L1 Combined Positive Score 
(CPS)≥10.
Hypothesis (H2):  In subjects with PD-L1 CPS≥10, pembrolizumab 200 mg every 3 
weeks (Q3W) prolongs OS compared to investigator’s choice of paclitaxel, docetaxel,
or irinotecan.
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3) Objective: To compare OS in all subjects.
Hypothesis (H3):  Pembrolizumab 200 mg Q3W prolongs OS in all subjects,
compared to investigator’s choice of paclitaxel, docetaxel, or irinotecan.
The study is considered to have met its primary objective if pembrolizumab is superior to 
investigator’s choice of paclitaxel, docetaxel, or irinotecan in any one of the three primary 
objectives.
Secondary Objective(s) & Hypothesis(es)
1) Objective: To evaluate the progression free survival (PFS) per RECIST 1.1 assessed 
by central vendor review in all subjects, when treated with pembrolizumab compared 
to investigator’s choice of paclitaxel, docetaxel, or irinotecan.
Hypotheses (H4): Pembrolizumab 200 mg Q3W improves PFS per RECIST 1.1 by 
central vendor review in all subjects, compared to investigator’s choice of paclitaxel,
docetaxel, or irinotecan.
2) Objective: To evaluate the Objective Response Rate (ORR) per RECIST 1.1 assessed 
by central vendor review in all subjects, when treated with pembrolizumab compared 
to investigator’s choice of paclitaxel, docetaxel, or irinotecan.
Hypotheses (H5): Pembrolizumab 200 mg Q3W improves ORR per RECIST 1.1 by 
central vendor review in all subjects, compared to investigator’s choice of paclitaxel,
docetaxel, or irinotecan.
3) Objective: To evaluate the PFS and ORR per RECIST 1.1 assessed by central vendor
review in subjects with squamous cell carcinoma of the esophagus and subjects with 
PD-L1 CPS≥10, when treated with pembrolizumab compared to investigator’s choice 
of paclitaxel, docetaxel, or irinotecan.
4) Objective: Evaluate the safety and tolerability profile of pembrolizumab in all 
subjects, when treated with pembrolizumab compared to investigator’s choice of 
paclitaxel, docetaxel, or irinotecan.
Exploratory Objectives
1) To evaluate PFS per irRECIST assessed by blinded central vendor review in all 
subjects when treated with pembrolizumab 200 mg Q3W compared to investigator’s 
choice of paclitaxel, docetaxel, or irinotecan.
2) To evaluate efficacy by GEP expression.
3) To explore the concordance of PD-L1 in archival compared to newly obtained tumor
tissue.
4) To evaluate score change of health related quality of life using the EORTC QLQ-C30 
and the EORTC QLQ-OES18 from baseline among subjects when treated with 
pembrolizumab 200 mg Q3W compared to investigator’s choice of paclitaxel,
docetaxel, or irinotecan. 
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5) To characterize utilities using EuroQol EQ-5D among subjects when treated with 
pembrolizumab 200 mg Q3W compared to investigator’s choice of paclitaxel,
docetaxel, or irinotecan.
6) 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.  
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 ipilimumab, a BRAF inhibitor, and 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. In particular, the presence of CD8+ T-cells and the 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 Cytotoxic T-Lymphocyte-Associated Antigen-4
(CTLA-4) which has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) [3] [4].  
The structure of murine PD-1 has been resolved [5]. 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 [3], [6], [7], [8]. The mechanism by which 
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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 [9], [10]. 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 [6] [11]. Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells, as well as subsets of macrophages and 
dendritic cells [12]. 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 [13] [14] [15] [16]. 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 [16]. 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) 
[17].
Pre-clinical and Clinical Trials
Preclinical 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 monotherapy or in combination with other treatment 
modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor 
responses as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, 
MEL and colorectal carcinoma. Blockade of the PD-1 pathway effectively 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 [18] [19] [20] [21] [4] [3]. Experiments have confirmed the in vivo 
efficacy of PD-1 blockade as a monotherapy as well as in combination with chemotherapy in 
syngeneic mouse tumor models (see the IB).
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, emerging data demonstrated 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 refer to the IB.
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Rationale
Rationale for the Trial and Selected Subject Population
Esophageal cancer is the 6th most common cause of cancer deaths in the world and is more 
prevalent in men than women. However, in the developing countries esophageal cancer is 
endemic and is the 4th most common cause of cancer deaths. Globally, close to 480,000 
cases occur annually with 53% of these cases arising in China [22] [23]. 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 [24]. In Japan, esophageal cancer is the 6th 
leading cause of cancer deaths and in 2008, there were 11,746 deaths from esophageal 
carcinoma with male patients outnumbering female patients 6:1 [25]. 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 [26]. 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 [27] [28] [29]. For the purpose of our 
study, we will use the Siewert classification for adenocarcinoma of the EGJ and thus type I 
patients (about 20% of the EGJ adenocarcinoma patients) will be eligible. Siewert type I 
tumors are adenocarcinomas of the lower esophagus with the center located within 1cm to 
5cm above the anatomic EGJ. Type II and III Siewert adenocarcinomas of the EGJ are 
managed as gastric cancer patients and therefore eligible to participate in the second line (2L)
gastric trial, KEYNOTE-061. 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 than adenocarcinoma, but 
the long-term outcome is similar for both histologies [30] [31] thus emphasizing the need for 
better improved therapies in both histologies. 
Phase III trials specifically designed for metastatic esophageal cancers have not been 
performed. 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 OS [32]. 
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 gastroesophageal 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 
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autoimmune disease. Pembrolizumab 10 mg/kg is being given every 2 weeks for up to 2 
years or until confirmed progression. Of the 90 patients with esophageal cancer who were 
screened, 37 (44.6%) had PD-L1+ tumors. Of the 23 patients treated between March and 
December 2014, 83% were men and median age was 65 years. Histology was squamous in 
17 patients (73.9%), adenocarcinoma in 5 patients (21.7%), and mucoepidermoid in 1 patient 
(4.3%). Eighty-seven percent of patients received ≥2 prior therapies for metastatic disease; 
all patients 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 patients died or discontinued due to a DRAE. Tumor 
shrinkage was seen in 52% of patients and objective response rate (ORR) was 30.4% (n = 7; 
5 squamous (29.4%) and 2 adenocarcinoma (40.0%)); best response was stable disease 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 (DOR) 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 
second-line esophageal carcinoma, across both the squamous cell and adenocarcinoma 
histologies.
Rationale for Dose Selection/Regimen/Modification
Rationale for the Use of Pembrolizumab
The planned dose of pembrolizumab for this trial is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated in the 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 OS at 200 mg 
Q3W across multiple indications
•Pharmacology data showing full target saturation in both systemic circulation (inferred from 
pharmacokinetic [PK] data) and tumor (inferred from physiologically based pharmacokinetic 
[PBPK] analysis) at 200 mg Q3W
Among the 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), 
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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 (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Secondly, a PBPK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other subject covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
Rationale for the Use of Comparator
Various palliative chemotherapy regimens have been investigated in studies including 
esophageal cancer patients and have been shown to have at least some activity in the first-
line setting, with responses ranging from 20% to 48% and 5-year survival rates of 
approximately 15% with significant toxicity rates [33]. Current guidelines recommend the 
combination of fluorouracil and cisplatin, either alone or in combination with a third drug 
such as epirubicin or a taxane, as the most effective first-line treatment option. In case of 
relapse or refractoriness, however, data on application of second-line therapy are scarce, and 
there is no consensus on the optimal second-line chemotherapy [34]. Approximately 40% of 
patients for whom first-line treatment fails will be potential candidates for second line 
therapy. NCCN guidelines endorse use of docetaxel, paclitaxel and irinotecan (level 
1 evidence) in second-line treatment of esophageal cancer. There are no clinically significant 
differences in response rates, PFS and OS that have been documented when using paclitaxel, 
docetaxel, or irinotecan in the treatment of second-line esophageal cancer.
The survival benefit of second-line chemotherapy compared to “best supportive care” has 
been demonstrated in a small cohort of patients with lower esophageal or EGJ 
adenocarcinoma included in gastric adenocarcinoma phase III trials [35] [36]. In a 
randomized phase III study, second-line chemotherapy with irinotecan significantly 
prolonged OS compared to best supportive care in patients with metastatic or locally 
advanced gastric or EGJ adenocarcinoma (n = 40) [35]. The study was closed prematurely 
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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 to 
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 [36]. 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. [37], 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 response(s) (PR)s were seen in 10 
patients (15%, 95% 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.
Taxanes have been shown to be effective in the first-line treatment of advanced esophageal 
cancer, with remission rates of approximately 20% [34]. Twenty-three patients were enrolled 
in a phase II study [38] of either paclitaxel or docetaxel to determine the efficacy and safety 
of these agents for second-line treatment of metastatic or recurrent esophageal SCC (n =15) 
and adenocarcinoma (AC) (n = 8). Patients (13 evaluable) received paclitaxel 175 mg/m2
(n=11) or docetaxel 100mg/m2 (n=12). For both agents, cycles were repeated every 3 weeks 
for a maximum of six courses of therapy. Two CRs (4.7%) and two PRs (4.7%) were 
achieved, and 30% of patients had stable disease (SD). In this limited number of patients, no 
apparent differences were seen between the single agents in terms of efficacy or adverse 
effects.
In another study [39], paclitaxel 140 mg/m2 administered as a continuous infusion over 
4 days every 3 weeks was found to be ineffective because no responses were observed in 
patients with either AC or SCC (n=13). Application of docetaxel at various doses 
(i.e., 100 mg/m2, 75 mg/m2, or 70 mg/m2 every 3 weeks) was tested in the setting of 
platinum-pretreated relapse [40], [41] and in [42] that included 25, 11, and 36 patients, 
respectively. The objective response rates were poor at 28% (three CRs and four PRs in 
25 patients), 0%, and 17% (six PRs in 36 patients), respectively, with the OS being 
8.1 months (range, 6.6 to 11.3 months) in one study. 
From the data presented above, we see that although the use of taxanes as monotherapies has 
resulted in at least some activity with up to 30% response rate, only approximately 40% of 
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patients qualify for second-line therapy because of their general condition and performance 
status. Even in these selected few individuals, response rates are low and accompanied by an 
extremely high rate of hematologic adverse effects that resulted in therapy-related deaths in 
some studies. In addition, these taxane-based second-line approaches have been used in 
patients who were taxane-naive, a practice that is changing, given the relatively high use of 
taxanes currently in the first-line setting. Apart from response rates, the time to progression 
was short in most studies, being less than 4 months in 13 trials. However, as second line 
combination regimens have seen World Health Organization (WHO)
Grades 3
to 
4 hematologic toxicities in half the patients enrolled, taxane monotherapy or combinations 
are preferred in the second-line setting [43].  
Rationale for using the Intratumoral Immune-related Gene Expression Profile 
(GEP) in Esophageal Cancer
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 [44] [45] [46] as well as in the esophageal cancer cohort in 
KEYNOTE-028. The predominant pattern indicates that tumors with relatively low 
expression of these genes have a low probability of response to pembrolizumab.  
Gene expression profiling of tumor specimens from clinical studies KEYNOTE-001 
(Melanoma), KEYNOTE-012 (Head and Neck, Bladder, Gastric cancers) and KEYNOTE-
028 (Ovarian, Esophageal, and other cancers) [44] [45] [46] led to the identification of an 
18-gene immune-related intratumoral GEP that is associated with response to 
pembrolizumab. Using data from KEYNOTE-012 and KEYNOTE-028, a GEP combining 
expression levels of 18 genes into a scalar score was developed and two cut-offs on that score 
which divide tumors into “low”, “intermediate”, and “high” were determined using data from 
KEYNOTE-028, KEYNOTE-012, and KEYNOTE-052. 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, the hypothesis is that subjects whose tumors are above the lower cut-off (i.e. are 
either GEP intermediate or GEP high) may show greater clinical benefit under treatment with 
pembrolizumab relative to the comparator in a manner that will be more substantial than 
what is observed in an all subjects population that includes subjects whose tumors are GEP 
low.  
Rationale for Endpoints
Primary Efficacy Endpoints
The primary efficacy endpoint is OS. The endpoint of OS is the standard for demonstrating 
superiority of antineoplastic therapy in clinical studies in the area of oncology.  
Secondary Efficacy Endpoints
The key secondary efficacy objectives of this study are to evaluate PFS and ORR per 
RECIST 1.1 as assessed by the central imaging vendor for all subjects.
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Other secondary efficacy objectives of this study are to evaluate PFS and ORR per RECIST 
1.1 as assessed by the central imaging vendor for subjects with SCC of the esophagus and 
subjects with PD-L1 CPS≥10.
RECIST 1.1 as assessed by central imaging vendor will be used to determine the dates of 
progression as this methodology is accepted by regulatory authorities. If the treatment 
assignment is unblinded, images read by central imaging vendor blinded to treatment 
assignment can minimize bias in the response assessments. In addition, final determination of 
radiologic progressive disease (PD) will be based on the central imaging vendor assessment 
of progression, rather than local site investigator/radiology assessment.  
RECIST 1.1 will also be used by the local site for treatment decisions for both arms of the 
study. When feasible, subjects within the pembrolizumab arm should not be discontinued 
until progression is confirmed. This allowance to continue treatment despite initial radiologic 
progression takes into account the observation that some subjects can have a transient tumor 
flare in the first few months after the start of immunotherapy, but with subsequent disease 
response. 
Safety Endpoints
The safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in subjects with advanced/metastatic adenocarcinoma or SCC of the 
esophagus or advanced/metastatic Siewert type I adenocarcinoma of the EGJ who have 
progressed on one previous line of therapy. The safety analysis will be based on subjects who 
experienced toxicities as defined by CTCAE version 4.0 (Section 12.6). Safety will be 
assessed by quantifying the toxicities and grades experienced by subjects who have received 
pembrolizumab compared to investigator’s choice of paclitaxel, docetaxel, or irinotecan 
including serious adverse events (SAEs) and events of clinical interest (ECIs).
The attribution to drug, time-of-onset, duration of the event, its resolution, and any 
concomitant medications administered will be recorded. AEs will be analyzed including but 
not limited to all AEs, SAEs, fatal AEs, and laboratory changes.  
Exploratory Endpoints
4.2.3.4.1 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 
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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 immunotherapeutics as described in Nishino et al., 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 
efficacy endpoint.
4.2.3.4.2 Patient Reported Outcomes
As part of the exploratory analyses, subjects will provide information regarding their health-
related quality of life (HRQoL) via the following assessment tools: EORTC QLQ-C30 and 
QLQ-OES18, eEuroQol-5D (EQ-5D) questionnaires. These measures are not pure efficacy or 
safety endpoints because they are affected by both disease progression and treatment 
tolerability.
EORTC QLQ-C30 and EORTC QLQ-OES18
The EORTC-QLQC30 is the most widely used cancer specific HRQoL instrument, which
contains 30 items and measures five functioning dimensions (physical, role, cognitive,
emotional, and social), three symptom items (fatigue, nausea/vomiting, pain), six single items
(dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a
global health and quality of life scale [47]. This instrument has been translated and validated
into 81 languages and used in more than 3,000 studies worldwide.
The EORTC QLQ-OES18 is a disease-specific questionnaire developed and validated to 
address measurements specific to esophageal cancer. It is one of multiple disease-specific 
modules developed by the EORTC QLG (Quality of Life Group) designed for use in clinical 
trials, to be administered in addition to the EORTC-QLQ-C30 to assess disease-specific 
treatment measurements. It contains 18 items with symptoms of dysphagia, pain, reflux, 
eating, trouble with swallowing saliva, choking, dry mouth, taste, cough, and speech [48].
The EORTC QLQ-C30 and EORTC QLQ-OES18 are to be completed at various time points 
as specified in the Trial Flow Chart, beginning with Cycle 1 until 30 days post-treatment 
discontinuation.
eEuroQol-5D
The eEuroQol-5D (eEQ-5D) is a standardized instrument for use as a measure of health 
outcome. The eEQ-5D will provide data for use in economic models and analyses including 
developing health utilities or quality adjusted life years (QALYs). The five health state 
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dimensions in this instrument include the following: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression [49]. Each dimension is rated on a three point scale 
from 1 (extreme problem) to 3 (no problem). The eEQ-5D also includes a graded (0 to 100) 
vertical visual analog scale on which the subject rates his or her general state of health at the 
time of the assessment. The eEQ-5D will always be completed by subjects first before 
completing the EORTC QLQ-C30 and QLQ-OES18 and is to be completed at various time 
points as specified in the Trial Flow Chart, beginning with Cycle 1 until 30 days post-
treatment discontinuation.
Biomarker Research
4.2.3.5.1 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 will be used to divide tumors into “low”, 
“intermediate”, and “high” for the GEP. Hypothesis testing to address the study’s objectives 
will be conducted in subjects whose tumors are “intermediate or high” and in the all subjects 
population (i.e. including those subjects whose tumors are GEP low).
Tumor PD-L1 expression
In 
the 
pembrolizumab 
KEYNOTE-001 
and 
KEYNOTE-012 
studies, 
PD-L1 
immunohistochemistry (IHC) has successfully been used as a biomarker in the NSCLC and 
head and neck cancer cohorts, respectively, to enrich for a subpopulation with high response 
to pembrolizumab [50]. 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 IHC and retrospectively tested for association with response to 
pembrolizumab. Tumor bank-derived, EC tissues matched for stage and grade with subjects 
in pembrolizumab studies, as well as EC tissues from KN180, were used to determine the 
prevalence of PD-L1 positivity greater than or equal to a combined positive score (CPS) of 1 
or 10. CPS is the number of PD-L1 positive cells (tumor cells, macrophages, lymphocytes) 
over total tumor cells, expressed as a percentage. The prevalence of PD-L1 > 10 CPS in 
tumor bank or KN180, respectively was 52% or 47.2%. The prevalence of PD-L1 > 1 CPS 
was greater in both the tumor bank (72%) as well as the KN180 study (85.8%). Utility of the 
PD-L1 CPS measure to enrich for EC patient response to pembrolizumab will be determined 
in KN180. Further studies of both prevalence as well as utility as a prognostic marker are 
being evaluated in epidemiology studies.
4.2.3.5.2 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 
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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 immune-related set of genes via the GEP, broad messenger RNA 
profiling may also be pursued. Expression of individual genes related to the immune system 
may also be evaluated such as immune signatures and critical cytokines (e.g., 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 
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 but 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-cell 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 
