Clinical trial NCT03066778
Conditions: Small Cell Lung Cancer (SCLC)
Keywords: Extensive stage small cell lung cancer (ES-SCLC) Programmed Cell Death-1 (PD1, PD-1) Programmed Cell Death Ligand 1 (PDL1, PD-L1) Programmed Cell Death Ligand 2 (PDL2, PD-L2)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2017-05-02; Completion date: 2021-09-21
Enrollment: 453 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the safety and efficacy of pembrolizumab plus standard of care (SOC) chemotherapy (etoposide/platinum \[EP\]) in participants with newly diagnosed extensive stage small cell lung cancer (ES-SCLC) who have not previously received systemic therapy for this malignancy.

The primary study hypotheses are that pembrolizumab+EP prolongs Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review (BICR) and Overall Survival (OS) compared with placebo+EP in adult participants with ES-SCLC. In this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

With protocol Amendment 07 (03-Oct-2018), the outcome measure of "Change from Baseline at Weeks 12 and 24 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale" was replaced with a single time point analysis at Week 18.

Detailed description:

Arms: arm 1: During each 21-day cycle, participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m\^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve \[AUC\] 5 IV on Day 1 OR cisplatin 75 mg/m\^2 IV on Day 1). Participants who stop pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stop after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, are eligible for up to an additional 1 year of treatment after progressive disease if they meet the criteria for retreatment. arm 2: During each 21-day cycle, participants receive placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m\^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m\^2 IV on Day 1).
Interventions: intervention 1: Pembrolizumab intervention 2: Normal saline solution intervention 3: Carboplatin intervention 4: Cisplatin intervention 5: Etoposide
Intervention descriptions: intervention 1: IV infusion on Day 1 of each cycle prior to chemotherapy intervention 2: IV infusion on Day 1 of each cycle prior to chemotherapy intervention 3: IV infusion on Day 1 of each cycle intervention 4: IV infusion on Day 1 of each cycle intervention 5: IV infusion on Days 1, 2 and 3 of each cycle

Protocol documents:
Prot_SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase 3 Randomized, Double-Blind, Placebo-controlled Trial of 
Pembrolizumab (MK-3475/SCH900475) in Combination with 
Etoposide/Platinum (Cisplatin or Carboplatin) for the First-line 
Treatment of Subjects with Extensive Stage Small Cell Lung 
Cancer(KEYNOTE-604)
23-Apr-2019
NCT03066778


Product:  MK-3475 
1
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
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 3 Randomized, Double-Blind, Placebo-controlled Trial of Pembrolizumab (MK-
3475/SCH900475) in Combination with Etoposide/Platinum (Cisplatin or Carboplatin) for 
the First-line Treatment of Subjects with Extensive Stage Small Cell Lung Cancer 
(KEYNOTE-604)
IND NUMBER:  116833
EudraCT NUMBER:  2016-004309-15


Product:  MK-3475 
2
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
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)........................................................... 20
Exploratory Objectives......................................................................................... 21
4.0
BACKGROUND & RATIONALE.......................................................................... 21
Background ........................................................................................................... 21
Pharmaceutical and Therapeutic Background .................................................... 21
Information on Other Trial-related Therapy....................................................... 22
Etoposide/Platinum Therapy........................................................................ 22
Prophylactic Cranial Irradiation................................................................... 23
Rationale................................................................................................................ 25
Rationale for the Trial and Selected Subject Population .................................... 25
Rationale for Dose Selection/Regimen/Modification......................................... 27
Rationale for the Dose of Pembrolizumab................................................... 27
Rationale for Use of Comparator/Placebo ................................................... 28
Rationale for Efficacy Endpoints........................................................................ 28
Primary Efficacy Endpoints......................................................................... 28
Secondary Efficacy Endpoints..................................................................... 29
Safety Endpoints.......................................................................................... 29
Patient Reported Outcomes.......................................................................... 29
Immune-related RECIST ............................................................................. 30
Planned Exploratory Biomarker Research................................................... 30


Product:  MK-3475 
3
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Future Biomedical Research........................................................................ 32
Benefit/Risk ........................................................................................................... 32
5.0
METHODOLOGY ................................................................................................... 33
Entry Criteria........................................................................................................ 33
Diagnosis/Condition for Entry into the Trial ...................................................... 33
Subject Inclusion Criteria.................................................................................... 33
Subject Exclusion Criteria .................................................................................. 35
Trial Treatment(s) ................................................................................................ 38
Dose Selection/Modification .............................................................................. 38
Dose Selection (Preparation) ....................................................................... 38
Dose Modification ....................................................................................... 39
5.2.1.2.1
Pembrolizumab..................................................................................... 40
5.2.1.2.2
Chemotherapeutic agents (etoposide/platinum).................................... 48
Timing of Dose Administration.......................................................................... 51
Pembrolizumab (or Saline Placebo)............................................................. 52
Chemotherapy.............................................................................................. 52
5.2.2.2.1
Carboplatin............................................................................................ 52
5.2.2.2.2
Cisplatin................................................................................................ 53
5.2.2.2.3
Etoposide .............................................................................................. 53
Trial Blinding...................................................................................................... 53
Randomization ...................................................................................................... 54
Stratification.......................................................................................................... 54
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 54
Acceptable Concomitant Medications ................................................................ 54
Prohibited/Restricted Concomitant Medications ................................................ 55
Rescue Medications & Supportive Care............................................................. 56
Supportive Care Guidelines ................................................................................ 56
Diet/Activity/Other Considerations..................................................................... 57
Diet...................................................................................................................... 57
Contraception...................................................................................................... 57
Use in Nursing Women....................................................................................... 59
Subject Withdrawal/Discontinuation Criteria................................................... 59


Product:  MK-3475 
4
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Discontinuation of Treatment ............................................................................. 59
Withdrawal from the Trial .................................................................................. 61
Subject Replacement Strategy............................................................................. 61
Beginning and End of the Trial ........................................................................... 61
Clinical Criteria for Early Trial Termination ................................................... 61
6.0
TRIAL FLOW CHART ........................................................................................... 62
Initial Treatment Phase........................................................................................ 62
Second Course Treatment Phase......................................................................... 68
7.0
TRIAL PROCEDURES ........................................................................................... 71
Trial Procedures ................................................................................................... 71
Administrative Procedures.................................................................................. 71
Informed Consent......................................................................................... 71
7.1.1.1.1
General Informed Consent.................................................................... 71
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 72
Inclusion/Exclusion Criteria ........................................................................ 72
Subject Identification Card .......................................................................... 72
Medical History ........................................................................................... 72
Prior and Concomitant Medications Review............................................... 72
7.1.1.5.1
Prior Medications.................................................................................. 72
7.1.1.5.2
Concomitant Medications..................................................................... 73
Assignment of Screening Number............................................................... 73
Assignment of Treatment/Randomization Number..................................... 73
Trial Compliance (Medication/Diet/Activity/Other) ................................... 73
Clinical Procedures/Assessments........................................................................ 73
Adverse Event Monitoring........................................................................... 73
Physical Examination................................................................................... 74
7.1.2.2.1
Full Physical Examination.................................................................... 74
7.1.2.2.2
Directed Physical Examination............................................................. 74
Vital Signs.................................................................................................... 74
12-Lead Electrocardiogram ......................................................................... 74
Eastern Cooperative Oncology Group Performance Status......................... 74


Product:  MK-3475 
5
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Prophylactic Cranial Irradiation................................................................... 75
Tumor Imaging and Assessment of Disease................................................ 75
7.1.2.7.1
Initial Tumor Imaging........................................................................... 76
7.1.2.7.2
Tumor Imaging During the Trial .......................................................... 76
7.1.2.7.3
End of Treatment and Follow-up of Tumor Imaging ........................... 77
7.1.2.7.4
Second Course (Retreatment) Phase Tumor Imaging........................... 77
7.1.2.7.5
RECIST 1.1 Assessment of Disease..................................................... 78
7.1.2.7.6
irRECIST Assessment of Disease......................................................... 78
Tumor Tissue Collection: PD-L1 Status...................................................... 83
Laboratory Procedures/Assessments .................................................................. 84
Clinical Laboratory Evaluations .................................................................. 84
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 86
Planned Genetic Analysis Sample Collection.............................................. 87
Future Biomedical Research Samples ......................................................... 87
Other Procedures................................................................................................. 87
Withdrawal/Discontinuation........................................................................ 87
Subject Blinding/Unblinding ....................................................................... 88
Calibration of Critical Equipment................................................................ 88
Visit Requirements.............................................................................................. 89
Screening...................................................................................................... 89
Treatment Period Visits ............................................................................... 89
Post-treatment Visits.................................................................................... 89
7.1.5.3.1
Safety Follow-up Visit.......................................................................... 89
7.1.5.3.2
Progression-free Survival Follow-up Visits ......................................... 90
7.1.5.3.3
Survival Follow-up ............................................................................... 90
Survival Status ............................................................................................. 90
Second Course Phase................................................................................... 91
Continued Treatment Following Verified Progressive Disease................... 92
Discontinued Subjects Continuing to be Monitored in the Trial................. 92
Assessing and Recording Adverse Events .......................................................... 93
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 94


Product:  MK-3475 
6
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 94
Immediate Reporting of Adverse Events  to the Sponsor................................... 95
Serious Adverse Events ............................................................................... 95
Events of Clinical Interest............................................................................ 96
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 97
Evaluating Adverse Events................................................................................. 97
Sponsor Responsibility for Reporting Adverse Events .................................... 100
TRIAL GOVERNANCE AND OVERSIGHT................................................. 100
Data Monitoring Committee............................................................................. 100
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 100
Statistical Analysis Plan Summary ................................................................... 101
Responsibility for Analyses/In-house Blinding ................................................ 102
Hypotheses/Estimation ....................................................................................... 103
Analysis Endpoints ............................................................................................. 103
Efficacy Endpoints............................................................................................ 103
Safety Endpoints ............................................................................................... 104
Analysis Populations........................................................................................... 104
Efficacy Analysis Populations .......................................................................... 104
Safety Analysis Populations ............................................................................. 104
Statistical Methods.............................................................................................. 105
Statistical Methods for Efficacy Analyses ........................................................ 105
Progression-free Survival........................................................................... 105
Overall Survival......................................................................................... 106
Objective Response Rate ........................................................................... 107
Duration of Response................................................................................. 107
Statistical Methods for Safety Analyses ........................................................... 108
Summaries of Baseline Characteristics and Demographics.............................. 110
Interim Analyses ................................................................................................. 110
Multiplicity .......................................................................................................... 110
Sample Size and Power Calculations ................................................................ 114
Subgroup Analyses and Effect of Baseline Factors ......................................... 114
Compliance (Medication Adherence)................................................................ 115


Product:  MK-3475 
7
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Extent of Exposure.............................................................................................. 115
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 115
Investigational Product ...................................................................................... 115
Packaging and Labeling Information ............................................................... 116
Clinical Supplies Disclosure............................................................................... 116
Storage and Handling Requirements................................................................ 117
Discard/Destruction/Returns and Reconciliation ............................................ 117
Standard Policies................................................................................................. 117
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 117
Confidentiality..................................................................................................... 117
Confidentiality of Data ..................................................................................... 117
Confidentiality of Subject Records................................................................... 118
Confidentiality of Investigator Information...................................................... 118
Confidentiality of IRB/IEC Information........................................................... 118
Compliance with Financial Disclosure Requirements..................................... 119
Compliance with Law, Audit and Debarment ................................................. 119
Compliance with Trial Registration and Results Posting Requirements ...... 121
Quality Management System............................................................................. 121
Data Management............................................................................................... 122
Publications ......................................................................................................... 122
11.0
LIST OF REFERENCES....................................................................................... 123
12.0
APPENDICES......................................................................................................... 135
Merck Code of Conduct for Clinical Trials...................................................... 135
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 137
ECOG Performance Status................................................................................ 141
Common Terminology Criteria for Adverse Events Version 4.0................... 142
Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 Criteria 
for Evaluating Response in Solid Tumors ........................................................ 143
List of Abbreviations .......................................................................................... 144


Product:  MK-3475 
8
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
13.0
SIGNATURES......................................................................................................... 148
Sponsor's Representative ................................................................................... 148
Investigator.......................................................................................................... 148


Product:  MK-3475 
9
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
LIST OF TABLES
Table 1
Adequate Organ Function Lab Values............................................................... 34
Table 2
Trial Treatments................................................................................................. 38
Table 3
Dose Modifications for Study Drugs ................................................................. 40
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
Related AEs Associated With Pembrolizumab.................................................. 42
Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines .......................................................................................................... 46
Table 6
Recommended Chemotherapy Dose Modifications for Hematological 
Toxicity.............................................................................................................. 49
Table 7
Recommended Chemotherapy Dose Modifications for Non-hematologic 
Toxicity.............................................................................................................. 50
Table 8
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease............................................................................................................... 82
Table 9
Clinical Laboratory Tests................................................................................... 85
Table 10
Evaluating Adverse Events................................................................................ 98
Table 11
Censoring Rules for Primary and Sensitivity Analyses of Progression-free 
Survival............................................................................................................ 106
Table 12
Censoring Rules for Duration of Response ..................................................... 107
Table 13
Efficacy Analysis Methods for Primary and Secondary Efficacy Endpoints.. 108
Table 14
Analysis Strategy for Safety Parameters.......................................................... 109
Table 15
Efficacy Boundaries and Properties for Progression-free Survival Analyses . 112
Table 16
Efficacy Boundaries and Properties for Overall Survival Analyses................ 113
Table 17
Possible Alpha-levels and Approximate ORR Difference Required to 
Demonstrate Efficacy for ORR........................................................................ 114
Table 18
Product Descriptions........................................................................................ 116


Product:  MK-3475 
10
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
LIST OF FIGURES
Figure 1
Trial Design Overview....................................................................................... 19
Figure 2
Imaging and Treatment for Clinically Stable Subjects After First 
Radiologic Evidence of PD Assessed by the Site.............................................. 83
Figure 3
Multiplicity Graph for Type I Error Control.................................................... 111


Product:  MK-3475 
11
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Original protocol
15 DEC-2016
Amendment 01
21-DEC-2016
Corrected a typographical error in the numbering of the inclusion criteria so 
that the structure of the trial database and the electronic data capture forms can 
be created correctly.
Amendment 02
23-FEB-2017
Corrected the wording of exclusion criterion #5, which stated the opposite of 
what was intended and to provide more detail and clarity where needed.
Amendment 03
10-APR-2017
Removed the option to cross over from the etoposide/platinum/saline placebo 
arm to pembrolizumab treatment to improve the interpretation of the long-term 
benefit.
Amendment 04
02-JUN-2017
Removed the requirement for unblinding treatment assignment after 
documentation of progressive disease (PD) because the option to cross over to 
pembrolizumab was removed and, with it, the need to unblind.  
Amendment 05
01-SEP-2017
Clarified exclusion criterion #4 regarding brain metastases to ensure that no 
subjects with brain metastases are enrolled in the study.
Amendment 06
30-NOV-2017
Updated the dose modification guidelines for pembrolizumab to include 
information regarding the treatment of myocarditis; revised the requirements 
for survival follow-up to allow for more frequent data collection; added a 
Day 8 visit during Cycles 1 through 4 to allow for more frequent safety 
monitoring.


Product:  MK-3475 
12
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Document
Date of Issue
Overall Rationale
Amendment 07
03-OCT-2018
 
 
 
 
; changed the alpha allocation 
between the primary (overall survival [OS] and PFS) and key secondary 
(objective response rate [ORR]) hypothesis on the basis of accumulating 
external data on PFS and OS in immunotherapy-chemotherapy combinations 
in small cell lung cancer to allow more alpha to be allocated to the primary 
endpoints.
Amendment 08
07-DEC-2018
 
 
 
 
 the assumption for median PFS in the 
control arm was changed to 4.3 months based on external data published from 
other clinical trials; and the power and efficacy bound calculations were 
updated to reflect the change in PFS median assumption and an alpha spending 
approach.
Amendment 09
23-APR-2019
Updated criteria for the final OS analysis to be a minimum of 294 events, or 31 
months from study start, whichever occurs later to ensure sufficient follow-up 
time for the final OS analysis. Added clarification to describe the alpha-
spending strategy for PFS and OS in detail. Corrected a publishing error in 
Amendment 08.
CCI
CCI


Product:  MK-3475 
13
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number
Section Title
Description of Change(s)
Rationale
8.7
Interim Analyses
The final analysis timing was updated as 
follows: “The final OS analysis is planned 
when a minimum of 294 deaths have been 
observed or approximately 31 months after 
first subject enrolled, whichever occurs 
later.”
By allowing the final OS analysis to occur 
after a minimum of 294 events have been 
observed or approximately 31 months after 
the first subject is enrolled, whichever 
occurs later, the trial ensures adequate
follow-up time for the final OS analysis.
8.8
Multiplicity
Added the following statements to describe 
the alpha-spending strategy for PFS and 
OS in detail: “The alpha spending at each 
interim analysis is determined using a Lan-
DeMets 
O'Brien-Fleming 
spending 
function, and the information fraction 
(ratio of the actual number of events at the 
interim analysis relative to a targeted 294 
events at the final analysis). The final 
analysis will use the remaining Type I 
error not spent at earlier analyses, 
regardless of the number of events 
observed at the final analysis. The p-value 
bounds at second interim and final analysis 
will be calculated by considering the 
correlation between the test statistics as 
determined by the actual number of OS 
events at the previous and current 
analysis.”
To clarify that the alpha spending is event 
based, and not subjected to change, if the 
actual number of events at the final 
analysis exceeds the targeted number of 
events at final analysis.


Product:  MK-3475 
14
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number
Section Title
Description of Change(s)
Rationale
11.0
List of References
Included all references cited in 
the text of the protocol.
Due to a publishing error, the list of references in 
protocol Section 11.0 was truncated when Amendment 
08 was finalized. Therefore, it is being updated here.


Product:  MK-3475 
15
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
1.0 TRIAL SUMMARY
Abbreviated Title
Phase 3 trial of first line etoposide/platinum (EP) with or without 
pembrolizumab in ES-SCLC (KEYNOTE-604)
Sponsor Product Identifiers
MK-3475
Pembrolizumab
Trial Phase
III
Clinical Indication
First-line treatment of extensive stage small cell lung cancer 
(ES-SCLC)
in combination with standard of care (SOC) 
chemotherapy
Trial Type
Interventional
Type of control
Placebo
Route of administration
Intravenous (IV)
Trial Blinding
Double-blind
Treatment Groups
Arm 1: Pembrolizumab + EP:  
Pembrolizumab 200 mg IV every 3 weeks (Q3W) on Day 1
Etoposide 100 mg/m2 IV Q3W on Days 1, 2, and 3
Platinum, investigator’s choice
Carboplatin titrated to an area under the plasma
drug
concentration-time curve (AUC) of 5 IV Q3W on Day 1
OR
Cisplatin 75 mg/m2 IV Q3W on Day 1
Arm 2: Placebo + EP:  
Placebo IV Q3W on Day 1
Etoposide 100 mg/m2 IV Q3W on Days 1, 2, and 3
Platinum, investigator’s choice
Carboplatin titrated to an AUC of 5 IV Q3W on Day 1
OR
Cisplatin 75 mg/m2 IV Q3W on Day 1
Number of trial subjects
Approximately 430 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 
4.5 years from the time the first subject signs the informed consent 
until the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial from the time the subject 
signs the informed consent form through the final protocol-specified 
contact.
After a screening phase of up to 28 days, each subject will be 
randomized to receive trial treatment (pembrolizumab + EP or 
placebo + EP). The SOC treatment component (EP) will be given 
for the first 4 cycles with pembrolizumab or placebo, after which 
partial and complete responders may receive prophylactic cranial 
irradiation at the discretion of the investigator. Treatment with 
pembrolizumab or placebo will continue until a total of 35 cycles of 
treatment have been administered or until one of the treatment 
discontinuation criteria occurs: confirmed disease progression,
unacceptable 
adverse 
event(s) 
(AEs), 
intercurrent 
illness,


Product:  MK-3475 
16
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
investigator decision to withdraw the subject, noncompliance, or 
administrative reasons requiring cessation of treatment.
Subjects who experience documented progressive disease (PD)
verified by blinded independent central review will have the option 
to remain on study and continue receiving the originally assigned 
trial treatment for a total of 35 cycles at the discretion of the 
investigator (Section 7.1.5.5).
Subjects who stop trial treatment after receiving 35 administrations 
of trial treatment for reasons other than PD or intolerability may be 
eligible for the Second Course Phase, up to 17 additional 
administrations of pembrolizumab (approximately 1 year), upon 
experiencing disease progression (Section 7.1.5.4). Subjects in the 
saline placebo arm are not eligible for the Second Course Phase.
After the end of treatment, each subject will be followed for the 
occurrence of AEs
and spontaneously
reported pregnancy 
(Section 7.2).
Subjects who discontinue for reasons other than PD will have 
post-treatment follow-up for disease status until experiencing PD
confirmed by the site per immune-related Response Evaluation 
Criteria in Solid Tumors (irRECIST) or per RECIST version 1.1
(modified to follow a maximum of 10 target lesions and a maximum 
of 5 target lesions per organ) as assessed by BICR, initiating a non-
study cancer treatment, withdrawing consent, or becoming lost to 
follow-up.  All subjects will be followed by telephone for overall 
survival until death, withdrawal of consent, or the end of the study.
A list of abbreviations used in this document can be found in Section 12.6.
2.0 TRIAL DESIGN
Trial Design
This is a worldwide, randomized, placebo-controlled, Phase 3, parallel group, multi-site, 
double-blind trial of pembrolizumab plus standard of care (SOC) chemotherapy (EP) in 
subjects with ES-SCLC who have not previously received systemic therapy for this 
malignancy.
Approximately 430 subjects will be randomized (1:1) to either pembrolizumab + EP or 
placebo + EP. Randomization will be stratified by type of platinum therapy (cisplatin or 
carboplatin), Eastern Cooperative Oncology Group (ECOG) performance status score 
(0 or 1), and lactate dehydrogenase (LDH) measurement (≤or > upper limit of normal 
[ULN]) at baseline. Positive tumor programmed cell death-ligand 1 (PD-L1) expression will 
not be required for enrollment; however, subjects’ tumors will be screened for PD-L1
expression. An overview of the trial design is depicted in Figure 1.
Prior to randomization, the investigator will determine whether the subject will receive 
cisplatin or carboplatin. Subjects are allowed to switch from cisplatin to carboplatin if the 
Randomization Ratio
1:1


Product:  MK-3475 
17
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
subject develops an adverse event (AE), becomes ineligible for further cisplatin therapy,
and/or the investigator considers switching to carboplatin to be in the best interest of the 
subject.
During the Treatment Phase, subjects will have a study visit every 3 weeks (Q3W) for 
assessments and trial treatment administration. In Cycles 1 to 4, subjects will receive the 
SOC treatment component (EP) along with either pembrolizumab 200 mg or placebo.
Subjects in either treatment arm who achieve a partial response (PR) or complete response 
(CR) at the completion of Cycle 4 may be offered prophylactic cranial irradiation (PCI) at the 
discretion of the investigator (Section 7.1.2.6). Treatment with PCI should begin within 2 to 
4 weeks (no later than 6 weeks) after the last trial treatment in Cycle 4. Trial treatment may 
continue during PCI; however, if it is necessary to suspend trial treatment, it must be 
restarted no later than 2 weeks after completion of PCI. Subjects will continue to receive 
treatment with pembrolizumab or placebo Q3W for up to an additional 31 cycles (up to 
35 cycles total) or until occurrence of one or more treatment discontinuation criteria: disease 
progression as assessed by blinded independent central review (BICR) confirmed per 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) (modified to 
follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ), 
intolerable toxicity or unacceptable AEs, intercurrent illness that prevents further 
administration of treatment, investigator decision to withdraw the subject, noncompliance 
with trial treatment or procedure requirements, or administrative reasons requiring cessation 
of treatment.
After randomization, subjects will be evaluated with radiographic imaging to assess response 
to treatment; treatment-based decisions should be made by the investigator based on 
immune-related RECIST (irRECIST) (Section 4.2.3.5). All imaging obtained on study will 
be submitted for BICR using RECIST 1.1 for verification of progressive disease (PD) and for 
determination of objective response rate (ORR) and progression-free survival (PFS). Adverse 
event monitoring will be ongoing throughout the trial and AEs will be graded for severity 
according to the guidelines outlined in the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0).
After verification of PD as assessed by BICR per RECIST 1.1 (modified to follow a 
maximum of 10 target lesions and a maximum of 5 target lesions per organ), subjects will 
have the option to remain on study and continue receiving the originally assigned trial 
treatment for a total of 35 cycles at the discretion of the investigator, provided they are 
deemed to be benefiting and are clinically stable (Section 7.1.2.7.6). Alternatively, subjects 
may choose to receive treatment with an appropriate second-line (2L) therapy as determined 
by the investigator.
At the discretion of the investigator and in consultation with the Sponsor, subjects assigned 
to the pembrolizumab arm who complete 35 treatment administrations may be eligible for 
retreatment with open-label pembrolizumab monotherapy at the time of radiographic disease 
progression (verified by BICR), provided that no other systemic therapy for SCLC has been 
administered. This retreatment is called the Second Course Phase (Section 6.2 and 
Section 7.1.5.5). Subjects in the saline placebo arm are not eligible for the Second Course 
Phase. Treatment assignment will be unblinded for those subjects who meet all criteria for 


Product:  MK-3475 
18
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
the Second Course Phase. Response or progression during the Second Course Phase will not 
be included in the analyses of the ORR or PFS endpoints in this trial.
After the end of treatment, each subject will be followed for a minimum of 30 days for AE
monitoring even if the subject started non-study antineoplastic treatment. Serious adverse 
events (SAEs) will be documented for up to 90 days following cessation of the Sponsor’s 
product, or 30 days following cessation of treatment if the subject initiates non-study cancer 
treatment, whichever is earlier. After this period, any SAEs considered to be related to the 
trial treatment must be reported. Subjects will have post-treatment follow-up for disease 
status, until initiating a non-study cancer treatment, experiencing disease progression or
death, withdrawing consent, or becoming lost to follow-up. After documented disease 
progression or the start of non-study cancer treatment, subjects will have contact with study 
personnel by telephone until death, withdrawing consent, or becoming lost to follow-up. The 
Sponsor may request survival status to be assessed at additional time points and entered into 
the database during the course of the trial. For example, survival status may be requested 
prior to, but not limited to, external Data Monitoring Committee (DMC) reviews, as well as 
at interim and/or final analyses.
This trial has dual primary endpoints: 1) PFS as assessed by BICR per RECIST 1.1 modified 
to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ and 2) 
overall survival (OS). Trial results will be considered positive if the hypothesis test for either 
one of these primary endpoints is successful. Efficacy also will be evaluated using ORR (key 
secondary endpoint) and duration of response (duration of response [DOR]; secondary 
endpoint) as assessed by BICR per RECIST 1.1 modified to follow a maximum of 10 target 
lesions and a maximum of 5 target lesions per organ (Details are provided in the Site Imaging 
Manual).
Safety will be assessed using NCI CTCAE 4.0 and is a secondary endpoint. Quality of life 
assessments encompass both secondary and exploratory endpoints. Additional exploratory 
analyses will include: PFS using investigator-assessed irRECIST; ORR using investigator-
assessed irRECIST; DOR using investigator-assessed irRECIST; PFS, OS, and ORR in 
PD-L1 subgroups; and identification of additional biomarkers of response.
Two interim efficacy analyses and 1 final analysis are planned in this study. This trial will 
use a group sequential design based on pre-specified criteria, using an independent, external
DMC to monitor safety and efficacy results. Details are described in Section 8.0.
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.


Product:  MK-3475 
19
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Trial Diagram
Abbreviations:  ECOG=Eastern Cooperative Oncology Group, EP=etoposide / platinum, LDH=lactate dehydrogenase, 
PD=progressive disease, PFS=progression-free survival, Q3W=every 3 weeks, RECIST 1.1=Response Evaluation Criteria 
in Solid Tumors version 1.1, SCLC=small cell lung cancer, ULN=upper limit of normal
See Study Flow Chart (Section 6.2) for details regarding Second Course Phase
Figure 1
Trial Design Overview


Product:  MK-3475 
20
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
To accomplish the objectives listed below, pembrolizumab + EP will be compared with 
placebo + EP for the treatment of subjects with newly diagnosed ES-SCLC.
Primary Objective(s) & Hypothesis(es)
1) Objective:  To evaluate PFS as assessed by BICR per RECIST 1.1 modified to 
follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Hypothesis (H1):  Pembrolizumab + EP prolongs PFS per RECIST 1.1 by BICR
compared with placebo + EP.
2) Objective:  To evaluate OS.
Hypothesis (H2):  Pembrolizumab + EP prolongs OS compared with placebo + EP.
The study is considered to have met its objective if the pembrolizumab + EP arm is superior 
to placebo + EP in PFS or OS.
Secondary Objective(s) & Hypothesis(es)
1) Objective:  To evaluate ORR as assessed by BICR per RECIST 1.1 modified to 
follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Hypothesis:  Pembrolizumab + EP improves ORR per RECIST 1.1 by BICR 
compared to placebo + EP.
2) Objective:  To evaluate DOR as assessed by BICR per RECIST 1.1 modified to 
follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
3) Objective:  To evaluate the safety profile in each treatment arm using NCI CTCAE 
4.0.
4) Objective: To evaluate the following patient-reported outcomes (PROs):

Mean change from baseline at Week 18 in global health status/quality of life 
using the European Organization for Research and Treatment of Cancer (EORTC)
Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/quality of 
life scale. If the overall PRO completion or compliance rates at Week 18 are less 
than 60% or 80%, respectively, then the primary analysis time point will be 
moved to the next earliest time point in which the rates are at least 60% for 
completion and at least 80% for compliance.

Time to true deterioration in the composite endpoint of cough, chest pain, and 
dyspnea using the EORTC QLQ-C30 and Lung Cancer Module 13 (QLQ-LC13).