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(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.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
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 I adenocarcinoma of the 
esophagogastric junction of at least 18 years of age will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide 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 (or 
acceptable age according to local regulations, whichever is older).
3. Have histologically or cytologically-confirmed diagnosis of adenocarcinoma or SCC
of the esophagus or Siewert type I adenocarcinoma of the EGJ (defined as 
adenocarcinomas of the lower esophagus with the center located within 1cm to 5cm 
above the anatomic EGJ).
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a.
Subjects with 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 a prior line of therapy 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 a prior line of therapy containing trastuzumab.
4. Have metastatic disease or locally advanced, unresectable disease. Subjects with 
direct invasion into adjacent organs such as the aorta or trachea (T4b disease) should 
be closely evaluated for bleeding risk prior to enrollment and a sponsor consultation 
before enrollment is required. 
5. Have a life expectancy of greater than 3 months.
6. Have measurable disease based on RECIST 1.1 as determined by local site 
investigator/radiology assessment. A lesion(s) situated in a previously irradiated area 
can be considered a target lesion(s) if progression has been demonstrated and the 
lesion(s) is considered measurable per RECIST 1.1 criteria. 
Note:  The same image acquisition and processing parameters should be used 
throughout the study for a given subject.
7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale.
8. Have experienced documented radiographic or clinical disease progression on one 
previous line of standard therapy. This study will only include second-line 
subjects. Second-line subjects are defined as those who have progressed during or 
after receiving at least one dose of standard therapy given in a first 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 
malignant effusion (documented by ultrasound) and confirmation by 
pathologic criteria (histology and/or cytology) may be 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 line agents due to 
toxicity/intolerability as deemed clinically appropriate by the investigator will 
not constitute a new line of therapy.
9. Provide either a newly obtained or archival tissue sample for intratumoral immune-
related GEP analysis and PD-L1 by immunohistochemistry analysis. Newly-obtained 
tissue is preferred. Formalin-fixed, paraffin-embedded (FFPE) block specimens are 
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preferred to slides. Repeat samples will be required if none of the samples submitted 
(archived or newly obtained) is adequate. For purposes of this study, newly-obtained 
tissue refers to tissue that was collected between the last line of therapy and the first 
dose of study medication. 
a.
Central laboratory confirmation of tumor tissue sample adequacy is required 
prior to subject randomization 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 (e.g. 
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 in newly obtained vs. archived tissue samples; 
however, a subject will not be excluded from participating in the study if 
he/she has provided newly obtained tissue and an archived tissue sample is not 
available or is otherwise insufficient for analysis.
10. Demonstrate adequate organ function as defined in Table 1.  
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
within 14 days.
Renal
Creatinine OR
Measured or calculated creatinine clearancea
(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 X 
institutional ULN
Hepatic
Total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 
ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN  OR
≤ 5 X ULN for subjects with liver metastases
Albumin
≧2.5 g/dL
Coagulation
International 
Normalized 
Ratio 
(INR) 
or 
Prothrombin Time (PT)
≤1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or aPTT is within therapeutic range of intended use 
of anticoagulants
Activated Partial Thromboplastin Time (aPTT)
≤1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or aPTT is within therapeutic range of intended use 
of anticoagulants
a Creatinine clearance should be calculated per institutional standard.
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11. 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.
12. 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 pembrolizumab or 
through 180 days after the last dose of paclitaxel, docetaxel, or irinotecan.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
13. 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 pembrolizumab or through 180 days after the last dose of paclitaxel, 
docetaxel, or irinotecan.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
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 active autoimmune disease that has required systemic treatment in past 2 years 
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., 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 central nervous system (CNS) metastases and/or carcinomatous 
meningitis (includes past history or current metastasis). 
5. Has received prior anti-cancer monoclonal antibody (mAb), chemotherapy, targeted 
small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1. The 
specified 2-week period between last dose of prior therapy and first dose of 
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pembrolizumab is the minimum amount of time required. Subjects may not receive 
study medication 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 study 
therapy. Subjects must have recovered from adverse events due to a previously 
administered agent to baseline toxicity grade or to Grade 1 or less prior to enrollment.
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 if 
the subject has previously participated in Merck pembrolizumab (MK-3475) clinical 
trials. 
7. Previously had a severe hypersensitivity reaction to treatment with another 
monoclonal antibody (mAb).
8. Has experienced documented objective radiographic or clinical disease progression 
during or after receiving more than 1 line of therapy.
9. Has a known additional malignancy that progressed or required active treatment 
within the last 5 years. Exceptions include curatively treated basal cell and SCC of 
the skin and/or curatively resected in situ cervical and/or breast cancers and in situ or 
intramucosal pharyngeal cancer. 
10. Has received a live vaccine within 30 days of planned start of pembrolizumab.
Note: The killed virus vaccines used for seasonal influenza vaccines for injection are 
allowed; however intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines, and are not allowed. 
11. 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.
12. Has a known history of Human Immunodeficiency Virus (HIV) infection. No HIV 
testing is required unless mandated by local health authority.
13. Has known history of or is positive for hepatitis B (hepatitis B surface antigen 
reactive) or known active hepatitis C (hepatitis C virus RNA or hepatitis C antibody 
is detected). No hepatitis testing is required unless mandated by local health authority.  
14. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
15. Has an active infection requiring systemic therapy.
16. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
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17. 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 pembrolizumab or through 180 days after the last dose of paclitaxel, 
docetaxel, or irinotecan.
18. Has a known
allergy, hypersensitivity, or contraindication to preselected 
chemotherapy agent (i.e., paclitaxel, docetaxel, or irinotecan) or any components used 
in their preparation.
19. Experienced weight loss > 10% over approximately 2 months prior to first dose of 
study therapy.
20. Has clinically apparent ascites or pleural effusion by physical exam.  (Note that small 
amount of ascites which is only detectable on imaging studies is allowed.)
Trial Treatment(s)
The treatments to be used in this trial are outlined below in Table 2.
Table 2
Trial Treatment
Drug
Dose
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment Period
Use
Pembrolizumab
(MK-3475)
200 mg
Every 
3 
weeks
IV infusion
Day 1 of each 21-day
(3-week) cycle
Experimental
Paclitaxel
80-100 
mg/m2
3 weeks on, 
1 week off
IV infusion
Days 1, 8, and 15 of 
each 
28-day 
(4-week) cycle
Active 
comparator
Docetaxel
75 mg/m2
Every 
3 
weeks
IV infusion
Day 1 of each 21-day
(3-week) cycle
Active 
comparator
Irinotecan
180 
mg/m2
Every 
2 
weeks
IV infusion
Day 1 of each 14-day
(2-week) cycle
Active 
comparator
Trial treatment for Cycle 1 should begin within 3 days of randomization. However, every 
effort should be made to begin trial treatment on day of randomization.
All supplies indicated in Table 2 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
Per local guidelines the trial site may be responsible for recording the lot number, 
manufacturer and expiry date of any locally purchased 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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
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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. Details on preparation and administration of pembrolizumab are 
provided in the Pharmacy Manual.  
Preparation and administration of paclitaxel, docetaxel, or irinotecan should be completed as 
per the approved product label. Body surface area (BSA) in m2 should be calculated per local 
guidance.
Dose Modification (Escalation/Titration/Other)
5.2.1.2.1 Immune-Related 
Events 
and 
Dose 
Modification 
(Withhold, 
Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 3. 
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin 
if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer 
corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone 
or 
equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate corticosteroid 
treatment
Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer 
corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone 
or 
equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
Participants with ≥Grade 2 diarrhea suspecting 
colitis 
should 
consider 
GI 
consultation 
and 
performing endoscopy to rule out colitis
Participants with diarrhea/colitis should be advised 
to drink liberal quantities of clear fluids. If sufficient 
oral fluid intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST 
/ 
ALT 
Elevation 
or 
Increased Bilirubin
Grade 2
Withhold
Administer 
corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone 
or 
equivalent) 
followed by taper
Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
Administer 
corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone 
or 
equivalent) 
followed by taper
T1DM 
or 
Hyperglycemia
New onset T1DM 
or 
Grade 
3 
or 
4 
hyperglycemia 
associated 
with 
evidence of β-cell 
failure
Withhold a
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer 
anti-
hyperglycemic in participants 
with hyperglycemia
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
Administer 
corticosteroids 
and 
initiate 
hormonal 
replacements 
as 
clinically 
indicated
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal insufficiency)
Grade 3 or 4
Withhold 
or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue
Treat 
with 
non-selective 
beta-blockers 
(eg, 
propranolol) or thionamides 
as appropriate
Monitor for signs and symptoms of thyroid disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
Monitor for signs and symptoms of thyroid disorders
Nephritis and renal 
dysfunction
Grade 2
Withhold
Administer 
corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold 
or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 
diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs (eg, 
vasculitis and sclerosing cholangitis).
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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 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 
(e.g., 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); 
prophylactic 
medications 
indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the 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 (e.g. from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab
with:
Diphenhydramine 50 mg po 
(or 
equivalent 
dose 
of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
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)
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.
No subsequent dosing
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further study drug treatment.
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.
5.2.1.2.2 Dose Modification for Paclitaxel, Docetaxel and Irinotecan
Investigators may follow the local label for dose modifications. If a toxicity is not otherwise 
specified, investigators should refer to the label or local standard of care for dose 
adjustments. These dose modification decisions must be documented in the subject’s study 
records and in the case report form.
Subjects who started therapy with paclitaxel, docetaxel, or irinotecan may not switch to one 
of the other chemotherapies.  Subjects who permanently discontinue treatment with 
paclitaxel, docetaxel, or irinotecan may continue to be monitored in the trial.  
Subjects receiving docetaxel should avoid concomitant use of strong inhibitors of CYP3A4; 
however, if strong inhibitors of CYP3A4 cannot be avoided, the docetaxel dose should be 
reduced per the drug label.
Caution should be exercised for subjects receiving paclitaxel concomitantly with substrates, 
inhibitors or inducers of CYP2C8 or CYP3A4.  
Timing of Dose Administration
All trial treatments may be administered on an outpatient basis. 
Pembrolizumab
Cycle 1 Day 1 dose may be administered up to 3 days after subject is randomized. Trial 
treatment of pembrolizumab may be administered up to 3 days before or after the scheduled 
Day 1 of each 21-day (3-week) cycle after Cycle 1 due to administrative reasons. 
Pembrolizumab should be administered after all procedures/assessments have been 
completed as detailed on the Trial Flow Chart (Section 6.0).  
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Pembrolizumab 200 mg will be administered as a 30 minute intravenous (IV) infusion Q3W. 
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted (i.e., infusion time is 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.
Paclitaxel
Trial treatment of paclitaxel may be administered up to 3 days after randomization for 
Cycle 1 Day 1 due to administrative reasons or if the subject requires premedication. The 
required premedication should be administered as close to randomization as possible. After 
Cycle 1 there is a 3 day window for all trial treatment. If dosing is delayed due to 
administrative reasons, the subsequent dosing visit should be re-calculated to account for 
future dosing visits.
Trial treatment of paclitaxel should be administered on Days 1, 8, and 15 of each 28 day 
(4 week) cycle after all procedures/assessments have been completed as detailed on the Trial 
Flow Chart (Section 6.0). 
Paclitaxel should be administered as an IV infusion according to manufacturer standards or 
local guidance, at a dose of 80-100 mg/m2. The first dose of paclitaxel is dependent upon the 
subject’s baseline body surface area. Subsequent doses of paclitaxel must be recalculated per 
local or institutional guidelines if there is a ≥ 10% change (increase or decrease) in body 
surface area from baseline or since the last recalculation of dose; subsequent doses may be 
recalculated if there is a < 10% change (increase or decrease) in body surface area from 
baseline or since the last recalculation of dose.
Premedication is recommended prior to infusion of paclitaxel according to the 
manufacturer’s instructions and local standards. Premedication will consist of an oral steroid 
(such as dexamethasone 8-20 mg or equivalent administered (PO) 12 and 6 hours or (IV) 
30-60 minutes before paclitaxel), an antihistamine (H1 antagonist) such as diphenhydramine 
hydrochloride 50 mg I.V. (or equivalent), cimetidine (H2 antagonist) 300 mg I.V. or 
equivalent, and an antiemetic (such as odansetron 8 mg/kg I.V. or equivalent), administered 
30 to 120 minutes before paclitaxel. Premedication may be provided per local guidance and 
all medications should be captured on the appropriate case report form.  
Docetaxel
Trial treatment of docetaxel may be administered up to 3 days after randomization for 
Cycle 1 Day 1 due to administrative reasons or if the subject requires premedication. The 
required premedication should be administered as close to randomization as possible. After 
Cycle 1 there is a 3 day window for all trial treatment. If dosing is delayed due to 
administrative reasons, the subsequent dosing visit should be re-calculated to account for 
future dosing visits.
Docetaxel should be administered on Day 1 of each 21-day (3-week) cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  
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Docetaxel should be administered as an IV infusion administered over 1 hour according to 
manufacturer standards, at a dose of 75 mg/m2. The first dose of docetaxel is dependent upon 
the subject’s baseline body surface area. Subsequent doses of docetaxel must be recalculated 
if there is a ≥ 10% change (increase or decrease) in body surface area from baseline or since 
the last recalculation of dose; subsequent doses may be recalculated if there is a < 10% 
change (increase or decrease) in body surface area from baseline.
All subjects should be premedicated with oral corticosteroids, such as dexamethasone 16 mg 
per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to docetaxel administration in 
order to reduce the incidence and severity of fluid retention as well as the severity of 
hypersensitivity reactions. The appropriate premedication regimen may be determined by the 
investigator and all medications should be captured on the appropriate case report form.
Irinotecan
Trial treatment of irinotecan may be administered up to 3 days after randomization for 
Cycle 1 Day 1 due to administrative reasons or if the subject requires premedication. The 
required premedication should be administered as close to randomization as possible. After 
Cycle 1 there is a 3 day window for all trial treatment. If dosing is delayed due to 
administrative reasons, the subsequent dosing visit should be re-calculated to account for the 
weekly dosing visits.
Subjects should be tested locally for the UGT1A1*28 allele at investigator discretion. The 
starting dose for irinotecan can be adjusted as outlined in the prescribing information or 
according to local guidelines. Tests performed prior to the subject signing consent is 
acceptable for screening.
Irinotecan should be administered on Day 1 of each 14-day (2-week) cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  
Irinotecan should be administered as an IV infusion administered according to manufacturer 
standards, at a dose of 180 mg/m2. The first dose of irinotecan is dependent upon the 
subject’s baseline body surface area. Subsequent doses of irinotecan must be recalculated if 
there is a ≥ 10% change (increase or decrease) in body surface area from baseline or since the 
last recalculation of dose; subsequent doses may be recalculated if there is a < 10% change 
(increase or decrease) in body surface area from baseline. 
Premedication is recommended prior to infusion of irinotecan
according to the 
manufacturer’s instructions and local standards. Premedication may consist of atropine and 
antiemetic agents, such as dexamethasone 10 mg given with another antiemetic agent 
(e.g., ondansetron) on the day of treatment in order to reduce the incidence and severity of 
fluid loss. The appropriate premedication regimen may be determined by the investigator and 
all medications should be captured on the appropriate case report form.  
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
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Imaging data will be reviewed by central imaging vendor without knowledge of subject 
treatment assignment.
See Section 7.1.5.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization or Treatment Allocation
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 2 treatment arms.  
Subjects will be assigned randomly in a 1:1 ratio to pembrolizumab or investigator’s choice
of chemotherapy (i.e. paclitaxel, docetaxel, or irinotecan). The selected regimen should not 
be in conflict with local regulations or guidance for patients randomized to the investigator’s 
choice treatment arm (paclitaxel, docetaxel, or irinotecan).   
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1. Tumor histology: Squamous cell carcinoma vs. adenocarcinoma/Siewert type I
adenocarcinoma of the EGJ
2. Geographic region: Asia (including but not limited to China, Japan, Korea, Hong 
Kong, Taiwan, Malaysia, Thailand, Singapore) vs. Rest of World (including but not 
limited to Europe/Israel/North America, Australia, South America)
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the electronic case report form 
(eCRF) including all prescription, over-the-counter (OTC), 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 eCRF. 
All concomitant medications received within 30 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant 
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medications administered within 30 days after the last dose of trial treatment should be
recorded for SAEs and ECIs as defined in Section 7.2.
Subjects receiving docetaxel should avoid concomitant use of strong inhibitors of CYP3A4; 
however, if strong inhibitors of CYP3A4 cannot be avoided, the docetaxel dose should be 
reduced per the product label.
Caution should be exercised for subjects receiving paclitaxel concomitantly with substrates, 
inhibitors or inducers of CYP2C8 or CYP3A4.  
Prohibited Concomitant Medication
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.

For all subjects, live vaccines within 30 days prior to the first dose of trial treatment 
are prohibited. For subjects randomized to treatment with pembrolizumab, live 
vaccines while participating in the trial are prohibited. 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 
as seasonal influenza vaccines for injection are allowed; however live attenuated 
intranasal influenza vaccines (e.g., 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.

Pembrolizumab arm only: 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.

Note: Use of prophylactic corticosteroids to avoid allergic reactions (e.g. IV 
contrast dye) is permitted.
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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 describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Pre-medication with steroids is acceptable for those subjects randomized to the 
paclitaxel/docetaxel/irinotecan arm of the study.
Rescue Medications & Supportive Care
Supportive Care Guidelines for Pembrolizumab
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents (other than immunotherapy) if symptoms do not improve 
with administration of corticosteroids. Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab. 
Note: If after the evaluation the event is determined not to be related to pembrolizumab, the 
investigator does not need to follow the treatment guidance (as outlined below). Refer to 
Section 5.2.1 for dose modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Supportive Care Guidelines for Paclitaxel, Docetaxel and Irinotecan
Palliative and supportive care for other disease-related symptoms and for toxicity associated 
with treatment will be offered to subjects within the paclitaxel/docetaxel/irinotecan arm of 
this trial. Supportive care measures may include but are not limited to antidiarrheal agents, 
antiemetic agents, opiate and non-opiate analgesic agents, appetite stimulants, and 
granulocyte and erythroid growth factors. Non-drug supportive care procedures may be 
performed as medically necessary and appropriate in the opinion of the investigator. Details 
of interventions, procedures, or blood products (e.g., blood cells, platelets, or fresh frozen 
plasma transfusions) should be recorded on the eCRF. The use of other specific supportive 
care agents is presented below.
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Diarrhea: In the event of Grade 3 or 4 diarrhea, supportive measures may include hydration, 
loperamide, octreotide, and antidiarrheals. If diarrhea is severe (i.e., requires intravenous 
hydration) and associated with fever or severe (Grade 3 or 4) neutropenia, broad-spectrum 
antibiotics may be prescribed. Subjects with severe diarrhea or any diarrhea associated with 
severe nausea or vomiting must be hospitalized for intravenous hydration and correction of 
electrolyte imbalance. In cases of irinotecan induced diarrhea, antibiotic therapy should be 
initiated if the subject develops ileus, fever or sever neutropenia.  
Nausea/Vomiting:  The use of antiemetic agents is permitted at the discretion of the 
investigator.
Additional Supportive Care Guidelines:
Analgesic Agents: The use of analgesic agents is permitted at the discretion of the 
investigator. The chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) with a high 
risk of bleeding (e.g., indomethacin, ibuprofen, naproxen, or similar agents) is strongly 
discouraged unless at the discretion and responsibility of the investigator after careful 
assessment of the individual bleeding risk of the subject. Chronic use of analgesic agents
with no or low bleeding risk (e.g., paracetamol/acetaminophen, metamizole, dipyrone, 
propyphenazone) is acceptable.
Granulocyte-Colony Stimulating Factors (G-CSF): The use of G-CSF is permitted during 
investigational therapy at the discretion of the investigator. G-CSF or similar agents are 
strongly recommended following Grade 3 or 4 neutropenia of duration > 5 days or following 
any incidence of febrile neutropenia (ANC < 1.0 x 109/L with temperature ≥38.5°C).
Erythroid Growth Factors: The use of erythroid-stimulating factors (e.g., erythropoietin) is 
permitted at the discretion of the investigator based on American Society of Clinical 
Oncology (ASCO) and Food and Drug Administration (FDA) guidelines, or according to 
local guidelines.
Refer to the product label or local standards of care for additional paclitaxel, docetaxel, or 
irinotecan supportive measures.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
Contraception
Pembrolizumab, paclitaxel, docetaxel, or irinotecan may have adverse effects on a fetus in 
utero. Furthermore, it is not known if pembrolizumab, paclitaxel, docetaxel, or irinotecan has 
transient adverse effects on the composition of sperm.  
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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 through 120 days 
after the last dose of pembrolizumab or through 180 days after the last dose of paclitaxel, 
docetaxel, or irinotecan 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
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
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†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 (e.g., 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 pembrolizumab or through 180 days after the last dose of 
paclitaxel, docetaxel, or irinotecan. 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
o
Implantable
o
Intrauterine device (IUD)
o
Intrauterine hormone-releasing system (IUS)
o
Bilateral tubal occlusion
o
Vasectomised partner
o
Sexual abstinence
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Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab or 
paclitaxel/docetaxel/irinotecan, 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 (e.g., 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 reported to the 
Sponsor and followed as described above and in Section 7.2.2.
Use in Nursing Women
It is unknown whether pembrolizumab, paclitaxel, docetaxel, or irinotecan 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 
Section 6.0 - Trial Flow Chart and Section 7.1.5.1 – 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.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
o
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
Confirmed radiographic disease progression outlined in Section 7.1.5 (exception if 
the Sponsor approves treatment continuation).
o
Unacceptable adverse experiences as described in Section 7.2
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o
Progression of current malignancy or recurrence of previously treated malignancy, or 
any occurrence of another malignancy that requires active treatment
o
Intercurrent illness other than another malignancy as noted above that prevents 
further administration of treatment
o
Recurrent Grade 2 pneumonitis
o
A confirmed positive serum pregnancy test
o
Noncompliance with trial treatment or procedure requirements
o
Investigator’s decision to discontinue the subject
o
Discontinuation of treatment may be considered for subjects who have attained a 
confirmed complete response (CR) and have been treated for at least 8 cycles (at least 
24 weeks), receiving at least 2 doses of pembrolizumab beyond the date when the 
initial CR was declared. 
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. 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 Chart 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 first.
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
all visits and procedures, as outlined in the trial flowchart, should be completed.
Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she shall 
not be allowed to restart treatment 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 
then experience radiographic disease progression may be eligible for up to 17 additional 
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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 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
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.5
– 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 documented informed consent.  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).
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
Clinical Criteria for Early Trial Termination
There are no pre-specified criteria for terminating the trial early.
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
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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.
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.
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6.0 TRIAL FLOW CHART
Trial Flow Chart – Initial Treatment Phase for Pembrolizumab Arm
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 9
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
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Xc
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)d
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram (Local)
X
ECOG Performance Status
Xe
X
X
X
X
X
X
X
X
X
PROs (HRQoL Measures)f
X
X
X
X
X
X
Xf
X
X
Survival Status
<------------------------------------------------------------------------------------------------------>
X
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Trial Period:
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 and 
Beyond
Discon
Safety 
Follow-up
Follow Up 
Visits
Survival 
Follow-Upa
At time of 
Discon
30 Days 
Post-discon
Every 9 Weeks 
Post-discon
Every 9
Weeks
Scheduling Window (Days)b
-28 to -1
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 3
± 3
± 7
± 7
± 7
Trial Treatment Administration
Pembrolizumab Administration
Xb
X
X
X
X
X
X
X
Laboratory Procedures/Assessments:  Analysis 
performed by LOCAL laboratory
Pregnancy Testg
X
X
X
X
X
X
X
X
X
X
PT/INR and aPTT
Xe
CBC with Differentialh
Xe
X
X
X
X
X
X
Xh
X
X
Chemistry Panelh
Xe
X
X
X
X
X
X
Xh
X
X
Urinalysish
Xe
X
X
X
Xh
X
T3, FT4, and TSHh
Xe
X
X
X
Xh
X
X
Laboratory Procedures/Assessments: Analysis 
performed by CENTRAL laboratory
Pembrolizumab Pharmacokineticsi
Xj
X
X
X
Xi
Pembrolizumab Anti-Drug Antibodies (ADA)i
X
X
X
X
Xi
Blood for Geneticsj
X
Whole Blood for Correlative Studies (DNA and 
RNA)k
X
X
X
X
Whole Blood for Biomarkers Studies (plasma and 
serum)k
X
085MB4