Product:  MK-3475 
21
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Exploratory Objectives
1) Objective: To evaluate changes in health-related quality of life assessments from 
baseline using the EORTC QLQ-C30 and EORTC QLQ-LC13.
2) Objective: To characterize utilities using the European Quality of Life 
Five-dimension Five-level Scale Questionnaire (EQ-5D-5L).
3) Objective: To evaluate ORR, PFS, and DOR per irRECIST as assessed by the 
investigator.
4) Objective: To evaluate ORR and PFS as assessed by BICR per RECIST 1.1 modified 
to follow a maximum of 10 target lesions and a maximum of 5 target lesions per 
organ, and OS by PD-L1 expression (tumor proportion score [TPS] <1% versus ≥1%, 
combined positive score [CPS] <1 versus ≥1).
5) Objective: To evaluate the relationship between deoxyribonucleic acid (DNA)
mutational burden and ribonucleic acid (RNA) immune signatures analyses and 
clinical outcome.
6) Objective: To identify molecular (genomic, metabolic and/or proteomic) biomarkers 
that may be indicative of clinical response/resistance, safety, pharmacodynamic
activity, and/or the mechanism of action of pembrolizumab + EP.
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
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] 
[19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37]. In 
particular, the presence of CD8+ T cells and the ratio of CD8+ effector T-cells to FoxP3+ 
regulatory T-cells seems to correlate with improved prognosis and long-term survival in solid 
malignancies such as ovarian, colorectal, and pancreatic cancer, hepatocellular carcinoma, 
malignant melanoma and renal cell carcinoma. Tumor-infiltrating lymphocytes can be 
expanded ex vivo and re infused, inducing durable objective tumor responses in cancers such 
as melanoma [38] [39].
The programmed cell death protein-1 (PD-1) receptor-ligand interaction is a major pathway 
hijacked by tumors to suppress immune control. The normal function of PD-1, expressed on 


Product:  MK-3475 
22
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
the cell surface of activated T cells under healthy conditions, is to down-modulate unwanted 
or excessive immune responses, including autoimmune reactions. The PD-1 receptor 
(encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily member related to 
CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
programmed cell death-ligand 2 [PD-L2]) [40] [41]. The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4, as both molecules 
regulate an overlapping set of signaling proteins [34] [42]. The PD-1 receptor was shown to 
be expressed on activated lymphocytes, including peripheral CD4+ and CD8+ T-cells, B-
cells, regulatory T cells, and natural killer cells [43] [44]. 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 [42] [45] [46] [47]. 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 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor. Expression of PD-L1 occurs at low levels on various non hematopoietic tissues, 
most notably on vascular endothelium, whereas expression of the PD L2 protein is only 
detectable on antigen-presenting cells found in lymphoid tissue or chronic inflammatory 
environments. Immune T-cell activation in lymphoid organs is thought to be controlled by 
PD-L2, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues 
[45]. Although healthy organs express little (if any) PD-L1, a variety of cancers were shown 
to express abundant levels of this T-cell inhibitor. High expression of PD-L1 on tumor cells 
(and to a lesser extent, expression of PD-L2) has been found to correlate with poor prognosis 
and survival in various cancer types, including renal cell [48], pancreatic [49], hepatocellular 
[50], and ovarian [51]. Furthermore, PD-1 may also regulate tumor-specific T-cell expansion 
in subjects with melanoma [52]. The prognostic implications of PD-L1 expression in 
advanced tumors are being investigated further in ongoing epidemiologic studies.
Because the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion, it is an 
attractive target for therapeutic intervention. Pembrolizumab is a potent and highly selective 
humanized monoclonal antibody of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, preventing attenuation of the immune system.
Pembrolizumab clinical trials are ongoing in a number of advanced cancer types, including
melanoma, non-small cell lung cancer (NSCLC), head and neck cancer, urothelial cancer, 
triple-negative breast cancer, gastric cancer, and hematologic malignancies. For study details,
refer to the IB.
Information on Other Trial-related Therapy
Etoposide/Platinum Therapy
Standard first-line (1L) treatment for the vast majority of patients with SCLC, regardless of 
stage, involves combination chemotherapy with etoposide plus cisplatin or carboplatin.
The etoposide/cisplatin regimen was tested in SCLC because this combination produced 
synergistic activity in preclinical systems. In addition, both agents could be given at full 
doses because of less myelosuppression with cisplatin. The first report of demonstrated 


Product:  MK-3475 
23
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
activity with the combination dates back to 1979 [53]. Subsequent randomized trials 
compared etoposide/cisplatin to cyclophosphamide, vincristine, and an anthracycline [54] 
[55] [56]. Less myelosuppression occurred with etoposide/cisplatin, and, when given with 
radiation, patients experienced less esophagitis and interstitial pneumonitis. Retrospective 
analyses and meta-analyses also support the superiority of a cisplatin- or carboplatin-
containing regimen for SCLC [57] [58] [59]. As a result, EP is now the standard 1L 
chemotherapy regimen for SCLC. Several randomized studies evaluating etoposide and 
cisplatin compared with other regimens have shown consistent results for this doublet with 
response rates of 45% to 60%, median time to progression of 5 months, and median OS of 10 
months [60] [61].  Notably, emerging data from recent global trials evaluating novel 
treatments in SCLC demonstrated a lower median PFS of approximately 4.3 to 4.4 months in 
the EP control arm, yet median OS remains consistent at approximately 10.3 to 10.9 months
[62] [63].
Carboplatin has been substituted for cisplatin in SCLC chemotherapy regimens in an effort to 
decrease non-hematologic toxicities. Randomized trials comparing cisplatin and carboplatin 
suggest that these compounds may have similar efficacy. One such study was conducted by 
the Hellenic Cooperative Oncology Group, which randomized 147 patients with either 
limited or extensive disease to receive etoposide 100 mg/m2 on Days 1 to 3 and cisplatin 
100 mg/m2 or carboplatin 300 mg/m2 on Day 1 of each cycle [64]. Concurrent radiation was 
also administered to responding patients starting with the third cycle. Response and survival 
were similar in the 2 arms. Nausea, vomiting, nephrotoxicity, and neurotoxicity were 
significantly lower in the patients who received carboplatin, as was Grade 4 leukopenia.
Unfortunately, the sample size was inadequate to confirm equivalent efficacy. A subsequent
meta-analysis evaluated individual subject data from 4 randomized trials with a total of 663 
patients and found that median OS, median PFS, and response rates were similar in the 
cisplatin and carboplatin arms. While hematologic toxicities were higher in patients treated 
with carboplatin, non-hematologic toxicities were increased in patients treated with cisplatin 
[65]. Based on these data, etoposide/carboplatin can be considered an appropriate 1L regimen
to treat SCLC, particularly in patients who cannot tolerate cisplatin.
Multiple randomized studies have evaluated whether continuation beyond 4 to 6 cycles of 
chemotherapy is necessary. Overall survival is not improved if patients receive additional 
cycles of the same regimen used for induction [66] [67], maintenance oral etoposide or 
sunitinib after an etoposide-containing 1L regimen [68] [60] [69], or consolidation with 
different chemotherapeutic regimens after 4 cycles of EP [70] [71]. Treatment beyond 6
cycles of chemotherapy is not recommended for ES-SCLC by the National Comprehensive 
Cancer Network [72], the European Society of Medical Oncology Guidelines [73], or the 
American Society of Clinical Oncology [74]. Recent trials in this patient population have 
administered 4 cycles of therapy [60] [61] [63].
Prophylactic Cranial Irradiation
Brain metastases are common in SCLC. Approximately 18% of patients have central nervous 
system involvement at diagnosis [75], and another 20% to 25% of patients develop brain 
metastasis during the course of their disease, the likelihood increasing with lengthening 


Product:  MK-3475 
24
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
survival [76] [77]. At postmortem examination, brain metastases are found in up to 65% of 
patients who had SCLC [78].
In a meta-analysis of almost 1,000 patients in 7 trials between 1977 and 1995, patients were 
evaluated with and without PCI after initially obtaining a complete response [79]. 
Prophylactic cranial irradiation doses ranged from 24 to 40 Gy in most patients. Three-year 
survival rates increased from 15% without PCI to almost 21% with PCI. Additional findings 
included a significantly decreased probability of brain metastases and increased likelihood of 
disease-free survival. Higher doses of radiation appeared to be more effective in preventing 
brain metastases, but had no impact on survival. A trend toward a decreased risk of brain 
metastases was observed when PCI was administered earlier.
A survival benefit with PCI in patients with ES-SCLC who had a response to chemotherapy 
was demonstrated in an EORTC randomized trial (N=286) [80]. Significantly, addition of 
PCI therapy improved the rate of 1-year freedom from symptomatic brain metastases from 
14.6% to 40.4% and improved the 1-year survival rate from 13.3% to 27.1%. Various 
fractionation schemes were used; the most common were 20 Gy in 5 fractions and 30 Gy in 
10 fractions. The trial did not mandate pre-treatment brain imaging to rule out clinically 
occult brain metastases, which has raised the question of whether the observed survival 
benefit was due to treatment of patients who already had detectable brain metastases.
Regardless, the results of the EORTC trial established PCI as a standard consideration for all 
patients with ES-SCLC who achieve a response to initial therapy. Yet, the American Society 
of Clinical Oncology Guidelines note that this may be subject to change upon final 
publication of a recently conducted study in Japan. The study randomized 163 patients with 
ES-SCLC who responded to 1L therapy to either PCI (25 Gy in 10 fractions) or observation 
and failed to demonstrate a survival advantage for PCI [74].
More recently, standard-dose versus higher-dose PCI has been evaluated after complete 
response (CR) in patients with limited stage small cell lung cancer (LS-SCLC) in an 
Intergroup trial [81]. Seven hundred twenty patients were randomized to either 25 Gy in 10 
fractions or 36 Gy delivered in 18 daily fractions of 2 Gy or 24 twice-daily fractions of 1.5 
Gy. There was no significant difference in incidence of brain metastases between the 
standard-dose group and the high-dose group. The OS was significantly worse in the higher-
dose group, further establishing 25 Gy in 10 fractions as the standard dose of PCI for patients
with LS-SCLC.
Prophylactic cranial irradiation is associated with AEs such as fatigue, hair loss, and 
decreased quality of life [73]. Long-term survivors have neurologic and intellectual 
impairment, as well as abnormalities on computed tomography (CT) imaging that may be 
related to PCI [82] [83], which for some, causes reluctance to propose this treatment.
Consequently, PCI guidelines recommend that patients who proceed with PCI have a good 
performance status and adequate neurocognitive functioning, and that a full discussion occurs 
between the patient and physician, especially in extensive stage disease [73] [72].


Product:  MK-3475 
25
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Rationale
Rationale for the Trial and Selected Subject Population
Small cell lung cancer remains a worldwide public health problem; it is a major cause of 
cancer mortality and is strongly associated with tobacco exposure [84] [85]. While in the 
United States there has been a decline in prevalence of tobacco use resulting in a gradual 
decrease in SCLC incidence over the past decades, SCLC still accounts for 14% of all lung 
cancers, with approximately 30,000 patients diagnosed annually [86] [87]. Approximately
275,000 patients worldwide are diagnosed with SCLC annually [84] [85].
Small cell lung cancer is an aggressive neuroendocrine malignancy with a unique natural 
history characterized by a short doubling time, high growth fraction, and early development 
of widespread metastases. Although a chemotherapy- and radiation-sensitive disease, SCLC 
typically recurs rapidly after primary treatment, with only 6% of patients surviving 5 years 
from diagnosis.
Treatment of SCLC is notable for the lack of major developments; nearly 4 decades after the 
introduction of an EP doublet, therapeutic options have remained virtually unchanged, with 
correspondingly little improvement in survival rates.
Radiation therapy is administered to patients with LS-SCLC, whose cancer is confined to the 
chest in a single tolerable radiation field. Patients with LS-SCLC or ES-SCLC who achieve a 
response to 1L platinum-based therapy generally are offered PCI, which has been shown to 
decrease the risk of intracranial recurrence and improve OS [79] [80]. Additional efforts at 
improving outcomes with 1L therapy for SCLC patients have been unsuccessful. Examples 
include the use of irinotecan instead of etoposide (in Western countries), alternating multi-
drug combinations, addition of a third chemotherapeutic drug to etoposide and cisplatin, and 
prolonging the number of cycles of etoposide and cisplatin or carboplatin [88].
First-line treatment for SCLC yields optimal tumor response rates as high as 60% to 80%, 
which unfortunately translates to cure in only approximately 20% of patients with LS-SCLC 
[89]. Essentially all patients with ES-SCLC, and the majority of patients with LS-SCLC, 
suffer relapse within months of completing initial therapy. The strongest predictor of 
outcome for patients with relapsed SCLC is the duration of remission. Patients with sensitive 
disease, who maintain a response to initial treatment for 3 months or more, have a response 
rate to additional chemotherapy of about 25% and a median survival of about 6 months from 
the time of relapse. In contrast, those patients with refractory disease who either have no 
response to initial therapy or progress within 3 months, rarely benefit from additional 
treatment, with response rates <10% and median survival of 4 months.
Topotecan is the only Food and Drug Administration (FDA)-approved agent for recurrent or 
progressive SCLC, based on the results of three Phase 3 trials [90] [91] [92]. There are no 
accepted regimens for patients whose disease has progressed after 1L and 2L treatments for 
SCLC. This is in stark contrast to the progress that has been made in the treatment of 
NSCLC, thus underscoring the critical need for more effective therapies in SCLC.


Product:  MK-3475 
26
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
When considering new approaches to 1L treatment of SCLC, the dramatic initial tumor 
response to an EP regimen seen in the large majority of SCLC patients must be 
acknowledged; however, in nearly all cases, the tumors become resistant to this treatment.
Several lines of evidence support modulation of immune response in SCLC as a treatment 
modality. The disease is associated with immunogenic effects, evidenced by the prolonged 
survival of patients with autoantibodies (ie, anti-Hu) and neurologic paraneoplastic 
syndromes [93]. The expression of major histocompatibility complex antigens is reduced in 
SCLC and this may play a role in this tumor’s ability to escape immune surveillance [94] 
[95]. Interestingly, effector T-cells associated with cytolytic responses are significantly 
higher in the peripheral blood of patients with LS-SCLC compared to those with ES-SCLC 
and in long term disease-free survivors relative to those with recurrent disease [96]. More
recently, the PD-1/PD-L1 pathway, a major target of anti-tumor immunotherapy, has been 
interrogated in SCLC utilizing immunohistochemistry (IHC) and RNA-expression to 
evaluate the presence of PD-L1 in primary and metastatic tumor tissue as well as in TILs [97] 
[98] [99] [100] [101]. In general, 50% to 80% of tumor specimens were PD-L1-positive (ie, 
>5% of cells in the specimen expressed PD-L1). In several of these reports, when other 
patient characteristics and treatment outcomes were considered, patients with PD-L1-positive 
tumors had a longer OS, and higher PD-L1 expression strongly correlated with limited-stage 
disease [98] [99] [100] [101]. However, each of these studies utilized different types of 
specimens, as well as antibodies.
Mutational burden appears to be an important determinant of response to immune checkpoint 
inhibitors. In a recent study analyzing tumor mutational burden in NSCLC patients treated 
with pembrolizumab, higher mutational burden was associated with improved objective 
response, durable clinical benefit, and prolonged PFS [102]. The association between 
response to PD-1 inhibitors, mutational burden, and tobacco exposure may have important 
implications for SCLC, as this disease is strongly associated with smoking and has a 
markedly elevated mutation burden, as highlighted previously.
KEYNOTE-028 is a Phase 1b multi-cohort study of pembrolizumab for the treatment of 
PD-L1-positive, advanced solid tumors including SCLC. Of the 147 subjects with evaluable 
ES-SCLC biopsy specimens who were screened, 42 (29%) had PD-L1-positive tumors and, 
of these, 24 previously treated subjects were eventually enrolled. Notably, 21 patients 
(87.5%) were in need of third-line or greater therapy. The patients were treated with 
pembrolizumab monotherapy for up to 2 years. Median duration of follow-up was
9.8 months (range: 0.5 to 24.0). The ORR was 37.5% (95% confidence interval [CI] 18.8 to 
59.4) and included 1 CR and 8 PRs. Median DOR was 9.0 months (range: 1.9 to 19.9+).
Median PFS was 1.9 months (range: 1.7 to 5.9) and at 6 and 12 months, 29.8% and 24.8% of 
subjects were alive and progression-free, respectively. Median OS was 9.7 months (95% CI 
4.1 to not reached); 66.0% and 35.7% of subjects were alive at 6 and 12 months, 
respectively. Treatment-related AEs were reported for 66.0% of subjects, including 
2 subjects with Grades 3 to 5 treatment-related AEs. No new safety concerns were identified
[103]. These results demonstrate that pembrolizumab monotherapy has meaningful anti-
tumor activity in heavily pre-treated subjects with PD-L1-positive SCLC. In contrast, studies 
of topotecan as 2L treatment of SCLC demonstrated response rates of approximately 18%, 


Product:  MK-3475 
27
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
median survival of 6 months, and duration of response of 7.5 months [104] [105] [106] [107].
Based on this information, incorporating pembrolizumab treatment in the 1L setting in SCLC 
patients may lead to further improvement in outcomes.
Recently, Langer and colleagues reported results from KEYNOTE-021 Cohort G, a Phase 2
randomized 
trial 
comparing
pembrolizumab/pemetrexed/carboplatin 
with
pemetrexed/carboplatin alone for the treatment of subjects with newly diagnosed NSCLC
regardless 
of 
PD-L1 
tumor 
expression 
[108].
The 
ORR 
was 
55% 
in 
the 
pembrolizumab/pemetrexed/carboplatin arm compared with 29% in the pemetrexed/ 
carboplatin alone arm
(p=0.0016), and responses occurred 1 month earlier in the 
pembrolizumab/pemetrexed/carboplatin arm. The improvement in response was observed in 
subjects with tumors of all PD-L1 expression levels. Progression-free survival was improved 
for the pembrolizumab/pemetrexed/carboplatin arm compared with
the pemetrexed/ 
carboplatin alone arm (13 months versus 8.9 months, respectively; p=0.0102). These data 
indicate that pembrolizumab with chemotherapy has the potential to be an effective 1L
treatment for SCLC and potentially may be a regimen that can change outcomes in this 
disease.
Based on the previously mentioned data and a critical need for new therapies in SCLC, we 
are undertaking this worldwide, randomized, placebo-controlled, Phase 3, parallel group, 
multi-site, double-blind trial of pembrolizumab plus SOC chemotherapy (EP) in subjects 
with ES-SCLC who have not previously received systemic therapy.
Rationale for Dose Selection/Regimen/Modification
Rationale for the Dose of Pembrolizumab
The planned dose of pembrolizumab for this trial is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda® development program, 200 mg Q3W is the appropriate dose 
of pembrolizumab across all indications regardless of tumor type. As outlined below, this 
dose is justified by: 
o
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),
o
Clinical data showing meaningful improvement in benefit-risk,
including 
improvement in OS at 200 mg Q3W across multiple indications, and
o
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from physiologically based PK analysis
[PBPK]) at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 subjects with melanoma 
or NSCLC were enrolled, 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 and 10 mg/kg 
Q3W (KEYNOTE-001 B2, KEYNOTE-001 D, KEYNOTE-002, KEYNOTE-010, and 


Product:  MK-3475 
28
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
KEYNOTE-021), and 3 studies compared 10 mg/kg Q3W and 10 mg/kg Q2W 
(KEYNOTE-001 B3, KEYNOTE-001 F2, and KEYNOTE-006). 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 subjects with 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 KEYNOTE-001 
evaluating 
target-mediated 
drug 
disposition 
conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression. This evaluation demonstrated that 
pembrolizumab 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 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 a 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 Use of Comparator/Placebo
The use of saline placebo in combination with standard chemotherapy will ensure the 
objectivity 
of 
investigator-assessed 
progression,
as 
well 
as 
any 
decisions 
to 
interrupt/discontinue therapy.
Rationale for Efficacy Endpoints
Primary Efficacy Endpoints
Primary: This trial has dual primary endpoints of PFS and OS.
PFS is an acceptable measure of clinical benefit for a randomized Phase 3 trial that 
demonstrates superiority of a new antineoplastic therapy, especially if the magnitude of 
effect is large and the therapy has an acceptable risk-benefit profile. PFS, as assessed by 
BICR per RECIST 1.1 (modified to follow a maximum of 10 target lesions and a maximum 
of 5 target lesions per organ), will be used to determine the dates of progression as this 
methodology is accepted by regulatory authorities. Images read by BICR blinded to 
treatment assignment can minimize bias in the response assessments. In addition, final 
determination of radiologic PD will be based on the BICR assessment of progression, rather 
than local site investigator/radiology assessment. Expedited assessment by the BICR in 


Product:  MK-3475 
29
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
instances of suspected radiologic progression identified at the site (verification of PD) will be 
communicated to the site study team.
Notably, PFS has demonstrated strong potential surrogacy for OS in 1L treatment of 
ES-SCLC and may be a good alternative endpoint to OS in this disease [109].
Overall survival has been recognized as the gold standard for the demonstration of 
superiority of a new antineoplastic therapy in randomized clinical studies.
Secondary Efficacy Endpoints
The key secondary efficacy endpoint of this study is ORR assessed by BICR using 
RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target 
lesions per organ. Additionally, DOR assessed by BICR according to RECIST 1.1 modified 
to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ is a 
secondary endpoint.
Safety Endpoints
The incidence of AE/SAEs (including fatal SAEs), immune-related AEs, laboratory 
abnormalities, and rates of dose interruption and discontinuation due to AEs are important 
endpoints for safety and tolerability evaluations.
Patient Reported Outcomes
The EORTC QLQ-C30 and EORTC QLQ-LC13 will be used to investigate: (1) quality of 
life and (2) disease-related symptoms. These questionnaires are not purely efficacy or safety 
endpoints because they are affected by both disease progression and treatment tolerability.
EQ-5D-5L is an exploratory endpoint that will be used to calculate health utilities for health 
economic models.
EORTC QLQ-C30 was developed to assess the quality of life of subjects with cancer. It has 
been translated into 81 languages, validated, and used in more than 3000 studies worldwide.
It contains 5 functioning scales (physical, role, cognitive, emotional, and social), 3 symptom 
scales (fatigue, nausea, and pain) and additional single symptom items. It is scored on a 
4-point scale (1 = not at all, 2 = a little, 3 = quite a bit, 4 = very much). The EORTC QLQ-
C30 instrument also contains 2 global scales that use 7-point scale scoring with anchors 
(1 = very poor and 7 = excellent).
The EORTC QLQ-LC13, a supplemental lung cancer-specific module, comprises multi-item 
and single-item measures of lung cancer-associated symptoms (ie, coughing, hemoptysis, 
dyspnea, and pain) and side effects from chemotherapy and radiation (ie, hair loss, 
neuropathy, sore mouth, and dysphagia). It is scored on a 4-point scale (1 = not at all, 2 = a 
little, 3 = quite a bit, 4 = very much) and has been translated into 64 languages and validated.
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome. The 
EQ-5D-5L will provide data for use in economic models and analyses including developing 


Product:  MK-3475 
30
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
health utilities or quality-adjusted life-years. The 5 health state dimensions addressed in this 
instrument are mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
Each dimension has 5 levels: no problems, slight problems, moderate problems, severe 
problems, and extreme problems.
Immune-related RECIST
Immune-related RECIST is RECIST 1.1 adapted to account for the unique tumor response 
seen with immunotherapeutics as described by Nishino et al [110]. 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 lesions, and tumor burden assessment in order to confirm radiographic 
progression.
Immunotherapeutic agents such as pembrolizumab may produce anti-tumor 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. Thus, standard RECIST 1.1 may not provide 
an accurate response assessment for immunotherapeutic agents such as pembrolizumab.
Based on an analysis of patients with melanoma enrolled in KEYNOTE-001 [111], 7% of 
evaluable patients experienced delayed or early tumor pseudo-progression. Of note, patients 
who had progressive disease by RECIST 1.1 but not by irRECIST, had longer OS than 
patients with PD 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 to immunotherapy and enable treatment beyond initial 
radiographic progression.
Local site investigators will use irRECIST to assess tumor response and progression and to 
make treatment decisions.
For further information on irRECIST, see Section 7.1.2.7.6.
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of anti-tumor agents.
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating subjects. Thus, to aid future subjects, it is important to investigate the 
determinants of response or resistance to cancer immunotherapy as well as determinants of 
AEs in the course of our clinical trials.
These efforts will identify novel 
predictive/pharmacodynamic biomarkers and generate information that will better guide 


Product:  MK-3475 
31
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
single-agent and combination therapy with immuno-oncology drugs. To identify novel 
biomarkers, we will collect biospecimens (eg, blood components, tumor material) to support 
analyses of cellular components (eg, protein, DNA, RNA, metabolites) and other circulating 
molecules. Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, single nucleotide polymorphism analyses, whole 
exome sequencing, whole genome sequencing): This research will evaluate whether genetic 
variation within a clinical trial population correlates with response to the treatment(s) under 
evaluation. If genetic variation is found to predict efficacy or AEs, the data might inform 
optimal use of therapies in the patient population. Furthermore, it is important to evaluate 
germline DNA variation across the genome in order to interpret tumor-specific DNA 
mutations. Finally, microsatellite instability may be evaluated as this is an important 
biomarker for some cancers (ie, colorectal cancer).
Genetic (DNA) analyses from tumor: The application of new technologies, such as next 
generation sequencing, has provided scientists the opportunity to identify tumor-specific 
DNA changes (ie, mutations, methylation status, microsatellite instability). Key molecular 
changes of interest to immuno-oncology drug development include the mutational burden of 
tumors and the clonality of T-cells in the tumor microenvironment. Increased mutational 
burden (sometimes referred to as a ‘hyper-mutated’ state) may generate neo-antigen 
presentation in the tumor microenvironment. In order to conduct this type of research, it is 
important to identify tumor-specific mutations that occur across all genes in the tumor 
genome. Thus, genome-wide approaches may be used for this effort. Note that in order to 
understand tumor-specific mutations; it is necessary to compare the tumor genome with the 
germline genome. Microsatellite instability may also be evaluated as this is an important 
biomarker for some cancers (ie, colorectal cancer).
Tumor and blood RNA analyses: Both genome-wide and targeted messenger RNA 
expression profiling and sequencing in tumor tissue and blood may be performed to define 
gene signatures that have a correlation to clinical response to treatment with pembrolizumab 
or other immunotherapies. Pembrolizumab induces a response in tumors that likely reflects 
an inflamed/immune phenotype. Specific immune-related gene sets (such as those capturing 
interferon-gamma transcriptional pathways) may be evaluated and new signatures may be 
identified. Individual genes related to the immune system may also be evaluated (eg, IL-10).
MicroRNA profiling may also be pursued.
Proteomics and IHC using blood and tumor: Tumor and blood samples from this study may 
undergo proteomic analyses (eg, PD-L1 IHC). PD-L1 protein level in tumor sections, 
assessed by IHC, has been shown to correlate with response to pembrolizumab in subjects
with NSCLC, and an in vitro diagnostic device has been developed for use with 
pembrolizumab in NSCLC. Preliminary data indicate that this association may also be true in 
additional cancer types (ie, triple-negative breast cancer, head and neck cancer, and gastric
cancer). Since many tumor or blood-derived proteins may correlate with response to 
pembrolizumab, tumor tissue may be subjected to proteomic analyses using a variety of 
platforms including, but not limited to, immunoassays and liquid chromatography/mass 


Product:  MK-3475 
32
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
spectrometry. This approach could identify novel protein biomarkers to aid in patient 
selection for pembrolizumab therapy.
Other blood derived biomarkers: In addition to expression on the tumor tissue, PD-L1 and 
other tumor-derived proteins can be shed from tumor and released into the blood. Assays 
such as enzyme-linked immunoassays measure these proteins in serum. The correlation of 
such expression with a response to pembrolizumab therapy may lead to identification of new 
approaches for using predictive biomarkers in blood, representing a major advance from 
today’s reliance on assessing tumor biomarkers. This research would serve to develop such 
assays for future clinical use.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting/retaining specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of this Future Biomedical Research sub-trial are presented in Section 12.2 – Collection and 
Management of Specimens for Future Biomedical Research.
Benefit/Risk
It cannot be guaranteed that subjects in clinical trials will directly benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
As described in Section 4.2.1,
KEYNOTE-028 demonstrated that pembrolizumab 
monotherapy has meaningful anti-tumor activity in heavily pre-treated subjects with 
PD-L1-positive SCLC. Pembrolizumab in combination with chemotherapy has significant 
clinical activity as 1L therapy in subjects with advanced NSCLC, regardless of PD-L1 
expression, as shown in KEYNOTE-021 Cohort G (Section 4.2.1). Considering the high 
unmet medical need for new and tolerable treatment options in subjects with newly 
diagnosed ES-SCLC, the anti-tumor activity and the favorable safety profile
of 
pembrolizumab in combination with chemotherapy regimens for other solid tumors, a 
combination of PD-1 blockade plus chemotherapy is a promising therapeutic strategy and the 
benefit-risk assessment for subjects included in this trial is considered to be favorable.


Product:  MK-3475 
33
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and informed consent documents.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male and female subjects with ES-SCLC will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Have a documented new diagnosis of SCLC by histology or cytology from brushing, 
washing, or needle aspiration of a defined lesion. Subjects who do not have histology 
samples (defined as core or excisional biopsy, or resections) will need to undergo a 
new biopsy to provide a tissue sample.
2. Have extensive stage disease defined as Stage IV (T any, N any, M 1a/b) by the 
American Joint Committee on Cancer, Seventh Edition.
3. Have at least 1 lesion that meets the criteria for being measurable, as defined by 
RECIST 1.1, and is appropriate for selection as a target lesion, as determined by local 
site investigator/radiology review. Lesions that appear measurable, but have 
undergone palliative irradiation, cannot be target lesions.
4. Have provided archival tumor tissue sample or newly obtained core or excisional 
biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin-embedded 
tissue blocks are preferred to slides.
5. Have ECOG Performance Status of 0 or 1. See Section 12.3 for definitions.
6. Have a life expectancy of at least 3 months.
7. Have adequate organ function as indicated by the following laboratory values
(Table 1).


Product:  MK-3475 
34
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Table 1
Adequate Organ Function Lab Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥8 g/d a
Renal
Serum creatinine OR
calculated creatinine clearance (CrCl)b
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5 × ULN OR
≥60 mL/min for subjects with creatinine levels >1.5× ULN 
receiving cisplatin
≥50 mL/min for subjects with creatinine levels >1.5 × ULN 
receiving carboplatin
Hepatic
Serum total bilirubin
≤1.5 × ULN OR
Direct bilirubin ≤ULN for subjects with total bilirubin levels 
>1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN 
≤5 × ULN for subjects with liver metastases
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
≤1.5 × ULN unless the subject is receiving anticoagulant 
therapy as long as PT or INR is within therapeutic range of 
intended use of anticoagulants
Abbreviations: ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); 
AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration 
rate; INR=International Normalized Ratio; ULN=upper limit of normal.
a Criterion must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion 
within last 2 weeks.
b Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of specific 
chemotherapies.
8. Be ≥18 years of age on day of signing informed consent.
9. If female subject of childbearing potential, 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.
10. If female and of childbearing potential, be willing to use an adequate method of 
contraception as outlined in Section 5.7.2, starting with the first dose of study 
medication through 120 days after the last dose of pembrolizumab or saline placebo
or up to 180 days after last dose of chemotherapeutic agents, whichever is later.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.