Product:  MK-3475 
59
Protocol/Amendment No.: 181-06 
MK-3475-181-06 Final Protocol
25-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 9
Weeks
Scheduling Window (Days)b
-28 to -1
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 3
± 3
± 7
± 7
± 7
Tumor Tissue Collection
Newly-Obtained Tumor Tissuel
Xl
Archival Tumor Tissuem
X
Efficacy Measurements
Tumor Imaging
Xn
<---------------------Xo -------------------->
Xp
X
085MB4


Product:  MK-3475 
60
Protocol/Amendment No.: 181-06 
MK-3475-181-06 Final Protocol
25-Jun-2021
Confidential
a.
After centrally verified PD, or the start of new anticancer treatment; contacts are approximately every 9 weeks by telephone. Updated survival status may be requested by 
the Sponsor at any time during the course of the study. 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 death event previously recorded).
b.
Cycle 1 treatment must be given within 3 days of allocation. Trial treatment of pembrolizumab  (administered on Day 1 of every 21-day [3-week] cycle) may be 
administered up to 3 days after randomization for Cycle 1 Day 1 due to administrative reasons or if the subject requires premedications. The window for each visit is ± 3 
days unless otherwise noted.  
c.
SAEs will be followed through 90 days following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier.
d.
Height will be measured at Visit 1 only. 
e.
ECOG Performance Status and Laboratory tests for screening are to be performed within 3 days prior to the first dose of trial treatment.
f.
See Section 7.1.2.6 for details regarding administration of Patient Reported Outcomes (PROs). All PROs are to be performed at Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 5,
and Cycle 7. After Cycle 7 (Week 18), PROs are to be performed every 3 cycles (e.g., Week 27, Week 36, Week 45). PROs are to be performed up to a year or End of 
Treatment, whichever comes first, and the 30-day post-treatment discontinuation follow-up visit. A visit window of ± 7 days will apply to PRO visit assessment.  
g.
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 positive test results. Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.  
h.
Urinalysis and thyroid function tests to be performed every other cycle. CBC (Hematology) and Chemistry to be performed every cycle (excluding Cycle 1 Day 1).
i.
Both PK and Anti-pembrolizumab-antibody 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.  
j.
Detailed instructions for the collection and management of specimens are provided in the Central Lab Manual and in Section 7.1.3 Laboratory Procedure/Assessments.
k.
Whole blood samples for biomarker studies (DNA and RNA) should be collected pre-dose on Day 1 of Cycle 1, Cycle 2, and Cycle 3, and again at treatment 
discontinuation. Whole blood for correlative studies (plasma and serum) to be collected pre-dose on Day 1 of Cycle 1 only. Leftover samples will be stored for FBR if the 
subject signs the FBR consent.
l.
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.
m.
Archival tumor tissue will also be requested (where available) to assess the clinical utility of immune-related GEP assessment in newly obtained vs. archived tissue 
samples.
n.
Screening tumor imaging will be performed within 14 days prior to randomization. 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.
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. Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts.
p.
In order to follow irRECIST criteria, this protocol requires confirmation of disease progression by repeat imaging > 4 weeks from initial disease progression. 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.
085MB4


Product:  MK-3475 
61
Protocol/Amendment No.: 181-06 
MK-3475-181-06 Final Protocol
25-Jun-2021
Confidential
Trial Flow Chart –Treatment Phase for Paclitaxel
Trial Period:
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3 and Beyond
Discon
Safety 
Follow-up
Follow Up 
Visits
Survival 
Follow-Upa
Day 
1
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
At time of 
Discon
30 Days 
Post-
discon
Every 9 
Weeks Post-
discon
Every 9 
Weeks
Scheduling Window (Days)b
-28 to -1
± 3
± 3
± 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
X
Post-study Anticancer Therapy Status
X
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
Xc
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
Height, 
Weight, 
and 
Vital 
Signs 
(T,P,RR,BP)d
X
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram (Local)
X
ECOG Performance Status
Xe
X
X
X
X
PROs (HRQoL Measures)f
<---------------------Xf -------------------->
X
X
085MB4


Product:  MK-3475 
62
Protocol/Amendment No.: 181-06 
MK-3475-181-06 Final Protocol
25-Jun-2021
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3 and Beyond
Discon
Safety 
Follow-up
Follow Up 
Visits
Survival 
Follow-Upa
Day 
1
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
At time of 
Discon
30 Days 
Post-
discon
Every 9 
Weeks Post-
discon
Every 9 
Weeks
Scheduling Window (Days)b
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Survival Status
<--------------------------------------------------------------------------------------------------------------------->
X
Trial Treatment Administration
Paclitaxel Administration
Xb
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments:  
Analysis performed by LOCAL 
laboratory
Pregnancy Testg
X
X
X
X
X
PT/INR and aPTT
Xe
CBC with Differentialh
Xe
X
Xh
X
X
Chemistry Panelh
Xe
X
Xh
X
X
Urinalysish
Xe
X
Xh
X
T3, FT4, and TSHh
Xe
X
Xh
X
X
Laboratory Procedures/Assessments:
Analysis performed by CENTRAL 
laboratory
Blood for Geneticsi
X
Whole Blood for Correlative Studies (DNA 
and RNA)j
X
X
Xj
X
Whole Blood for Biomarkers Studies 
(plasma and serum)j
X
085MB4


Product:  MK-3475 
63
Protocol/Amendment No.: 181-06 
MK-3475-181-06 Final Protocol
25-Jun-2021
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3 and Beyond
Discon
Safety 
Follow-up
Follow Up 
Visits
Survival 
Follow-Upa
Day 
1
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
At time of 
Discon
30 Days 
Post-
discon
Every 9 
Weeks Post-
discon
Every 9 
Weeks
Scheduling Window (Days)b
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Tumor Tissue Collection
Newly-Obtained Tumor Tissuek
X
Archival Tumor Tissuel
X
Efficacy Measurements
Tumor Imaging
Xm
<---------------------Xn -------------------->
X
X
085MB4


Product:  MK-3475 
64
Protocol/Amendment No.: 181-06 
MK-3475-181-06 Final Protocol
25-Jun-2021
Confidential
a.
After centrally verified PD, or the start of new anticancer treatment; contacts are approximately every 9 weeks by telephone. Updated survival status may be requested by the 
Sponsor at any time during the course of the study. 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 death event previously recorded).
b. Cycle 1 treatment must be given within 3 days of allocation. Trial treatment of paclitaxel (administered on Days 1, 8, and 15 of every 28-day [4-week] cycle) may be 
administered up to 3 days after randomization for Cycle 1 Day 1 due to administrative reasons or if the subject requires premedications. The required premedications should 
be administered as close to randomization as possible. After Cycle 1 there is a 3 day window for all trial treatment. The window for each visit is ± 3 days unless otherwise 
noted.  
c.
SAEs will be followed through 90 days following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever 
is earlier.
d. Height will be measured at Visit 1 only. 
e.
Laboratory tests for screening and ECOG performance status are to be performed within 3 days prior to the first dose of trial treatment.
f.
See Section 7.1.2.6 for details regarding administration of Patient Reported Outcomes (PROs). All PROs are to be performed prior to Cycle 1-Day 1, Cycle 2-Day 1, Cycle 
2-Day 15, Cycle 3-Day 8, Cycle 4-Day 1, Cycle 5-Day 15, Cycle 7-Day 22, Cycle 10-Day 1, and Cycle 12-Day 8. PROs are to be performed up to a year or End of 
Treatment, whichever comes first, and the 30-day post-treatment discontinuation follow-up visit. A visit window of ± 7 days will apply to PRO visit assessment.  
g. 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 positive test results. Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines. 
h. Urinalysis and Thyroid function tests are performed Day 1 of every other cycle (more testing is allowed if required per local guidance/regulation). CBC (Hematology) and 
Chemistry to be performed on Day 1 of every cycle (excluding Cycle 1 Day 1) (more testing is allowed if required per local guidance/regulation). 
i.
Detailed instructions for the collection and management of specimens are provided in the central laboratory manual and in Section 7.1.3 Laboratory Procedure/Assessments.
j.
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 again at treatment discontinuation. 
Whole blood for correlative studies (plasma and serum) to be collected pre-dose on Day 1 of Cycle 1 only. Leftover samples will be stored for FBR if the subject signs the 
FBR consent
k. 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.
l.
Archival tumor tissue will also be requested (where available) to assess the clinical utility of immune-related GEP assessment in newly obtained vs. archived tissue samples.
m. Screening tumor imaging will be performed within 14 days prior to randomization. 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.
n. The first on-study imaging time point will be performed at 9 weeks (63 days ± 7 days) calculated from the date of allocation and will continue to be performed Q9W (63 days 
± 7 days), or earlier if clinically indicated. Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts.
085MB4


Product:  MK-3475 
65
Protocol/Amendment No.: 181-06 
MK-3475-181-06 Final Protocol
25-Jun-2021
Confidential
Trial Flow Chart –Treatment Phase for Docetaxel
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 9 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
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Xc
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)d
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram (Local)
X
ECOG Performance Status
Xe
X
X
X
X
X
X
X
X
X
PROs (HRQoL Measures)f
X
X
X
X
X
X
Xf
X
X
Survival Status
<------------------------------------------------------------------------------------------------------>
X
085MB4


Product:  MK-3475 
66
Protocol/Amendment No.: 181-06 
MK-3475-181-06 Final Protocol
25-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 9 Weeks
Scheduling Window (Days)b
-28 to -1
+3
± 
3
± 
3
± 
3
± 
3
± 
3
± 3
± 3
± 7
± 7
± 7
Trial Treatment Administration
Docetaxel Administration
Xb
X
X
X
X
X
X
X
Laboratory Procedures/Assessments:  Analysis 
performed by LOCAL laboratory
Pregnancy Testg
X
X
X
X
X
X
X
X
X
X
PT/INR and aPTT
Xe
CBC with Differentialh
Xe
X
X
X
X
X
X
Xh
X
X
Chemistry Panelh
Xe
X
X
X
X
X
X
Xh
X
X
Urinalysish
Xe
X
X
X
Xh
X
T3, FT4, and TSHh
Xe
X
X
X
Xh
X
X
Laboratory Procedures/Assessments: Analysis 
performed by CENTRAL laboratory
Blood for Geneticsi
X
Whole Blood for Correlative Studies (DNA and RNA)j
X
X
X
X
Whole Blood for Biomarkers Studies (plasma and 
serum)j
X
Tumor Tissue Collection
Newly-Obtained Tumor Tissuek
X
Archival Tumor Tissuel
X
Efficacy Measurements
Tumor Imaging
Xm
<---------------------Xn -------------------->
X
X
085MB4


Product:  MK-3475 
67
Protocol/Amendment No.: 181-06 
MK-3475-181-06 Final Protocol
25-Jun-2021
Confidential
a.
After centrally verified PD, or the start of new anticancer treatment; contacts are approximately every 9 weeks by telephone. Updated survival status may be requested by 
the Sponsor at any time during the course of the study. 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 death event previously recorded).  
b. Cycle 1 treatment must be given within 3 days of allocation. Trial treatment of docetaxel (administered on Days 1 of every 21-day [3-week] cycle) may be administered up 
to 3 days after randomization for Cycle 1 Day 1 due to administrative reasons or if the subject requires premedications. The required premedication should be administered 
as close to randomization as possible. After Cycle 1 there is a 3 day window for all trial treatment. The window for each visit is ± 3 days unless otherwise noted.  
c.
SAEs will be followed through 90 days following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier.
d. Height will be measured at Visit 1 only. 
e.
Laboratory tests for screening and ECOG performance status are to be performed within 3 days prior to the first dose of trial treatment.
f.
See Section 7.1.2.6 for details regarding administration of Patient Reported Outcomes (PROs). All PROs are to be performed at Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 
5, and Cycle 7. After Cycle 7 (Week 18), PROs are to be performed every 3 cycles (e.g., Week 27, Week 36, Week 45). PROs are to be performed up to a year or End of 
Treatment, whichever comes first, and the 30-day post-treatment discontinuation follow-up visit. A visit window of ± 7 days will apply to PRO visit assessment.  
g. 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 positive test results. Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.  
h. Urinalysis and thyroid function tests to be performed every other cycle. CBC (Hematology) and Chemistry to be performed every cycle (excluding Cycle 1 Day 1).
i.
Detailed instructions for the collection and management of specimens are provided in the central laboratory manual and in Section 7.1.3 Laboratory 
Procedure/Assessments.
j.
Whole blood samples for biomarker studies (DNA and RNA) should be collected pre-dose on Day 1 of Cycle 1, Cycle 2, and Cycle 3, and again at treatment 
discontinuation. Whole blood for correlative studies (plasma and serum) to be collected pre-dose on Day 1 of Cycle 1 only. Leftover samples will be stored for FBR if the 
subject signs the FBR consent.
k. 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.
l.
Archival tumor tissue will also be requested (where available) to assess the clinical utility of immune-related GEP assessment in newly obtained vs. archived tissue 
samples.
m. Screening tumor imaging will be performed within 14 days prior to randomization. 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 for each cohort.
n. The first on-study imaging time point will be performed at 9 weeks (63 days ± 7 days) calculated from the date of allocation and will continue to be performed Q9W 
(63 days ± 7 days), or earlier if clinically indicated. Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts.
085MB4