Product:  MK-3475 
35
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
11. If male and of childbearing potential, agree to use an adequate method of 
contraception as outlined in Section 5.7.2, starting with the first dose of study 
medication through 120 days after the last dose of pembrolizumab or saline placebo
or up to 180 days after last dose of chemotherapeutic agents, whichever is later.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
12. Have voluntarily agreed to participate by giving written informed consent/assent for 
the trial. The subject may also provide consent/assent for Future Biomedical 
Research. However, the subject may participate in the main trial without participating 
in Future Biomedical Research.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has received prior systemic therapy for the treatment of SCLC.
Note: Palliative radiation therapy is allowed until 7 days prior to the first dose of trial
medication, provided that the radiated lesion is clinically stable and the patient is not 
receiving steroids for at least 7 days prior to the first dose of study medication. The 
radiated lesion must not be a thoracic lesion and must not be included as a target 
lesion for RECIST 1.1 measurements.
2. 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 for another health-related problem.
Note: Subjects who have entered the follow-up phase of an investigational trial may 
participate as long as it has been at least 4 weeks since the last dose of the previous 
investigational agent.
3. Is expected to require any other form of antineoplastic therapy for SCLC, including 
radiation therapy, while on study.
Note: Patients with PR or CR will be offered PCI therapy at the completion of the 
4 cycles of chemotherapy with or without pembrolizumab.
4. Has known central nervous system (ie, brain and/or spinal cord) metastases and/or 
carcinomatous meningitis. Subjects with brain metastases may participate only if they
satisfy all of the following:

Completed treatment (eg, whole brain radiation treatment [WBRT], stereotactic 
radiosurgery, or equivalent) at least 14 days prior to the first dose of trial 
treatment, 


Product:  MK-3475 
36
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential

Have no evidence of new or enlarging brain metastases confirmed by 
post-treatment repeat brain imaging (using the same modality) performed at least 
3 weeks after pre-treatment brain imaging, and 

Are neurologically stable without the need for steroids for at least 7 days before 
first dose of trial treatment as per local site assessment. 
5. Has had major surgery within 3 weeks prior to receiving the first dose of trial
treatment or has not recovered adequately from toxicity and/or complications from an 
intervention prior to receiving the first dose of study treatment.
6. Has a history of non-infectious pneumonitis that required steroids or has current 
pneumonitis.
7. Has a known history of interstitial lung disease.
8. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include early stage cancers (carcinoma in situ or Stage 1) treated with 
curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
in situ cervical cancer, or in situ breast cancer that has undergone potentially curative 
therapy.
9. Has active autoimmune disease that has required systemic treatment in the past 
2 years 
(ie, 
with 
use 
of 
disease-modifying 
agents, 
corticosteroids, 
or 
immunosuppressive drugs).
Replacement therapy (eg, thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 
is not considered a form of systemic treatment.
10. Has a known history of, or active, neurologic paraneoplastic syndrome.
11. Has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal
obstruction, and/or abdominal carcinomatosis.
12. Has a history of a severe hypersensitivity reaction to treatment with another 
monoclonal antibody.
13. Is taking chronic systemic steroids (in doses exceeding 10 mg daily of prednisone 
equivalent) within 7 days prior to the first dose of trial treatment.
Note: Subjects with asthma or chronic obstructive pulmonary disease that require 
intermittent use of bronchodilators, inhaled steroids, or local steroid injections would 
not be excluded from the study. 
14. Has a diagnosis of immunodeficiency or is receiving any form of immunosuppressive 
therapy within 7 days prior to the first dose of trial treatment.


Product:  MK-3475 
37
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
15. Has received a live vaccine within 30 days prior to the first dose of trial drug.
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus 
Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or 
with an agent directed to another co-inhibitory T-cell receptor (ie, CTLA-4, OX-40, 
CD137) or has previously participated in a Merck pembrolizumab (MK-3475) clinical 
trial.
17. Has severe hypersensitivity (Grade ≥3) to pembrolizumab and/or any of its 
excipients.
18. Has an active infection requiring systemic therapy.
19. Has a known history of HIV infection. No HIV testing is required unless mandated by 
local health authority.
20. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] 
reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection. 
Note: No testing for hepatitis B and hepatitis C is required unless mandated by local 
health authority.
21. Has a known history of active TB (Bacillus Tuberculosis).
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation 
for the full duration of the study, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.
23. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
24. Has symptomatic ascites or pleural effusion. A subject who is clinically stable 
following treatment for these conditions (including therapeutic thoraco-
or 
paracentesis) is eligible.
25. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study starting with the screening visit through 120 days after 
the last dose of pembrolizumab or saline placebo or up to 180 days after last dose of 
chemotherapeutic agents, whichever is later.


Product:  MK-3475 
38
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Trial Treatment(s)
The treatments to be used in this trial are outlined below in Table 2.
Table 2
Trial Treatments
Drug or
Biologic
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Period
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each 
cycle prior to 
chemotherapy
Experimental
Saline
Not 
applicable
Q3W
IV infusion
Day 1 of each 
cycle prior to 
chemotherapy
Placebo 
comparator
Carboplatin
AUC 5
Q3W
IV infusion
Day 1 of each 
cycle
Standard of 
care
Cisplatin
75 mg/m2
Q3W
IV infusion
Day 1 of each 
cycle
Etoposide
100 mg/m2
Q3W
IV infusion
Days 1, 2, 3 of 
each cycle
Trial treatment should begin on the day of randomization or as soon as possible, but no later 
than 3 days after 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. 
The trial site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
Dose Selection (Preparation)
Pembrolizumab: The amount required to prepare the pembrolizumab infusion solution will 
be based on a fixed dose of 200 mg. Details on the preparation and administration are 
provided in the Pharmacy Manual.


Product:  MK-3475 
39
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Standard chemotherapeutic agents (etoposide and carboplatin or cisplatin) will be prepared 
and administered as per the local approved product label. Appropriate infusion times for each 
agent are noted in the respective subsections of Section 5.2.2.2.
The rationale for selection of doses to be used in this trial is provided in Section 4.0.
Dose Modification
If a subject experiences a >10% weight change during Cycles 1 to 4, the doses of etoposide 
and cisplatin/carboplatin should be recalculated.
Dose modifications due to AEs will depend on the investigator’s assessment of causality. If 
appropriate, 
the 
investigator
may 
attribute 
each 
toxicity 
event 
to 
etoposide, 
cisplatin/carboplatin, or pembrolizumab alone or to the combination and use a stepwise dose 
reduction according to Table 3 through Table 7. Dose modifications must be based on the 
maximum toxicity experienced during a cycle. Toxicity must resolve to Grade ≤1 or baseline 
prior to resuming the subsequent cycle, with the exception of alopecia, Grade 2 fatigue, 
endocrine-related AEs requiring treatment or hormone replacement, which may be Grade ≤2, 
and creatinine clearance, for which the guidelines in Section 5.2.1.2.2 may be followed.
If a dose reduction for toxicity occurs with any agent, the dose may not be re-escalated. 
Subjects can have a maximum of 2 dose modifications (if applicable) to each of the 
components of study therapy throughout the course of the study for toxicities. If a subject 
experiences several toxicities and there are conflicting recommendations, the most 
conservative dose adjustment recommended should be followed (ie, dose reduction 
appropriate to the most severe toxicity). Subjects who require a third dose modification to 
any particular component will have that agent discontinued. In the absence of the agent 
thought to be causing toxicity, treatment can continue with pembrolizumab or saline placebo 
and the remaining chemotherapeutic drug.
Reduction of 1 chemotherapy agent and not the other agent is appropriate if, in the opinion of 
the investigator, the toxicity is clearly related to one of the treatments. If, in the opinion of 
the investigator, the toxicity is related to the combination of both chemotherapy agents, both 
drugs should be reduced according to recommended dose modifications. If the toxicity is 
related to the combination of 3 agents, all 3 agents should be reduced (if applicable),
interrupted, or discontinued according to the recommended dose modifications.
Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
delayed/interrupted for a maximum of 12 weeks or discontinued due to toxicity.
Subjects may have chemotherapy discontinued and continue on pembrolizumab or saline 
placebo alone. Similarly, subjects may discontinue pembrolizumab or saline placebo and 
continue on chemotherapy alone during the first 4 cycles, if appropriate. Any requests for 
unblinding will be considered on an individual subject basis and only after consultation with 
the Sponsor.


Product:  MK-3475 
40
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
During Cycles 1 through 4 of pembrolizumab + EP or placebo + EP:

If etoposide dosing is delayed or interrupted, the platinum agent and pembrolizumab 
or saline placebo should also be delayed/interrupted. If EP is delayed or interrupted 
during Cycles 1 through 4, patients should be seen weekly until toxicity resolves.

If cisplatin/carboplatin dosing is delayed or interrupted, etoposide and pembrolizumab or 
saline placebo should also be delayed/interrupted. If EP is delayed or interrupted during 
Cycles 1 through 4, patients should be seen weekly until toxicity resolves.

If pembrolizumab or saline placebo dosing is delayed or interrupted, EP therapy can 
continue as scheduled. Pembrolizumab or saline placebo administration should be 
attempted at the next cycle of therapy.

Each chemotherapy cycle may not be delayed by more than 3 weeks (>21 consecutive 
days) despite supportive treatment. If only one of the agents is thought to be causing 
the specified toxicity leading to a 21-day delay of administration of the next cycle, 
that chemotherapeutic agent can be stopped and treatment can continue with 
pembrolizumab or saline placebo
and the remaining chemotherapy
drug.
Pembrolizumab/placebo dosing can continue with 1 agent or as monotherapy.
The NCI CTCAE 4.0 must be used to grade the severity of AEs. All dose modifications 
should be based on the AE requiring the greatest dose modification. Dose modifications are 
detailed in Table 3 through Table 7.
Table 3
Dose Modifications for Study Drugs
Etoposide
Cisplatin
Carboplatin
Pembrolizumab/
Placebo
Dose Level 0 
(starting dose)
100mg/m2/day
75mg/m2
AUC 5
200 mg
fixed dose
Dose Level -1
75mg/m2/day
56mg/m2
AUC 4
Dose reduction not 
permitted
Dose Level -2
50mg/m2/day
38mg/m2
AUC 3
Dose reduction not 
permitted
Dose Level -3
Discontinue
Discontinue
Discontinue
Dose reduction not 
permitted
5.2.1.2.1 Pembrolizumab
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
have an immunologic etiology. These immune-related AEs (irAEs) may occur shortly after 
the first dose or several months after the last dose of treatment and may affect more than one 
body system simultaneously. Therefore, early recognition and initiation of treatment is 


Product:  MK-3475 
41
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
critical to reduce complications. Based on existing clinical trial data, most irAEs were 
reversible and could be managed with interruptions of pembrolizumab, administration of 
corticosteroids, and/or other supportive care. For suspected irAEs, ensure adequate 
evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, or skin biopsy may be included as part of the evaluation. Based on 
the severity of the irAE, withhold or permanently discontinue pembrolizumab and administer 
corticosteroids. Dose modification and toxicity management guidelines for irAEs associated 
with pembrolizumab are provided in Table 4.


Product:  MK-3475 
42
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-Related AEs Associated With Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot 
be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should 
be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up
Pneumonitis 
Grade 2
Withhold 

Administer 
corticosteroids 
(initial dose of 1-2
mg/kg 
prednisone 
or 
equivalent) 
followed by taper

Monitor subjects for signs and symptoms of 
pneumonitis

Evaluate 
subjects 
with 
suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add 
prophylactic 
antibiotics 
for 
opportunistic infections
Grade 
3 
or 
4, 
or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / colitis 
Grade 2 or 3
Withhold

Administer 
corticosteroids 
(initial dose of 1-2
mg/kg 
prednisone 
or 
equivalent) 
followed by taper

Monitor subjects 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).

Subjects with Grade ≥2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Subjects with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
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 returns to baseline or is stable


Product:  MK-3475 
43
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up
Grade 3 or 4 
Permanently 
discontinue

Administer 
corticosteroids 
(initial dose of 1-2
mg/kg 
prednisone 
or 
equivalent) 
followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
New
onset T1DM or 
Grade 
3 
or 
4 
hyperglycemia 
associated with evidence 
of -cell failure
Withhold

Initiate insulin replacement 
therapy 
for 
subjects 
with 
T1DM 

Administer 
anti-
hyperglycemic 
in 
subjects 
with hyperglycemia 

Monitor subjects for hyperglycemia or other 
signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer 
corticosteroids 
and 
initiate 
hormonal 
replacements 
as 
clinically 
indicated.

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers (eg, propranolol) or 
thioamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
Permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine 
or 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 or 2
Withhold

Based on severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue


Product:  MK-3475 
44
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up
All Other 
immune-related 
AEs
Intolerable/ 
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 
based on the type 
of event. Events 
that 
require 
discontinuation 
include and not 
limited 
to: 
Guillain-Barre 
Syndrome, 
encephalitis
Grade 4 or recurrent 
Grade 3 
Permanently 
discontinue
Abbreviations:  AE=adverse event, ALT=alanine transaminase, AST=aspartate transaminase, CTCAEv4.0=Common Terminology Criteria for Adverse Events version 4.0,
irAE=immune-related adverse event, IV=intravenous, T1DM=Type 1 diabetes mellitus
1.
Withholding or permanently discontinuing pembrolizumab is at the discretion of the investigator or treating physician.
2.
For subjects with Grade 3 or 4 immune-related endocrinopathy where withholding of pembrolizumab is required, pembrolizumab may be resumed when AE resolves 
to Grade ≤2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).


Product:  MK-3475 
45
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines for pembrolizumab associated 
infusion reactions are provided in Table 5.


Product:  MK-3475 
46
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically indicated until the subject 
is deemed medically stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 h
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically indicated until the subject 
is deemed medically stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug infusion, the infusion 
may be restarted at 50% of the original infusion rate (eg, from 100 mL/h
to 50 mL/h). Otherwise dosing will be held until symptoms resolve and 
the subject should be premedicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
study drug treatment
Subject may be premedicated 1.5 h 
(± 30 minutes) prior to infusion of 
pembrolizumab with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic).


Product:  MK-3475 
47
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically indicated until the subject 
is deemed medically stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used immediately.
Subject is permanently discontinued from further study drug 
treatment.
No subsequent dosing
Abbreviations:  CTCAE=Common Terminology Criteria for Adverse Events, IV=intravenous, NCI=National Cancer Institute, NSAID=nonsteroidal anti-inflammatory 
drug
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


Product:  MK-3475 
48
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Other allowed dose interruptions for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy. 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 Chemotherapeutic agents (etoposide/platinum)
Study drug-related toxicities must be resolved to baseline or Grade ≤1 (with the exception of 
alopecia, Grade 2 fatigue, and endocrine-related AEs requiring treatment or hormone 
replacement, which may be Grade ≤2, and creatinine clearance, for which the guidelines 
provided below may be followed) prior to administering the next dose. Subjects must not 
receive the next cycle of chemotherapy if any of the following apply:

Absolute neutrophil count (ANC) <1,500/mm3

Platelet count <100,000/mm3

Hemoglobin level <8 g/dL

Total bilirubin level >1.5 × ULN

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels 
≥2.5 × ULN, or ≥5 × ULN if liver metastases are present
Recommended dose modifications for key chemotherapy toxicities (etoposide and 
cisplatin/carboplatin) are outlined in Table 6 and Table 7. These serve as a guide and do not 
replace investigator judgment and applicable local label recommendations, if more stringent.
A subject is allowed to switch from cisplatin to carboplatin if the subject develops
unexpected toxicities with the use of cisplatin (including hearing loss), becomes ineligible for 
further cisplatin therapy, and/or the investigator considers switching to carboplatin to be in 
the best interest of the subject.
A maximum of 2 dose reductions per chemotherapy agent are permitted; if additional 
reductions are required, that particular agent must be discontinued. Once the dose has been 
decreased, it should remain reduced for all subsequent administrations or be further reduced,
if necessary. There will be no dose escalations in this study. Each chemotherapy cycle may 
not be delayed by more than 3 weeks (>21 consecutive days) despite supportive treatment. If 
unacceptable toxicities related to etoposide, cisplatin, or carboplatin occur, and only one of 
the agents is thought to be causing a specified toxicity leading to a 21-day delay of 
administration of the next cycle, as determined by investigator judgment, the agent will be 
discontinued but the other drugs may be continued.


Product:  MK-3475 
49
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Table 6
Recommended Chemotherapy Dose Modifications for Hematological Toxicity
Drug Related Toxicitya
Etoposide
Cisplatin
Carboplatin
Dose Level (DL) from Table 3
Neutrophils (ANC) <500/mm3 without fever
DL -1
DL -1
DL -1
Febrile neutropenia (fever ≥38.5C and ANC 
<1,000/mm3)
DL -1
DL -1
DL -1
Platelets <50,000/mm3 without significant bleeding 
or requiring blood transfusion
DL -1
DL -1
DL -1
Platelets <50,000/mm3 with Grade ≥2 hemorrhage or 
requiring blood transfusion
DL -2
DL -2
DL -2
Grade 4 hemoglobin
DL -1
DL -1
DL -1
Abbreviations:  ANC=absolute neutrophil count, DL=dose level
Note: If toxicity can clearly be attributed to one of the drugs, the investigator may choose to only reduce the 
dose of one of the chemotherapy agents. Investigators may decide to use supportive measures/treatment 
and/or secondary prophylaxis as per institutional standards (eg, filgrastim, pegfilgrastim, transfusions) 
instead of dose reductions for the next cycle, if considered in the best interest of the subject.
a Should the hematologic toxicity recur, the dose of the agent could be reduced further. However, not more 
than 2 dose reductions per chemotherapy agent are permitted.


Product:  MK-3475 
50
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Table 7
Recommended Chemotherapy Dose Modifications for Non-hematologic Toxicity
Drug Related Toxicitya CTCAE Grade
Etoposide
Cisplatin
Carboplatin
Dose Level (DL) from Table 3
Nausea/vomiting
Grade ≥3b
DL 0
DL -1
DL -1
Mucositis
Grade ≥3b
DL -1
DL -1
DL -1
Diarrhea
Grade ≥3b
DL -1
DL -1
DL -1
Peripheral neuropathy
Grade 2
No modification
DL -1c
No modification
Grade 3
No modification
Discontinued
DL -1
Grade 4
No modification
Discontinue
DL -1
Total bilirubin
Grade 2
DL -2
No modification
No modification
Grade 3
Discontinue
No modification
No modification
Grade 4
Discontinue
No modification
No modification
AST or ALT Elevation
Grade 3
DL -1
DL -1
DL -1
Grade 4
Discontinue
Discontinue
Discontinue
Other Non-
hematologic Toxicity 
(except fatigue and 
transient arthralgia and 
myalgia)
Grade ≥3
DL -1
DL -1
DL -1
Note: If considered in the best interest of the subject, and consistent with local practice, investigators may 
decide to use supportive measures/treatment, and/or secondary prophylaxis instead of dose reductions for the 
next cycle. Also, if toxicity can clearly be attributed to one of the drugs, the investigator may choose to only 
reduce the dose of one of the chemotherapy agents.
a Should the toxicity recur, the dose of the agent could be reduced further. However, not more than 2 dose 
reductions per chemotherapy agent are permitted.
b The first occurrence of Grade ≥3 nausea/vomiting, mucositis, and diarrhea should be managed 
symptomatically with optimal medical therapy, and improve to Grade ≤1 prior to proceeding with additional 
therapy. Should these events recur despite aggressive management, a dose modification can be employed 
once the AE improves to Grade ≤1.
c If Grade 2 neurotoxicity recurs after DL -1, drug will be given at DL -2 or switch can be made to the 
appropriate dose of carboplatin at the discretion of the investigator in consultation with the Sponsor. If 
Grade 2 neurotoxicity persists after 2 dose level reductions and 21-day hold, switch can be made to the 
appropriate dose of carboplatin at the discretion of the investigator in consultation with the Sponsor.
d If Grade 3 neurotoxicity occurs, cisplatin will be discontinued and, upon improvement, a switch can be 
made to the appropriate dose of carboplatin at the discretion of the investigator in consultation with the 
Sponsor.
Creatinine clearance:
Creatinine clearance (CrCl) will be based on either the Cockcroft-Gault formula 
(Section 5.2.2.2.1) or another acceptable standard formula.


Product:  MK-3475 
51
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
For patients receiving cisplatin, the scheduled dose of cisplatin may only be administered if 
the calculated CrCl is ≥50 mL/min:

If CrCl falls to <50 mL/min, delay the start of that cycle for ≤21 days. In the interim, 
monitor renal function weekly and consider intravenous (IV) hydration. When CrCl
improves to ≥50 mL/min, decrease cisplatin to dose level (DL) -1 (Table 3).
Alternatively, if in the investigator’s judgment it is in the best interest of the patient, 
cisplatin can be switched to carboplatin if the calculated CrCl is appropriate, and in 
consultation with the Sponsor.

At the second occurrence of CrCl <50 mL/min, decrease cisplatin to DL -2 upon 
improvement of CrCl to ≥50 mL/min. Alternatively, if in the investigator’s judgment 
it is in the best interest of the patient, cisplatin can be switched to carboplatin if the 
calculated CrCl is appropriate, and in consultation with the Sponsor.

At the third occurrence of CrCl <50 mL/min, cisplatin should be discontinued. If in 
the investigator’s judgment it is in the best interest of the patient, cisplatin can be 
switched to carboplatin if the calculated CrCl is appropriate, at the discretion of the 
investigator and in consultation with the Sponsor.
For patients receiving carboplatin, the scheduled dose of carboplatin may only be 
administered if the calculated CrCl is ≥40 mL/min:

If CrCl falls to <40 mL/min, delay the start of that cycle for ≤21 days. In the interim, 
monitor renal function weekly and consider IV hydration. When CrCl improves to 
≥40 mL/min, decrease carboplatin to DL -1 (Table 3).

At the second occurrence of CrCl <40 mL/min, decrease carboplatin to DL -2 upon 
improvement of CrCl to ≥40 mL/min.

At the third occurrence of CrCl <40 mL/min, carboplatin should be discontinued.
Timing of Dose Administration
All trial treatments will be administered on an outpatient basis.
Trial treatment should be administered beginning on Day 1 of each cycle after all procedures
and assessments have been completed (time points listed in Section 6). Day 1 of each cycle
should occur as scheduled (or in a window of ± 3 days for administrative reasons only).
Etoposide must be administered on 3 consecutive days without interruption (Days 1, 2, 
and 3) in Cycles 1 to 4.
For subjects who experience disease progression, investigators may elect to continue trial 
treatment until confirmation of disease progression or may elect to interrupt treatment by 
deferring the decision to continue/discontinue treatment in the trial until confirmation of 
disease progression per modified RECIST 1.1 at least 28 days from the date of imaging 


Product:  MK-3475 
52
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
demonstrating disease progression. Subjects for whom disease progression is not confirmed 
on subsequent imaging may resume treatment. Please see Section 5.8 for other exceptions.
Pembrolizumab (or Saline Placebo)
Pembrolizumab or saline placebo will be administered first in the sequence of medications.
Upon completion of the pembrolizumab or saline placebo infusion, premedication for the 
chemotherapy should be administered as per local SOC, followed by chemotherapy.
Pembrolizumab or saline placebo will be administered as a 30-minute IV infusion Q3W on 
Day 1 of each cycle. 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 to +10 minutes is permitted (ie, infusion time is 25 to 40 minutes).
The Pharmacy Manual contains specific instructions for pembrolizumab dose calculation, 
reconstitution, infusion fluid preparation, and administration.
Chemotherapy
Chemotherapy should be administered as described in the following subsections. Subjects are 
allowed to switch from cisplatin to carboplatin, if the subject becomes ineligible for further 
cisplatin therapy according to local guidelines and the investigator considers switching to 
carboplatin to be in the best interest of the subject.
5.2.2.2.1 Carboplatin
Carboplatin at a dose calculated to achieve an area under the plasma drug concentration time 
curve (AUC) of 5 will be administered as an IV infusion over approximately 60 minutes 
Q3W on Day 1 for 4 cycles. Carboplatin dose should not exceed 750 mg. AUC should be 
calculated using the Calvert formula:

Total dose (mg) = (target AUC) (CrCl + 25)

The estimated CrCl in the Calvert formula should not exceed 125 mL/min

Maximum carboplatin dose (mg) = target AUC 5 (125 + 25)
= 5 150
= 750 mg
Creatinine clearance must be calculated using either the Cockcroft-Gault formula or another 
acceptable standard formula for estimating CrCl in mL/min based on serum creatinine:

Men: [(140 - age (y)) weight (kg)]/[72 serum creatinine (mg/dL)]

Women: [(140 - age (y)) weight (kg)] 0.85/[72 serum creatinine (mg/dL)] 
Note: Due to differences in serum creatinine units, sites may use either the standard 
Cockcroft-Gault formula or another acceptable standard formula used at their institution.


Product:  MK-3475 
53
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Dose may be rounded to the nearest 50 mg at the discretion of the investigator, and according 
to institutional standards.
Unless there is a change in weight >10%, the same dose of carboplatin can be used 
throughout the 4 cycles (provided there are no additional toxicities).
Additional premedications should be administered as per standard practice.
5.2.2.2.2 Cisplatin
Cisplatin 75 mg/m2 will be administered as an IV infusion Q3W on Day 1 for 4 cycles. An 
infusion time of 60 minutes is recommended, but cisplatin may be administered over 30 to 
180 minutes to accommodate local SOCs. Body surface area (BSA) will be obtained using
the Dubois and Dubois or Mosteller formula. The BSA calculated on Cycle 1, Day 1 of 
therapy can be used throughout the 4 cycles, unless there is a change in weight >10%.
Cisplatin will be given for up to 4 cycles. Additional premedications should be administered 
as per standard practice.
5.2.2.2.3 Etoposide
Etoposide 100 mg/m2 will be administered as an IV infusion Q3W on Days 1, 2, and 3 of 
Cycles 1 to 4. Days 1, 2, and 3 must be consecutive days without interruption. An infusion 
time of 30 to 60 minutes is recommended, but etoposide may be administered over 30 to 
120 minutes to accommodate local standards of care. Body surface area will be obtained 
using the Dubois and Dubois or Mosteller formula. The BSA calculated on Cycle 1, Day 1 of 
therapy can be used throughout the 4 cycles, unless there is a change in weight >10%.
Additional premedications should be administered as per standard practice.
Trial Blinding 
This is a double-blinded trial with respect to pembrolizumab and placebo treatment. The 
subject, the investigator, and Sponsor personnel or delegate(s) who are involved in the 
treatment administration or clinical evaluation of the subjects will be unaware of the 
treatment assignments. The chemotherapy agents will be open-label. Pembrolizumab will be 
supplied to the sites in an open label manner. The study site’s unblinded pharmacist will 
obtain each subject’s study identification number and study drug assignment from the 
interactive voice response system/integrated web response system (IVRS/IWRS) and prepare 
the solutions for infusion. The unblinded pharmacist will provide the investigative staff with 
ready-to-use blinded pembrolizumab or saline placebo infusion solutions, packaged 
identically in order to maintain the blinding, for administration at scheduled infusion visits.
In addition to emergency unblinding for severe or life-threatening AEs with potential 
immunologic etiology, non-emergency unblinding to pembrolizumab versus placebo 
administration may occur on an individual subject basis and only after consultation with the 
Sponsor at the time of (1) centrally verified disease progression and subject has discontinued 
all study treatments or, (2) when the subject has discontinued all study treatments and a new 
anti-cancer treatment is going to be started. Non-emergency unblinding, only after 


Product:  MK-3475 
54
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
consultation and approval from the Sponsor, is implemented through interactive response 
technology (IRT) by following the instructions in the IRT site user manual.
Additionally, imaging data will be centrally reviewed by radiologists who are blinded to 
subject treatment assignment, and the allocation schedule will be blinded in the database, 
preventing aggregate analysis.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization
Treatment randomization will occur centrally using an interactive voice response system / 
integrated web response system (IVRS/IWRS). There are 2 treatment arms.  Subjects will be 
assigned randomly in a 1:1 ratio to pembrolizumab + EP or placebo + EP. Prior to 
randomization, the investigator’s choice of platinum agent (cisplatin or carboplatin) will be 
documented in the IVRS/IWRS system.
Stratification
Treatment randomization will be stratified according to the following factors:

Type of platinum therapy (carboplatin or cisplatin) 

Baseline ECOG performance status (0 or 1)

Baseline LDH (≤or >ULN)
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 medications 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 will also be included on the eCRF.


Product:  MK-3475 
55
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Palliative and supportive care is permitted during the course of the trial for underlying 
medical conditions and management of symptoms. Surgery or radiotherapy for tumor control 
is not permitted during the study; however, radiotherapy or procedures for symptom 
management are allowed.
All concomitant medications received within 28 days before the first dose of trial treatment 
and up to 30 days after the last dose of trial treatment should be recorded. Concomitant 
medications administered more than 30 days after the last dose of trial treatment should be 
recorded for SAEs and events of clinical interest (ECIs) as defined in Section 7.2.
Colony-Stimulating Factors
The use of colony-stimulating factors (CSFs) is highly recommended as primary prophylaxis 
to reduce the risk of febrile neutropenia in this patient population, especially as many 
subjects have multiple co-morbidities and advanced disease. The American Society of 
Clinical Oncology guidelines for use of CSFs should be followed for this trial [112].
Antiemetic therapy
Antiemetic therapy should follow the Multinational Association of Supportive Care in 
Cancer guidelines [113]. 
Prohibited/Restricted Concomitant Medications
Subjects are prohibited from receiving the following therapies during Screening, Initial 
Treatment Phase, and Second Course Phase of this trial:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Surgery for tumor control

Radiation therapy
Note: Subjects are allowed to receive palliative radiotherapy for painful bone lesions. 
Targeted external beam irradiation should not be used in the primary lung field where 
assessment for tumor is indicated.
Note: PCI is permitted in subjects achieving CR or PR after Cycle 4.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial (eg, measles, mumps, rubella, varicella/zoster, yellow fever, 
rabies, BCG, and typhoid vaccine); seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza 
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed


Product:  MK-3475 
56
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential

Systemic glucocorticoids for any purpose other than:
o
To modulate symptoms of an AE that is suspected to have an immunologic 
etiology
o
As required during and after PCI (subjects requiring chronic glucocorticoid 
use following PCI should be discontinued from study therapy)
o
As needed for the prevention of emesis (as outlined in Section 5.5.1)
o
For topical use or ocular use
o
Premedication for IV contrast allergies
o
For inhalation in the management of asthma or chronic obstructive pulmonary 
disease
Subjects who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.
Subjects may receive other medications that the investigator deems to be medically 
necessary.
Other medications that are prohibited in this trial are discussed in Section 5.1.3.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Rescue Medications & Supportive Care
No rescue or supportive medications are specified to be used in this trial.
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.1.2.1, [Table 4]. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab.
Note: If after evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. It may be necessary to 
perform conditional procedures such as bronchoscopy, endoscopy, or skin photography as 
part of evaluation of the event.


Product:  MK-3475 
57
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Instructions regarding supportive care needed with the chemotherapeutic agents administered 
in this study can be found in the local product label for each agent. Infusion reactions and 
injection site reactions will be managed by the investigator according to local product 
labeling.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition). 
Chemotherapy can cause fetal harm if administered to pregnant women. Therefore, 
non-pregnant, non-breastfeeding women may be enrolled if they are considered of 
non-reproductive potential.
Female subjects will be considered of non-reproductive potential if they meet one of the 
following criteria:

She is postmenopausal, defined as at least 12 months with no menses without an 
alternative medical cause. In women <45 years of age who are not using hormonal 
contraception or hormonal replacement therapy, a high follicle-stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a post-menopausal 
state. In the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.

She had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or 
bilateral tubal ligation/occlusion at least 6 weeks prior to screening.

She has a congenital or an acquired condition that prevents childbearing.


Product:  MK-3475 
58
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving trial drug and for 120 days after the 
last dose of pembrolizumab and for 180 days after the last dose of chemotherapy by 
complying with one of the following:

Practice abstinence from heterosexual activity.

Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and Ethics Review 
Committees
(ERCs)/Institutional Review Boards (IRBs).
Periodic abstinence 
(eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are 
not acceptable methods of contraception.

Use (or have their partner use) acceptable contraception during heterosexual activity.
Acceptable methods of contraception are‡:

Single method (one of the following is acceptable):
o
Intrauterine device (IUD)
o
Vasectomy of a female subject’s male partner
o
Contraceptive rod implanted into the skin

Combination method (requires use of 2 of the following):
o
Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
o
Cervical cap with spermicide (nulliparous women only)
o
Contraceptive sponge (nulliparous women only)
o
Male condom or female condom (cannot be used together)
o
Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region.
Subjects should be informed that taking the trial medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the trial. In order to participate in 


Product:  MK-3475 
59
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
the trial, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of trial medication initiation (or 14 days prior to the initiation 
of trial medication for oral contraception) throughout the trial period up to 120 days after the 
last dose of pembrolizumab and up to 180 days after last dose of chemotherapeutic agents. 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 trial.
If a female subject inadvertently becomes pregnant while on treatment in this study, the 
subject will immediately be removed from the study. 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 an SAE (eg, death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn). The study investigator 
will make every effort to obtain permission to follow the outcome of the pregnancy and 
report the condition of the fetus or newborn to the Sponsor. If a male subject impregnates his 
female partner, the study personnel at the site must be informed immediately and the 
pregnancy reported to the Sponsor and followed as described above and in Section 7.2.
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk. As many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment.
Subject Withdrawal/Discontinuation Criteria
Discontinuation of Treatment
Discontinuation of trial treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be/are important to 
the study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued trial treatment.  Therefore, all subjects who discontinue trial 
treatment prior to completion of the treatment period will still continue to participate in the 
trial as specified in Section 6.0 and Section 7.1.5.7.
Subjects may discontinue treatment at any time for any reason or be dropped from trial 
treatment at the discretion of the investigator should any untoward effect occur.  In addition, 
a subject may be discontinued from trial treatment by the investigator or the Sponsor if 
treatment is inappropriate, the trial plan is violated, or for administrative and/or other safety 
reasons.  Specific details regarding procedures to be performed at treatment discontinuation
are provided in Section 7.1.4 – Other Procedures.


Product:  MK-3475 
60
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
A subject must be discontinued from trial 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 trial 
treatment.
o
Confirmed radiographic disease progression, as outlined in Section 7.1.5 (exception if 
the Sponsor approves treatment continuation)
Note: Subjects with new asymptomatic brain metastasis may be eligible to continue 
study treatment at the discretion of the investigator after consultation with the 
Sponsor. Section 7.1.2.7.6 provides details regarding eligibility requirements and 
subsequent radiographic assessments.
o
Unacceptable AEs, as described in Section 7.2
o
Any progression or recurrence of any 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
Recurrent Grade 3 diarrhea
o
A confirmed positive serum pregnancy test
o
Noncompliance with trial treatment or procedure requirements
o
Investigator’s decision to withdraw the subject
o
Completion of 35 cycles of trial treatments (approximately 2 years)
Note: The number of treatments is calculated starting with the first dose. Subjects who stop 
trial treatment after receiving 35 doses of pembrolizumab or saline placebo may be eligible 
for the Second Course Phase (retreatment) if they progress after stopping trial treatment,
provided they meet the requirements detailed in Section 7.1.5.5. Only subjects who were 
assigned to the pembrolizumab arm may be retreated in the Second Course Phase for up to an 
additional 17 cycles (approximately 1 year).
For subjects who are discontinued from trial treatment but continue to be monitored in the 
trial, all visits and procedures, as outlined in the trial flowchart, should be completed.
Discontinuation from trial treatment is “permanent.” Once a subject is discontinued, he/she 
shall not be allowed to restart treatment.


Product:  MK-3475 
61
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
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 trial treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.4 
– Other Procedures.
Subject Replacement Strategy
A subject who is discontinued from trial treatment or withdraws from the trial will not be 
replaced.
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit, withdraws 
from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the 
investigator).
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
The trial will be stopped early if the risk/benefit ratio to the trial population as a whole is 
unacceptable.
Statistical criteria for stopping the trial are provided in Section 8.0.
Further recruitment in the trial or at 1 or more particular trial sites may be stopped due to 
insufficient compliance with the protocol, Good Clinical Practice (GCP), or other applicable 
regulatory 
requirements;
procedure-related 
problems;
or 
excessive 
number 
of 
discontinuations for administrative reasons.


Product:  MK-3475 
62
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
6.0 TRIAL FLOW CHART
Initial Treatment Phase
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treatment
Follow-up
Treatment Cycle
Screening 
(Visit 1)
1
1
1
2
2
2
3
3
3
4
4
4
5-35
Discon1
Safety 
Follow-
up2
PFS 
Follow-
up 
Visits3
Survival
Follow-
up4
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
NA
NA
NA
NA
Scheduling Window 
(Days):5
-28 to -1
+ 3
± 1
± 3
± 1
± 3
± 1
± 3
± 1
± 3
At Time of 
Discon
± 3
30 Days 
From 
Last 
Dose
+ 7 
Every 6 
or 9 
Weeks 
(± 7 
days) 
per 
imaging 
schedule
Every 8 
Weeks
± 7 days
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 
Medications6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SCLC Disease Details
X
Obtain allocation number 
using IVRS
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X7
X7
X7


Product:  MK-3475 
63
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treatment
Follow-up
Treatment Cycle
Screening 
(Visit 1)
1
1
1
2
2
2
3
3
3
4
4
4
5-35
Discon1
Safety 
Follow-
up2
PFS 
Follow-
up 
Visits3
Survival
Follow-
up4
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
NA
NA
NA
NA
Scheduling Window 
(Days):5
-28 to -1
+ 3
± 1
± 3
± 1
± 3
± 1
± 3
± 1
± 3
At Time of 
Discon
± 3
30 Days 
From 
Last 
Dose
+ 7 
Every 6 
or 9 
Weeks 
(± 7 
days) 
per 
imaging 
schedule
Every 8 
Weeks
± 7 days
Full Physical Examination
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height and Weight8
X
X
X
X
X
X
X
X
12-Lead ECG
X
ECOG Performance Status
X9
X
X
X
X
X
X
X
X
X
X
X
Prophylactic Cranial 
Irradiation10
X
Laboratory Procedures/Assessments: Analysis Performed by Local Laboratory
Pregnancy Test – Urine or 
Serum β-HCG11
X
PT/INR12
X
CBC with Differential12
X
X
X
X
X
X
X
X
X
X
X
X
Comprehensive Chemistry 
Panel12
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis12,13
X
X
X
Thyroid Function 
Tests12,14
X
X
X
X
X
Hepatitis Serologies12
X


Product:  MK-3475 
64
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treatment
Follow-up
Treatment Cycle
Screening 
(Visit 1)
1
1
1
2
2
2
3
3
3
4
4
4
5-35
Discon1
Safety 
Follow-
up2
PFS 
Follow-
up 
Visits3
Survival
Follow-
up4
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
NA
NA
NA
NA
Scheduling Window 
(Days):5
-28 to -1
+ 3
± 1
± 3
± 1
± 3
± 1
± 3
± 1
± 3
At Time of 
Discon
± 3
30 Days 
From 
Last 
Dose
+ 7 
Every 6 
or 9 
Weeks 
(± 7 
days) 
per 
imaging 
schedule
Every 8 
Weeks
± 7 days
Analysis Performed by Central Laboratory
Blood for Genetic 
Analysis15
X
X
C5D1 
only
X
Blood for RNA Analyses
X
X
C5D1 
only
X
Blood for Plasma 
Biomarker Analyses
X
X
C5D1 
only
X
Blood for Serum 
Biomarker Analyses
X
X
C5D1 
only
X
Tumor Tissue Collection
Archival or Newly 
Obtained Tissue 
Collection
X
Efficacy Measurements
CT/MRI Imaging of 
Chest, Abdomen, and 
Pelvis16
X
X17
X17
X18
X17
MRI of Brain19
X
X17,20
X17,21
X18
X
Bone Scan22
X
Survival Status4
Subsequent Anti-cancer 
Therapies
X
X
X
X


Product:  MK-3475 
65
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treatment
Follow-up
Treatment Cycle
Screening 
(Visit 1)
1
1
1
2
2
2
3
3
3
4
4
4
5-35
Discon1
Safety 
Follow-
up2
PFS 
Follow-
up 
Visits3
Survival
Follow-
up4
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
NA
NA
NA
NA
Scheduling Window 
(Days):5
-28 to -1
+ 3
± 1
± 3
± 1
± 3
± 1
± 3
± 1
± 3
At Time of 
Discon
± 3
30 Days 
From 
Last 
Dose
+ 7 
Every 6 
or 9 
Weeks 
(± 7 
days) 
per 
imaging 
schedule
Every 8 
Weeks
± 7 days
Study Drug Administration23
Pembrolizumab or Saline 
Placebo24
X
X
X
X
X
Carboplatin or Cisplatin25
X
X
X
X
Etoposide26
X
X
X
X
X
X
X
X
Patient Reported Outcomes27
EQ-5D-5L
X
X
X
X
X
X
X
EORTC QLQ-C30
X
X
X
X
X
X
X
EORTC QLQ-LC13
X
X
X
X
X
X
X
1.
The Discontinuation Visit should occur at the time study drug is discontinued for any reason. If the Discontinuation Visit occurs 30 days from the last dose of study 
treatment (ie, at the time of the mandatory Safety Follow up Visit), procedures required at both visits only need to be performed once.
2.
The mandatory Safety Follow-up Visit for all subjects should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of new 
antineoplastic treatment, whichever comes first. Subjects with an AE of Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or until beginning of 
a new antineoplastic therapy, whichever occurs first. If the Discontinuation Visit occurs approximately 30 (± 3) days from last dose trial treatment the same procedures do 
not need to be repeated for the Safety Follow-up Visit.
3.
Subjects who discontinue from the treatment phase prior to disease progression will continue to be followed in PFS follow-up until they experience disease progression or 
start a new antineoplastic therapy. Subjects with an AE of Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or until beginning of a new 
antineoplastic therapy, whichever occurs first.
4.
Once the subject stops the imaging assessments (eg, for PD or starting a new antineoplastic therapy), the subject moves into the Survival Follow-up Phase and should be 
contacted by telephone approximately every 8 weeks to assess for survival status. Post-study antineoplastic treatments and the subject’s response to them will also be 
collected. 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).


Product:  MK-3475 
66
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
5.
In general, the window for Day 1 of each cycle is ±3 days unless otherwise noted. Days 1, 2, and 3 must be consecutive without interruption for Cycles 1 to 4; therefore,
there is no visit window for Days 2 and 3 during the first 4 cycles. If treatment cycles are adjusted, all procedures except imaging will be completed according to the cycle 
number and not weeks on treatment; imaging will not be adjusted for delays in treatment cycles and will be performed per calendar schedule.
6.
All concomitant medications received within 28 days before the first dose of trial treatment through the Safety Follow-up Visit (30 days after the last dose of trial 
treatment) should be recorded. Serious AEs that occur within 90 days after the end of treatment or before initiation of a non-study anticancer treatment must be 
documented and reported to the Sponsor immediately; after the Safety Follow-up Visit, all medications taken during the 14 days prior to an SAE and all medications taken 
to treat the SAE must be recorded as defined in Section 7.2. All non-study antineoplastic treatments should be documented.
7.
See Section 7.2.3.1 for details on reporting timeframe for SAEs.
8.
Height will be measured only at Visit 1. Only if there is a change in weight of >10%, should the dose of chemotherapy administered during Cycles 1 to 4 change.
9.
ECOG for screening should be performed within 10 days prior to the first dose of trial treatment.
10. Subjects in either arm who achieve CR or PR after Cycle 4 may be offered PCI at the discretion of the treating investigator. See Section 7.1.2.6 for details.
11. For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment. A serum test can be considered if 
urine is not appropriate. Monthly pregnancy testing should be conducted as per local regulations where applicable.
12. Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment, with the exception of hepatitis serologies which may be 
performed within 28 days of the first dose of trial treatment. Testing for Hepatitis B and Hepatitis C should be performed as mandated by the local health authority.
Starting with Cycle 1, laboratory safety tests must be conducted within 72 hours prior to the first dose of trial treatment in each cycle, with the exception of the thyroid 
function tests and LDH, which may be conducted up to 10 days prior to first dose of trial treatment. Laboratory results must be known prior to dosing.
13. Urinalysis is to be repeated every 6 cycles beginning at Cycle 6.
14. Thyroid tests are to be repeated every 2 cycles beginning at Cycle 2.
15. 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 Future Biomedical Research consent. If the planned genetic 
analysis is not approved, but Future Biomedical Research is approved and consent is given, this sample will be collected for the purpose of Future Biomedical Research.
16. CT with contrast (preferred) of the chest, abdomen and pelvis is required for all subjects; non-contrast CT of the chest and MRI of the abdomen and pelvis may be used 
for subjects in whom iodinated contrast is contraindicated.
17. Tumor imaging to be performed every 6 weeks (42 [± 7] days) for the first 48 weeks of treatment from the date of randomization, then every 9 weeks (63 [± 7] days) 
subsequently until documented disease progression, or the start of new anti-cancer treatment. Refer to Section 7.1.2.7 for additional details. Imaging is to follow calendar 
days regardless of any delays in dosing. For patients treated beyond progression of disease as verified by BICR, the timing of imaging should continue from the date of 
randomization (every 6 weeks (42 [± 7] days) for the first 48 weeks, then every 9 weeks (63 [± 7] days) or at shorter intervals, as deemed necessary by the investigator).
18. If previous tumor imaging was obtained within 4 weeks prior to the date of discontinuation, then tumor imaging at treatment discontinuation is not mandatory.
19. MRI (strongly preferred) or CT with contrast of the brain at baseline for all subjects. For subjects without brain metastases at diagnosis, brain imaging is required prior to 
initiating PCI and as clinically indicated. For subjects with brain metastases at diagnosis that have undergone treatment, repeat brain imaging is to be performed at all post-
baseline imaging assessments.
20. MRI (strongly preferred) or CT with contrast of the brain for subjects with metastases at diagnosis that have undergone treatment, repeat brain imaging is to be performed 
at all post-baseline imaging assessments. 
21. MRI (strongly preferred) or CT with contrast of the brain for all subjects prior to initiating PCI.
22. Nuclear Medicine bone scan for all subjects, at baseline, to assess for bone lesions. Bone scan is to be repeated in patients with bone lesions at baseline who achieve a 
radiographic CR (to confirm osseous response) and as clinically indicated.
23. Study drug administration should begin on the day of randomization, but no later than 3 days after randomization.
24. Pembrolizumab 200 mg (or saline placebo) will be administered as a 30-minute IV infusion every 3 weeks (Q3W) for up to 35 cycles. During Cycles 1 to 4 
pembrolizumab (or saline placebo) will be administered prior to administration of chemotherapy.
25. Carboplatin dosed to a target AUC of 5 and cisplatin 75 mg/m2 will be administered as an IV infusion over approximately 60 minutes Q3W and over 30 to 180 minutes 
Q3W, respectively, on Day 1. Dose should be recalculated if there is a >10% weight change.


Product:  MK-3475 
67
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
26. Etoposide 100 mg/m2 will be administered as an IV infusion over 30 to 60 minutes (up to 120 minutes to accommodate local standards of care) Q3W on Days 1, 2, and 3.
Days 1, 2, and 3 must be consecutive days without interruption. Dose should be recalculated if there is a >10% weight change.
27. PROs are completed every cycle for Cycles 1 to 9 while the subject is receiving study treatment, then every other cycle up to Cycle 17 (ie, Cycles 11, 13, 15, and 17).
PROs will also be obtained at the Treatment Discontinuation visit and 30-day Safety Follow-up visit. If the Treatment Discontinuation visit occurs 30 days from the last 
dose of study treatment, at the time of the mandatory Safety Follow-up visit, PROs do not need to be repeated. PROs are to be administered by trained site personnel and 
completed electronically by subjects prior to all other study procedures and receiving results of any tests (including disease status). The PROs should be administered in 
the following order: EQ-5D-5L, EORTC QLQ-C30, EORTC QLQ-LC13.


Product:  MK-3475 
68
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Second Course Treatment Phase
Second course retreatment subjects may receive up to 17 cycles (approximately 1 year) of pembrolizumab therapy. For subjects to be 
eligible for the Second Course Treatment Phase, it is necessary to fulfill conditions outlined in Section 7.1.5.5 and verify progression 
of disease by BICR.
Treatment Phase
End of Treatment Phase
Follow-up Phase
Treatment Cycle / Scheduled 
Time
11
2-17
Discontinuation Visit2
Safety Follow up 
Visit3
PFS Follow-up4
Survival Follow-up 5
Day in cycle
1
NA
NA
NA
NA
Scheduling Window (Days):6
± 3
± 3
At Study Drug 
Discontinuation
(±3)
30 Days From 
Last Dose 
(+7)
Every 6 or 9weeks 
per imaging schedule
(±7)
Every 8 Weeks ± 7
Administrative Procedures
Eligibility Criteria
X
Prior and Concomitant 
Medications
X
X
X
X
X7
X7
Clinical Procedures / Assessments
Review Adverse Events
X
X
X
X8
X8
X8
Full Physical Examination
X
Directed Physical Examination
X
X
X
Vital Signs and Weight
X
X
X
X
ECOG Performance Status
X
X
X
X
Laboratory Procedures / Assessments: analysis performed by local laboratory
CBC with Differential9
X
X
X
X
PT/INR9
X
Comprehensive Chemistry Panel9
X
X
X
X
Urinalysis9,10
X
X
X
X
Thyroid Function Tests9,11
X
X
X
X
Pregnancy Test – Serum or 
Urine12
X


Product:  MK-3475 
69
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Treatment Phase
End of Treatment Phase
Follow-up Phase
Treatment Cycle / Scheduled 
Time
11
2-17
Discontinuation Visit2
Safety Follow up 
Visit3
PFS Follow-up4
Survival Follow-up 5
Day in cycle
1
NA
NA
NA
NA
Scheduling Window (Days):6
± 3
± 3
At Study Drug 
Discontinuation
(±3)
30 Days From 
Last Dose 
(+7)
Every 6 or 9weeks 
per imaging schedule
(±7)
Every 8 Weeks ± 7
Efficacy Measurements
CT/MRI Imaging of Chest, 
Abdomen, and Pelvis13,14
X
X
X
X
X
MRI of Brain14,15
X
X
X
X
X
Bone Scan14,16
X
Subsequent Antineoplastic 
Therapy Status
X
X
X
X
Survival Status5
Study Drug Administration
Pembrolizumab17
X
X
1.
Procedures and assessments completed at the time of withdrawal from the main study may be used, as appropriate, for the start of the Second Course Phase of the study.
Otherwise, assessments and procedures are to be performed on Day 1 and prior to the first dose of trial treatment for each cycle, unless specified.
2.
The Discontinuation Visit should occur at the time study drug is discontinued for any reason. If the Discontinuation Visit occurs 30 days from the last dose of study 
treatment (ie, at the time of the mandatory Safety Follow-up Visit), procedures required at both visits only need to be performed once.
3.
The mandatory Safety Follow-up Visit for all subjects should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of new 
antineoplastic treatment, whichever comes first. Subjects with an AE of Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or until beginning of a 
new antineoplastic therapy, whichever occurs first. If the Discontinuation Visit occurs approximately 30 (± 3) days from last dose trial treatment the same procedures do not 
need to be repeated for the Safety Follow-up Visit.
4.
Subjects who discontinue from the treatment phase prior to disease progression will continue to be followed in PFS follow-up until they experience disease progression or 
start a new antineoplastic therapy. Subjects with an AE of Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or until beginning of a new 
antineoplastic therapy, whichever occurs first.
5.
Once the subject stops the imaging assessments for this protocol (eg, for PD or starting a new antineoplastic therapy), the subject moves into the Survival Follow-up and 
should be contacted by telephone every 8 weeks to assess for survival status. Post-study treatments and the subject’s response to them will also be collected. 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).
6.
In general, the window for each visit is ±3 days unless otherwise noted. If treatment cycles are adjusted all procedures except imaging will be completed according to the 
Cycle number and not weeks on treatment; imaging will not be adjusted for delays in treatment cycles and will be performed per calendar schedule. The visit windows for 
follow-up are indicated in days.


Product:  MK-3475 
70
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
7.
After the Safety Follow-up Visit, record all medications taken during the 14 days prior to an SAE and all medications taken to treat an SAE as defined in Section 7.2. All 
non-study antineoplastic treatments should be documented.
8.
See Section 7.2.3.1 for details on reporting timeframe for SAEs.
9.
Laboratory tests for determining eligibility for retreatment are to be performed within 10 days prior to the first dose of pembrolizumab. Starting with Cycle 1 Day 1, 
laboratory safety tests must be conducted within 72 hours prior to first dose of trial treatment in each cycle, with the exception of the thyroid function tests and LDH which 
may be conducted up to 10 days prior to first dose of trial treatment. Laboratory results, with the exception of thyroid function tests and LDH, must be known prior to 
dosing.
10. Urinalysis is to be performed every 6 cycles.
11. Thyroid tests are to be repeated every 2 cycles beginning at Cycle 2.
12. For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment. A serum test can be considered if urine
is not appropriate. Monthly pregnancy testing should be conducted as per local regulations where applicable.
13. CT with contrast (preferred) of the chest, abdomen and pelvis is required for all subjects; non-contrast CT of the chest and MRI of the abdomen and pelvis may be used for 
subjects in whom iodinated contrast is contraindicated.
14. Tumor imaging to be performed within 28 days prior to restarting treatment with pembrolizumab. Tumor response assessment is required every 6 weeks (42 [± 7] days) for 
the first 26 weeks of the Second Course Phase, then every 9 weeks (63 [± 7] days) until the subject starts a non-study cancer therapy. Refer to site imaging manual for 
additional details. Additional imaging at Discontinuation Visit and Safety Follow-up Visit is not required provided that previous imaging assessments have been performed 
per schedule. Additional imaging after study drug discontinuation is not required for subjects who start a non-study cancer therapy. Refer to Section 7.1.2.7 for additional 
details.
15. MRI (strongly preferred) or CT with contrast of the brain at baseline for all subjects. For subjects without brain metastases at diagnosis, brain imaging is required as 
clinically indicated. For subjects with brain metastases at diagnosis that have undergone treatment, repeat brain imaging is to be performed at all post-baseline imaging 
assessments.
16. Nuclear medicine bone scan for all subjects, at baseline, to assess for bone lesions. Bone scan is to be repeated in subjects with bone lesions at baseline who achieve a 
radiographic CR (to confirm osseous response) and as clinically indicated.
17. Pembrolizumab can be administered for up to 17 cycles.


Product:  MK-3475 
71
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
7.0
TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  


Product:  MK-3475 
72
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements.
7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written 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 written informed consent. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically significant. Details regarding the 
disease for which the subject has enrolled in this trial will be recorded separately and not 
listed as medical history.
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial treatment. Any treatment provided for the disease for 
which the subject has enrolled in this trial will be recorded separately and not listed as a prior 
medication.


Product:  MK-3475 
73
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial through the Safety Follow-up visit. In addition, new medications started 
during the Second Course Phase through the respective Safety Follow-up visit should be 
recorded. All medications related to reportable SAEs and ECIs should be recorded as defined 
in Section 7.2.
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.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the Screening Visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after randomization.  Once a treatment/randomization number is assigned to a 
subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
pembrolizumab doses for non-drug-related or administrative reasons require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
Administration of trial medication(s) will be witnessed by the investigator and/or trial staff.
The total volume of pembrolizumab infused will be compared to the total volume prepared to 
determine compliance with each dose administered. Start and stop times of drug 
administration should be recorded in the source documents.
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 (Section 6.0) and more frequently if 


Product:  MK-3475 
74
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
clinically indicated. Adverse experiences will be graded and recorded throughout the study 
and during the follow-up period according to NCI CTCAE 4.0 (see Section 12.4). Toxicities 
will be characterized in terms including seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
Physical Examination
7.1.2.2.1 Full Physical Examination
The investigator or qualified designee will perform a full physical examination during the 
screening period before the Initial Treatment Phase, and on Cycle 1, Day 1 of the Second 
Course Treatment Phase. Clinically significant abnormal findings should be recorded as 
medical history. The time points for full physical examination are described in the Trial Flow 
Chart (Section 6). After the first dose of trial treatment new clinically significant abnormal 
findings should be recorded as AEs.
7.1.2.2.2 Directed Physical Examination
For cycles/visits that do not require a full physical examination per the Trial Flow Chart
(Section 6), the investigator or qualified designee will perform a directed physical 
examination as clinically indicated prior to trial treatment administration and at other times 
according to the Trial Flow Chart (Section 6). New clinically significant abnormal findings 
should be recorded as AEs.
Vital Signs
Vital signs include temperature, pulse, respiratory rate, weight, and blood pressure. The 
investigator or qualified designee will take vital signs at screening, prior to the administration 
of each dose of trial treatment, during the follow-up phase, and at other visits as specified in 
the Trial Flow Chart (Section 6.0). Height will be measured at Visit 1 only.
12-Lead Electrocardiogram
A standard 12-lead electrocardiogram will be performed using local standard procedures 
once at screening. Clinically significant abnormal findings should be recorded as medical 
history.
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG status (see Section 12.3) at 
screening, prior to each cycle of trial treatment and during the Follow-up period as specified 
in the Trial Flow Chart (Section 6).


Product:  MK-3475 
75
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Prophylactic Cranial Irradiation
Subjects in either arm who achieve CR or PR after Cycle 4 may be offered PCI at the 
discretion of the treating investigator. Imaging of the brain must occur after the completion 
of 4 cycles of trial treatment, just prior to PCI.
Subjects selected to receive PCI may receive up to 25 Gy in 10 fractions (or the biologic
equivalent), as tolerated by the subject. If given, PCI must begin within 6 weeks (preferably 
within 2 to 4 weeks) after the last dose of study medication in Cycle 4. Study medication may 
continue during PCI; however, if it is necessary to suspend study treatment, dosing must be 
restarted no later than 2 weeks after completion of PCI. Steroids can be administered, as 
required, during and after PCI.
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to BICR can be found in the Site Imaging 
Manual. The same imaging technique regarding modality and use of contrast should be used
consistently throughout the trial. Imaging schedule should follow calendar days and should 
not be adjusted for cycle delays.
Screening (baseline) imaging:

CT with IV and oral contrast (preferred) of the chest, abdomen and pelvis for all 
subjects, or non-contrast CT of the chest and magnetic resonance imaging (MRI) of 
the abdomen and pelvis with IV gadolinium for subjects in whom iodinated contrast 
is contraindicated

MRI (strongly preferred) or CT with contrast (when MRI is medically 
contraindicated) of the brain for all subjects

Nuclear medicine bone scan for bone lesions
Post baseline imaging:

CT or MRI of the chest, abdomen and pelvis, consistent with the method used at 
baseline

Imaging of the brain, consistent with the method used at baseline:
o
At all post-baseline visits for subjects with baseline brain metastases 
o
For subjects who will undergo PCI, should be performed prior to PCI
o
If clinically indicated


Product:  MK-3475 
76
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential

Nuclear medicine bone scan for bone lesions:
o
If clinically indicated
o
In subjects with bone lesions at baseline who achieve a radiographic CR to 
confirm osseous response
Local site investigator/radiology assessment based on RECIST 1.1 (modified to follow a 
maximum of 10 target lesions and a maximum of 5 target lesions per organ) will be used to 
determine subject eligibility. All scheduled images for all study subjects from the sites will 
be submitted to the BICR. In addition, all other imaging (including all modalities) obtained at 
an unscheduled time point to determine disease progression, as well as supplemental imaging 
obtained for other reasons that captures radiologic progression, should be submitted to the 
BICR.
The BICR will review images for the verification of progression following the first
radiologic evidence of PD based on local investigator assessment. Expedited verification of 
radiologic PD by the BICR will be communicated to the study site and Sponsor (See 
Section 7.1.2.7.2). Details can be found in the Site Imaging Manual.
7.1.2.7.1 Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 28 days prior to the date of 
randomization. The site investigator/local radiology reviewer must review screening images 
to confirm the subject has measurable disease per RECIST 1.1 (modified to follow a 
maximum of 10 target lesions and a maximum of 5 target lesions per organ). The screening 
images must be submitted to the BICR for retrospective review.
Tumor imaging via CT performed as part of routine clinical management (prior to informed 
consent form signature) is acceptable for use as screening tumor imaging if they are of 
diagnostic quality, are performed within 28 days prior to the date of randomization, and can 
be assessed by BICR.
7.1.2.7.2 Tumor Imaging During the Trial
The first on-trial imaging assessment should be performed at 6 weeks (42 ± 7 days) from the 
date of randomization. Subsequent tumor imaging should be performed every 6 weeks 
(42 ± 7 days) for the first 48 weeks of treatment, then every 9 weeks (63 [± 7] days), or more 
frequently if clinically indicated. Timing of tumor imaging should follow calendar days and 
should not be adjusted for delays in cycle starts. (Note: the date imaging is performed is the 
date of the imaging, not the date the images are reviewed.) Imaging should continue to be 
performed until disease progression verified by BICR (unless site PI elects to continue 
treatment and follow irRECIST), the start of a non-study anti-cancer treatment, withdrawal of 
consent, or death, whichever occurs first. Supplemental imaging must be submitted to the 
central imaging vendor if it shows evidence of progression or if it is used to support a 
determination of PR or CR.