Product:  MK-3475 
68
Protocol/Amendment No.: 181-06 
MK-3475-181-06 Final Protocol
25-Jun-2021
Confidential
Trial Flow Chart –Treatment Phase for Irinotecan
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 9 
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
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Xc
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)d
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram (Local)
X
ECOG Performance Status
Xe
X
X
X
X
X
X
X
X
X
PROs (HRQoL Measures)f
<---------------------Xf -------------------->
X
X
Survival Status
<--------------------------------------------------------------------------------------------------------------------------->
X
085MB4


Product:  MK-3475 
69
Protocol/Amendment No.: 181-06 
MK-3475-181-06 Final Protocol
25-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 9 
Weeks
Scheduling Window (Days)b
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Trial Treatment Administration
Irinotecan Administration
Xb
X
X
X
X
X
X
X
Laboratory Procedures/Assessments:  
Analysis performed by LOCAL 
laboratory
Pregnancy Testg
X
X
X
X
X
X
X
X
X
X
PT/INR and aPTT
Xe
CBC with Differentialh
Xe
X
X
X
X
X
X
Xh
X
X
Chemistry Panelh
Xe
X
X
X
X
X
X
Xh
X
X
Urinalysish
Xe
X
X
X
Xh
X
T3, FT4, and TSHh
Xe
X
X
X
Xh
X
X
UGT1A1*28 allele
X
Laboratory Procedures/Assessments:
Analysis performed by CENTRAL 
laboratory
Blood for Geneticsi
X
Whole Blood for Correlative Studies 
(DNA and RNA)j
X
X
X
X
Whole Blood for Biomarkers Studies 
(plasma and serum)j
X
085MB4


Product:  MK-3475 
70
Protocol/Amendment No.: 181-06 
MK-3475-181-06 Final Protocol
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Trial Period:
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 and 
Beyond
Discon
Safety 
Follow-up
Follow Up 
Visits
Survival 
Follow-
Upa
At time of 
Discon
30 Days Post-
discon
Every 9 Weeks 
Post-discon
Every 9 
Weeks
Scheduling Window (Days)b
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Tumor Tissue Collection
Newly-Obtained Tumor Tissuek
X
Archival Tumor Tissuel
X
Efficacy Measurements
Tumor Imaging
Xm
<---------------------Xn -------------------->
X
X
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a.
After centrally verified PD, or the start of new anticancer treatment; contacts are approximately every 9 weeks by telephone. Updated survival status may be requested by the 
Sponsor at any time during the course of the study. 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 death event previously recorded).
b. Cycle 1 treatment must be given within 3 days of allocation. Trial treatment of irinotecan (administered on Days 1 of every 14-day [2-week] cycle) may be administered up to 
3 days after randomization for Cycle 1 Day 1 due to administrative reasons or if the subject requires premedications. The required premedications should be administered as 
close to randomization as possible. After Cycle 1 there is a 3 day window for all trial treatment. The window for each visit is ± 3 days unless otherwise noted.  
c.
SAEs will be followed through 90 days following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever 
is earlier.
d. Height will be measured at Visit 1 only. 
e.
Laboratory tests for screening and ECOG performance status are to be performed within 3 days prior to the first dose of trial treatment.
f.
See Section 7.1.2.6 for details regarding administration of Patient Reported Outcomes (PROs). All PROs are to be performed prior to Cycle 1-Day 1, Cycle 2-Day 1, Cycle 4-
Day 1, Cycle 5-Day 8, Cycle 7-Day 1, Cycle 10-Day 1, Cycle 14-Day 8, Cycle 19-Day 1, and Cycle 23-Day 8. PROs are to be performed up to a year or End of Treatment, 
whichever comes first, and the 30-day post-treatment discontinuation follow-up visit. A visit window of ± 7 days will apply to PRO visit assessment.  
g. 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 positive test results. Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
h. Urinalysis and thyroid function tests to be performed every other cycle. CBC (Hematology) and Chemistry to be performed every cycle (excluding Cycle 1 Day 1).
i.
Detailed instructions for the collection and management of specimens are provided in the central laboratory manual and in Section 7.1.3 Laboratory Procedure/Assessments.
j.
Whole blood samples for biomarkers studies (DNA and RNA) should be collected pre-dose on Day 1 of Cycle 1, Cycle 2, and Cycle 3, and again at treatment discontinuation. 
Whole blood for correlative studies (plasma and serum) to be collected pre-dose on Day 1 of Cycle 1 only. Leftover samples will be stored for FBR if the subject signs the 
FBR consent.
k. 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.
l.
Archival tumor tissue will also be requested (where available) to assess the clinical utility of immune-related GEP assessment in newly obtained vs. archived tissue samples.
m. Screening tumor imaging will be performed within 14 days prior to randomization. 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 for each cohort.
n. The first on-study imaging time point will be performed at 9 weeks (63 days ± 7 days) calculated from the date of allocation and will continue to be performed Q9W (63 days 
± 7 days), or earlier if clinically indicated. Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts.
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Second Course Phase (Retreatment with Pembrolizumab)      
Trial Period:
Treatment Cycles
End of Treatment
Post-treatment
Treatment Cycle/Title:
1
2
3
4
5
6
7
8 -
17
Discon
Safety Follow-up
Follow Up Visits
Survival Follow-
Upa
At time of 
Discon
30 Days Post-
discon
Every 9 Weeks Post-
discon
Every 9 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
Post-study anticancer Therapy Status
X
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
Xc
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
X
X
X
X
X
X
X
X
X
Survival Status
<--------------------------------------------------------------------------------------------------------------------------->
X
Trial Treatment Administration
Pembrolizumab
X
X
X
X
X
X
X
X
LOCAL Laboratory Assessments
Pregnancy Testd
X
X
X
X
X
X
X
X
X
PT/INR and aPTT
Xe
CBC with Differentialf
Xe
X
X
X
X
X
X
Xf
X
X
Chemistry Panelf
Xe
X
X
X
X
X
X
Xf
X
X
Urinalysisf
Xe
X
X
X
Xf
X
T3, FT4, and TSH f
Xe
X
X
X
Xf
X
X
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Trial Period:
Treatment Cycles
End of Treatment
Post-treatment
Treatment Cycle/Title:
1
2
3
4
5
6
7
8 -
17
Discon
Safety Follow-up
Follow Up Visits
Survival Follow-
Upa
At time of 
Discon
30 Days Post-
discon
Every 9 Weeks Post-
discon
Every 9 Weeks
Scheduling Window (Days)b
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 3
± 3
± 7
± 7
± 7
Efficacy Measurements
Tumor Imaging
<------------------- Xg ------------------->
Xh
X
a.
After the start of new anti-cancer treatment or PD contacts are approximately every 9 weeks by telephone. Updated survival status may be requested by the Sponsor at 
any time during the course of the study. 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 death event previously recorded).
b.
In general, the window for each visit is ± 3 days unless otherwise noted.  
c.
SAEs will be followed through 90 days following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier.
d.
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 positive test results. Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
e.
Laboratory tests for determining eligibility are to be performed within 3 days prior to the first retreatment dose of pembrolizumab.
f.
Urinalysis and thyroid function tests to be performed every other cycle. CBC (Hematology) and Chemistry to be performed every cycle (excluding Cycle 1 Day 1). 
g.
Tumor imaging should be performed within 14 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. Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts.
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 for each cohort.
h.
Tumor imaging should be performed at the time of treatment discontinuation (i.e., 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.
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
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.
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain documented informed consent 
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 three 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
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.
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Prior treatment for esophageal carcinoma will be recorded separately and not listed as a prior 
medication.
Prior Treatment Details for Esophageal or EGJ 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 Section 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 randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Subjects who undergo Second Course Therapy with pembrolizumab will maintain the 
treatment/randomization number assigned at the beginning of First Course Therapy.
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In a situation where rerandomization of the subjects is planned (eg, study extension periods), 
the rerandomization will be based on a new randomization schedule; however, each subject 
will retain his/her original treatment/randomization number. Only the study intervention 
regimen associated with the rerandomization period or phase may change.
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
pembrolizumab, docetaxel,
paclitaxel
or irinotecan 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.
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.
Preparation and administration of paclitaxel, docetaxel, or irinotecan should be completed as 
per the approved product label.
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 for 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. 
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 exam (PE) 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 
exams should be performed as specified in the Trial Flow Chart-Section 6. After the first 
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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, the 
investigator or qualified designee will perform a directed physical exam 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. Height will be measured at Visit 1 only.
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) within 3 days prior to dosing Cycle 1 and prior to dosing on Day 1 of each subsequent 
treatment cycle and at discontinuation of trial treatment as specified in the Trial Flow Chart –
Section 6.
Patient Reported Outcome
It is strongly recommended that Patient Reported Outcomes (PROs) are administered prior to 
drug administration, adverse event evaluation and disease status notification starting with the 
EQ-5D, followed by EORTC QLQ-C30, and EORTC QLQ-OES18; an exception to this 
recommendation may occur at the treatment discontinuation visit where patients may have 
already been notified of their disease status or an AE evaluation is Known prior to them 
arriving to the clinic. All PROs are to be performed as specified in the Trial Flow Chart –
Section 6. If the subject does not complete the PROs, the MISS_MODE form must be 
completed to capture the reason the assessment was not performed. A visit window of ± 7 
days will apply to PRO visit assessment.  
If at the time of the enrollment of a subject, the translated version of the OES-18, one of the 
PRO measures, is not available for that language/country, and therefore cannot be completed 
by the subject at Cycle 1 Day 1, then the OES-18 will not be required for this subject at any 
point during the study. The other study PRO measures must be completed as scheduled. 
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NOTE: For some sites, the translated OES-18 might become available after study startup and 
should be administered to subjects at their time of enrollment; for some sites the OES-18 
translation might not be available for the entire duration of the study.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. 
Refer to the Trial Flow Chart - Section 6 for the schedule of laboratory assessments.
Laboratory Safety Evaluations
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 5.
Table 5
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Alkaline phosphatase
Specific gravity
Thyroid-Stimulating 
Hormone (TSH)
Hemoglobin
Blood urea nitrogen/Ureaa
Microscopic exam, if 
abnormal results are 
noted
Pregnancy test (serum or 
urine)b
Platelet count
Lactate dehydrogenase 
(LDH)
Protein
Free thyroxine (FT4)
Red blood count
Alanine aminotransferase 
(ALT)
Glucose
Total triiodothyronine (T3) 
or Free T3c
White blood cell count 
(total and differential)d
Aspartate aminotransferase 
(AST)
Blood
aPTT
Absolute neutrophil 
counte
Bicarbonate or Carbon 
dioxidef
PT 
Absolute lymphocyte 
counte
Calcium
(INR)
Chloride
Creatinine
Glucose
Potassium
Sodium
Total bilirubin  
Direct bilirubin, if total 
bilirubin is elevated above 
the upper limit of normal
Total protein
Albuming
a. Blood Urea Nitrogen is preferred; if not available urea may be tested.
b. Perform on women of childbearing potential only, 72 hours prior to Day 1 of each cycle and 30 days post treatment.  
c. 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. 
d. Report % or absolute results per standard of practice. Report the results in the same manner throughout the study.
e. Results should be calculated per local standard of practice.
f. If these tests are not done as part of standard of care in your region, then these test do not need to be performed.
g. Screening only
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Laboratory tests for screening should be performed within 3 days prior to the first dose of 
trial treatment. Subjects eligible for retreatment with pembrolizumab should have lab tests
performed within 3 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 laboratory results are within normal range.
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 are provided the central laboratory manual.
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. Blood samples for PK and ADA collected may be 
stored at this time. Further 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. 
7.1.3.3.1 Blood Collection for Serum MK-3475
Sample collection, storage and shipment instructions for serum samples will be provided in 
the laboratory manual. PK samples should be drawn according to the PK collection schedule 
for subjects who receive pembrolizumab.
7.1.3.3.2 Blood Collection for Anti-pembrolizumab (MK-3475) Antibodies 
Sample collection, storage and shipment instructions for serum samples will be provided in 
the laboratory manual. Anti- pembrolizumab antibody samples should be drawn according to 
the ADA collection schedule for subjects who receive pembrolizumab. Simultaneous PK 
sampling is required for interpretation of ADA analysis.
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7.1.3.3.3 Correlative and Biomarker Blood Samples 
Additional biomarker research to identify factors important for pembrolizumab therapy may 
also be pursued. Analysis to be inclusive of all testing is in Section 4.2.3.5. If the samples are 
collected, any leftovers will be stored for future biomedical research if the subject signs the 
FBR consent.
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 signs the FBR consent. If the planned genetic analysis is 
not approved, but FBR is approved and consent is given, this sample will be collected for the 
purpose of FBR.
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:

(DNA) for future research.