Product:  MK-3475 
77
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Per RECIST 1.1 (modified to follow a maximum of 10 target lesions and a maximum of 
5 target lesions per organ), PR and CR should be confirmed by a repeat tumor imaging 
assessment not less than 4 weeks from the date the response was first documented. The tumor 
imaging for confirmation of response may be performed at the next scheduled tumor imaging
(ie, 6 or 9 weeks later), whichever is clinically indicated. Subjects will then return to regular 
scheduled imaging every 6 or 9 weeks, starting with the next scheduled imaging time point.
Subjects who obtain confirmatory imaging do not need to undergo the next scheduled tumor 
imaging if it is <4 weeks later; tumor imaging may resume at the subsequent scheduled 
imaging time point.
Per irRECIST (see Section 7.1.2.7.6), disease progression should be confirmed by the site at 
least 4 weeks after BICR verification of site-assessed first radiologic evidence of PD in 
clinically stable subjects. Subjects who have unconfirmed disease progression may continue 
on treatment at the discretion of the site investigator until progression is confirmed (by the 
site) provided they have met the conditions detailed in Section 7.1.2.7.6. Subjects who have
confirmatory imaging 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 trial treatment, except in some cases as detailed in Section 7.1.2.7.6.
7.1.2.7.3 End of Treatment and Follow-up of Tumor Imaging
For subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation. If previous tumor imaging was obtained within 4 weeks prior to 
the date of discontinuation, then tumor imaging at treatment discontinuation is not required.
For 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 disease status by tumor imaging using the same 
imaging schedule and modality used while on treatment (every 6 weeks [42 7 days] for the 
first 48 weeks after randomization, then every 9 weeks [63 7 days]) to monitor disease 
status until the start of non-study anticancer treatment, disease progression, death, or the end 
of the trial, whichever occurs first.
7.1.2.7.4 Second Course (Retreatment) Phase Tumor Imaging
Tumor imaging must be performed within 28 days prior to restarting treatment with 
pembrolizumab in the Second Course Phase. Disease progression must be verified by BICR 
using RECIST 1.1 (modified to follow a maximum of 10 target lesions and a maximum of 
5 target lesions per organ).
The first on study imaging assessment of the Second Course Phase should be performed at 
6 weeks (42 [± 7] days) after the first dose of trial treatment in that phase. Subsequent tumor 
imaging should be performed every 6 weeks (42 [± 7] days) for the first 26 weeks of that 
phase, then every 9 weeks (63 [± 7] days), or more frequently if clinically indicated.


Product:  MK-3475 
78
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Per irRECIST (Section 7.1.2.7.6), if tumor imaging shows initial PD, tumor assessment 
should be repeated ≥4 weeks later in order to confirm PD. Investigators and subjects have the 
option to continue treatment while awaiting radiologic confirmation of progression. Subjects 
who have confirmatory imaging are not required to complete the next scheduled tumor 
imaging if it is <4 weeks later and may wait until the following scheduled imaging time point 
if clinically stable.
Imaging should continue to be performed until disease progression, the start of a non-study
anticancer treatment, withdrawal of consent, death, or notification by the Sponsor, whichever 
occurs first. Disease progression may be confirmed ≥4 weeks after the first tumor imaging 
indicating PD in clinically stable subjects.
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation. If previous tumor imaging was obtained within 4 weeks prior to 
the date of discontinuation, then tumor imaging at treatment discontinuation is not required.
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 disease status by radiologic imaging every 
6 weeks (42 [± 7] days) for the first 26 weeks after the first dose of trial treatment in that 
phase, then every 9 weeks (63 [± 7] days) until either the start of a non-study anticancer 
treatment, disease progression, death, or the end of the trial, whichever occurs first.
7.1.2.7.5 RECIST 1.1 Assessment of Disease
RECIST 1.1 (see Section 12.5) will be applied by the BICR as the primary measure for 
assessment of tumor response, date of disease progression, and as a basis for all protocol 
guidelines related to disease status (eg, discontinuation of study therapy). Although RECIST 
1.1 references a maximum of 5 target lesions in total and 2 per organ, Merck allows a 
maximum of 10 target lesions in total and 5 per organ, if clinically relevant, to enable a 
broader sampling of tumor burden. Initial tumor imaging showing site-assessed PD should be 
submitted to the BICR immediately. The site will be notified of the result of BICR tumor 
imaging assessment using RECIST 1.1, ie, verification of progression. Figure 2 illustrates the 
imaging flow involving verification of PD for clinically stable subjects.
7.1.2.7.6 irRECIST Assessment of Disease
To account for the unique tumor response seen with immunotherapeutic drugs, irRECIST is 
RECIST 1.1 adapted as described below. The site investigator/local radiology review will use 
irRECIST to assess tumor response and progression, and to make treatment decisions. This 
data will be collected in the clinical database. Treatment efficacy based on irRECIST will be 
evaluated retrospectively as an exploratory endpoint.
When feasible, subjects should not be discontinued until progression is confirmed by the 
local site investigator/radiology assessment. This allowance to continue treatment despite 
initial radiologic PD takes into account the observation that some subjects can have a 


Product:  MK-3475 
79
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
transient tumor flare during the first few months after the start of immunotherapy, and then 
experience subsequent disease response. Subjects that are deemed clinically unstable are not 
required to have repeat tumor imaging for confirmation of PD. Tumor flare includes any of 
the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing non-target lesion(s)

Development of new lesion(s)
In subjects who have shown initial evidence of radiologic disease progression as assessed by 
BICR per RECIST 1.1 (modified to follow a maximum of 10 target lesions and a maximum 
of 5 target lesions per organ), it is at the discretion of the principal investigator whether to 
continue a subject on study treatment until repeat imaging is obtained (using irRECIST for 
subject management, see Table 8 and Figure 2). This clinical judgment decision by the site 
investigator should be based on the subject’s overall clinical condition, including 
performance status, clinical symptoms, and laboratory data. Subjects may receive 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:

Neurologically stable without the need for steroids (for subjects with brain 
metastasis);

Absence of symptoms and signs indicating clinically significant progression of 
disease, including worsening of laboratory values;

No decline in ECOG performance status;

Absence of rapid progression of disease; and

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention (including immediate need for 
surgery or WBRT in the case of new brain metastases).
Any subject deemed clinically unstable should be discontinued from trial treatment at BICR 
verification of site-assessed first radiologic evidence of PD and is not required to have repeat 
imaging for PD confirmation.
In determining whether or not the tumor burden has increased or decreased per irRECIST, 
the local site investigator should consider all target and non-target lesions as well as any 
incremental new lesion(s).


Product:  MK-3475 
80
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Disease progression will be considered to be “not confirmed” at repeat imaging if ALL of the 
following occur (as assessed by irRECIST):

Target lesion sum of diameters is <20% or <5 mm absolute increase compared to 
nadir

Non-target disease resulting in initial PD is stable or qualitatively improved

New lesion resulting in initial PD is stable or qualitatively improved

No incremental new lesion(s) since last evaluation

No incremental new non-target lesion progression since last evaluation
If repeat imaging does not confirm PD per irRECIST as assessed by the local site 
investigator and the subject continues to be clinically stable, treatment may continue and 
follow the regular imaging schedule.
Disease progression will be considered to be “confirmed” at repeat imaging if ANY of the 
following occur (as assessed by irRECIST):

Target lesion sum of diameters reaches or remains ≥20% and ≥5 mm absolute 
increase compared to nadir

Non-target disease shows unequivocal progression, or the non-target disease resulting 
in initial PD is qualitatively worse

New lesions appear for the first time, or the new lesions resulting in initial PD are 
increased in size or number
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 (ie, 2 scans at least 4 weeks apart 
demonstrating PD) per irRECIST, but the subject is achieving a clinically meaningful 
benefit, and there is no further increase in the tumor burden at the confirmatory tumor 
imaging, an exception to continue treatment may be considered following consultation with 
the Sponsor (see Section 7.1.5.6 for details). In this case, if treatment is continued, tumor 
imaging should continue to be performed following the intervals as outlined in the Trial
Flowchart (Section 6.0) and be submitted to the BICR.


Product:  MK-3475 
81
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
If a subject develops a new brain metastasis during treatment, the following steps will be 
taken:

Subjects with symptomatic brain metastases will be removed from study treatment.

Subjects with asymptomatic brain metastases (no need for steroids, no symptoms and 
signs indicating clinically significant progression of disease, no decline in ECOG 
performance status) can continue on study treatment under the following conditions:
o
If no immediate WBRT, both systemic lesions and brain lesions can be followed 
by irRECIST.
o
If immediate WBRT is chosen, the brain lesions will be non-evaluable for 
irRECIST.
o
Brain MRI will be required at each subsequent image assessment.
Additional details about irRECIST are referenced in the Merck Imaging Tip Sheet for 
RECIST 1.1 and irRECIST.


Product:  MK-3475 
82
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Table 8
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1
(modified to follow a 
maximum of 10 target 
lesions and a 
maximum of 5 target 
lesions per organ),
which has been 
verified by the BICR
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 (Imaging 
should be reviewed by 
radiology as soon as 
possible.)
Discontinue treatment
Repeat tumor 
imaging confirms PD
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 imaging should 
occur according to the 
regular imaging schedule
outlined in the protocol
Abbreviations:  BICR=blinded independent central review; CR=complete response; irRECIST=immune-related Response Evaluation Criteria in Solid Tumors; 
N/A=not applicable; PD=progressive disease; PR=partial response; SD=stable disease


Product:  MK-3475 
83
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Abbreviations:  BICR=blinded independent central review, irRECIST=immune-related Response Evaluation 
Criteria in Solid Tumors, PD=progressive disease, PI=principal investigator, RECIST=Response Evaluation 
Criteria in Solid Tumors
*If subject is clinically stable, may continue study treatment at the local site investigator’s discretion while 
awaiting verification of PD per RECIST 1.1 by BICR and/or confirmatory tumor imaging by site by irRECIST.
Figure 2
Imaging and Treatment for Clinically Stable Subjects After First Radiologic 
Evidence of PD Assessed by the Site
Tumor Tissue Collection: PD-L1 Status
Participation in this trial will be dependent upon supplying tumor tissue for PD-L1 testing 
from locations not radiated prior to biopsy. Subjects whose submitted tissue is not evaluable 
for PD-L1 status can still be eligible to participate in the study.


Product:  MK-3475 
84
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
All subjects should submit either a newly obtained core or excisional biopsy or archival 
tissue (fine needle aspiration
[FNA], endobronchial ultrasound [EBUS],
guided 
transbronchial needle aspiration [TBNA], cell pellets, cytology, and blood smears are not 
adequate for both archival and new tissue samples) to a central laboratory for 
characterization of PD-L1 status prior to treatment allocation.
Note: Submission of formalin-fixed paraffin embedded tumor tissue sample blocks are 
preferred; if submitting unstained slides, the slides should be freshly cut and submitted to the 
testing laboratory within 14 days from the site slide section date, otherwise a new specimen 
will be requested.
If the sample is determined to be non-evaluable prior to testing by the central laboratory, a 
new sample should be submitted if available. This may include additional cut slides that are 
outside of the 14-day window noted above.
Individual subject PD-L1 status will not be disclosed to investigative sites and study subjects.
Analyses by PD-L1 biomarker status will be limited and documented.
If the subject signs the Future Biomedical Research consent, any leftover samples that would 
be ordinarily discarded at the end of the main study will be retained for Future Biomedical 
Research.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Laboratory
Manual. Refer to the Trial Flow Chart (Section 6.0) for the timing of laboratory assessments.
Clinical Laboratory Evaluations
Clinical laboratory tests are specified in Table 9.


Product:  MK-3475 
85
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Table 9
Clinical Laboratory Tests
Hematology
Hematocrit, hemoglobin, platelet count, WBC (total and 
differential), RBC, absolute lymphocyte count, absolute 
neutrophil count
Chemistry
Albumin, alkaline phosphatase, alanine aminotransferase, 
aspartate aminotransferase, bicarbonate (only required if done as 
part of standard of care by local laboratory), calcium, chloride, 
creatinine, glucose, phosphorus, potassium, sodium, total 
bilirubin, direct bilirubin (if total bilirubin >ULN), total protein, 
blood urea nitrogen or urea (one or the other should be collected 
per institutional standard; both of these laboratory tests are not 
required), LDHa
Thyroid Function Testsa
Total T3 or free T3 (T3 is preferred; if not available, free T3 may 
be tested), FT4, and TSH
Coagulation Parameters
PT/INR
Hepatitis Serologiesb
HbsAg, HCV RNA (qualitative), Anti-HCV
Pregnancy test 
If the urine test is not negative, then a serum test must be 
performed.
Urinalysis
Blood, glucose, protein, specific gravity
Microscopic exam should be performed if abnormal results are 
noted
Abbreviations:  FT4=free thyroxine; HbsAg=hepatitis B surface antigen; HCV=hepatitis C virus; LDH=Lactate 
dehydrogenase; PT=prothrombin time; RBC=red blood cells; T3=triiodothyronine; TSH=thyroid-stimulating 
hormone; ULN=upper limit of normal; WBC=white blood cells.
a If the local laboratory is unable to perform these tests, the site should submit the sample to the central 
laboratory for testing. Details are provided in the Laboratory Manual.
b Hepatitis C antibody testing is allowed in countries where HCV RNA is not part of standard of care.  Testing 
for Hepatitis B and Hepatitis C should be performed as mandated by the local health authority.  
For both the Initial Treatment Phase and the Second Course Phase:

Screening laboratory tests should be performed within 10 days prior to the first dose 
of trial treatment, with the exception of the hepatitis serologies which may be 
performed within 28 days of the first dose of trial treatment in the Initial Treatment 
Phase only. Testing for hepatitis B and hepatitis C should be performed as mandated 
by the local health authority.

Clinical laboratory tests must be conducted within 72 hours prior to first dose of trial 
treatment in each cycle, with the exception of laboratory tests performed by the 
central lab, which may be conducted up to 10 days prior to first dose of trial 


Product:  MK-3475 
86
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
treatment. Laboratory test results must be reviewed by the investigator or qualified 
designee and found to be acceptable prior to administration of first trial treatment.

For laboratory tests performed by the central laboratory, any results not available 
prior to dosing must be reviewed by the investigator or qualified designee within 
48 hours of receipt and found to be acceptable prior to subsequent administration of 
trial treatment.

During the Initial Treatment Phase, laboratory tests will also be performed at the
Day 8 Visit of each cycle. Results must be reviewed by the investigator or qualified 
designee within 48 hours of receipt.

Unresolved abnormal laboratory test results 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 test results 
are within the normal range.
Pharmacokinetic/Pharmacodynamic Evaluations
Pembrolizumab
The accumulation of robust PK and anti-drug antibodies (ADA) data has allowed for the 
adequate characterization of the clinical pharmacology of pembrolizumab across indications. 
Therefore, upon approval of Amendment 07, each site is to stop the collection of PK and 
ADA samples for all subjects. Blood samples for PK and ADA collected prior to 
Amendment 07 may be stored. Analysis will be performed only if required.
Exploratory drug-drug interaction analysis
The accumulation of robust PK data has allowed for adequate characterization of the 
potential for drug-drug interactions between pembrolizumab and chemotherapy. Therefore, 
upon approval of protocol amendment 06, each site is to stop the collection of PK samples 
for etoposide only.
Blood samples for etoposide PK collected prior to protocol 
amendment 06 may be stored. Analysis will be performed only if required.
Patient-reported Outcomes
For PROs, the EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-LC13 questionnaires will 
be administered by trained study site personnel and completed electronically by the subjects
themselves.
It is strongly recommended that electronic PROs are administered prior to drug 
administration, AE evaluation, and disease status notification. The electronic PROs are 
completed in the following order: EQ-5D-5L first, then EORTC QLQ-C30, and lastly, the 
EORTC QLQ-LC13 at the time points specified in the Trial Flow Charts and briefly 
summarized below.


Product:  MK-3475 
87
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
The EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-LC13 are completed every cycle for 
Cycles 1 to 9, then every other cycle up to Cycle 17 (ie, Cycles 11, 13, 15, and 17) while the 
subject is receiving study treatment. Patient-reported outcomes will also be obtained at the
treatment discontinuation visit and 30-day Safety Follow-up visit.
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Laboratory Manual.
Future Biomedical Research Samples
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research

Leftover RNA

Leftover plasma and serum from biomarker analyses

Leftover tumor
Other Procedures
Withdrawal/Discontinuation
Subjects who discontinue treatment prior to completion of the treatment regimen should be 
encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial 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.
Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research.  Subjects may 
withdraw consent at any time by contacting the principal investigator for the main trial.  If 
medical records for the main trial are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com).  Subsequently, 
the subject's consent for Future Biomedical Research will be withdrawn.  A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the subject of completion of withdrawal.  Any analyses in progress at 
the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research trial data and results.  
No new analyses would be generated after the request is received.


Product:  MK-3475 
88
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
Subject Blinding/Unblinding
When the investigator or delegate needs to identify the drug used by a subject and the dosage 
administered in case of emergency e.g., the occurrence of serious adverse events, he/she will 
contact the emergency unblinding call center by telephone and make a request for emergency 
unblinding.  As requested by the investigator or delegate the emergency unblinding call 
center will provide the information to him/her promptly and report unblinding to the Sponsor.  
Prior to contacting the emergency unblinding call center to request unblinding of a subject’s 
treatment assignment, the investigator or delegate must enter the toxicity grade of the adverse 
events observed, the relation to study drug, the reason thereof, etc., in the medical chart etc.
Subjects whose treatment assignment has been unblinded by the investigator/delegate and/or 
non-study treating physician must be discontinued from study drug, but should continue to be 
monitored in the trial.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. Once an emergency unblinding or a 
non-emergency unblinding has taken place, the principal investigator, site personnel, and 
Sponsor personnel may be unblinded so that the appropriate follow-up medical care can be 
provided to the subject.
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:
None


Product:  MK-3475 
89
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
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
Within 28 days prior to randomization, potential subjects will be evaluated to determine that 
they fulfill the entry requirements as set forth in Section 5.1. Visit requirements are outlined 
in the Trial Flow Chart (Section 6.0). Screening procedures may be repeated.
Written consent must be obtained prior to performing any protocol-specific procedure.
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose of trial 
treatment except for the following:

Laboratory tests are to be performed within 10 days prior to the first dose of trial 
treatment with the exception of hepatitis serologies testing, which may be done up to 
28 days prior to the first dose of trial treatment. Testing for hepatitis B and hepatitis C 
should be performed as mandated by the local health authority.

For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to first dose of trial treatment. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test performed by the local study site 
laboratory will be required.

Tumor imaging must be performed within 28 days prior to randomization.
Subjects may be rescreened once after initially failing to meet the inclusion/exclusion 
criteria. Results from assessments performed during the initial screening period are 
acceptable in lieu of repeating a screening test if performed within the specified time frame
and the results meet the inclusion/exclusion criteria.
Treatment Period Visits
Visit requirements are outlined in Section 6.0. Specific procedure-related details are provided 
above in Section 7.1.
Post-treatment Visits
7.1.5.3.1 Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new antineoplastic 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 further followed until the resolution of the 


Product:  MK-3475 
90
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
AE to Grade ≤1 or until beginning of a new antineoplastic therapy, whichever occurs first.
Serious AEs that occur within 90 days of the end of treatment or before initiation of a non-
study anticancer treatment should also be followed and recorded; additionally, all 
medications taken during the 14 days prior to an SAE and all medications taken to treat the 
SAE must be recorded.
Subjects who are eligible for retreatment with pembrolizumab may have up to 2 Safety 
Follow-up visits, the first after the Initial Treatment Phase and the second after the Second 
Course Phase.
7.1.5.3.2 Progression-free Survival Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the PFS Follow-up Phase and should be assessed as follows to monitor disease 
status by imaging depending on the trial phase:

Initial Treatment Phase: tumor imaging every 6 weeks (42 [± 7] days) for the first 
48 weeks after randomization, then every 9 weeks (63 [± 7] days) per the imaging 
schedule.

Second Course Phase: tumor imaging every 6 weeks (42 [± 7] days) for the first 
26 weeks from the date of the first dose of trial medication in this phase, then every 
9 weeks (63 [± 7] days) per the imaging schedule.
The Sponsor may request survival status to be assessed at additional time points during the 
course of the study (not to exceed approximately every 8 weeks). Every effort should be 
made to collect information regarding disease status until the start of new anti-cancer 
therapy, disease progression, death, end of trial. Information regarding post-trial anticancer 
treatment will be collected if new treatment is initiated.
Follow-up visit requirements are outlined in the Trial Flow Chart (Section 6.0).
7.1.5.3.3 Survival Follow-up
Once a subject experiences PD or starts a non-study anti-cancer therapy, the subject will 
move into the Survival Follow-up Phase and should be contacted by telephone approximately 
every 8 weeks to assess for survival status until death, withdrawal of consent, or the end of 
the study, whichever occurs first. Post-study treatments and the subject’s response to them 
will also be collected.
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to. But not limited to, an external 
DMC review, interim and/or final analyses. Upon Sponsor notification, all participants who 
do not/will not have a scheduled study visit or study contact during the Sponsor defined time 


Product:  MK-3475 
91
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
period will be contacted for their survival status (excluding participants that have previously 
recorded a death event in the collection tool).
Second Course Phase
Subjects who have stable disease (SD), PR, or CR after receiving 35 pembrolizumab 
treatments may be eligible for retreatment with up to an additional 17 cycles (approximately 
1 year) of pembrolizumab treatment. This retreatment is termed the Second Course Phase of 
this trial and will only be available upon consultation with the Sponsor if the trial remains 
open and if the subject meets the following conditions:

Had SD, PR, or CR and stopped treatment after completion of 35 administrations 
(approximately 2 years) of pembrolizumab
in the Initial Treatment Phase.
(Consultation with the Sponsor will be needed in those cases where pembrolizumab 
was stopped for reasons other than disease progression or intolerability before 
35 cycles.)
AND

Experienced a BICR-verified
radiographic disease progression by modified 
RECIST 1.1 after stopping initial treatment, and
o
No new anticancer treatment was administered after the last dose of trial 
treatment, and
o
The subject meets all of the safety parameters listed in the inclusion criteria 
and none of the safety parameters listed in the exclusion criteria, and
o
The trial is ongoing.
Treatment assignment will be unblinded only for those subjects who meet all criteria for the 
Second Course Phase. Subjects in the saline placebo arm are not eligible for the Second 
Course Phase.
Procedures and assessments for the Second Course Phase will be initiated once radiographic 
disease progression by modified RECIST 1.1 has been determined by the investigator and 
verified by BICR, and the subject has met the criteria listed above. All procedures and 
assessments completed at the time of withdrawal from the Initial Treatment Phase may be 
used, as appropriate, for the start of the Second Course Phase of the study. Procedures and 
assessments must be completed within 28 days after radiographic progression by modified 
RECIST 1.1.
An objective response or disease progression that occurs during the Second Course Phase for 
a subject will not be counted as an event for the primary analysis of any endpoint in this trial.


Product:  MK-3475 
92
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Visit requirements are outlined in the Trial Flow Chart (Section 6.2). Survival assessments 
and their respective entries into the database may be required more frequently around the 
time of the projected analyses (eg, DMC reviews, interim analyses).
Specific procedure-related details are provided above in Section 7.1.
Continued Treatment Following Verified Progressive Disease
Subjects who are deemed by the investigator to be benefiting clinically despite documented 
PD assessed by BICR using RECIST 1.1 (modified to follow a maximum of 10 target lesions 
and a maximum of 5 target lesions per organ), may remain on study and continue receiving 
the originally assigned trial treatment for a total of 35 cycles. Continued post-PD treatment is 
optional and will be determined at the discretion of the investigator (in consultation with the 
Sponsor).
Subjects who meet the following criteria will be eligible for continued post-PD treatment:

Documentation of PD will be defined as BICR assessment.

AEs (except alopecia and peripheral neuropathy) due to therapy must have improved 
to NCI CTCAE 4.0 Grade ≤1.

If a subject is unstable as a result of a new or progressing brain metastasis(es), the 
subject will not be eligible for continued treatment.

ECOG Performance Status of 0 or 1.

Subject must not have received any non-study systemic anti-cancer therapies.

Subject has adequate organ function as indicated by the laboratory assessments listed 
in Section 5.1.2.
Visit requirements are outlined in the Trial Flow Chart (Section 6.1). Survival assessments 
and their respective entries into the database may be required more frequently around the 
time of the projected analyses (eg, DMC reviews, interim analyses). Specific procedure-
related details are provided above in Section 7.1.
Discontinued Subjects Continuing to be Monitored in the Trial
Subjects who discontinue from the treatment phase prior to disease progression will continue 
to be followed in PFS follow-up until they experience disease progression or start a new 
antineoplastic therapy. Subjects with an AE of Grade >1 will be further followed until the 
resolution of the AE to Grade ≤1 or until beginning of a new antineoplastic therapy, 
whichever occurs first.
Date of disease recurrence or metastatic progression, start and stop dates of subsequent 
anti-cancer treatments, and reasons for treatments should be recorded in the appropriate 


Product:  MK-3475 
93
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
eCRF. Survival assessments and their respective entries into the database may be required 
more frequently around the time of the projected analyses (eg, DMC reviews, interim 
analyses). For subjects who die during the follow-up period, the date and cause of death 
should be recorded in the appropriate eCRF.
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.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
Section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).


Product:  MK-3475 
94
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab by ≥1000 mg (5 times the dose). For subjects treated with 
pembrolizumab an overdose will be defined as any dose exceeding 5X the 
protocol-prescribed dose. No specific information is available on the treatment of overdose 
of pembrolizumab. In the event of overdose, pembrolizumab 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, 
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 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 AEs, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 
180 days after last dose of chemotherapeutic agents, or 30 days following cessation of trial 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator. All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.


Product:  MK-3475 
95
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
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
An SAE is any AE 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 another important medical event.
*Note: In addition to the above criteria, AEs meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by the Sponsor for collection purposes.

Is a new cancer (that is not a condition of the study);

Is associated with an overdose.
Refer to Table 10 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any SAE, or follow up to an SAE, including death due to any cause
other than progression of the cancer under study (see Section 7.2.3.3 for additional details), 
that occurs to any subject must be reported within 24 hours to the Sponsor if it causes the 
subject to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of trial treatment, or 30 days following cessation of trial treatment if the 
subject initiates new anticancer therapy, whichever is earlier, any SAE, or follow up to a 
SAE, including death due to any cause other than progression of the cancer under study (see
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 


Product:  MK-3475 
96
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
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 SAE, 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 SAEs must be followed up for outcome.
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:

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. 

an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).


Product:  MK-3475 
97
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
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.
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 unblinded aggregated efficacy endpoint events and 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. 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.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse event to the single agent.


Product:  MK-3475 
98
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Table 10
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 
CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of 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


Product:  MK-3475 
99
Protocol/Amendment No.: 604-09
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to 
Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with 
Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, 
there
is 
a 
reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)


Product:  MK-3475 
100
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
DMC regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.7 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
A DMC recommendation will be communicated to the Sponsor as agreed in the DMC 
Charter.  
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E9). Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analysis, will be
documented in a supplemental statistical analysis plan (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study. The PRO analysis plan will also be included in the sSAP.


Product:  MK-3475 
101
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Statistical Analysis Plan Summary
Key elements of the Statistical Analysis Plan (SAP) are summarized below. The 
comprehensive plan is provided in Section 8.2 through Section 8.12.
Analysis Strategy for Key Efficacy Endpoints
Study Design Overview
This is a Phase 3, randomized, multi-site, double-blind study of 1L
pembrolizumab+EP versus saline placebo+EP in ES-SCLC (KEYNOTE-
604)
Treatment Assignment
Approximately 430 subjects were planned to be randomized in a 1:1 ratio to
receive pembrolizumab+EP or saline placebo+EP. The stratification factors 
used for this study are a) cisplatin vs carboplatin, b) ECOG status (0 vs 1), 
and, c) LDH at baseline (≤ vs > ULN). This is a double-blind study.
By the time of the current amendment, 453 subjects were randomized for 
the study.
Analysis Populations
Efficacy: Intention-to-Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoints
1)
PFS as assessed by BICR RECIST 1.1 modified to follow a maximum 
of 10 target lesions and a maximum of 5 target lesions per organ
2)
OS
Secondary Endpoints
3)
ORR as assessed by BICR per RECIST 1.1 modified to follow a 
maximum of 10 target lesions and a maximum of 5 target lesions per 
organ
4)
DOR as assessed by BICR per RECIST 1.1 modified to follow a 
maximum of 10 target lesions and a maximum of 5 target lesions per 
organ
5)
AEs
Statistical Methods for
Key Efficacy Analyses
The 
primary 
hypotheses 
will 
be 
evaluated 
by 
comparing 
1L 
pembrolizumab+EP to 1L saline placebo+EP based on PFS as assessed by 
BICR RECIST 1.1 modified to follow a maximum of 10 target lesions and 
a maximum of 5 target lesions per organ and OS in subjects with ES-SCLC 
using a stratified log-rank test. Hazard ratios (HRs) will be estimated 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. There are no 
Tier 1 safety parameters in this trial. All safety parameters are considered 
either Tier 2 or Tier 3. Tier 2 parameters will be assessed via point 
estimates with 95% CIs provided for between-group comparisons; only 
point estimates by treatment group are provided for Tier 3 safety 
parameters. The between-treatment difference will be analyzed using the 
Miettinen and Nurminen method.


Product:  MK-3475 
102
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Interim and Final 
Analyses
Two interim analyses are planned in this study. Results will be reviewed 
by the external DMC. Details are provided in Section 8.7 – Interim 
Analyses.

Interim analysis 1
o Timing:
To be performed at approximately 18 months from 
study start, where study start is the date on which the first 
subject was randomized. ORR p-value from the first interim 
analysis (IA1) may be evaluated for statistical significance if PFS 
and OS null hypotheses are rejected at IA1 or at a later analysis 
time.
o Purpose: Interim PFS and OS analyses to demonstrate superiority 
of pembrolizumab+EP over saline placebo+EP.

Interim analysis 2
o Timing: To be performed at approximately 22 months from study 
start. Purpose: Final PFS analysis and interim OS analysis to 
demonstrate superiority of pembrolizumab+EP over saline 
placebo+EP.

Final analysis
o Timing: To be performed after a minimum of 294 deaths are 
observed or approximately 31 months after first subject enrolled, 
whichever occurs later.
o Purpose: Final analysis of OS to demonstrate superiority of 
pembrolizumab+EP over saline placebo+EP.
Multiplicity
The family-wise type I error rate for this study is strongly controlled at 
2.5% (one-sided) for the hypothesis testing of PFS, OS, and ORR. The 
multiplicity strategy will follow the graphical approach of Maurer and 
Bretz [114] as described in Section 8.8, with 0.6% and 1.9% alpha initially 
allocated to the PFS and OS hypotheses, respectively. Group sequential 
methods will be used to allocate alpha between the interim and final 
analyses for PFS and OS endpoints. Further details of the interim analysis 
strategy can be found in Section 8.7 and Section 8.8.
Sample Size and Power
The planned sample size is approximately 430 subjects. The actual sample 
size is 453 subjects. For PFS, based on 387 events, the study has 95.6% 
power to detect a HR of 0.65 (pembrolizumab+EP vs saline placebo+EP) at 
α=0.6% (one-sided). For OS, based on a minimum of 294 events, the study 
has at least 94.4% power to detect a HR of 0.65 (pembrolizumab+EP vs
saline placebo+EP) at α=1.9% (one-sided).
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 for study treatment 
assignment for this protocol and the randomization will be implemented in IVRS/IWRS.
Planned interim analyses are described in Section 8.7. Participant-level unblinding will be 
restricted to an external unblinded statistician and scientific programmer performing the 
interim analysis, who will have no other responsibilities associated with the study.


Product:  MK-3475 
103
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
An external DMC will be convened to review accumulating safety data to provide an 
opportunity to terminate the study early if there are concerns regarding safety. 
Treatment-level results at the interim analyses will be provided by the external unblinded 
statistician to the DMC. The DMC will also review the unblinded efficacy results at the 
planned interim analyses. The DMC responsibilities and review schedules will be outlined in 
the DMC charter. The recommendation of the DMC will be communicated to the Sponsor
EOC and, in the event of a recommendation to halt the trial early due to safety concerns, to 
the appropriate regulatory agencies. If the DMC recommends modifications to the design of 
the protocol or discontinuation of the study, the EOC may be unblinded to results at the 
treatment level in order to act on these recommendations. Participant-level unblinding to 
support regulatory filing, should one occur before the end of the study, will be restricted to a 
designated Sponsor/MSD team, who will have no other responsibilities associated with the 
study.
The extent to which individuals are unblinded with respect to the results will be documented.
Additional logistical details, revisions to the above plan, and data monitoring guidance will 
be provided in the DMC Charter.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
Efficacy Endpoints
Primary
Progression-free Survival – RECIST 1.1 assessed by BICR
Progression-free survival is defined as the time from randomization to the first documented 
disease progression as assessed by BICR per RECIST 1.1 modified to follow a maximum of 
10 target lesions and a maximum of 5 target lesions per organ or death due to any cause, 
whichever occurs first. See Section 8.6.1 for definition of censoring.
Overall Survival
Overall survival is defined as the time from randomization to death due to any cause.
Subjects without documented death at the time of analysis will be censored at the date of 
last known contact.


Product:  MK-3475 
104
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Secondary
Objective Response Rate – RECIST 1.1 assessed by BICR
Objective response rate is defined as the proportion of subjects who have a CR or a PR. 
Responses are based on confirmed assessments by BICR per RECIST 1.1 modified to follow 
a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Duration of Response – RECIST 1.1 assessed by BICR
For subjects who demonstrate CR or PR, DOR is defined as the time from first documented 
evidence of CR or PR until disease progression or death due to any cause, whichever occurs 
first. DOR will be assessed by BICR per RECIST 1.1 modified to follow a maximum of 10 
target lesions and a maximum of 5 target lesions per organ.
Safety Endpoints
Safety measurements are described in Section 4.2.3.3 and Section 7. Safety and tolerability 
will be assessed by clinical review of all relevant parameters including AEs, laboratory tests, 
and vital signs. Safety parameters to be analyzed include, but are not limited to, AEs, SAEs, 
fatal AEs, and laboratory changes. Furthermore, specific events will be collected and 
designated as ECIs as described in Section 7.2.3.
Analysis Populations
Efficacy Analysis Populations
The analyses of primary efficacy endpoints are based on the intention-to-treat (ITT)
population (ie, 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.
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 
1 dose of study treatment. Subjects will be included in the treatment group corresponding to 
the study treatment they actually received. 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 1 cycle, but 
receives the correct treatment for all other cycles will be analyzed according to the correct 
treatment group and a narrative will be provided for any events that occur during the cycle 
for which the subject is incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.


Product:  MK-3475 
105
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
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. Nominal p-values will be computed 
for other efficacy analyses, but should be interpreted with caution due to potential issues of 
multiplicity.
Progression-free Survival
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test (based on the stratification factors defined in Section 5.4). A stratified Cox proportional 
hazard model with Efron's method of tie handling will be used to assess the magnitude of the 
treatment difference (ie, the hazard ratio [HR]) between the treatment arms. The HR and its 
95% CI from the stratified Cox model with Efron's method of tie handling and with a single 
treatment covariate will be reported. The stratification factors used for randomization (See 
Section 5.4) will be applied to both the stratified log-rank test and the stratified Cox model.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. For the primary analysis, for the subjects who have PD, the true date of disease 
progression will be approximated by the date of the first assessment at which PD is 
objectively documented as assessed by BICR per RECIST 1.1 modified to follow a 
maximum of 10 target lesions and a maximum of 5 target lesions per organ, regardless of 
discontinuation of study drug. Death is always considered as a confirmed PD event.
In order to evaluate the robustness of the PFS endpoint per modified RECIST 1.1 by central 
imaging vendor, we will perform 2 sensitivity analyses with a different set of censoring rules. 
The first sensitivity analysis is the same as the primary analysis except that data for any 
subject who misses more than one disease assessment (with or without a subsequent death or 
progression) are censored at the last disease assessment prior to missing visits. 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 11.


Product:  MK-3475 
106
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Table 11
Censoring Rules for Primary and Sensitivity Analyses of Progression-free 
Survival
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 
otherwise
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 missed 
disease assessments
Progressed at date of 
documented PD or 
death
Censored at last disease 
assessment prior to the 
≥2 missed disease 
assessment
Progressed at date of 
documented PD or death
Overall Survival
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test (based on the 
stratification factor defined in Section 5.4). A stratified Cox proportional hazard model with 
Efron's method of tie handling will be used to assess the magnitude of the treatment 
difference (ie, the HR). The HR and its 95% CI from the stratified Cox model with a single 
treatment covariate will be reported. The stratification factors used for randomization (See 
Section 5.4) will be applied to both the stratified log-rank test and the stratified Cox model. 
Restricted Mean Survival Time (RMST) method may be conducted for OS to account for the 
possible non-proportional hazards effect.
Since subjects in the placebo+EP arm are expected to discontinue from the study earlier 
compared to subjects in the pembrolizumab arm because of earlier onset of PD and may 
switch to another anti PD-1 treatment following confirmation of PD, adjustment for the effect 
of crossover on OS may be performed based on recognized methods, (eg, the Rank 
Preserving Structural Failure Time (RPSFT) model proposed by Robins and Tsiatis [115]), 
based on an examination of the appropriateness of the data to the assumptions required by the 
method used.


Product:  MK-3475 
107
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Objective Response Rate
The ORR is defined as the proportion of subjects who achieve a best objective response of 
PR or CR.
Stratified Miettinen and Nurminen’s method will be used for comparison of ORR between 
the treatment groups. The difference in ORR and its 95% CI from the stratified Miettinen and 
Nurminen method with strata weighting by sample size will be provided. The same 
stratification factors used for randomization (see Section 5.4) will be used as stratification 
factors in the analysis.
Duration of Response
For subjects who demonstrate CR or PR, DOR is defined as the time from first documented 
evidence of CR or PR until disease progression or death due to any cause, whichever occurs 
first. Censoring rules for DOR are summarized in Table 12. DOR will be assessed by BICR 
per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 
5 target lesions per organ.
For each DOR analysis, a corresponding summary of the reasons responding subjects are 
censored will also be provided. Subjects who are alive, have not progressed, have not 
initiated new anti-cancer treatment, have not been determined to be lost to follow-up, and 
have had a disease assessment within ~ 5 months of the data cutoff date are considered 
ongoing responders at the time of analysis. If a subject meets multiple criteria for censoring, 
the censoring criterion that occurs earliest will be applied.
Table 12
Censoring Rules for Duration of Response
Situation
Date of 
Progression or Censoring
Outcome
No progression nor death, no new anti-
cancer therapy initiated
Last adequate disease 
assessment
Censor
(non-event)
No progression nor death, new anti-
cancer therapy initiated
Last adequate disease 
assessment before new anti-
cancer therapy initiated
Censor
(non-event)
Death or progression after 
≥2 consecutive missed disease 
assessments
Last adequate disease 
assessment prior to ≥2 missed 
adequate disease assessments
Censor
(non-event)
Death or progression after ≤1 missed 
adequate disease assessments
Progressive disease or death
End of response
(Event)
Note:  A missed disease assessment includes any assessment that is not obtained or is considered inadequate 
for evaluation of response.
A summary of the primary analysis strategy for the primary and secondary efficacy endpoints 
is provided in Table 13.


Product:  MK-3475 
108
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Table 13
Efficacy Analysis Methods for Primary and Secondary Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis Population
Missing Data Approach
Primary Analyses:
PFS (RECIST 1.1*) by 
BICR
Testing: Stratified Log-
rank test
Estimation: Stratified Cox 
model with Efron's tie 
handling method 
ITT
Censored according to 
rules in Table 11
OS
Testing: Stratified Log-
rank test
Estimation: Stratified Cox 
model with Efron's tie 
handling method
ITT
Censored at last known 
alive date
Secondary Analyses:
ORR (RECIST 1.1*) by 
BICR
Testing: Stratified 
Miettinen and Nurminen 
method
ITT
Subjects with missing 
data are considered non-
responders
DOR (RECIST 1.1*) by 
BICR
Summary statistics using 
Kaplan-Meier method
All responders in ITT 
Non-responders are 
excluded in analysis
*As assessed by BICR per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum 
of 5 target lesions per organ
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and laboratory tests.
The analysis of safety results will follow a tiered approach (Table 14). The tiers differ with 
respect to the analyses that will be performed. Safety parameters or AEs of special interest 
that are identified a priori constitute “Tier 1” safety endpoints that will be subject to 
inferential testing for statistical significance with p-values and 95% CIs 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% CIs provided for 
between-group comparisons; only point estimates by treatment group are provided for Tier 3 
safety parameters.
Adverse events of special interest (AEOSIs) that are immune-mediated or potentially 
immune-mediated are well documented and will be evaluated separately; however, these 
events have been characterized consistently throughout the pembrolizumab clinical 
development program and determination of statistical significance is not expected to add 
value to the safety evaluation. Further, pembrolizumab added to platinum doublets studied 
thus far have not been found to impact safety, and in an ongoing Phase 1 clinical trial, the 
chemotherapeutic regimen used here with pembrolizumab has not led to increased toxicity 


Product:  MK-3475 
109
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
(NCT02402920). Additionally, there are no known AEs associated with subjects with SCLC 
for which determination of a p-value is expected to impact the safety assessment. For these 
reasons, there are no events of interest that warrant inferential testing. Therefore, there are no 
Tier I events in this study.
Adverse experiences (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 10% of 
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 10% was chosen for membership in Tier 2 because subjects enrolled 
in this study are in critical condition and usually experience various AEs of similar types 
regardless of treatment, events reported less frequently than in 10% of subjects would 
obscure the assessment of the overall safety profile and add little to the interpretation of 
potentially meaningful treatment differences. In addition, Grades 3 to 5 AEs (≥5% of 
subjects in one of the treatment arms) and SAEs (≥5% of subjects in one of the treatment 
arms) will be considered Tier 2 events. For Tier 2 events, 95% CIs 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 [116], an unconditional, asymptotic 
method. Because many 95% CIs may be provided without adjustment for multiplicity, the 
CIs should be regarded as a helpful descriptive measure to be used in safety review, not a 
formal method for assessing the statistical significance of the between-treatment differences.
For laboratory parameters, the number and percentage of subjects with increases from 
baseline in laboratory test toxicity grades based on the highest post-baseline toxicity grade 
and shift of toxicity grade from baseline to the worst post-baseline toxicity grade will be 
summarized by treatment arm.
Table 14
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE (≥10% of subjects in one of the 
treatment arms)
X
X
Any Grades 3 to 5 AE (≥5% of subjects in one 
of the treatment arms)
X
X
Any serious AE (≥5% of subjects in one of the 
treatment arms)
X
X
Tier 3
Any AE
X
Any change from baseline results (laboratory 
tests)
X
Abbreviations: AE=adverse event, CI=confidence interval


Product:  MK-3475 
110
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Summaries of Baseline Characteristics and Demographics
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 randomized, and the primary reason 
for discontinuation will be displayed. Demographic variables (such as age) and baseline 
characteristics will be summarized by treatment either by descriptive statistics or categorical 
tables. The reasons for exclusion from the ITT population (if any) will be summarized.
Interim Analyses
Two interim efficacy analyses are planned for this study.

The (IA1) will be performed approximately 18 months from study start. PFS and 
OS will be evaluated at IA1. ORR p-value from IA1 may be evaluated for 
statistical significance if PFS and OS null hypotheses are rejected at IA1 or at a 
later analysis time.

The second interim analysis (IA2) is the final formal analysis of PFS. It will be 
performed at approximately 22 months after first subject enrolled. The second 
interim analysis evaluation of OS will be performed at this time.

The final analysis will evaluate OS only. It is planned when a minimum of 294
deaths have been observed or approximately 31 months after first subject
enrolled, whichever occurs later.
In addition to the formal efficacy analyses, the DMC will conduct regular safety monitoring, 
the timing of which is specified in the DMC charter. Decisions to stop the trial early will be 
based on DMC recommendations with review by the EOC.
Type I error control for the efficacy analyses as well as efficacy bounds are described in the 
next section.
Multiplicity
The trial uses the graphical method of Maurer and Bretz [114] to control multiplicity for 
multiple hypotheses as well as interim analyses. Figure 3 shows the initial one-sided α 
allocation for each hypothesis in the ellipse representing the hypothesis. The weights for 
reallocation from each hypothesis to the others are represented in the boxes on the lines 
connecting hypotheses.


Product:  MK-3475 
111
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Note: If both PFS and OS null hypotheses are rejected, the reallocation strategy allows testing of ORR at 
alpha=0.025.
Figure 3
Multiplicity Graph for Type I Error Control
Progression-free Survival
If the null hypothesis for OS is rejected, Figure 3 shows that its α=0.019 is essentially fully 
reallocated to PFS hypothesis testing. Thus, the PFS null hypothesis may be tested at 
α=0.006 or at α=0.025. For PFS hypotheses, the targeted number of events at the final PFS 
analysis will be 387. A Lan-DeMets O'Brien-Fleming spending function will be used for 
information fraction-based alpha-spending to generate the group sequential design. The 
bounds provided in Table 15 are based on the assumption that the number of events at IA1 
and IA2 are 332 and 387, respectively. The actual boundaries and the nominal alpha level 
will be determined based on the actual number of PFS events observed at the time of the 
analyses and from the overall alpha level after any potential alpha-shifting as the result of a 
successful OS analysis. The final PFS analysis at IA2 will use the remaining Type I error not 
spent at the IA1, regardless of the actual number of PFS events observed. The p-value bound 
at the final PFS analysis will be calculated by considering the correlation between the test 
statistics as determined by the actual number of PFS events at IA1 and the final PFS analysis
at IA2. The bounds given in Table 15 will be adjusted accordingly.


Product:  MK-3475 
112
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Table 15
Efficacy Boundaries and Properties for Progression-free Survival Analyses
Analysis
Targeted Analysis 
Time
Cumulative 
alpha spent1
Efficacy Bars1
IA1 (86%2)
Approximately 
18 months from study 
start3
0.003
(One-sided) p-value <0.003
Observed HR <~ 0.74
IA2 (100%2)
Approximately 
22 months from study 
start3
0.006
(One-sided) p-value <0.0051
Observed HR <~ 0.77
1 Nominal alpha, boundaries, and cumulative alpha are based on the assumption that 332 and 387 events are at 
IA1 and IA2, respectively. The p-value boundaries will be updated at the time of analyses based on actual 
number of PFS events.
2 Percentage of expected number of events at final analysis targeted at interim analysis.
3 Study start is defined as the date when the first subject was randomized.
Note that if the α-reallocation from OS hypothesis testing occurs at the final analysis after 
hypothesis testing for PFS has been completed, the previously computed PFS test statistic for 
the PFS final analysis may be re-evaluated based on the updated bounds.
Overall Survival
The OS hypothesis may be tested at α=0.019 (initially allocated α) or at α=0.025 (if PFS null 
hypothesis is rejected) following the multiplicity strategy as outlined in Figure 3. The bounds 
and boundary properties for OS hypothesis testing at the initial alpha level are demonstrated 
in Table 16. The alpha spending at each interim analysis is determined using a Lan-DeMets 
O'Brien-Fleming spending function, and the information fraction (ratio of the actual number 
of events at the interim analysis relative to a targeted 294 events at the final analysis). The 
final analysis will use the remaining Type I error not spent at earlier analyses, regardless of 
the number of events observed at the final analysis. The p-value bounds at second interim 
and final analysis will be calculated by considering the correlation between the test statistics 
as determined by the actual number of OS events at the previous and current analysis. The p-
value bounds at each analysis time may also be updated after potential alpha-shifting as the 
result of a successful PFS analysis.


Product:  MK-3475 
113
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Table 16
Efficacy Boundaries and Properties for Overall Survival Analyses
Analysis
Targeted Analysis 
Time
Cumulative 
alpha spent1
Efficacy Bars1
IA1 (60%2)
Approximately 18 months 
from study start3
0.0024

(One-sided) p-value <0.0024

Observed HR <~ 0.65
IA2 (76%2)
Approximately 22 months 
from study start3
0.0071

(One-sided) p-value <0.0064

Observed HR <~ 0.72
FA (100%2)
A minimum of 294 deaths 
observed in 2 arms or
approximately 31 months 
from study start, 
whichever occurs later3
0.019

(One-sided) p-value <0.0167

Observed HR <~ 0.78
1 Nominal alpha, boundaries, and cumulative alpha are based on the number of deaths expected assuming the 
projected number of events using protocol assumptions, ie, 175, 224, and 294 at IA1, IA2 and final 
analysis, respectively. The p-value boundaries will be updated at the time of analyses based on actual 
number of deaths.
2 Percentage of expected number of events at final analysis targeted at interim analysis.
3 Study start is defined as the date when the first subject was randomized.
The DMC has responsibility for assessment of overall risk: benefit. When prompted by safety 
concerns, the DMC can request corresponding efficacy data. DMC review of efficacy data to 
assess the overall risk: benefit to study participants will not require a multiplicity adjustment 
typically associated with a planned efficacy IA. However, to account for any multiplicity 
concerns raised by the DMC review of unplanned efficacy data when prompted by safety 
concerns, a sensitivity analysis for OS adopting a conservative multiplicity adjustment will 
be pre-specified in the sSAP.
Objective Response Rate
The trial does not allocate initial alpha to ORR. ORR will be formally tested only if the 
hypotheses for PFS and OS are significant. The testing of ORR will be based on the first 
352 subjects enrolled in the trial. If the null hypotheses for OS and PFS are rejected at IA1 or
at a time later than IA1, the p-value of ORR from the IA1 analysis will be compared to an α-
level of 0.025. Power at the possible α-level as well as the approximate treatment difference 
required to reach the bound (ΔORR) are shown in Table 17, assuming underlying 50% and 
70% response rates in the control and experimental groups, respectively. 


Product:  MK-3475 
114
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Table 17
Possible Alpha-levels and Approximate ORR Difference
Required to 
Demonstrate Efficacy for ORR
α
~ΔORR
Power
0.025
0.1002
0.9719
Sample Size and Power Calculations
Four hundred and thirty subjects were planned to be randomized in 1:1 ratio into 
pembrolizumab+EP and the saline placebo+EP arms. By the time of the current amendment,
453 subjects were enrolled for this study.
The final PFS analysis for the study will occur about 22 months from study start. If 387 PFS 
events occur by the time of the final PFS analysis, the study will have a power of 96% 
approximately to demonstrate a HR of 0.65 on PFS at initially allocated α=0.006. 
The final OS analysis will occur when at least 294 events have occurred or approximately 31 
months from study start, whichever occurs later. With a minimum of 294 events at the time 
of final analysis, the study has at least 94% power to demonstrate a HR of 0.65 on OS at
initially allocated α=0.019.
The above power calculations for OS and PFS are based on the following assumptions: 
1) 453 subjects were enrolled over 14.5 months following the actual enrollment pattern; 
2) median PFS is 4.3 months in the control arm and HR is 0.65; 3) median OS is 10 months 
in the control arm and HR is 0.65; 4) The exponential dropout rates assumed for OS and PFS 
are 1% per month.
The sample size and power calculations were performed in the software R (package 
“gsDesign”).
Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for OS, PFS and ORR (with a nominal 95% CI) will be 
estimated and plotted within each category of the following classification variables:

Stratification factors
o
Platinum chemotherapy (cisplatin, carboplatin)
o
LDH (≤ULN, >ULN)
o
ECOG Performance Scale (0, 1)

Age category (<65, 65 years)


Product:  MK-3475 
115
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential

Sex (female, male)

Race (white, all others)

Smoking status (former, current)

Brain/liver metastasis status at diagnosis (yes, no)

Region (East Asia, non-East Asia)

Sites of metastasis at diagnosis (<3, ≥3)

PD-L1 expression positive (TPS<1% vs ≥1%, CPS <1 vs ≥1)
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
Extent of exposure for a subject is defined as number of cycles in which the subject receives 
the study medication infusion. Summary statistics will be provided on extent of exposure for 
the ASaT population.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 18. All other 
supplies not indicated in Table 18 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.


Product:  MK-3475 
116
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Table 18
Product Descriptions
Product 
Name 
& 
Potency
Dosage Form
Source/Additional Information
Pembrolizumab 25 
mg/mL
(MK-3475)
Solution for Infusion
Provided centrally by the Sponsor
Carboplatin
Solution for Infusion
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee. 
Product is not IMP
Cisplatin
Solution for Infusion
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee
Product is not IMP
Etoposide
Solution for Infusion
Provided centrally by the Sponsor 
or locally by the trial site, 
subsidiary, or designee
Product is not IMP
Abbreviations:  IMP=investigational medicinal product
All supplies indicated in Table 18 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 18 will be provided by the trial 
site, subsidiary or designee. Every attempt should be made to source these supplies from a 
single lot/batch number. The trial site is responsible for recording the lot number, 
manufacturer, and expiry date for any locally purchased product as per local guidelines 
unless otherwise instructed by the Sponsor.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Open-label pembrolizumab will be provided in 2 vial kits. Open-label carboplatin, cisplatin,
and etoposide will be provided as single-vial kits.
Clinical Supplies Disclosure
The pembrolizumab treatment in the trial is blinded but supplies are provided open label; 
therefore, an unblinded pharmacist or qualified trial site personnel will be used to blind 


Product:  MK-3475 
117
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
supplies. Trial treatment identity (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 trial 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.


Product:  MK-3475 
118
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.


Product:  MK-3475 
119
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
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.
The investigator also agrees to allow monitoring, audits, IRB/IEC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
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.


Product:  MK-3475 
120
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The Sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
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 


Product:  MK-3475 
121
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
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 Protocol/CSR 
CI during the anticipated review process, thorough understanding of clinical trial methods, 
appropriate enrollment of subject cohort, timely achievement of trial milestones).  The 
Protocol CI must be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  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 FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.


Product:  MK-3475 
122
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 


Product:  MK-3475 
123
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
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.
11.0 LIST OF REFERENCES
[1]
Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8.
[2]
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune 
evasion. Nat Med 2002;8(8):793-800.
[3]
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol 
2002;2(2):116-26.
[4]
Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. 
Blockade of programmed death-1 ligands on dendritic cells enhances T cell 
activation and cytokine production. J Immunol 2003;170(3):1257-66.
[5]
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010;236:219-42.
[6]
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. 
PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor 
outcome for patients with renal cell carcinoma. Clin Cancer Res 2007;13(6):1757-
61.
[7]
Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, et al. Tumor cell 
expression of programmed cell death-1 ligand 1 is a prognostic factor for 
malignant melanoma. Cancer 2010;116:1757-66.


Product:  MK-3475 
124
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
[8]
Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical 
significance 
and 
therapeutic 
potential 
of 
the 
programmed 
death-1 
ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res 
2007;13(7):2151-7.
[9]
Gao Q, Wang X-Y, Qiu S-J, Yamato I, Sho M, Nakajima Y, et al. Overexpression 
of PD-L1 significantly associates with tumor aggressiveness and postoperative 
recurrence in human hepatocellular carcinoma. Clin Cancer Res 2009;15(3):971-9.
[10]
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. 
Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are 
prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A 
2007;104(9):3360-5.
[11]
Fourcade J, Kudela P, Sun Z, Shen H, Land SR, Lenzner D, et al. PD-1 is a 
regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. J 
Immunol 2009;182:5240-9.
[12]
Cai G, Karni A, Oliveira EML, Weiner HL, Hafler DA, Freeman GJ. PD-1 
ligands, negative regulators for activation of naïve, memory, and recently 
activated human CD4+ T cells. Cell Immunol 2004;230(2):89-98.
[13]
Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell 
exhaustion: an update on implications for chronic infections and tumor evasion. 
Cancer Immunol Immunother. 2007 May;56(5):739-45.
[14]
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-
L1 on tumor cells in the escape from host immune system and tumor 
immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 
2002;99(19):12293-7.
[15]
Tsushima F, Tanaka K, Otsuki N, Youngnak P, Iwai H, Omura K, et al. 
Predominant expression of B7-H1 and its immunoregulatory roles in oral 
squamous cell carcinoma. Oral Oncol 2006;42:268-74.
[16]
Korman A, Chen B, Wang C, Wu L, Cardarelli P, Selby M. Activity of anti-PD-1 
in murine tumor models: role of "host" PD-L1 and synergistic effect of anti-PD-1 
and anti-CTLA-4 [Abstract]. J Immunol 2007;178:48.37.
[17]
Oble DA, Loewe R, Yu P, Mihm MC Jr. Focus on TILs: prognostic significance 
of tumor infiltrating lymphocytes in human melanoma. Cancer Immun. 2009 Apr 
2;9:3.
[18]
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et 
al. Safety, activity, and immune correlates of Anti-PD-1 antibody in cancer. N 
Engl J Med. "in press" 2012.


Product:  MK-3475 
125
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
[19]
Patnaik A, Kang SP, Tolcher AW, Rasco DW, Papadopoulos KP, Beeram M, et al.  
2012 ASCO Annual Meeting:  Phase I study of MK-3475 (anti-PD-1 monoclonal 
antibody) in patients with advanced solid tumors.
[20]
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. 
Improved survival with ipilimumab in patients with metastatic melanoma. N Engl 
J Med 2010;363(8):711-23.
[21]
Chapman PB, Hauschild A, Robert C, Hannen JB, Ascierto P, Larkin J, et al. 
Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N 
Engl J Med 2011;364(26):2507-16.
[22]
Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab 
plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 
2011;364(26):2517-26.
[23]
Bellati F, Visconti V, Napoletano C, Antonilli M, Frati L, Benedetti Panici P, et al. 
Immunology of gynecologic neoplasms: analysis of the prognostic significance of 
the immune status. Curr Cancer Drug Targets 2009;9(4):541-65.
[24]
Ruffell B, DeNardo DG, Affara NI, Coussens LM. Lymphocytes in cancer 
development: polarization towards pro-tumor immunity. Cytokine Growth Factor 
Rev 2010;21:3-10.
[25]
Shirabe K, Motomura T, Muto J, Toshima T, Matono R, Mano Y, et al. Tumor-
infiltrating lymphocytes and hepatocellular carcinoma: pathology and clinical 
management. Int J Clin Oncol 2010;15:552-8.
[26]
Al-Shibli K, Al-Saad S, Andersen S, Donnem T, Bremnes RM, Busund L-T. The 
prognistic value of intraepithelial and stromal CD3-, CD117- and CD138-positive 
cells in non-small cell lung carcinoma. APMIS 2010;118:371-82.
[27]
Clark CE, Beatty GL, Vonderheide RH. Immunosurveillance of pancreatic 
adenocarcinoma: insights from genetically engineered mouse models of cancer. 
Cancer Lett 2009;279:1-7.
[28]
Diederichsen ACP, Hjelmborg JvB, Christensen PB, Zeuthen J, Fenger C. 
Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in 
colorectal cancer and HLA-DR expression on tumour cells. Cancer Immunol 
Immunother 2003;52:423-8.
[29]
Gao Q, Qiu S-J, Fan J, Zhou J, Wang X-Y, Xiao Y-S, et al. Intratumoral balance 
of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular 
carcinoma after resection. J Clin Oncol 2007;25(18):2586-93.


Product:  MK-3475 
126
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
[30]
Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are 
parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol 
Immunother 2008;57(1):97-106.
[31]
Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, et al. CD3+ cells 
at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of 
post-surgical metastatsis: a longitudinal study. Lancet Oncol 2009;10:877-84.
[32]
Li JF, Chu YW, Wang GM, Zhu TY, Rong RM, Hou J, et al. The prognostic value 
of peritumoral regulatory T cells and its correlation with intratumoral 
cyclooxygenase-2 expression in clear cell renal cell carcinoma. BJU Intern 
2008;103:399-405.
[33]
Nemolato S, Fanni D, Naccarato AG, Ravarino A, Bevilacqua G, Faa G. 
Lymphoepithelioma-like hepatocellular carcinoma: a case report and a review of 
the literature. World J Gastroenterol 2008;14(29):4694-6.
[34]
Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive 
lymphocyte and dendritic cell infiltration after interleukin-2 immunotherapy. 
Report of a case. Tumori 2008;94(3):426-30.
[35]
Oshikiri T, Miyamoto M, Shichinohe T, Suzuoki M, Hiraoka K, Nakakubo Y, et 
al. Prognostic value of intratumoral CD8+ T lymphocyte in extrahepatic bile duct 
carcinoma as essential immune response. J Surg Oncol 2003;84:224-8.
[36]
Piersma SJ, Welters MJP, van der Burg SH. Tumor-specific regulatory T cells in 
cancer patients. Human Immunol 2008;69:241-9.
[37]
Rao UNM, Lee SJ, Luo W, Mihm Jr. MC, Kirkwood JM. Presence of tumor-
infiltrating lymphocytes and a dominant nodule within primary melanoma are 
prognostic factors for relapse-free survival of patients with thick (T4) primary 
melanoma: pathologic analysis of the E1690 and E1694 intergroup trials. Am J 
Clin Pathol 2010;133:646-53.
[38]
Sasaki A, Tanaka F, Mimori K, Inoue H, Kai S, Shibata K, et al. Prognostic value 
of tumor-infiltrating FOXP3+ regulatory T cells in patients with hepatocellular 
carcinoma. EJSO 2008;34:173-9.
[39]
Shen Z, Zhou S, Wang Y, Li R, Zhong C, Liang C, et al. Higher intratumoral 
infiltrated Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with 
adverse prognosis in resectable gastric cancer. J Cancer Res Clin Oncol 
2010;136:1585-95.


Product:  MK-3475 
127
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
[40]
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: 
Jekyll or Hyde. Cancer Metastasis Rev 2007;26(3-4):373-400.
[41]
Usubütün A, Ayhan A, Uygur MC, Özen H, Toklu C, Ruacan S. Prognostic 
factors in renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.
[42]
Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema 
H, et al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary 
and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol 
Immunother 2009;58(3):449-59.
[43]
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.
[44]
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.
[45]
Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, et al. 
Intratumoral CD8+ T/FOXP3+ cell ratio is a predictive marker for survival in 
patients with colorectal cancer. Cancer Immunol Immunother 2010;59:653-61.
[46]
Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, et al. Inflammatory tumor 
microenvironment is associated with superior survival in hepatocellular carcinoma 
patients. J Hepatol 2010;52:370-9.
[47]
Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes 
correlates with poor prognosis in renal cell carcinoma. BJU Int 2011;107(9):1500-
6.
[48]
Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic 
value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 
1997;182(3):318-24.
[49]
Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J 
Clin Oncol 2005;23(10):2346-57.
[50]
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.