Leftover archival or newly obtained 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 tumor tissue for biomarker analysis as 
described under eligibility criteria. Repeat samples may be required if adequate tissue is not 
provided. If the subject signs the FBR consent, any leftover tissue that would ordinarily be 
discarded at the end of the main study will be retained for FBR.
Newly-obtained tissue is preferred (no intervening treatment [local or systemic] involving the 
site of tissue biopsy once tissue biopsy is obtained and time of study enrollment). Formalin-
fixed, paraffin-embedded (FFPE) block specimens are preferred to slides. 
Detailed instructions for tissue collection, processing and shipment are provided in the 
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 is strongly preferred to be acquired 
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by computed tomography (CT). Magnetic resonance imaging (MRI) should be used only 
when CT is contraindicated or for imaging of the brain. The same imaging technique 
regarding modality and the use of contrast should be used in a subject throughout the trial to 
optimize the visualization of existing and new tumor burden. 
Local site investigator/radiology assessment based on RECIST 1.1 will be used to determine 
subject eligibility. 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, additional 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.
The central imaging vendor will verify progressive disease (PD) following local site 
investigator-assessed 1st radiologic evidence of PD. Expedited verification of radiologic PD 
by the central imaging vendor will be communicated to the study site and sponsor (See 
Section 7.1.4.1.2).
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 14 days prior to the date of randomization. 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 retrospective review.
Scans performed as part of routine clinical management are acceptable for use as baseline
tumor imaging if they are of diagnostic quality and performed within 14 days prior to the 
date of randomization and can be assessed by the central imaging vendor. 
A scan performed outside 14 days but within 28 days prior to the first dose of study 
medication may be acceptable as the baseline scan if (1) it was performed as part of routine 
clinical management, (2) the subject is participating at a site where the local regulatory body 
and/or IRB/ERC would not permit a repeat scan to be performed to meet the 14 day criteria, 
and (3) permission is given by the Sponsor.
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 randomization. Subsequent tumor imaging should be performed every 
9 weeks (63 days ± 7 days) or more frequently if clinically indicated. Imaging timing should 
follow calendar days and should not be adjusted for delays in cycle starts. Imaging should 
continue to be performed until disease progression verified by central imaging vendor (unless 
site PI elects to continue treatment and follow irRECIST), the start of new anti-cancer 
treatment, withdrawal of consent, or death, whichever occurs first. All supplemental imaging 
must be submitted to the central imaging vendor.
Per RECIST 1.1, partial and complete response should be confirmed by a repeat tumor 
imaging assessment not less than 4 weeks from the date the response was first documented. 
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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 scan (i.e. 9 weeks later), 
whichever is clinically indicated. Subjects will then return to regular scheduled imaging 
every 9 weeks, starting with the next scheduled imaging time point. Subjects who obtain a 
confirmation scan do not need to undergo the next scheduled tumor imaging if it is < 4 weeks 
later; tumor imaging may resume at the subsequent scheduled imaging time point.
For subjects in the pembrolizumab arm and per irRECIST (Section 4.2.3.4.1), disease 
progression should be confirmed by the site at least 4 weeks after central verification of 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 4.2.3.4.1. 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. 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  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 (Retreatment) Tumor Imaging
A scan must be performed within 14 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 weeks (63 days ± 7 days) 
after the restart of treatment. Subsequent tumor imaging should be performed every 9 weeks 
(63 days ± 7 days) or more frequently if clinically indicated.
Per irRECIST (Section 4.2.3.4.1), 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.
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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.
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 (e.g., discontinuation of study therapy). Initial tumor 
imaging showing site-assessed PD should be submitted to the central imaging vendor 
immediately. The site will be notified if the central imaging vendor verifies progressive 
disease (PD) using RECIST 1.1. Figure 3 illustrates the imaging flow involving verification 
of PD for clinically stable subjects.
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. These 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)
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In subjects who have shown initial evidence of radiological PD by RECIST 1.1, it is at the 
discretion of the investigator whether to continue a subject on study treatment until repeat 
imaging is obtained (using irRECIST for subject management, see Table 6 and Figure 3). 
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 
central verification of site-assessed 1st radiologic evidence of PD and is not required to have 
repeat imaging for PD confirmation.
In determining whether or not the tumor burden has increased or decreased per irRECIST, 
the local site investigator should consider all target and non-target lesions as well as any 
incremental new lesion(s).
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 stable or qualitatively improved

New lesion resulting in initial PD is stable or qualitatively improved 

No incremental new lesion(s) since last evaluation

No incremental new non-target lesion progression since last evaluation
If repeat imaging does not confirm PD per irRECIST as assessed by the local site 
investigator and the subject continues to be clinically stable, treatment may continue and 
follow the regular imaging schedule. 
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
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
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 Flow Chart and be submitted to the central imaging vendor.
Additional details about irRECIST are referenced in Merck TIP Sheet for RECIST 1 1 and 
irRECIST. 
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 
which has been 
verified by the 
central imaging 
vendor
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
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Figure 3
Imaging and Treatment for Clinically Stable Subjects after First Radiologic 
Evidence of PD Assessed by the Site
Other Procedures
Withdrawal/Discontinuation
Subjects who discountinue/withdraw from treatment prior to completion of the treatment
period should be encouraged to continue to be followed for all remaining study visits, and 
encouraged to participate in the Survival Follow-Up Phase (as outlined in the Trial Flow 
Chart and Section 7.1.6.3).
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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).
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.
7.1.5.1.2 Lost to Follow-up
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit. If the 
subject is contacted, the subject should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the 
subject at each missed visit (e.g. phone calls and/or a certified letter to the 
subject’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the subject’s medical record.
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Note:  A subject is not considered lost to follow up until the last scheduled visit 
for the individual subject. The amount of missing data for the subject will be 
managed via the pre-specified data handling and analysis guidelines
7.1.5.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical trial that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
trial site.
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.
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.
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose of trial 
treatment except for the following:

Laboratory tests and ECOG PS are to be performed within 3 days prior to the first 
dose of trial treatment.

Initial tumor imaging for First Course Treatment will be performed within 14 days of 
randomization and initial tumor imaging for Second Course Treatment will be 
performed prior to the first dose of second course treatment.

For women of reproductive potential, a serum 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.

For subjects who are to receive therapy with irinotecan, subjects should be tested 
locally for the UGT1A1*28 allele at investigator discretion. The starting dose for 
irinotecan can be adjusted as outlined in the prescribing information or according to 
local guidelines.
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An allele test performed prior to the subject signing consent can be used to support subject 
eligibility as long as that test was performed as part of standard of care and not specifically 
for this study.  
Subjects will not be allowed to rescreen in this study.
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 two 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
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. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required.
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 pembrolizumab 
or through 180 days after the last dose of paclitaxel, docetaxel, or irinotecan.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
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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 pembrolizumab or through 180 days after the last dose of 
paclitaxel, docetaxel, or irinotecan.

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 6.5).
Post-Trial 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 two safety 
follow-up visits, one after the Initial Treatment Period and one after the Second Course 
Treatment Phase.
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. 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.  
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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. Details are provided in the Trial Flow Chart (Section 6) 
for retreatment with pembrolizumab.
7.1.6.3.3 Survival Follow-up
Subjects, who have had centrally verified disease progression or start a new anti-cancer 
therapy, will move into the Survival Follow-Up Phase. Subjects should be contacted by 
telephone approximately every 9 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, these additional time points may be requested prior to; an eDMC safety review, 
efficacy interim analysis, and/or final analysis. Upon Sponsor notification, all subjects who 
do not/will not have a scheduled study visit or study contact during the Sponsor defined time 
period will be contacted for their survival status.
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.
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.
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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 over dose 
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.
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 
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procedure. Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days after the last dose of pembrolizumab or through 
180 days after the last dose of paclitaxel, docetaxel or irinotecan 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.
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 
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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, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, 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 
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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 in this section 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.
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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
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of the 
Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED 
BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS 
PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology or 
toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's product 
is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
external Data Monitoring Committee (eDMC) regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.7 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
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8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes made to primary and/or key secondary hypotheses, or the statistical 
methods related to those hypotheses, then the protocol will be amended (consistent with ICH 
Guideline E-9). Changes to exploratory or other non-confirmatory analyses made after the 
protocol has been finalized, but prior to the conduct of any analysis, will be documented in a 
supplemental SAP (sSAP) and referenced in the Clinical Study Report (CSR) for the study. 
There will be a separate PK analysis plan as well as biomarker analysis plan. Post hoc 
exploratory analyses will be clearly identified in the CSR. The PRO analysis plan will be 
included in the sSAP.
Statistical Analysis Plan Summary
The key elements of the statistical analysis plan that are summarized in Table 8 below are 
applicable to the Global Cohort; the comprehensive plan is provided in Sections 8.2 through 
8.12. Statistical analysis plan for the China Cohort will be provided in a supplemental SAP.
Table 8
Statistical Plan Analysis Summary
Study
Design
Overview
A Phase III Randomized Open-Label Study of Single Agent Pembrolizumab vs. 
Physicians’ Choice of Single Agent Docetaxel, Paclitaxel, or Irinotecan in Subjects 
with Advanced/Metastatic Adenocarcinoma and Squamous Cell Carcinoma of the 
Esophagus that have Progressed after First-Line Standard Therapy (KEYNOTE-
181)
Treatment
Assignment
Subjects will be randomized in a 1:1 ratio to receive pembrolizumab or 
investigator’s choice of paclitaxel, docetaxel, or irinotecan (Control Arm).
Stratification factors are in Section 5.4. This is an open-label study. 
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary
Endpoints/Hypotheses
1. Overall Survival (OS) in subjects with squamous cell carcinoma of the 
Esophagus.
2. Overall Survival (OS) in subjects with PD-L1 CPS≥10
3. Overall Survival (OS) in all subjects.
Statistical Methods for
Key
Efficacy Analyses
The primary hypotheses will be evaluated by comparing pembrolizumab to the 
control on OS in subjects with squamous cell carcinoma of the esophagus and OS 
in subjects with PD-L1 CPS≥10 using a stratified Log-rank test. The primary 
hypotheses on OS in all subjects will be evaluated using a stratified maximum 
weighted log-rank test (max-combo test) [51], [52]. Estimation of the hazard ratio
will be done using a stratified Cox regression model. Event rates over time will be
estimated within each treatment group using the Kaplan-Meier method.
Statistical
Methods
for
Key
Safety
Analyses
The analysis of safety results will follow a tiered approach. The tiers differ with 
respect to the analyses that will be performed. “Tier 1” safety endpoints will be 
subject to inferential testing for statistical significance with p-values and 95% 
confidence intervals provided for between-group comparisons. Other safety 
parameters will be considered Tier 2 or Tier 3. Tier 2 parameters will be assessed 
via point estimates with 95% confidence intervals provided for between-group 
comparisons; only point estimates by treatment group are provided for Tier 3 safety 
parameters. There are no Tier 1 events in this trial. The between-treatment 
difference will be analyzed using the Miettinen and Nurminen method [53].
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Interim Analyses
One interim efficacy analysis will be performed in this study. Results will be 
reviewed by an external data monitoring committee. Details are provided in Section
8.7.

Interim Efficacy Analysis
o
Timing: To be performed after (1) enrollment is completed, (2) 
approximately 251 OS events and 385 OS events have been observed 
among subjects with squamous cell carcinoma of the esophagus and all 
subjects, respectively, and (3) 8 months after last subject randomized. 
In addition, if there are fewer than 172 OS events among subjects with 
PD-L1 CPS≥10 at the time, the interim efficacy analysis may be 
delayed for up to 2 months or when the target number of OS events in 
subjects with PD-L1 CPS≥10 is reached, whichever occurs first.
o
Primary purpose: Interim efficacy analysis for OS