Product:  MK-3475 
128
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
[51]
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 
2001;98(24):13866-71.
[52]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48.
[53]
Sierocki JS, Hilaris BS, Hopfan S, Martini N, Barton D, Golbey RB, et al. cis-
Dichlorodiammineplatinum(II) and VP-16-213: an active induction regimen for 
small cell carcinoma of the lung. Cancer Treat Rep. 1979 Sep-Oct;63(9-10):1593-
7.
[54]
Fukuoka M, Furuse K, Saijo N, Nishiwaki Y, Ikegami H, Tamura T, et al. 
Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus 
cisplatin and etoposide versus alternation of these regimens in small-cell lung 
cancer. J Natl Cancer Inst. 1991 Jun 19;83(12):855-61.
[55]
Roth BJ, Johnson DH, Einhorn LH, Schacter LP, Cherng NC, Cohen HJ, et al. 
Randomized study of cyclophosphamide, doxorubicin, and vincristine versus 
etoposide and cisplatin versus alternation of these two regimens in extensive 
small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J 
Clin Oncol. 1992 Feb;10(2):282-91.
[56]
Sundstrom S, Bremnes RM, Kaasa S, Aasebo U, Hatlevoll R, Dahle R, et al. 
Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and 
vincristine regimen in small-cell lung cancer: results from a randomized phase III 
trial with 5 years' follow-up. J Clin Oncol. 2002 Dec 15;20(24):4665-72.
[57]
Chute JP, Venzon DJ, Hankins L, Okunieff P, Frame JN, Ihde DC, et al. Outcome 
of patients with small-cell lung cancer during 20 years of clinical research at the 
US National Cancer Institute. Mayo Clin Proc. 1997 Oct;72(10):901-12.
[58]
Mascaux C, Paesmans M, Berghmans T, Branle F, Lafitte JJ, Lemaitre F, et al. A 
systematic review of the role of etoposide and cisplatin in the chemotherapy of 
small cell lung cancer with methodology assessment and meta-analysis. Lung 
Cancer. 2000 Oct;30(1):23-36.
[59]
Pujol JL, Carestia L, Daures JP. Is there a case for cisplatin in the treatment of 
small-cell lung cancer? A meta-analysis of randomized trials of a cisplatin-
containing regimen versus a regimen without this alkylating agent. Br J Cancer. 
2000 Jul;83(1):8-15.


Product:  MK-3475 
129
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
[60]
Hanna N, Bunn PA, Jr., Langer C, Einhorn L, Guthrie T, Jr., et al. Randomized 
phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients 
with previously untreated extensive-stage disease small-cell lung cancer. J Clin 
Oncol 2006;24(13):2038-43.
[61]
Lara PN Jr, Natale R, Crowley J, Lenz HJ, Redman MW, Carleton JE, et al. Phase 
III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-
stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG 
S0124. J Clin Oncol. 2009 May 20;27(15):2530-5.
[62]
Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, et al. 
First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung 
cancer. N Engl J Med. In press 2018.
[63]
Reck M, Luft A, Szczesna A, Havel L, Kim SW, Akerley W, et al. Phase III 
Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo 
Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. J Clin 
Oncol. 2016 Nov 25;34:3740-8.
[64]
Skarlos DV, Samantas E, Kosmidis P, Fountzilas G, Angelidou M, Palamidas P, et 
al. Randomized comparison of etoposide-cisplatin vs. etoposide-carboplatin and 
irradiation in small-cell lung cancer. A Hellenic Co-operative Oncology Group 
study. Ann Oncol. 1994 Sep;5(7):601-7.
[65]
Rossi A, Di Maio M, Chiodini P, Rudd RM, Okamoto H, Skarlos DV, et al. 
Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell 
lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol. 
2012 May 10;30(14):1692-8.
[66]
Spiro SG, Souhami RL, Geddes DM, Ash CM, Quinn H, Harper PG, et al. 
Duration of chemotherapy in small cell lung cancer: a Cancer Research Campaign 
trial. Br J Cancer. 1989 Apr;59(4):578-83.
[67]
Giaccone G, Dalesio O, McVie GJ, Kirkpatrick A, Postmus PE, Burghouts JT, et 
al. Maintenance chemotherapy in small-cell lung cancer: long-term results of a 
randomized trial. J Clin Oncol. 1993 Jul;11(7):1230-40.
[68]
Hanna NH, Sandier AB, Loehrer PJ Sr, Ansari R, Jung SH, Lane K, et al. 
Maintenance daily oral etoposide versus no further therapy following induction 
chemotherapy with etoposide plus ifosfamide plus cisplatin in extensive small-cell 
lung cancer: a Hoosier Oncology Group randomized study. Ann Oncol. 2002 
Jan;13(1):95-102.


Product:  MK-3475 
130
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
[69]
Ready NE, Pang HH, Gu L, Otterson GA, Thomas SP, Miller AA, et al. 
Chemotherapy With or Without Maintenance Sunitinib for Untreated Extensive-
Stage Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled 
Phase II Study-CALGB 30504 (Alliance). J Clin Oncol. 2015 May 
20;33(15):1660-5.
[70]
Beith JM, Clarke SJ, Woods RL, Bell DR, Levi JA. Long-term follow-up of a 
randomised trial of combined chemoradiotherapy induction treatment, with and 
without maintenance chemotherapy in patients with small cell carcinoma of the 
lung. Eur J Cancer. 1996 Mar;32A(3):438-43.
[71]
Schiller JH, Adak S, Cella D, DeVore III RF, Johnson DH. Topotecan versus 
observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: 
E7593 - A phase III trial of the Eastern Cooperative Oncology Group. J Clin 
Oncol 2001;19(8):2114-22.
[72]
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in 
Oncology- Non-Small Cell Lung Cancer: version 2.2017 [Internet]. Fort 
Washington, PA: National Comprehensive Cancer Network (NCCN); 2016. 
Available 
from:  
https://www.nccn.org/professionals/physician_gls/f_guidelines.asp
[73]
Fruh M, De Ruysscher D, Popat S, Crino L, Peters S, Felip E, et al. Small-cell 
lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment 
and follow-up. Ann Oncol. 2013 Oct;24 Suppl 6:vi99-105.
[74]
Rudin CM, Ismaila N, Hann CL, Malhotra N, Movsas B, Norris K, et al. 
Treatment of Small-Cell Lung Cancer: American Society of Clinical Oncology 
Endorsement of the American College of Chest Physicians Guideline. J Clin 
Oncol. 2015 Dec 1;33(34):4106-11.
[75]
Seute T, Leffers P, ten Velde GP, Twijnstra A. Neurologic disorders in 432 
consecutive patients with small cell lung carcinoma. Cancer. 2004 Feb 
15;100(4):801-6.
[76]
Komaki R, Cox JD, Whitson W. Risk of brain metastasis from small cell 
carcinoma of the lung related to length of survival and prophylactic irradiation. 
Cancer Treat Rep. 1981 Sep-Oct;65(9-10):811-4.
[77]
Nugent JL, Bunn PA Jr, Matthews MJ, Ihde DC, Cohen MH, Gazdar A, et al. CNS 
metastases in small cell bronchogenic carcinoma: increasing frequency and 
changing pattern with lengthening survival. Cancer. 1979 Nov;44(5):1885-93.
[78]
Hirsch FR, Paulson OB, Hansen HH, Vraa-Jensen J. Intracranial metastases in 
small cell carcinoma of the lung: correlation of clinical and autopsy findings. 
Cancer. 1982 Dec 1;50(11):2433-7.


Product:  MK-3475 
131
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
[79]
Auperin A, Arriagada R, Pignon JP, Le Pechoux C, Gregor A, Stephens RJ, et al. 
Prophylactic cranial irradiation for patients with small-cell lung cancer in 
complete remission. Prophylactic Cranial Irradiation Overview Collaborative 
Group. N Engl J Med. 1999 Aug 12;341(7):476-84.
[80]
Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton M, et al. 
Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 
2007 Aug 16;357(7):664-72.
[81]
Le Pechoux C, Dunant A, Senan S, Wolfson A, Quoix E, Faivre-Finn C, et al. 
Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients 
with limited-stage small-cell lung cancer in complete remission after 
chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, 
RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol. 2009 
May;10(5):467-74.
[82]
Johnson BE, Becker B, Goff WB 2nd, Petronas N, Krehbiel MA, Makuch RW, et 
al. Neurologic, neuropsychologic, and computed cranial tomography scan 
abnormalities in 2- to 10-year survivors of small-cell lung cancer. J Clin Oncol. 
1985 Dec;3(12):1659-67.
[83]
Fleck JF, Einhorn LH, Lauer RC, Schultz SM, Miller ME. Is prophylactic cranial 
irradiation indicated in small-cell lung cancer? J Clin Oncol. 1990 Feb;8(2):209-
14.
[84]
Varghese AM, Zakowski MF, Yu HA, Won HH, Riely GJ, Krug LM, et al. Small-
cell lung cancers in patients who never smoked cigarettes. J Thorac Oncol. 2014 
Jun;9(6):892-6.
[85]
Ou SH, Ziogas A, Zell JA. Prognostic factors for survival in extensive stage small 
cell lung cancer (ED-SCLC): the importance of smoking history, socioeconomic 
and marital statuses, and ethnicity. J Thorac Oncol. 2009 Jan;4(1):37-43.
[86]
American Cancer Society. Cancer facts and figures 2014 [Internet]. Atlanta: 
American 
Cancer 
Society; 
2014. 
Available 
from: 
http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acsp
c-042151.pdf.
[87]
Gaspar LE, McNamara EJ, Gay EG, Putnam JB, Crawford J, Herbst RS, et al. 
Small-cell lung cancer: prognostic factors and changing treatment over 15 years. 
Clin Lung Cancer. 2012 Mar;13(2):115-22.
[88]
Pietanza MC, Krug LM, Wu AJ, Kris MG, et al. Small Cell and Neuroendocrine 
Tumors of the Lung. In Devita, Hellman & Rosenberg, ed. Cancer: Principles and 
practice of Oncology. 10th ed. Philadelphia (PA): Lippincott, Williams & Wilkins; 
2015. p. 536-559.


Product:  MK-3475 
132
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
[89]
Simon GR, Turrisi A. Management of small cell lung cancer: ACCP evidence-
based clinical practice guidelines (2nd edition). Chest. 2007 Sep;132(3 
Suppl):324S-339S.
[90]
von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, et 
al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the 
treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999 Feb;17(2):658-
67.
[91]
O'Brien ME, Ciuleanu TE, Tsekov H, Shparyk Y, Cucevia B, Juhasz G, et al. 
Phase III trial comparing supportive care alone with supportive care with oral 
topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol. 2006 Dec 
1;24(34):5441-7.
[92]
Eckardt JR, von Pawel J, Pujol JL, Papai Z, Quoix E, Ardizzoni A, et al. Phase III 
study of oral compared with intravenous topotecan as second-line therapy in 
small-cell lung cancer. J Clin Oncol. 2007 May 20;25(15):2086-92. Erratum in: J 
Clin Oncol. 2007 Aug 1;25(22):3387.
[93]
Graus F, Dalmou J, Rene R, Tora M, Malats N, Verschuuren JJ, et al. Anti-Hu 
antibodies in patients with small-cell lung cancer: association with complete 
response to therapy and improved survival. J Clin Oncol. 1997 Aug;15(8):2866-
72.
[94]
Tanio Y, Watanabe M, Osaki T, Tachibana I, Kawase I, Kuritani T, et al. High 
sensitivity to peripheral blood lymphocytes and low HLA-class I antigen 
expression of small cell lung cancer cell lines with diverse chemo-radiosensitivity. 
Jpn J Cancer Res. 1992 Jul;83(7):736-45.
[95]
Yazawa T, Kamma H, Fujiwara M, Matsui M, Horiguchi H, Satoh H, et al. Lack 
of class II transactivator causes severe deficiency of HLA-DR expression in small 
cell lung cancer. J Pathol. 1999 Jan;187(2):191-9.
[96]
Koyama K, Kagamu H, Miura S, Hiura T, Miyabayashi T, Itoh R, et al. Reciprocal 
CD4+ T-cell balance of effector CD62Llow CD4+ and CD62LhighCD25+ CD4+ 
regulatory T cells in small cell lung cancer reflects disease stage. Clin Cancer Res. 
2008 Nov 1;14(21):6770-9.
[97]
Schultheis AM, Scheel AH, Ozretic L, George J, Thomas RK, Hagemann T, et al. 
PD-L1 expression in small cell neuroendocrine carcinomas. Eur J Cancer. 2015 
Feb;51(3):421-6.
[98]
Komiya T, Madan R. PD-L1 expression in small cell lung cancer. Eur J Cancer. 
2015 Sep;51(13):1853-5.


Product:  MK-3475 
133
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
[99]
Ishii H, Azuma K, Kawahara A, Yamada K, Imamura Y, Tokito T, et al. 
Significance of programmed cell death-ligand 1 expression and its association 
with survival in patients with small cell lung cancer. J Thorac Oncol. 2015 
Mar;10(3):426-30.
[100]
Miao L, Lu Y, Xu Y, Zhang G, Huang Z, Gong L, et al. PD-L1 and c-MET 
expression and survival in patients with small cell lung cancer. Oncotarget. 
Forthcoming 2016.
[101]
Berghoff AS, Ricken G, Wilhelm D, Rajky O, Widhalm G, Dieckmann K, et al. 
Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small 
cell lung cancer (SCLC). J Neurooncol. 2016 Oct;130(1):19-29.
[102]
Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. 
Cancer immunology. Mutational landscape determines sensitivity to PD-1
blockade in non-small cell lung cancer. Science. 2015 Apr 3;348(6230):124-8.
[103]
Ott PA, Felip E, Hiret S, Kim DW, Morosky A, Saraf S, et al. Pembrolizumab in 
Patients With Extensive-Stage Small Cell Lung Cancer: Updated Survival Results 
From KEYNOTE-028. Poster session presented at: IASLC 17th World 
Conference on Lung Cancer; 2016 Dec 4-7; Vienna, AUT.
[104]
Ardizzoni A, Hansen H, Dombernowsky P, Gamucci T, Kaplan S, Postmus P, et 
al. Topotecan, a new active drug in the second-line treatment of small-cell lung 
cancer: a phase II study in patients with refractory and sensitive disease. The 
European Organization for Research and Treatment of Cancer Early Clinical 
Studies Group and New Drug Development Office, and the Lung Cancer 
Cooperative Group. J Clin Oncol. 1997 May;15(5):2090-6.
[105]
Depierre A, von Pawel J, Hans K, Moro D, Clark P, Gatzemeier U, et al. 
Evaluation of topotecan (Hycamtin) in relapsed small cell lung cancer (SCLC). A 
multicenter phase II study [abstract]. Lung Cancer. 1997; 18(1 Suppl):35. Abstract 
no. 126.
[106]
Eckardt J, Gralla R, Palmer MC, Gandara D, Laplante J, Sandier A, et al. 
Topotecan (T) as Second-Line Therapy In Patients (Pts) with Small Cell Lung 
Cancer (SCLC): A Phase II Study [abstract]. Ann Oncol. 1996;7 Suppl 5:107. 
Abstract no. 513P.
[107]
Eckardt J, Depierre A, Ardizzoni A, Von Pawel J, Fields S. Pooled analysis of 
topotecan (T) in the second-line treatment of patients (pts) with sensitive small cell 
lung cancer (SCLC). Proc Am Soc Clin Oncol. 1997;16. Abstract no. 1624.


Product:  MK-3475 
134
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
[108]
Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, 
Powell SF, et al. Carboplatin and pemetrexed with or without pembrolizumab for 
advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 
cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Oct 9. [Epub 
ahead of print].
[109]
Foster NR, Renfro LA, Schild SE, Redman MW, Wang XF, Dahlberg SE, et al. 
Multitrial evaluation of progression-free survival as a surrogate end point for 
overall survival in first-line extensive stage small-cell lung cancer. J Thorac 
Oncol. 2015 Jul;10(7):1099-106.
[110]
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. 
Developing a common language for tumor response to immunotherapy: immune-
related response criteria using unidimensional measurements. Clin Cancer Res. 
2013 Jul 15;19(14):3936-43.
[111]
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. 
Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer. N Engl J Med. 
2015 Apr 19.
[112]
Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. 
Recommendations for the Use of WBC Growth Factors: American Society of 
Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015 Oct 
1;33(28):3199-212.
[113]
Gralla RJ, Roila F, Tonato M, Herrstedt J.  MASCC/ESMO Antiemetic Guideline 
2013: Multinational association of supportive care in cancer.
[114]
Maurer W, Bretz F. Multiple testing in group sequential trials using graphical 
approaches. Stat Biopharm Res 2013;5(4):311-20.
[115]
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using 
rank preserving structural failure time models. Commun Stat-Theor M 
1991;20(8):2609-31.
[116]
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 
1985;4:213-26.


Product:  MK-3475 
135
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 


Product:  MK-3475 
136
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, Sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.  Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."


Product:  MK-3475 
137
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease.  A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this trial as outlined in Section 7.1.3.4 will 
be used in various experiments to understand:

The biology of how drugs work

Biomarkers responsible for how a drug enters and is removed by the body

Other pathways drugs may interact with

The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical 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 the visit designated in the 


Product:  MK-3475 
138
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
trial flow chart.  If delayed, present consent at next possible Subject Visit.  Consent 
forms signed by the subject will be kept at the clinical trial site under secure storage 
for regulatory reasons.  
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens.  This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between subject identifiers 
and this unique code will be held at the trial site.  No personal identifiers will appear on 
the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.


Product:  MK-3475 
139
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and ask that their 
biospecimens not be used for Future Biomedical Research.  Subjects may withdraw 
consent at any time by contacting the principal investigator for the main trial. If medical 
records for the main trial are still available, the investigator will contact the Sponsor 
using 
the 
designated 
mailbox
(clinical.specimen.management@merck.com). 
Subsequently, the subject's specimens will be flagged in the biorepository and restricted 
to main study use only. If specimens were collected from study participants specifically 
for Future Biomedical Research, these specimens will be removed from the biorepository 
and destroyed. Documentation will be sent to the investigator confirming withdrawal 
and/or destruction, if applicable. It is the responsibility of the investigator to inform the 
subject of completion of the withdrawal and/or destruction, if applicable.  Any analyses 
in progress at the time of request for withdrawal/destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.


Product:  MK-3475 
140
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and subjects.  Subjects will not be identified by 
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. Risks include 
those associated with venipuncture to obtain the whole blood specimen. This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial.
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: Definitions for Genomic Biomarkers, 
Pharmacogenomics, Pharmacogenetics,
Genomic Data and Sample Coding 
Categories - E15; http://www.ich.org/LOB/media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/


Product:  MK-3475 
141
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
ECOG Performance Status 
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2
In bed <50% of the time. 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
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, 
McFadden ET, Carbone PP: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;5:649-655. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair.


Product:  MK-3475 
142
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Common Terminology Criteria for Adverse Events Version 4.0
The descriptions and grading scales found in the revised NCI CTCAE 4.0 will be utilized for 
AE reporting (http://ctep.cancer.gov/reporting/ctc.html).


Product:  MK-3475 
143
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 Criteria for 
Evaluating Response in Solid Tumors
A modification to RECIST Version 1.1* will be used in this study for subject management.
While either CT or MRI may be used utilized, as per RECIST 1.1, CT is the preferred 
imaging technique in this study. Details are provided in the Image Acquisition Guidelines.
* As published in the European Journal of Cancer:
New response evaluation criteria in solid tumours: revised RECIST guideline (Version 1.1). 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck 
S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij 
J. New response evaluation criteria in solid tumors: Revised RECIST guideline (Version 
1.1). Eur J Cancer. 2009 Jan;45(2):228-247. 


Product:  MK-3475 
144
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
List of Abbreviations
Abbreviation/Term
Definition
1L
first-line
2L
second-line
ADA
anti-drug antibodies
AE
adverse event
AEOSI
adverse event of special interest
ALT
alanine aminotransferase
ANC
Absolute neutrophil count
ASaT
All Subjects as Treated
AST
aspartate aminotransferase
AUC
area under the plasma drug concentration time curve
β-HCG
beta-human chorionic gonadotropin
BCG
Bacillus Calmette–Guérin
BICR
blinded independent central review
BSA
body surface area
CBC
complete blood count
CI
confidence interval
Cmax
maximum concentration
CR
complete response
CrCl
creatinine clearance
CSF
colony-stimulating factors
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DL
dose level
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
ECIs
events of clinical interest


Product:  MK-3475 
145
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Abbreviation/Term
Definition
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EORTC
European Organization for Research and Treatment of Cancer
EP
etoposide/platinum
EQ-5D-5L
European Quality of Life Five-dimension Five-level Scale Questionnaire
ERC
Ethics Review Committee
ES-SCLC
extensive stage small cell lung cancer
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone
FT4
free thyroxine
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
IA1
first interim analysis
IA2
second interim analysis
IB
Investigator’s Brochure
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (formerly International Conference on 
Harmonisation)
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgC
immunoglobulin constant
IgG
immunoglobulin G
IgV
immunoglobulin variable
IHC
immunohistochemistry


Product:  MK-3475 
146
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Abbreviation/Term
Definition
INR
international normalized ratio
irAE
immune-related adverse event
IRB
Institutional Review Board
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
IRT
interactive response technology
ITT
intention-to-treat
IV
intravenous
IVRS/IWRS
interactive voice response system/integrated web response system
LDH
lactate dehydrogenase
LS-SCLC
limited-stage small cell lung cancer
MRI
magnetic resonance imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
N/A
not applicable
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PBPK
physiologically based pharmacokinetics
PCI
prophylactic cranial irradiation
PD
progressive disease
PD-1
programmed cell death protein-1
PD-L1
programmed cell death-ligand 1
PD-L2
programmed cell death-ligand 2
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PRO
patient-reported outcome 
PT
prothrombin time
Q2W
every 2 weeks
Q3W
every 3 weeks
QLQ-C30
Quality of Life Questionnaire Core 30


Product:  MK-3475 
147
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
Abbreviation/Term
Definition
QLQ-LC13
Quality of Life Questionnaire and Lung Cancer Module 13
RBC
red blood cell
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RNA
ribonucleic acid
SAE
serious adverse events
SAP
Statistical Analysis Plan
SCLC
small cell lung cancer
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOC
standard of care
sSAP
supplemental statistical analysis plan
T1DM
Type 1 diabetes mellitus
T3
triiodothyronine
TB
Bacillum Tuberculosis
TIL
tumor-infiltrating lymphocyte
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
WBRT
whole brain radiation therapy


Product:  MK-3475 
148
Protocol/Amendment No.:  604-09 
MK-3475-604-09 Final Protocol
23-Apr-2019
Confidential
13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED


MK-3475
PAGE 1
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
Supplemental Statistical Analysis Plan (sSAP)
0575BN
082JZZ


MK-3475
PAGE 2
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
TABLE OF CONTENTS
1. INTRODUCTION .........................................................................................................5
2. SUMMARY OF CHANGES.........................................................................................5
3. STATISTICAL ANALYSIS PLAN SUMMARY ........................................................5
3.1 RESPONSIBILITY FOR ANALYSES/IN-HOUSE BLINDING .................6
3.2 HYPOTHESES/ESTIMATION .....................................................................7
3.3 ANALYSIS ENDPOINTS .............................................................................7
3.3.1
Efficacy Endpoints..............................................................................7
3.3.2
Safety Endpoints.................................................................................8
3.3.3
Patient Reported Outcome (PRO) Endpoints .....................................8
3.4 ANALYSIS POPULATIONS ........................................................................9
3.4.1
Efficacy Analysis Populations............................................................9
3.4.2
Safety Analysis Populations ...............................................................9
3.4.3
PRO Analysis Population ...................................................................9
3.5 STATISTICAL METHODS...........................................................................9
3.5.1
Statistical Methods for Efficacy Analyses........................................10
3.5.1.1
Progression-Free Survival (PFS) ..........................................10
3.5.1.2
Overall Survival (OS)...........................................................11
3.5.1.3
Objective Response Rate (ORR) ..........................................12
3.5.1.4
Duration of Response (DOR) ...............................................12
3.5.2
Statistical Methods for Safety Analyses ...........................................13
3.5.3
Summaries of Baseline Characteristics and Demographics .............15
3.5.4
Patient Reported Outcomes (PRO) Analysis....................................15
3.6 INTERIM ANALYSES................................................................................19
3.7 MULTIPLICITY ..........................................................................................19
3.8 SAMPLE SIZE AND POWER CALCULATIONS.....................................23
3.9 SUBGROUP ANALYSES AND EFFECT OF BASELINE
FACTORS ....................................................................................................23
3.10
COMPLIANCE (MEDICATION ADHERENCE) ................................24
3.11
EXTENT OF EXPOSURE.....................................................................24
4. REFERENCES ............................................................................................................24
0575BN
082JZZ


MK-3475
PAGE 3
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
List of Tables
Table 1 Censoring rules for Primary and Sensitivity Analyses of PFS ....................................... 11
Table 2  Censoring Rules for DOR............................................................................................... 12
Table 3 Efficacy Analysis Methods for Primary and Secondary Efficacy Endpoints.................. 13
Table 4 Analysis Strategy for Safety Parameters ......................................................................... 14
Table 5 Mapping Relative Day to Analysis Visit ......................................................................... 16
Table 6 Censoring Rules for Time-to-Deterioration..................................................................... 18
Table 7   Efficacy Boundaries and Properties for Progression-free Survival Analyses ............... 21
Table 8    Efficacy Boundaries and Properties for Overall Survival Analyses............................. 22
Table 9  Possible Alpha-levels and Approximate ORR Difference Required to Demonstrate 
Efficacy for ORR .................................................................................................................. 23
0575BN
082JZZ


MK-3475
PAGE 4
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
List of Figures
Figure 1 Multiplicity Graph for Type I Error Control .................................................................. 20
0575BN
082JZZ


MK-3475
PAGE 5
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
1. INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of confirmatory 
analyses for this trial, this supplemental SAP provides additional statistical analysis details/data 
derivations and documents modifications or additions to the analysis plan that are not “principal” 
in nature and result from information that was not available at the time of protocol finalization.  
2. SUMMARY OF CHANGES
This sSAP was amended to update the timing of the final analysis to match the SAP of protocol 
amendment 09.
3. STATISTICAL ANALYSIS PLAN SUMMARY
Key elements of the statistical analysis plan are summarized below; the comprehensive plan is 
provided in Sections 3.2 through 3.11.  
Study Design Overview
This is a Phase 3, randomized, multi-site, double-blind study of 1L 
pembrolizumab+Etoposide/Platinum (EP) versus saline placebo+EP in 
Extensive Stage Small Cell Lung Cancer ES-SCLC 
Treatment Assignment
Approximately 430 subjects will be randomized in a 1:1 ratio to receive 
pembrolizumab+EP or saline placebo+EP. The stratification factors used for 
this study are a) cisplatin vs carboplatin, b) ECOG status (0 vs 1), and, c) 
LDH at baseline (≤ vs > ULN).  This is a double-blind study.
Analysis Populations
Efficacy: Intention-to-Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoints
1)
PFS per RECIST 1.1 assessed by BICR
2)
Overall survival (OS)
Secondary Endpoints
3)
ORR per RECIST 1.1 assessed by BICR
4)
DOR per RECIST 1.1 assessed by BICR
5)
AEs
Statistical Methods for
Key Efficacy Analyses
The 
primary 
hypotheses 
will 
be 
evaluated 
by 
comparing 
1L 
pembrolizumab+EP to 1L saline placebo+EP based on PFS per RECIST 1.1 
(BICR) and OS in subjects with ES-SCLC using a stratified log-rank test. 
Hazard ratios (HRs) will be estimated 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.  There are no 
Tier 1 safety parameters in this trial.  All safety parameters are considered 
either Tier 2 or Tier 3.  Tier 2 parameters will be assessed via point estimates 
with 95% CIs provided for between-group comparisons; only point estimates 
by treatment group are provided for Tier 3 safety parameters.  The between-
treatment difference will be analyzed using the Miettinen and Nurminen 
method.
Interim Analyses
Two interim analyses are planned in this study.  Results will be reviewed by
the external DMC.  Details are provided in Section 3.6 – Interim Analyses.

Interim analysis 1
0575BN
082JZZ


MK-3475
PAGE 6
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
o Timing: To be performed approximately 18 months from study 
start, where study start is the date on which the first subject 
was randomized.
o Purpose: Interim PFS and OS analyses to demonstrate superiority of 
pembrolizumab+EP over saline placebo+EP.