Final Analysis
o
Timing: after approximately 310 OS events and 473 OS events have 
been observed among subjects with squamous cell carcinoma of the 
esophagus and all subjects, respectively , and 16 months after last 
subject randomized.
Multiplicity
The multiplicity strategy specified in this section will be applied to the three 
primary hypotheses (superiority of pembrolizumab on OS in subjects with 
squamous cell carcinoma of the esophagus, or subjects with PD-L1 CPS≥10 or in all 
subjects) and two secondary hypotheses (superiority of pembrolizumab on PFS in 
all subjects or ORR in all subjects). 
The overall Type-I error is strongly controlled at 2.5% (one-sided), with initially 
0.8% allocated to OS hypothesis in subjects with squamous cell carcinoma of the 
esophagus, 0.9% allocated to OS hypothesis in subjects with PD-L1 CPS≥10 and 
0.8% allocated to the OS hypotheses in all subjects, and 0% to the PFS and ORR 
hypotheses. By using the graphical approach of Maurer and Bretz [54], if OS 
hypothesis in subjects with squamous cell carcinoma of the esophagus is rejected, 
the corresponding alpha level can be shifted to OS hypothesis in all subjects. If OS 
hypothesis in subjects with PD-L1 CPS≥10 is rejected, the corresponding alpha 
level can also be shifted to OS hypotheses in all subjects. 
The secondary hypotheses of PFS and ORR will be tested only if pembrolizumab 
arm is superior to the control in OS in all subjects. If OS hypothesis in all subjects is 
rejected, the corresponding alpha level can be shifted by half to PFS in all subjects 
and by half to ORR in all subjects, respectively. 
Sample
Size
and
Power
For the hypotheses in all subjects, the sample size is approximately 600.
Among all subjects, it is expected that about 400 subjects with squamous cell 
carcinoma of the esophagus will be enrolled. For the hypotheses in subjects with 
PD-L1 CPS≥10, the sample size is approximately 280 (based on an observed 
prevalence rate of ~47% from KN180). 
For the primary endpoint, OS in subjects with squamous cell carcinoma of the 
esophagus, with 310 OS events, the trial has 91.3% power to demonstrate that 
pembrolizumab is superior to the control at a one-sided 0.8% alpha-level, if the 
underlying hazard ratio of OS is 0.65.
For the primary endpoint, OS in subjects with PD-L1 CPS≥10, with 213 OS events, 
the trial has 90.9% power to demonstrate that pembrolizumab is superior to the 
control at a one-sided 0.9% alpha-level, if the underlying hazard ratio of OS is 0.6.
For the primary endpoint, OS in all subjects, with 473 OS events, the trial has 
92.6% power to demonstrate that pembrolizumab is superior to the control at a one-
sided 0.8% alpha-level, if the underlying hazard ratio of OS is 0.7.
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Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
The SPONSOR will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IVRS/IWRS. 
Although the trial is open label, analyses or summaries generated by randomized treatment 
assignment, actual treatment received will be limited and documented. In addition, the 
central imaging vendor will perform the central imaging review without knowledge of 
treatment group assignment.
The eDMC will serve as the primary reviewer of the unblinded results of the interim analyses 
and will make recommendations for discontinuation of the study or modification to an 
executive oversight committee of the Sponsor.
Depending on the recommendation of the 
eDMC, the Sponsor may prepare a regulatory submission.
If the eDMC recommends 
modifications to the design of the protocol or discontinuation of the study, this executive 
oversight committee and limited additional Sponsor personnel may be unblinded to results at 
the treatment level in order to act on these recommendations. The extent to which individuals 
are unblinded with respect to results of interim analyses will be documented. Additional 
logistical details, revisions to the above plan and data monitoring guidance will be provided 
in the eDMC Charter. 
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
Efficacy Endpoints
Primary
Overall Survival
Overall Survival (OS) is defined as the time from randomization to death due to any cause. 
Subjects without documented death at the time of the final analysis will be censored at the 
date of the last follow-up.
Secondary
Progression-free survival (PFS) – RECIST 1.1 by central imaging vendor review in all 
subjects;
Progression-free-survival (PFS) is defined as the time from randomization to the first 
documented disease progression per RECIST 1.1 based on central imaging vendor review or
death due to any cause, whichever occurs first. See Section 8.6.1 for definition of censoring;
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Objective Response Rate (ORR) – RECIST 1.1 by central imaging vendor review in all 
subjects;
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).
Safety Endpoints
Safety measurements are described in Section 7.
Analysis Populations
Efficacy Analysis Populations
The Intention-to-Treat (ITT) population will serve as the population for primary efficacy 
analysis. All randomized subjects will be included in this population. Subjects will be 
included in the treatment group to which they are randomized.
Details on the approach to handling missing data are provided in Section 8.6 Statistical
Methods.
The China Cohort
After the sample size required for the Global Cohort is reached, the study will continue to 
randomize subjects in China until the sample size for the Chinese subjects meets the target
for China. The Chinese subjects randomized after the enrollment of the Global Cohort is 
closed will not be included in the above primary efficacy analysis population which is based 
on the Global Cohort. The China Cohort will also be analyzed separately per local regulatory 
requirement.
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be included in the treatment group corresponding 
to the study treatment they actually received for the analysis of safety data using the ASaT 
population. For most subjects this will be the treatment group to which they are randomized. 
Subjects who take incorrect study treatment for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received. Any subject who 
receives the incorrect study medication for one cycle but receives the correct treatment for all 
other cycles will be analyzed according to the correct treatment group and a narrative will be 
provided for any events that occur during the cycle for which the subject is incorrectly dosed.
At least 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.
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The China Cohort
The Chinese subjects randomized and treated in the China extension enrollment period will 
not be included in the above primary safety analysis population. The China Cohort will also 
be analyzed separately per local regulatory requirement. 
Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the supplemental 
SAP.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 8.8, Multiplicity. Nominal p-values 
may be computed for other efficacy analyses, but should be interpreted with caution due to 
potential issues of multiplicity.
Overall Survival (OS)
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. A 
stratified Cox proportional hazard model with Efron's method of tie handling will be used to 
estimate the magnitude of the treatment difference (i.e., the hazard ratio). The hazard ratio 
and its 95% confidence interval from the stratified Cox model with a single treatment 
covariate will be reported. The hypotheses of treatment difference for OS curves in subjects 
with squamous cell carcinoma of the esophagus and OS in subjects with PD-L1 CPS≥10 will 
be tested using the stratified log-rank test. The hypotheses of treatment difference for OS 
curves in all subjects will be tested using the stratified max-combo test. The stratification 
factors used for randomization (See Section 5.4) will be applied to both the stratified log-
rank test, stratified max-combo test, and the stratified Cox model if applicable.
The max-combo test statistic is the maximum of the log-rank test statistic and a weighted 
log-rank variation of the Fleming-Harrington test statistic; Zm = max (Z1, Z2), where Z1 and 
Z2 are the test statistics from the FH (0, 0) and FH (0, 1) family of test statistics, respectively. 
FH (0, 0) corresponds to the log-rank test, while FH (0, 1) is more sensitive to late-difference 
alternatives. 
A sensitivity analysis, which tests the hypothesis of treatment difference for OS in all 
subjects using the stratified log-rank test, will be conducted.
Subjects in the control arm are expected to discontinue treatment earlier compared to subjects 
in the pembrolizumab arm, and may switch to another anti PD-1 treatment. Exploratory 
analyses to adjust for the effect of crossover to other PD-1 therapies on OS may be 
performed based on recognized methods, e.g. the Rank Preserving Structural Failure Time 
(RPSFT) model proposed by Robins and Tsiatis (1989) [55], two stage model, etc., based on 
an examination of the appropriateness of the data to the assumptions required by the 
methods.
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Progression-Free Survival (PFS)
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. A stratified Cox proportional hazard model with Efron's method of tie 
handling will be used to estimate the magnitude of the treatment difference (i.e., hazard ratio) 
between the treatment arms. The hazard ratio and its 95% confidence interval from the 
stratified Cox model with Efron's method of tie handling and with a single treatment 
covariate will be reported. The hypotheses of treatment difference for PFS curves in subjects 
with squamous cell carcinoma of the esophagus and PFS in subjects with PD-L1 CPS≥10 
will be tested using the stratified log-rank test. The hypotheses of treatment difference for 
PFS curves in all subjects will be tested using the stratified max-combo test. The 
stratification factors used for randomization (See Section 5.4) will be applied to both the 
stratified log-rank test, stratified max-combo test, and the stratified Cox model if applicable.
Since disease progression is assessed periodically, progressive disease (PD) can occur any 
time in the time interval between the last assessment where PD was not documented and the 
assessment when PD is documented. For the primary analysis, for the subjects who have PD, 
the true date of disease progression will be approximated by the date of the first assessment 
at which PD is objectively documented per RECIST 1.1 by central imaging vendor review, 
regardless of discontinuation of study drug. Death is always considered as a confirmed PD 
event. Sensitivity analyses will be performed for comparison of PFS based on investigator's 
assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by central imaging 
vendor review, we will perform two sensitivity analyses with a different set of censoring 
rules. The first sensitivity analysis is the same as the primary analysis except that it censors at 
the last disease assessment without PD when PD or death is documented after more than one 
missed disease assessment. The second sensitivity analysis is the same as the primary 
analysis except that it considers discontinuation of treatment or initiation of an anticancer 
treatment subsequent to discontinuation of study-specified treatments, whichever occurs 
later, to be a PD event for subjects without documented PD or death. If a subject meets 
multiple criteria for censoring, the censoring criterion that occurs earliest will be applied. The 
censoring rules for primary and sensitivity analyses are summarized in Table 9.
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Table 9
Censoring rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and no death; 
new 
anticancer 
treatment 
is 
not 
initiated
Censored at last disease 
assessment 
Censored at last disease 
assessment 
Censored at last disease 
assessment if still on study 
therapy; 
progressed 
at 
treatment 
discontinuation 
No PD and no death; 
new 
anticancer 
treatment is initiated
Censored at last disease 
assessment before new 
anticancer treatment
Censored at last disease 
assessment before new 
anticancer treatment
Progressed at date of new 
anticancer treatment
No PD and no death; ≥ 
2 consecutive missed 
disease assessments
Censored at last disease 
assessment
Censored at last disease 
assessment prior to ≥2 
consecutive 
missed 
visits
Censored at last disease 
assessment
PD 
or 
death 
documented after ≤ 1 
missed 
disease 
assessment
Progressed at date of 
documented PD or death
Progressed at date of 
documented 
PD 
or 
death
Progressed 
at 
date 
of 
documented PD or death
PD 
or 
death 
documented 
at 
any 
time 
after 
≥ 
2 
consecutive 
missed 
Progressed at date of 
documented PD or death
Censored at last disease 
assessment 
prior 
to 
the
≥ 2 consecutive 
missed 
disease 
Progressed 
at 
date 
of 
documented PD or death
The proportional hazards assumption on PFS will be examined using both graphical and 
analytical methods if warranted. The log[-log] of the survival function vs. time for PFS will 
be plotted for the comparison between pembrolizumab and the control arm. If the curves are 
not parallel, indicating that hazards are not proportional, supportive analyses may be 
conducted to account for the possible non-proportional hazards effect associated with 
immunotherapies: for example, using Restricted Mean Survival Time (RMST) method [56], 
parametric method [57], etc. Further details of sensitivity analyses will be described in
supplemental SAP.
Objective Response Rate (ORR)
Stratified Miettinen and Nurminen’s method [53] will be used for comparison of the 
objective response rates between the treatment arms. The difference in ORR and its 95% 
confidence interval from the stratified Miettinen and Nurminen’s method with strata 
weighting by sample size will be reported. The stratification factors used for randomization 
(See Section 5.4) will be applied to the analysis if applicable.
Table 10 summarizes the primary analysis approach for primary and secondary efficacy 
endpoints. Sensitivity analysis methods are described above for each endpoint.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, 
multiple populations, and interim analyses is described in Section 8.7 Interim Analyses and 
in Section 8.8 Multiplicity.
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Table 10
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
†Statistical Method
Analysis Population
Missing Data
Approach
Primary Hypothesis #1
OS in subjects with squamous 
cell 
carcinoma 
of 
the 
Esophagus.
Test: Stratified Log-
rank test Estimation: 
Stratified Cox model 
with 
Efron’s 
tie 
handling method
ITT in subjects 
with 
squamous 
cell carcinoma of 
the Esophagus.
Censored at last known 
alive date
Primary Hypothesis #2
OS
in subjects with PD-L1 
CPS≥10.
Test: Stratified Log-
rank test Estimation: 
Stratified Cox model 
with 
Efron’s 
tie 
handling method
ITT in subjects with
PD-L1 CPS≥10
Censored at last known 
alive date
Primary Hypothesis #3
OS in all subjects
Test: 
Max-combo 
test 
Estimation: 
Stratified Cox model 
with 
Efron’s 
tie 
handling method
ITT in all subjects
Censored at last known 
alive date
Key Secondary Endpoints
PFS per RECIST 1.1 by central 
imaging vendor review in all 
subjects
Test: Max-combo test 
Estimation: Stratified 
Cox 
model 
with 
Efron’s tie handling 
method
ITT in all 
subjects
Primary 
censoring 
rule
Sensitivity analysis 1
Sensitivity analysis 2 
(More
details
are in
Table 9)
ORR per RECIST 1.1 by central 
imaging vendor review in all 
subjects
Test: Stratified M & 
N method‡
ITT in all subjects
Subjects with missing 
data are considered non-
responders
† Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for
randomization (See Section 5.4) will be applied to the analysis model if applicable.
‡  Miettinen and Nurminen method [53]
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), laboratory tests, vital signs, etc.
Tiered Approach
The analysis of safety results will follow a tiered approach (Table 11). The tiers differ with 
respect to the analyses that will be performed. “Tier 1” safety endpoints that will be subject 
to inferential testing for statistical significance with p-values and 95% confidence intervals 
provided for between-group comparisons. Other safety parameters will be considered Tier 2 
or Tier 3. Tier 2 parameters will be assessed via point estimates with 95% confidence 
intervals provided for between-group comparisons; only point estimates by treatment group 
are provided for Tier 3 safety parameters.
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AEs (specific terms as well as system organ class terms) that are not pre-specified as Tier 1 
endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on the number of 
events observed. Membership in Tier 2 requires that at least 4 subjects in any treatment group 
exhibit the event; all other AEs and predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in AEs and predefined 
limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, that are not 
pre-specified as Tier 1 endpoints will be considered Tier 3 safety parameters. Summary 
statistics for baseline, on-treatment, and change from baseline values will be provided by 
treatment group in table format.
Based on the mechanism of action of pembrolizumab and safety data observed in historic 
pembrolizumab trials to date, there are no events of interest that warrant classification as Tier 
I events for this protocol. In addition, the broad clinical and laboratory AE categories 
consisting of the percentage of subjects with any AE, any drug related AE, any Grade 3-5 
AE, any serious AE, any AE which is both drug-related and Grade 3-5, any AE which is both 
serious and drug-related, dose modification due to AE, and who discontinued due to an AE, 
and death will be considered Tier 2 endpoints. 95% confidence intervals (Tier 2) will be 
provided for between-treatment differences in the percentage of subjects with events; these 
analyses will be performed using the Miettinen and Nurminen method (1985) [53], an 
unconditional, asymptotic method.
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Table 11
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Serious AE 
X
X
Any Grade 3-5 AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade 3-5 and Drug-Related AE
X
X 
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
Specific AEs, SOCs, or PDLCs‡ (incidence ≥4 of 
subjects in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <4 of 
subjects in all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, Vital 
Signs)
X
Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed. 
Demographic variables (e.g., age), baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
Interim Analyses
There is one planned interim efficacy analysis in this trial. Results will be reviewed by an 
external data monitoring committee (eDMC).
The primary purpose of the interim efficacy analysis is to evaluate superiority of 
pembrolizumab in OS. In order to account for potential delayed treatment effects that have 
been observed with immunotherapy, the interim efficacy analysis will be performed after: (1) 
enrollment is completed, (2) approximately 251 OS events and 385 OS events have been 
observed among subjects with squamous cell carcinoma of the Esophagus and all subjects,
respectively, and (3) 8 months after last subject randomized. In addition, if there are fewer than 
172 OS events among subjects with PD-L1 CPS≥10 at the time, the interim efficacy analysis 
may be delayed for up to 2 months or when the target number of OS events in subjects with 
PD-L1 CPS≥10 is reached, whichever occurs first. Thus, adequate follow-up time is 
incorporated into the trial to ensure that the interim efficacy analysis is conducted at an 
appropriate time to characterize the potential benefit of immunotherapy. The boundary for 
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the final analysis will be adjusted according to the actual alpha spent at IA and the actual 
number of events at IA and FA. 
For the OS hypotheses, Lan-DeMets O'Brien-Fleming alpha spending function with specified 
calendar time fraction (0.76)[58] will be used to construct group sequential boundaries to 
control the Type-I error. 
The actual boundaries for interim analysis will be determined from the number of OS events 
observed at the time of the interim efficacy analysis using the alpha spending function. The 
actual boundaries for final analysis will be determined from the number of OS events 
observed at the time of the interim efficacy analysis and final analysis using the alpha
spending function. 
Table 12 summarizes the timing, sample size and decision guidance of the interim efficacy 
analysis and final analysis. Bounds are based on estimated number of events and will be 
updated at times of analyses using spending functions as noted above.
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Table 12
Summary of Timing, Sample Size and Decision Guidance of Interim Efficacy 
Analysis and Final Analysis
Criteria for Conduct of Analysis
Endpoint
Value
Efficacy
Interim Efficacy 
Analysis
~ 25  months after first subject 
randomized
Approximately 251 OS events 
and 385 OS events have been 
observed among subjects with 
squamous cell carcinoma of the 
esophagus 
and 
all 
subjects,
respectively, and 8 months after 
last subject randomized. 
If there are fewer than 172 OS 
events among subjects with PD-
L1 CPS≥10 at the time, the 
interim efficacy analysis may be 
delayed for up to 2 months or 
when the target number of OS 
events in subjects with PD-L1 
CPS≥10 is reached, whichever 
occurs first. OS events among 
subjects with squamous cell 
carcinoma of the esophagus: 
~251
OS events among subjects with 
PD-L1 CPS≥10: ~172
OS events among all subjects: 
385
OS in
subjects 
with 
squamous 
cell carcinoma of 
the esophagus
p value (1-sided)
at boundary
~ 
HR 
at 
boundary
≤0.0023
0.70
OS in
subjects 
with 
PD-L1 
CPS≥10
p value (1-sided)
at boundary
~ 
HR 
at 
boundary
≤0.0027
0.65
OS in
all 
subjects
p value (1-sided)
at boundary
~ 
HR 
at 
boundary
≤0.0023
0.75
Final Analysis
~ 33 months after first subject 
randomized 
Approximately 310 OS events 
and 473 OS events have been 
observed among subjects with 
squamous cell carcinoma of the 
esophagus 
and 
all 
subjects,
respectively, and 16 months after 
last subject randomized. 
OS events among subjects with 
squamous cell carcinoma of the 
esophagus: ~310
OS events among subjects with
PD-L1 CPS≥10: ~213
OS events among all subjects: 
473
OS in subjects 
with 
squamous 
cell carcinoma of 
the esophagus
p value (1-sided)
at boundary
~ 
HR 
at 
boundary
≤0.0075
0.76
OS in
subjects 
with 
PD-L1 
CPS≥10
p value (1-sided)
at boundary
~ 
HR 
at 
boundary
≤0.0084
0.72
OS in
all 
subjects
p value (1-sided)
at boundary
~ 
HR 
at 
boundary
≤0.0075
0.80
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Multiplicity
The multiplicity strategy specified in this section will be applied to the three primary 
hypotheses (superiority of pembrolizumab on OS in subjects with squamous cell carcinoma 
of the esophagus or subjects with PD-L1 CPS≥10 or all subjects) and two secondary 
hypotheses (superiority of pembrolizumab on PFS in all subjects and ORR in all subjects). 
The overall Type-I error is strongly controlled at 2.5% (one-sided), with initially 0.8% 
allocated to OS hypothesis in subjects with squamous cell carcinoma of the esophagus, 0.9% 
allocated to OS hypothesis in subjects with PD-L1 CPS≥10 and 0.8% allocated to OS 
hypothesis in all subjects, and 0% to PFS and ORR hypotheses.
Within each hypothesis, the Type-I error rate for the interim efficacy analysis and final 
analysis is controlled through alpha spending functions as described in Section 8.7 Interim 
Analyses.
By using the graphical approach of Maurer and Bretz [54], if OS hypothesis in subjects with 
squamous cell carcinoma of the esophagus is rejected, the corresponding alpha level can be 
shifted to OS hypothesis in all subjects. If the OS hypothesis in subjects with PD-L1 CPS≥10
is rejected, the corresponding alpha level can also be shifted to the OS hypothesis in all 
subjects.
The secondary hypotheses of PFS and ORR will be tested only if pembrolizumab arm is 
superior to the control on OS in all subjects. If the OS hypothesis in all subjects is rejected, 
the corresponding alpha level can be shifted by half to PFS in all subjects and half to ORR in 
all subjects.
See Figure 4 for the multiplicity strategy diagram of the study.
Figure 4
Multiplicity Strategy
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Sample Size and Power Calculations
The study will randomize subjects in a 1:1 ratio into pembrolizumab arm and the control arm. 
The enrollment is driven by all subjects. The total sample size in the Global Cohort is 
approximately 600. It is expected that approximately 400 subjects with squamous cell 
carcinoma of the esophagus will be enrolled. Based on the observed preliminary prevalence 
of PD-L1 CPS≥10 in subjects with esophageal carcinoma of ~47% from MK-3475 KN180, 
for the hypotheses in subjects with PD-L1 CPS≥10, the sample size is approximately 280.
The final analysis of the study will complete after approximately 310 OS events and 473 OS 
events have been observed among subjects with squamous cell carcinoma of the esophagus 
and all subjects, respectively, and 16 months after last subject randomized.
OS analysis 
The sample size and power calculations are based on the following assumptions: 1) OS
follows an exponential distribution with a median of 8 months in the control arm; 2) an 
enrollment period of 17 months and a minimum of 16 months follow-up after enrollment 
completion; 3) a yearly dropout rate of 2%.
The final OS analysis will be carried out after approximately 310 OS events and 473 OS 
events have been observed among subjects with squamous cell carcinoma of the esophagus 
and all subjects, respectively, and 16 months after last subject randomized. It is expected that 
approximately 213 OS events would have been observed in subjects with PD-L1 CPS≥10. 
With 310/213/473
OS events
in subjects with squamous cell carcinoma of the 
esophagus/subjects with PD-L1 CPS≥10/all subjects, respectively, the trial has at least 
91.3%/90.9%/92.6% power to demonstrate that pembrolizumab is superior to the control at a 
one-sided 0.8%/0.9%/0.8% alpha-level, if the underlying hazard ratio of OS is 0.65/0.6/0.7. 
Success for OS at the final analysis approximately corresponds to an observed hazard ratio of 
< 0.76 for subjects with squamous cell carcinoma of the esophagus, 0.72 for subjects with 
PD-L1 CPS≥10, and < 0.80 for all subjects. To further investigate the impact of the delayed 
separation of OS curve on the actual power in all subjects, a simulation was carried out using 
the current study design parameters described above but with a piece-wise time varying 
hazard ratio: the hazard ratio was specified as 1 and 0.6 at the beginning of time intervals of 
Month 0 and 5 since randomization respectively. With 1,000 simulations the overall study 
power with 473 events at the final analysis given the hazard ratio assumption above is 
approximately 74.7% using log-rank test statistics and 86% using max-combo test statistics.
The China Cohort
After the enrollment for the Global Cohort has completed, the study will continue to 
randomize subjects in a 1:1 ratio into the pembrolizumab arm and the SOC arm in China 
until the sample size for the Chinese subjects overall reaches approximately 120. Chinese 
subjects randomized after completion of enrollment in the Global Cohort will not be included 
in the analyses of the Global Cohort.
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Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the three primary 
endpoints will be estimated and plotted within each category of the following classification 
variables:

Age category (<65 vs. ≥65 years)

Sex (Female vs. Male)

Geographic region (Asia vs. Rest of the World)

ECOG Performance Scale (0 vs. 1)

Histological subtype (Squamous cell carcinoma vs. adenocarcinoma/Siewert type 1 
adenocarcinoma of the EGJ)
Country specific population (e.g. Chinese, Japanese, etc.) may also be analyzed per local 
regulatory requirements.
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
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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 13.
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.
Table 13
Product Descriptions
Product Name & 
Potency
Dosage Form
Source/Additional Information
MK-3475
Injection
Provided centrally by the Sponsor
Paclitaxel, 6 mg/mL *
Injection
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee.
Docetaxel, 20 mg/mL *
Injection
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee.
Irinotecan, 20 mg/mL *
Injection
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee.
* NOTE:  Concentration may be different for products sourced in China.
All other supplies not indicated in Table 13 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 and/or kits for each treatment cycle. The MK-3475 will 
not be kitted. The standard of care drugs will be kitted. Each kit will contain 1 vial.
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Clinical Supplies Disclosure
The 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.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
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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.
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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.
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The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
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 
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functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
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 
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investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
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activation. J Immunol 2004;173:945-54.
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Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 
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Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009;229:114-25.
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Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi 
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Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
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Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are 
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Immunother 2008;57(1):97-106.
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[13]
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implications of type and density of tumour-infiltrating lymphocytes in gastric 
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2009;58(3):449-59.
[15]
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.
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Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: 
molecular biology. Int J Clin Oncol 2010;15(6):544-51.
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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-
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Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
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chemotherapy for the treatment of patients with refractory metastatic melanoma. J 
Clin Oncol 2005;23(10):2346-57.
[20]
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.
[21]
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.
[22]
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer 
statistics. CA Cancer J Clin 2011;61:69-90.
[23]
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.
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[24]
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015 
Jan;65(1):5-29.
[25]
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.
[26]
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.
[27]
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.
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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.
[29]
Pickens A, Orringer MB. Geographical distribution and racial disparity in 
esophageal cancer. Ann Thorac Surg. 2003 Oct;76(4):S1367-9.
[30]
Siewert JR, Ott K. Are squamous and adenocarcinomas of the esophagus the same 
disease? Semin Radiat Oncol. 2007 Jan;17(1):38-44.
[31]
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.
[32]
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.
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Grunberger B, Raderer M, Schmidinger M, Hejna M. Palliative chemotherapy for 
recurrent and metastatic esophageal cancer. Anticancer Res. 2007 Jul-
Aug;27(4C):2705-14.
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Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al. 
Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 
2008 Jan 3;358(1):36-46.
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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.
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[36]
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.
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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.
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Fenchel K, Karthaus M, Steffens C, Dreher K, Boehme V, Pralle H, et al. Taxanes: 
An effective 2nd line treatment of advanced esophageal cancer - A randomised trial 
[abstract]. Abstracts of the 1999 ASCO Annual Meeting; 1999 May 15 - 18; 
Atlanta, Georgia. ASCO; 1999. p. 283a.
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Anderson SE, O'Reilly EM, Kelsen DP, Ilson DH. Phase II trial of 96-hour 
paclitaxel in previously treated patients with advanced esophageal cancer. Cancer 
Invest. 2003;21(4):512-6.
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docetaxel chemotherapy in patients with incurable adenocarcinoma of the 
esophagus. Invest New Drugs. 2002 Feb;20(1):95-9.
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Muro K, Hamaguchi T, Ohtsu A, Boku N, Chin K, Hyodo I, et al. A phase II study 
of single-agent docetaxel in patients with metastatic esophageal cancer. Ann Oncol. 
2004 Jun;15(6):955-9.
[42]
Metges J, Hennequin C, Ychou M, Malhaire J, Gouerou H, Maylin C, et al. 
Docetaxel (DOC) as a second line chemotherapy in metastatic esophageal cancer 
(MEC): a french study [abstract]. Abstracts of the 2001 ASCO Annual Meeting; 
2001 May 12 - 15; San Francisco, California. ASCO; 2001. p. 160a.
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Shim HJ, Cho SH, Hwang JE, Bae WK, Song SY, Cho SB, et al. Phase II study of 
docetaxel and cisplatin chemotherapy in 5-fluorouracil/cisplatin pretreated 
esophageal cancer. Am J Clin Oncol. 2010 Dec;33(6):624-8.
[44]
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.
[45]
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.
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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.
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and psychometric validation of an EORTC questionnaire module, the EORTC 
QLQ-OES18, to assess quality of life in patients with oesophageal cancer. Eur J 
Cancer. 2003 Jul;39(10):1384-94.
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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. 
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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."
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Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.5 – 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.  
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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 
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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 
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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 (i.e., only leftover samples are being retained).’
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@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/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
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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
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ECOG Performance Status
Grade
Description
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of light or sedentary nature, e.g.,
light housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of
waking hours .
3
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair .
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., 
Group Chair.
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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. 
(http://ctep.cancer.gov).
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List of Abbreviations
Abbreviation/Term
Definition
2L
Second Line
AE
Adverse Event
AC
adenocarcinoma
ADA
Anti-Drug Antibodies
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
ASaT
All Subjects as Treated
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
ß-HCG
Beta Human Chorionic Gonadotropin
BSA
Body Surface Area
CBC
Complete Blood Count
CI
Confidence Interval
CNS
Central Nervous System
CPS
Combined Positive Score
CR
Complete Response
CrCl
Calculated Creatinine Clearance
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4
DKA
diabetic ketoacidosis 
DNA
Deoxyribonucleic acid
DOR
Duration of Response
DRAE
Drug-related Adverse Events
ECI
Events of Clinical Interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eDMC
external Data Monitoring Committee
EGJ
esophagogastric junction
EOC
Executive Oversight Committee
EORTC
European Organisation for Research and Treatment of Cancer
PRO
Patient Reported Outcomes
EQ-5D
eEuroQol-5D
ER
emergency room
ERC
Ethics Review Committee
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FFPE
Formalin-fixed, paraffin-embedded
GCP
Good Clinical Practice
GCSF
Granulocyte-Colony Stimulating Factors
GEP
Gene Expression Profile
GI
Gastrointestinal
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Abbreviation/Term
Definition
GFR
Glomerular Filtration Rate
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HEA
Health Economic Assessment
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio
HRQoL
health-related quality of life
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
INR
International Normalized Ratio
irAEs
Immune-related Adverse Events
irPD
imaging confirms PD
irRECIST
Immune related RECIST (Modification of RECIST 1.1)
IRB
Institutional Review Board
ITIM
Immunoreceptor Tyrosine-based Inhibition Motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
ITT
Intention To Treat
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
Kg
Kilogram
LDH
Lactate Dehydrogenase
mAb
Monoclonal Antibody
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.
NA or N/A
Not Applicable
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 Pharmacokinetics 
PD
Progressive Disease
PD-1
Programmed Death-1
PD-L1
Programmed Death ligand-1
PE
Physical Exam
PFS
Progression Free Survival
PI
principal investigator
PIN
Personal Identification Number
PK
Pharmacokinetic
PO
Oral Administration
PR
Partial Response
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Abbreviation/Term
Definition
PRO
Patient Reported Outcomes
PT
Prothrombin Time
PS
Performance Status
QALYs
quality adjusted life years
QLG 
Quality of Life Group
QoL
Quality of Life
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
ROC
receiver operating characteristic
RMST
Restricted Mean Survival Time
RPSFT
Rank Preserving Structural Failure Time
Q2W
Every 3 Weeks
Q3W
Every 3 Weeks
Q9W
Every 9 Weeks
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
sSAP
supplemental SAP
SCC
squamous cell carcinoma
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SOP
Standard Operating Procedures
TIL
Tumor Infiltrating Lymphocytes
TSH
Thyroid Stimulating Hormone
TTP
Time to Progression
ULN
Upper Limit of Normal
V-type
Variable-type
WHO
World Health Organization
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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
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