Interim analysis 2
o Timing: To be performed approximately 22 months from study 
start. 
o Purpose: Final PFS analysis and interim OS analysis to demonstrate 
superiority of pembrolizumab+EP over saline placebo+EP

Final analysis
o Timing: To be performed after a minimum of 294 deaths are 
observed or approximately 31 months after first subject enrolled, 
whichever occurs later.
o Purpose: Primary analysis of OS to demonstrate superiority of 
pembrolizumab+EP over saline placebo+EP.
Multiplicity
The family-wise type I error rate for this study is strongly controlled at 2.5% 
(one-sided) for the hypothesis testing of ORR, PFS and OS. The multiplicity 
strategy will follow the graphical approach of Maurer and Bretz as described 
in Section 3.7 – Multiplicity, with 0.6% and 1.9% alpha initially allocated to 
the PFS and OS hypotheses, respectively. Group sequential methods will be 
used to allocate alpha between the interim and final analyses for PFS and OS 
endpoints. Further details of the interim analysis strategy can be found in 
Section 3.6 – Interim Analyses.
Sample Size and Power
The planned sample size is approximately 430 subjects. The actual sample 
size is 453 subjects. For PFS, based on 387 events, the study has 95.6% 
power to detect a HR of 0.65 (pembrolizumab+EP vs saline placebo+EP) at 
α=0.6% (one-sided). For OS, based on a minimum of 294 events, the study 
has at least 94.4% power to detect a HR of 0.65 (pembrolizumab+EP vs 
saline placebo+EP) at α=1.9% (one-sided).  
3.1
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 for study treatment assignment for 
this protocol and the randomization will be implemented in IVRS/IWRS.
Planned interim analyses are described in Section 3.6. Participant-level unblinding will be 
restricted to an external unblinded statistician and scientific programmer performing the interim 
analysis, who will have no other responsibilities associated with the study.
An external DMC will be convened to review accumulating safety data to provide an opportunity 
to terminate the study early if there are concerns regarding safety. Treatment-level results at the 
interim analyses will be provided by the external unblinded statistician to the DMC. The DMC 
will also review the unblinded efficacy results at the planned interim analyses. The DMC 
responsibilities and review schedules will be outlined in the DMC charter. The recommendation 
of the DMC will be communicated to the Sponsor EOC and, in the event of a recommendation to 
0575BN
082JZZ


MK-3475
PAGE 7
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
halt the trial early due to safety concerns, to the appropriate regulatory agencies. If the DMC 
recommends modifications to the design of the protocol or discontinuation of the study, the EOC
may be unblinded to results at the treatment level in order to act on these recommendations.
Participant-level unblinding to support regulatory filing, should one occur before the end of the 
study, will be restricted to a designated Sponsor/MSD team, who will have no other responsibilities 
associated with the study.
The extent to which individuals are unblinded with respect to the results will be documented. 
Additional logistical details, revisions to the above plan, and data monitoring guidance will be 
provided in the DMC Charter.
3.2
HYPOTHESES/ESTIMATION
Objectives and hypotheses of the study are stated in Protocol Section Section 3.0 – Objective(s) 
and hypothesis(es).
3.3
ANALYSIS ENDPOINTS
Efficacy and safety endpoints that will be evaluated are listed below.
3.3.1
Efficacy Endpoints
Primary
Progression-free Survival – RECIST 1.1 assessed by BICR
Progression-free-survival is defined as the time from randomization to the first documented 
disease progression per RECIST 1.1 based on BICR or death due to any cause, whichever occurs 
first. See Section 3.5.1 – Statistical Methods for Efficacy Analyses for definition of censoring.
Overall Survival
Overall Survival is defined as the time from randomization to death due to any cause.  Subjects
without documented death at the time of analysis will be censored at the date of last known 
contact.
Secondary
Objective Response Rate – RECIST 1.1 assessed by BICR
Objective Response Rate is defined as the proportion of subjects who have a CR or a PR. 
Responses are based on confirmed assessments by BICR per RECIST 1.1.
Duration of Response – RECIST 1.1 assessed by BICR
For subjects who demonstrate CR or PR, DOR is defined as the time from first documented 
evidence of CR or PR until disease progression or death due to any cause, whichever occurs first.
Exploratory 
0575BN
082JZZ


MK-3475
PAGE 8
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
Exploratory endpoints of this study include:
1. ORR, DOR and PFS per immune-related RECIST (irRECIST) as assessed by the 
investigator.
2. ORR and PFS per RECIST 1.1 by BICR, and OS by PD-L1 expression (TPS <1% versus 
≥1%, CPS <1 versus ≥1).
3.3.2
Safety Endpoints
Safety measurements are described in the protocol in Section 4.2.3.3 – Safety Endpoints and 
Section 7 – Trial Procedures. Safety and tolerability will be assessed by clinical review of all 
relevant parameters including AEs, laboratory tests, and vital signs. Safety parameters to be 
analyzed include, but are not limited to, AEs, SAEs, fatal AEs, and laboratory changes.
Furthermore, specific events will be collected and designated as ECIs as described in Section 7.2.3
– Immediate Reporting of Adverse Events in the protocol.
3.3.3
Patient Reported Outcome (PRO) Endpoints
Secondary
Mean change in Score
Mean change from baseline at Week 18 in the European Organization for Research and Treatment 
of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/quality 
of life scores (Items 29-30). If the overall PRO completion or compliance rates at Week 18 are less 
than 60% or 80%, respectively, then the primary analysis time point will be moved to the next 
earliest time point in which the rates are at least 60% for completion and at least 80% for 
compliance.
Time-to-deterioration (TTD)
For the EORTC QLQ-C30 and QLQ-LC13, a 10 points or greater worsening from baseline for 
each scale represents a clinically relevant deterioration based on prior literature. Time-to-
deterioration is defined as the time to first onset of 10 or more (out of 100) deterioration from 
baseline in a given scale/sub-scale/item and confirmed by a second adjacent 10 or more 
deterioration from baseline under a right-censoring rule. The endpoint of interest is the composite 
endpoint of cough (QLQ-LC-13 Item 1), chest pain (QLQ-LC-13 Item 10), or dyspnea (QLQ-C30 
Item 8).
Exploratory 
The PRO endpoints which will be used for exploratory analyses are:

mean change in score from baseline at weeks 18 of Physical functioning scale (QLQ-C30 Items 
1-5) and EQ-5D-5L Health State Score using visual analogue scale (VAS)

time-to deterioration for Global Health Status/QoL scale (QLQ-C30 Items 29-30) and Physical 
functioning scale (QLQ-C30 Items 1-5)
0575BN
082JZZ


MK-3475
PAGE 9
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     

Proportion improved/stable in Global Health Status/QoL scale (QLQ-C30 Items 29-30) and
Physical functioning scale (QLQ-C30 Items 1-5). Improved/Stable is defined as an 
improvement or less than 10 points worsening in score from baseline at any time during the 
trial and confirmed by improvement or less than 10 points worsening at the next consecutive 
visit.
3.4
ANALYSIS POPULATIONS
3.4.1
Efficacy Analysis Populations
The analyses of primary efficacy endpoints are based on the intention-to-treat (ITT) population, 
i.e., 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 3.5 Statistical Methods.
3.4.2
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 1 dose of 
study treatment.  Subjects will be included in the treatment group corresponding to the study 
treatment they actually received.  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 1 cycle but receives the correct treatment 
for all other cycles will be analyzed according to the correct treatment group and a narrative will 
be provided for any events that occur during the cycle for which the subject is incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of study 
treatment is required for inclusion in the analysis of each specific parameter.  To assess change 
from baseline, a baseline measurement is also required.
3.4.3
PRO Analysis Population
The primary analysis approach for the pre-specified 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.
3.5
STATISTICAL METHODS
This section describes the statistical methods that address the primary, secondary and exploratory
objectives as stated in the protocol.
Statistical methods for efficacy analyses are described in Section 3.5.1. Statistical testing and 
inference for safety analyses are described in Section 3.5.2. Efficacy results that will be deemed 
to be statistically significant after consideration of the Type I error control strategy are described 
in Section 3.7, Multiplicity. Nominal p-values may be computed for other efficacy analyses as a 
measure of strength of association between the endpoint and the treatment effect rather than formal 
tests of hypotheses.  
0575BN
082JZZ


MK-3475
PAGE 10
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
3.5.1
Statistical Methods for Efficacy Analyses
3.5.1.1
Progression-Free Survival (PFS)
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each treatment 
group. The treatment difference in PFS will be assessed by the stratified log-rank test. A stratified 
Cox proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (ie, the HR) between the treatment arms. The HR and its 
95% CI from the stratified Cox model with Efron's method of tie handling and with a single 
treatment covariate will be reported. The stratification factors used for randomization will be 
applied to both the stratified log-rank test and the stratified Cox model. In case there is a stratum
which has =<10 subjects, the stratum will be combined with the stratum with the next smallest
number of subjects till the number of subject in the smallest stratum is >10. The same strategy will 
be used for determining the strata for the stratified analyses of OS, ORR and PROs.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. For the primary analysis, for the subjects who have PD, the true date of disease 
progression will be approximated by the date of the first assessment at which PD is objectively 
documented per RECIST 1.1 (BICR), 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, 
we will perform 2 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. The censoring rules for primary and sensitivity analyses are summarized 
in Table 1.  
0575BN
082JZZ


MK-3475
PAGE 11
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
Table 1 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 
otherwise
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 missed disease 
assessments
Progressed at date of 
documented 
PD 
or 
death
Censored at last disease 
assessment prior to the ≥ 
2 
missed 
disease 
assessment
Progressed 
at 
date 
of 
documented PD or death
Restricted Mean Survival Time (RMST) method (Uno et al. [5]) may be conducted for PFS to 
account for the possible non-proportional hazards effect.
3.5.1.2
Overall Survival (OS)
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test (based on the 
stratification factor defined in Section 5.4 of the Protocol– Stratification). A stratified Cox 
proportional hazard model with Efron's method of tie handling will be used to assess the magnitude 
of the treatment difference (ie, the HR). The HR and its 95% CI from the stratified Cox model 
with a single treatment covariate will be reported. The same stratification factors as used for PFS 
analysis in the overall population will be applied to both the stratified log-rank test and the 
stratified Cox model. Restricted Mean Survival Time (RMST) method may be conducted for OS 
to account for the possible non-proportional hazards effect.
Since subjects in the Placebo+EP arm are expected to discontinue from the study earlier compared 
to subjects in the pembrolizumab arm because of earlier onset of PD and may switch to another 
anti PD-1 treatment following confirmation of PD, adjustment for the effect of crossover on OS 
may be performed based on recognized methods, (eg, the Rank Preserving Structural Failure Time 
(RPSFT) model proposed by Robins and Tsiatis ), based on an examination of the appropriateness 
of the data to the assumptions required by the method used.  
0575BN
082JZZ


MK-3475
PAGE 12
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
3.5.1.3
Objective Response Rate (ORR)
Stratified Miettinen and Nurminen’s method will be used for comparison of ORR between the 
treatment groups.  The difference in ORR and its 95% CI from the stratified Miettinen and 
Nurminen method with strata weighting by sample size will be provided.  The same stratification 
factors as used for PFS and OS analyses will be used as stratification factors in the analysis.
3.5.1.4
Duration of Response (DOR)
For subjects who demonstrate CR or PR, DOR is defined as the time from first documented 
evidence of CR or PR until disease progression or death due to any cause, whichever occurs first.  
Censoring rules for DOR are summarized in Table 2.  DOR will be assessed using RECIST 1.1 by 
BICR.
For each DOR analysis, a corresponding summary of the reasons responding subjects are 
censored will also be provided.  Subjects who are alive, have not progressed, have not initiated 
new anti-cancer treatment, have not been determined to be lost to follow-up, and have had a 
disease assessment within ~5 months of the data cutoff date are considered ongoing responders 
at the time of analysis.  If a subject meets multiple criteria for censoring, the censoring criterion 
that occurs earliest will be applied.
Table 2 Censoring Rules for DOR
Situation
Date of 
Progression or Censoring
Outcome
No progression nor death, no new anti-
cancer therapy initiated
Last 
adequate 
disease 
assessment
Censor
(non-event)
No progression nor death, new anti-
cancer therapy initiated
Last 
adequate 
disease 
assessment before new anti-
cancer therapy initiated
Censor
(non-event)
Death 
or 
progression 
after 
≥2 
consecutive missed disease assessments
Last 
adequate 
disease 
assessment prior to ≥2 missed 
adequate disease assessments
Censor
(non-event)
Death or progression after ≤1 missed 
adequate disease assessments
Progressive disease or death
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
Table 3 summarizes the key efficacy analyses.
0575BN
082JZZ


MK-3475
PAGE 13
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
Table 3 Efficacy Analysis Methods for Primary and Secondary Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis Population
Missing Data Approach
Primary Analyses:
PFS (RECIST 1.1)
by 
BICR
Testing: Stratified Log-
rank test
Estimation: Stratified Cox 
model with Efron's tie 
handling method 
ITT
Censored according to 
rules in Table 1
OS
Testing: Stratified Log-
rank test
Estimation: Stratified Cox 
model with Efron's tie 
handling method
ITT
Censored at last known 
alive date
Secondary Analyses:
ORR (RECIST 1.1) by 
BICR
Stratified Miettinen and 
Nurminen method
ITT
Subjects with missing 
data are considered non-
responders
DOR (RECIST 1.1) by 
BICR
Summary statistics using 
Kaplan-Meier method
All responders in ITT 
Non-responders 
are 
excluded in analysis
The strategy to address multiplicity issues with regard to multiple treatment comparisons, multiple 
endpoints, multiple populations, and interim analyses is described in Section 3.6, Interim Analyses 
and in Section 3.7, Multiplicity.
3.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including AEs
and laboratory tests.
The analysis of safety results will follow a tiered approach (Table 4).  The tiers differ with respect 
to the analyses that will be performed. Safety parameters or AEs of special interest that are 
identified a priori constitute “Tier 1” safety endpoints that will be subject to inferential testing for 
statistical significance with p-values and 95% CIs 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% CIs provided for between-group comparisons; only point estimates by 
treatment group are provided for Tier 3 safety parameters.
Adverse events of special interest (AEOSIs) that are immune-mediated or potentially immune-
mediated are well documented and will be evaluated separately; however, these events have been 
characterized consistently throughout the pembrolizumab clinical development program and 
determination of statistical significance is not expected to add value to the safety evaluation.  
Further, pembrolizumab added to platinum doublets studied thus far have not been found to impact 
safety, and in an ongoing Phase 1 clinical trial, the chemotherapeutic regimen used here with 
pembrolizumab has not led to increased toxicity (NCT02402920).  Additionally, there are no 
known AEs associated with subjects with SCLC for which determination of a p-value is expected 
0575BN
082JZZ


MK-3475
PAGE 14
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
to impact the safety assessment.  For these reasons, there are no events of interest that warrant 
inferential testing.  Therefore, there are no Tier I events in this study.
Adverse experiences (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 10% was chosen for membership in Tier 2 because subjects enrolled in 
this study are in critical condition and usually experience various AEs of similar types regardless 
of treatment, events reported less frequently than in 10% of subjects would obscure the assessment 
of the overall safety profile and add little to the interpretation of potentially meaningful treatment 
differences. In addition, Grades 3 to 5 AEs (≥5% of subjects in one of the treatment arms) and 
SAEs (≥5% of subjects in one of the treatment arms) will be considered Tier 2 events. For Tier 2 
events, 95% CIs 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 , an 
unconditional, asymptotic method. Because many 95% CIs may be provided without adjustment 
for multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in safety 
review, not a formal method for assessing the statistical significance of the between-treatment
differences. 
For laboratory parameters, the number and percentage of subjects with increases from baseline in 
laboratory test toxicity grades based on the highest post-baseline toxicity grade and shift of toxicity 
grade from baseline to the worst post-baseline toxicity grade will be summarized by treatment arm.
Table 4 Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE (≥10% of subjects in one of the 
treatment arms)
X
X
Any Grades 3 to 5 AE (≥5% of subjects in one of 
the treatment arms)
X
X
Any serious AE (≥5% of subjects in one of the 
treatment arms)
X
X
Tier 3
Any AE
X
Any change from baseline results (laboratory 
tests)
X
Abbreviations: AE=adverse event, CI=confidence interval
0575BN
082JZZ


MK-3475
PAGE 15
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
Exposure-Adjusted Approach
To properly account for the potential difference in follow-up time between the study arms, which 
is expected to be longer in the pembrolizumab arm, summary of AE incidence adjusted for 
treatment exposure analyses may be provided as appropriate.  
3.5.3
Summaries of Baseline Characteristics and Demographics
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 randomized, and the primary reason for 
discontinuation will be displayed.  Demographic variables (such as age) and baseline 
characteristics will be summarized by treatment either by descriptive statistics or categorical 
tables.  The reasons for exclusion from the ITT population (if any) will be summarized.
3.5.4
Patient Reported Outcomes (PRO) Analysis 
This section describes the planned analyses for the key PRO endpoints. As there is no formal 
hypothesis testing for PRO endpoints, nominal p-values will be provided for treatment 
comparisons of pembrolizumab combination therapy vs. standard of care. No multiplicity 
adjustment will be performed. 
PRO compliance summary
Completion and compliance of QLQ-C30, LC13 and EQ-5D-5L by visit and by treatment will be 
described within the 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 is defined as the percentage of observed visit over number of randomized 
subjects 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
The reasons of non-completion and non-compliance will be provided in supplementary table:
–
Completed as scheduled
–
Not completed as scheduled
–
Off-study: not scheduled to be completed.
%1
-==


MK-3475
PAGE 16
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
In addition, reasons for non-completion as scheduled of these measures will be collected using 
“miss_mode” forms filled by site personnel and will be summarized in table format. An instrument 
is considered complete as at least one valid score available according to the missing item rules 
outlined in the EORTC Manual.
The schedule for PRO data collection:
PROs were scheduled to be completed every cycle for Cycles 1 to 9 while the subject was
receiving study treatment, then every other cycle up to Cycle 17 (ie, Cycles 11, 13, 15, and 17).  
PROs were also scheduled to be obtained at the Treatment Discontinuation visit and 30-day 
Safety Follow-up visit. For analysis purposes, relative visit days were mapped into analysis 
visits. The general rule of mapping relative day to analysis visit is provided in Table 5. Due to 
space restrictions visit windows until week 30 are provided.
Table 5 Mapping Relative Day to Analysis Visit
Analysis of Mean Score Change
To assess the treatment effects on the PRO, for each continuous endpoint defined, a constrained 
longitudinal data analysis (cLDA) method proposed by Liang and Zeger [1] will be used. This 
model assumes a common mean across treatment groups at baseline and a different mean for each 
treatment at each of the post-baseline time points. In this model, the response vector consists of 
baseline and the values observed at each post-baseline time point. Time is treated as a categorical 
variable so that no restriction is imposed on the trajectory of the means over time. The analysis 
model will include the PRO score as the response variable, with covariates including treatment by 
study visit interaction, and the same stratification factors as used in the stratified analyses of 
efficacy endpoints. The treatment difference in terms of mean PRO score change from baseline at 
week 18 (time defined by time windows instead of study visit) will be estimated and tested from 
this model. If the overall PRO completion or compliance rates at Week 18 are less than 60% or 
80%, respectively, then the primary analysis time point will be moved to the next earliest time 
point in which the rates are at least 60% for completion and at least 80% for compliance.
An unstructured covariance matrix will be used to model the correlation among repeated 
measurements. The cLDA model is specified as follows:
k
t
j
X
t
I
Y
E
i
jt
ijt
,..
2,1,0
    
2
,1
    
,
)
0
(
)
(
0









Treatment
Week
Week
Baseline
3
6
9
12
15
18
21
24
30
Day
1
21
42
63
84
105
136
147
168
210
Range
[-7,7]
[8,31]
[32,52]
[53,73]
[74,94]
[95,115]
[116,136]
[137,157]
[158,188]
[189,230]
0575BN
082JZZ


MK-3475
PAGE 17
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
where Yijt is the PRO score for subject i, with treatment assignment j, at visit t, 
0

is the baseline 
mean for all treatment groups,
jt

is the mean change from baseline for treatment group j at time 
t, 
i
X is the stratification factor (binary) vector for this patient, and is the coefficient vector for 
stratification factors.
Based on the cLDA model, group-wise comparisons 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. In addition, model-based lsmean score with 95% C.I. will be 
provided by treatment group and study visit.
The analysis of mean change will be based primarily under the assumption of missing-at-random 
(MAR) mechanism. The cLDA model implicitly treats missing data as missing at random (MAR). 
Analyses of change from baseline to Week 18 will be displayed in tables for the following scales 
as listed in section 3.2.3:  EORTC QLQ-C30 GHS/QoL (QLQ-C30 Items 29-30), Physical 
functioning scale (QLQ-C30 Items 1-5), and EQ-5D-5L VAS.
The empirical mean change (with 95% CIs) from baseline across time will be displayed graphically 
for the following scales:  EORTC QLQ-C30 GHS/QoL (QLQ-C30 Items 29-30), Physical 
functioning scale (QLQ-C30 Items 1-5), and EQ-5D-5L VAS.
Analyses of LS mean change (95% CI) from baseline to Week 18 will be displayed in bar plot 
format for the following questionnaires in 3 separate figures: 1) EORTC QLQ-C30 global health 
status and functional status scales, 2) EORTC QLQ-C30 symptom scales, 3) EORTC QLQ-LC13 
scales.
0575BN
082JZZ


MK-3475
PAGE 18
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
Time-to-Deterioration (TTD) Analysis
The TTD is defined as the time to first onset of 10 or more points deterioration from baseline with 
confirmation under right-censoring rule. The non-parametric Kaplan-Meier method will be used 
to estimate the deterioration curve in each treatment group. The estimate of median time to 
deterioration and its 95% confidence interval will be obtained from the Kaplan-Meier survival 
estimates. The treatment difference in TTD will be assessed by the stratified log-rank test. A 
stratified Cox proportional hazard model with Efron's method of tie handling and with a single 
treatment covariate will be used to assess the magnitude of the treatment difference (hazard ratio). 
The same stratification factors as used for efficacy endpoints will be used as stratification factors 
for both Cox model and log-rank test.
The primary approach for the time-to-deterioration analysis will be based on the assumption of 
non-informative censoring. The patients who do not have deterioration on the last date of 
evaluation will be censored. Table 6 provides censoring rule for TTD analysis.
Table 6 Censoring Rules for Time-to-Deterioration 
Scenario
Outcome
No baseline assessments
Right censored at treatment start date
Deterioration documented
Event observed at time of assessment (first 
deterioration)
Ongoing or discontinued from study without 
deterioration
Right censored at time of last assessment
Analysis of Overall Improvement/Stability
Overall Improved/Stable rate will be calculated as the percentage of subjects who have 
improvement or less than 10 points worsening in score from baseline at any time during the trial 
and confirmed by an improvement or a less than 10 points worsening at the next consecutive visit. 
The stratified Miettinen and Nurminen method will be used for comparison of the overall 
improvement/stability
rate between the treatment groups. The difference in overall 
improvement/stability rate and its 95% CI from the stratified Miettinen and Nurminen method with 
strata weighting by sample size will be provided. The same stratification factors as used for 
efficacy endpoints will be used for analysis.
0575BN
082JZZ


MK-3475
PAGE 19
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
3.6
INTERIM ANALYSES
Two interim efficacy analyses are planned for this study.

The first interim analysis (IA1) will be performed approximately 18 months from study 
start, 3.5 months after the last patient was enrolled.  PFS and OS will be evaluated at IA1.  
ORR p-value from IA1 may be evaluated for statistical significance if PFS and OS null 
hypotheses are rejected at IA1 or at a later analysis time.

The second interim analysis (IA2) will be performed approximately 22 months from study 
start, 7.5 months after the last patient was enrolled. The second interim analysis evaluation 
of OS and the final evaluation of PFS will be performed at this time.    

The final analysis will evaluate OS only. It is planned when a minimum of 294 deaths have 
been observed or approximately 31 months after first subject enrolled, whichever occurs 
later. 
In addition to the formal efficacy analyses, the DMC will conduct regular safety monitoring, the 
timing of which is specified in the DMC charter. Decisions to stop the trial early will be based 
on DMC recommendations with review by the EOC.
Type I error control for the efficacy analyses as well as efficacy bounds are described in the next 
section.
3.7
MULTIPLICITY
The trial uses the graphical method of Maurer and Bretz to control multiplicity for multiple 
hypotheses as well as interim analyses. Figure 1 shows the initial one-sided α allocation for each 
hypothesis in the ellipse representing the hypothesis.  The weights for reallocation from each 
hypothesis to the others are represented in the boxes on the lines connecting hypotheses.
0575BN
082JZZ


MK-3475
PAGE 20
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
Note: If both PFS and OS null hypotheses are rejected, the reallocation strategy allows testing of ORR at 
alpha=0.025.
Figure 1 Multiplicity Graph for Type I Error Control
Progression-free Survival
If the null hypothesis for OS is rejected, shows that its α=0.019 is essentially fully reallocated to 
PFS hypothesis testing.  Thus, the PFS null hypothesis Figure 1 may be tested at α=0.006 or at
α=0.025. For PFS hypotheses, the targeted number of events at the final PFS analysis will be 387. 
A Lan-DeMets O'Brien-Fleming spending function will be used for information fraction-based 
alpha-spending to generate the group sequential design. The bounds provided in Table 7 are based 
on the assumption that the number of events at IA1 and IA2 are 332 and 387 respectively. The 
actual boundaries and the nominal alpha level will be determined based on the actual number of 
PFS events observed at the time of the analyses and from the overall alpha level after any potential 
alpha-shifting as the result of a successful OS analysis. The final PFS analysis at IA2 will use the 
remaining Type I error not spent at IA1, regardless of the actual number of PFS events observed.  
The p-value bound at the final PFS analysis will be calculated by considering the correlation 
between the test statistics as determined by the actual number of PFS events at IA1 and the final 
PFS analysis at IA2. The bounds given in Table 7 will be adjusted accordingly.
0575BN
082JZZ


MK-3475
PAGE 21
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
Table 7   Efficacy Boundaries and Properties for Progression-free Survival Analyses
Analysis
Targeted 
Analysis 
Time
Cumulative 
alpha 
spent3
Efficacy Bars3
IA1 (86%2)
Around 18 months 
from study start1
0.003

(One-sided) 
p-
value <0.003
Observed HR <~0.74
IA2 (100%2)
Around 22 months 
from study start1
0.006

(One-sided) 
p-
value <0.0051
Observed HR <~0.77
1Study start is defined as the date when the first subject was randomized.
2Percentage of expected number of events at final analysis targeted at interim analysis
3Nominal alpha, boundaries and cumulative alpha are based on the assumption that 332 and 
387 events are at IA1 and IA2 respectively. The p-value boundaries will be updated at the time 
of analyses based on actual number of PFS events.
Note that if the α-reallocation from OS hypothesis testing occurs at the final analysis after 
hypothesis testing for PFS has been completed, the previously computed PFS test statistic for the 
PFS final analysis may be re-evaluated based on the updated bounds. 
Overall Survival
The OS hypothesis may be tested at α=0.019 (initially allocated α) or at α=0.025 (if PFS null 
hypothesis is rejected) following the multiplicity strategy as outlined in Figure 1 bounds and 
boundary properties for OS hypothesis testing at the initial alpha level are demonstrated in Table 8  
The alpha spending at each interim analysis is determined using a Lan-DeMets O'Brien-Fleming 
spending function, and the information fraction (ratio of the actual number of events at the 
interim analysis relative to a targeted 294 events at the final analysis). The final analysis will use 
the remaining Type I error not spent at earlier analyses, regardless of the number of events 
observed at the final analysis. The p-value bounds at second interim and final analysis will be 
calculated by considering the correlation between the test statistics as determined by the actual 
number of OS events at the previous and current analysis. The p-value bounds at each analysis 
time may also be updated after potential alpha-shifting as the result of a successful PFS analysis.
0575BN
082JZZ


MK-3475
PAGE 22
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
Table 8    Efficacy Boundaries and Properties for Overall Survival Analyses
Analysis
Targeted 
Analysis 
Time
Cumulative 
alpha spent3
Efficacy Bars3
IA1 (60%2)
Approximately
18 
months from study 
start1
0.0024

(One-sided) 
p-value 
<0.0024

Observed HR <~0.65 
IA2 (76%2)
Approximately 
22 
months from study 
start1
0.0071

(One-sided) 
p-value 
<0.0064

Observed HR <~0.72 
FA (100%2)
Approximately 
294 
deaths observed in 
two
arms; 
approximately
31 
months from study 
start
0.019

(One-sided) 
p-value 
<0.0167

Observed HR <~0.78 
1Study start is defined as the date when the first subject was randomized.
2Percentage of expected number of events at final analysis targeted at interim analysis
3 Nominal alpha, boundaries and cumulative alpha are based on the number of deaths expected 
assuming the projected number of events using protocol assumptions, i.e., 175, 224 and 294 at 
IA1, IA2 and final analysis respectively. The p-value boundaries will be updated at the time of 
analyses based on actual number of deaths.
The DMC has responsibility for assessment of overall risk: benefit. When prompted by
safety concerns, the DMC can request corresponding efficacy data. DMC review of efficacy
data to assess the overall risk: benefit to study participants will not require a multiplicity
adjustment typically associated with a planned efficacy IA. However, if the DMC confirms that 
efficacy data were considered in the overall risk: benefit assessment during periodic safety 
reviews, a sensitivity analysis for OS taking a nominal alpha penalty of 0.000001 for each of such 
incidence will be conducted.
Objective Response Rate
The trial does not allocate initial alpha to ORR. ORR will be formally tested only if the 
hypotheses for PFS and OS are significant. The testing of ORR will be based on the first 
352 subjects enrolled in the trial. If the null hypotheses for OS and PFS are rejected at IA1 or at a 
time later than IA1, the p-value of ORR from the IA1 analysis will be compared to an α-level of 
0.025. Power at the possible α-level as well as the approximate treatment difference required to 
0575BN
082JZZ


MK-3475
PAGE 23
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     
reach the bound (ΔORR) are shown in Table 9 assuming underlying 50% and 70% response rates 
in the control and experimental groups, respectively. 
Table 9  Possible Alpha-levels and Approximate ORR Difference Required to Demonstrate 
Efficacy for ORR
α
~ΔORR
Power
0.025
0.1002
0.9719
3.8
SAMPLE SIZE AND POWER CALCULATIONS
Four hundred and thirty subjects were planned to be randomized in 1:1 ratio into 
pembrolizumab+EP and the saline placebo+EP arms. By the time of the current amendment, 453 
subjects were enrolled for this study.
The final PFS analysis for the study will occur about 22 months from study start. If 387 PFS events 
occur by the time of the final PFS analysis, the study will have a power of 96% approximately to 
demonstrate a hazard ratio of 0.65 on PFS at initially allocated α=0.006.
The final OS analysis will occur when at least 294 events have occurred or approximately 31 
months from study start, whichever occurs later. With a minimum of 294 events at the time of final 
analysis, the study has at least 94% power to demonstrate a HR of 0.65 on OS at initially allocated 
α=0.019. The above power calculations for OS and PFS are based on the following assumptions: 
1) 453 subjects were enrolled over 14.5 months following the actual enrollment pattern; 2) median 
PFS is 4.3 months in the control arm and hazard ratio is 0.65; 3) median OS is 10 months in the 
control arm and hazard ratio is 0.65; 4) The exponential dropout rates assumed for OS and PFS 
are 1% per month.
The sample size and power calculations were performed in the software EAST 6.2 and R (package 
“gsDesign”).
3.9
SUBGROUP ANALYSES AND EFFECT OF BASELINE FACTORS
To determine whether the treatment effect is consistent across various subgroups, the between-
group treatment effect for OS, PFS and ORR (with a nominal 95% CI) will be estimated and plotted 
within each category of the following classification variables:

Stratification factors
o
Platinum chemotherapy (cisplatin, carboplatin)
o
LDH (≤ULN, >ULN)
o
ECOG Performance Scale (0, 1)

Age category (≤65, >65 years)

Sex (female, male)
0575BN
082JZZ


MK-3475
PAGE 24
PROTOCOL NO. 604-09                                 
Supplemental SAP                                                                                                                       21 APRIL 2019 - AMENDMENT 04     

Race (white, non-white)

Smoking status (former, current)

Brain/liver metastasis status at diagnosis (yes, no)

Region (East Asia, non-East Asia)

Sites of metastasis at diagnosis (<3, ≥3)

PD-L1 expression positive (TPS<1% vs ≥1%, CPS <1 vs ≥1)
For PFS and OS, the unstratified Cox model will be used for computing the hazard ratio and its 
95% CI in the subgroups. For ORR, the unstratified Miettinen and Nurminen method 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. The subgroup factor platinum chemotherapy will be determined 
based on the platinum which was administered to a subject at the first dose. If a subject did not 
receive any platinum, they will be excluded from subgroup analysis. In general, a subject with
a missing subgroup factor will be excluded from analysis of that subgroup. 
3.10 COMPLIANCE (MEDICATION ADHERENCE)
Drug accountability data for trial treatment will be collected during the study.  Any deviation from 
protocol-directed administration will be reported.
3.11 EXTENT OF EXPOSURE
Extent of exposure for a subject is defined as number of cycles in which the subject receives the 
study medication infusion. Summary statistics will be provided on extent of exposure for the ASaT 
population.
4. REFERENCES
1. Liang K, Zeger, S (2000). Longitudinal data analysis of continuous and discrete 
responses for pre-post designs. Sankhyā: The Indian Journal of Statistics, 62 (Series B), 
134-148. 
2. Maurer W, Bretz F. Multiple Testing in Group Sequential Trials using Graphical 
Approaches. Statistics in Biopharmaceutical Research 2013; 5(4): 311-320.
3. Miettinen O, Nurminen M. Comparative analysis of two rates. Statistics in Medicine 
1985; 4:213-226.
4. 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
5. 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. 
0575BN
082JZZ